Methods of treating a disease or condition associated with weight gain

Abstract

This disclosure provides methods for treating a condition or disease associated with weight gain that include administration of an apelin receptor agonist alone or in combination with a GLP-1 receptor agonist. Methods for increasing total weight loss in the subject relative to weight loss that would be caused by administration of a pre-determined amount of a GLP- 1 receptor agonist alone are also provided. In some embodiments, the method is for preserving, or maintaining muscle mass, muscle function, and / or muscle strength in a subject undergoing weight loss therapy. Also provided are method of treating diabetes or diabetic obesity. Also provided are method of treating heart failure with preserved ejection fraction. Also provided are pharmaceutical compositions, such as fixed dose combinations, that include an apelin receptor agonist and a GLP-1 receptor agonist. In some embodiments, the pharmaceutical composition is formulated for oral administration.

Description

Attorney Docket No.: 32554- 61636 (022 / 23WO) METHODS OF TREATING A DISEASE OR CONDITION ASSOCIATED WITH WEIGHT GAIN 1. BACKGROUND

[0001] Obesity is a globally increasing health problem associated with various diseases, particularly cardiovascular disease (CVD), type 2 diabetes, obstructive sleep apnea, certain types of cancer, and osteoarthritis. As a result, obesity has been found to reduce life expectancy. The rise in obesity drives an increase in diabetes, and approximately 90% of people with type 2 diabetes may be classified as obese. There are 246 million people worldwide with diabetes, and by 2025 it is estimated that 380 million will have diabetes.

[0002] Glucagon-like peptide-1 (GLP-1) receptor agonists are glucose-lowering drugs that induce clinically significant reductions in body weight. However, GLP-1 receptor agonists not only reduce fat mass, but have also been shown to reduce lean body mass and skeletal muscle.

[0003] Methods are presently needed to implement treatment with GLP-1 receptor agonist and / or apelin receptor agonists while preventing muscle loss and inducing preservation of muscle function in patients having a condition or disease associated with weight gain, including patients who are undergoing weight loss treatments. 2. SUMMARY

[0004] This disclosure provides methods for treating a condition or disorder associated with weight gain by co-administration of an apelin receptor agonist and a glucagon-like-peptide-1 (GLP-1) receptor agonist. Also provided are methods for treating a condition or disorder associated with weight gain by administration of an apelin receptor agonist as monotherapy. Also provided are method of treating diabetes or diabetic obesity. Also provided are method of treating heart failure with preserved ejection fraction.

[0005] Incretins, such as GLP-1RAs, have many potential applications in indications driven by obesity, where weight loss improves or resolves disease symptoms. The present inventors focused on azelaprag indication expansion on two indications where the apelin mechanism, in combination with an incretin, has the potential to provide therapeutic benefits beyond those driven by increased weight loss: Type 2 diabetes.

[0006] According to the CDC, 90% of people with type 2 diabetes are overweight or obese. While incretins improve glucose control, efficacy currently lags with oral medications: Rybelsus (oral semaglutide 14mg), the only oral GLP-1RA approved for type 2 diabetes, led 1 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) to 64% of T2D patients achieving hemoglobin A1c < 6.5% (target range for T2D at which disease is well-controlled) vs.79% with tirzepatide.

[0007] Obesity is a significant risk factor for heart failure with preserved ejection fraction (HFpEF), where at least 80% of patients with HFpEF are overweight or obese. Two major phenotypes of HF are recognized: HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). HFpEF represents nearly half of all heart failure cases in the U.S. with prevalence of more than 3 million.

[0008] The unmet need for treatment of HFpEF is very high as there are very few effective therapies, resulting in high morbidity and mortality, and poor quality of life. There are several ongoing clinical trials in HFpEF with incretins and other weight loss interventions. A recent trial of semaglutide administered at a dose of 2.4 mg weekly via injection showed significant improvements in symptoms and exercise function, in addition to greater weight loss, after 52 weeks of treatment.

[0009] Although weight loss therapies provide a treatment of weight-gain induced comorbidities, such as obesity-associated comorbidities, weight loss therapies can have an impact on body composition. Body composition includes free mass (FM), fat free mass (FFM), lean body mass (LBM), skeletal muscle mass, bone mineral content, and total body water (TBW). Free mass is a mass of all adipose tissue, FFM is a total body mass minus total fat mass, LBM includes organs, skin, bones, total body water, and muscle mass minus total fat mass, skeletal muscle mass includes lean body mass minus connective tissue, skin, and other organs, and TBW is the summation of intra- and extra-cellular water. A GLP-1 receptor agonist (GLP-1RA) used to induce weight loss in a subject in need of weight loss therapy, can also induce loss of LBM and / or skeletal muscle associated with weight loss induced by the GLP-1RA. Such loss in LBM and / or skeletal muscle associated with weight loss can make these patients susceptible to muscle atrophies, sarcopenia, and frailty. In some embodiments, a subject who is overweight and recommended for weight loss therapy is already vulnerable to an increased risk of conditions such as diabetes, insulin resistance physical frailty, sarcopenia, and muscle atrophy. Subjects considered overweight include patients with a body mass index (BMI) of 25 or greater.

[0010] Apelin has the potential to directly improve insulin sensitivity and glucose control. In a small clinical trial study of overweight men, infusion of apelin-13 peptide significantly improved insulin sensitivity. In the preclinical literature, apelin knockout mice experienced 2 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) impaired insulin sensitivity whereas administration of apelin peptide to obese mice restored glucose tolerance.

[0011] The present inventors discovered that co-administration of an apelin receptor agonist with a GLP-1 receptor agonist can induce or increase total weight loss (e.g., fat mass loss) but also preserve muscle function and muscle mass (e.g., lean muscle), and thus prevent loss of skeletal muscle and lean body mass that follows treatment with a GLP-1 receptor agonist. The present inventors discovered that the combination therapy can lead to increased total weight loss, reduction of fat mass percentage, increase in lean mass percentage, and / or improvement in body composition (higher lean mass / fat mass ratio) relative to that caused by administration of a pre-determined amount of a GLP-1 receptor agonist alone, as described in PCT Application Publication No.: WO2024148104, which is hereby incorporated by reference in its entirety.

[0012] The present inventors also discovered that administration of an apelin receptor agonist as monotherapy inhibits weight gain but also preserves muscle function and muscle mass (e.g., lean muscle), and thus prevents loss of skeletal muscle and lean body mass that follows treatment with, for example a GLP-1 receptor agonist. The present inventors discovered that the monotherapy with a apelin receptor agonist can lead to reduction of fat mass percentage, increase in lean mass percentage, increase in muscle percentage, decreased inguinal fat percentage, and / or improvement in body composition (higher lean mass / fat mass ratio) relative to that is typically caused by administration of a pre-determined amount of a GLP-1 receptor agonist alone. The present inventors found that Azelaprag demonstrated significant glycemic benefits in preclinical models of diabetes and diabetic obesity as a monotherapy treatment.

[0013] Agonists of the apelin receptor were tested in combination with various GLP-1 receptor agonists and separately as monotherapy in mouse models of obesity. The apelin receptor agonists tested included BGE-105, BAL-1480, and AMG-8123. BGE-105 has the structure shown below:, 3 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) or a pharmaceutically acceptable salt thereof.

[0014] AMG-8123 has the structure shown below:

[0015] or a pharmaceutically acceptable salt thereof.

[0016] The GLP-1 receptor agonists tested in combinations with the apelin receptor agonist included semaglutide and tirzepatide.

[0017] Accordingly, a first aspect of the present disclosure is a method for treating a disease or condition associated with weight gain, including co-administering to a subject in need thereof: an effective dose of an apelin receptor agonist or a pharmaceutically acceptable salt thereof, and an effective dose of a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is obese. In some embodiments, the apelin receptor agonist is BGE-105, or a pharmaceutically acceptable salt thereof.

[0018] Aspects of this disclosure include a method inducing weight loss and increasing insulin sensitivity in a subject with obesity-induced insulin resistance, the method comprising: co-administering to a subject in need thereof: an effective dose of an apelin receptor agonist; and an effective dose of a GLP-1 receptor agonist, to induce fat and weight loss, and insulin sensitivity, in the subject.

[0019] Aspects of this disclosure include a method of increasing total weight loss caused by administration of a pre-determined amount of a GLP-1 receptor agonist to a subject in need thereof. In some embodiments, the method includes co-administering to a subject in need thereof an effective dose of an apelin receptor agonist and an effective dose of a GLP-1 receptor agonist, to increase total weight loss in the subject. The increase in total weight loss in the subject can be relative to weight loss that would be caused by administration of a pre- determined amount of a GLP-1 receptor agonist alone.

[0020] The present disclosure also provides a method for inducing weight loss with maintenance of muscle mass and / or muscle strength (e.g., lean muscle mass) in a subject in need thereof (e.g., a subject undergoing weight loss therapy). The method can include co- 4 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) administering to the subject in need thereof an effective dose of an apelin receptor agonist or a pharmaceutically acceptable salt thereof, and an effective amount of a GLP-1 receptor agonist, or a pharmaceutically acceptable salt thereof to maintain lean muscle mass while inducing fat and weight loss in the subject.

[0021] The present disclosure also provides a method for treating or preventing further muscle mass decrease caused by administration of a GLP-1 receptor agonist in a subject in need thereof. The method can include adding an effective dose of an apelin receptor agonist to the GLP-1 receptor agonist treatment regimen of a subject in need thereof to treat or prevent lean muscle mass decrease in the subject after administration of the GLP-1 receptor agonist.

[0022] The inventors discovered that co-administering of the apelin receptor agonist in conjunction with the GLP-1 receptor agonist according to the methods of this disclosure stimulates muscle mass preservation or an increase in muscle mass in the subject. In some embodiments, the subject exhibits loss of fat mass after the co-administration of the apelin receptor agonist, while at the same time maintaining lean muscle mass and / or improving the ratio of lean muscle to fat mass, e.g., relative to baseline values prior to the co-administration.

[0023] In some embodiments of the methods, the apelin receptor agonist is of formula (I) or (II), or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the apelin receptor agonist is BGE-105, or a pharmaceutically acceptable salt thereof.

[0024] In some embodiments of the methods of this disclosure, the subject is an obese human and / or has, or is identified as having, or susceptible to or at risk of having, one or more of: diabetes mellitus, insulin insensitivity, cardiovascular disease, cardiorenal disease, neurologic disease, obesity, is obesity, obesity-linked gallbladder disease, obesity-induced sleep apnea, diabetes, excessive appetite, fatty liver disease, non-alcoholic fatty liver disease (NASH), metabolic dysfunction–associated steatohepatitis (MASH), dyslipidemia, metabolic syndrome, insufficient satiety, hyperinsulinemia, or nighttime hypoglycemia. In some embodiments, the diabetes is type 1 diabetes, type 2 diabetes, or gestational diabetes.

[0025] Also provided are pharmaceutical compositions, such as fixed dose combinations, that include an apelin receptor agonist and a GLP-1 receptor agonist. In some embodiments, the pharmaceutical composition is formulated for oral administration, e.g., an oral fixed dose combination.

[0026] Also provided herein include a bifunctional compound comprising: (a) an apelin receptor binding moiety; and (b) a GLP-1 receptor binding moiety. 5 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)

[0027] In some embodiments, the apelin receptor binding moiety is an apelin receptor agonist. In some embodiments, the apelin receptor agonist is an apelin receptor agonist described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the GLP-1 receptor binding moiety is a GLP-1 receptor agonist.

[0028] Also provided herein include a trifunctional compound comprising: (a) an apelin receptor binding moiety; (b) a GLP-1 receptor binding moiety; and (c) a gastric inhibitory polypeptide receptor (GIP-R) binding moiety.

[0029] In some embodiments, the apelin receptor binding moiety is an apelin receptor agonist. In some embodiments, the GLP-1 receptor binding moiety is a GLP-1 receptor agonist. In some embodiments, the GIP receptor binding moiety is a GIP-1 receptor agonist.

[0030] Also provided herein is a bifunctional compound comprising: (a) an apelin receptor binding moiety; and (b) a satiety inducing agent.

[0031] In some embodiments, the apelin receptor binding moiety is an apelin receptor agonist. In some embodiments, the apelin receptor agonist is an apelin receptor agonist described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the satiety inducing agent is an appetite suppressant. In some embodiments, the satiety inducing agent is a cannabinoid receptor antagonist.

[0032] Also provided herein is a bifunctional compound comprising:(a) an apelin receptor binding moiety; and (b) a gastric inhibitory polypeptide receptor (GIP-R) binding moiety. In some embodiments, the apelin receptor binding moiety is an apelin receptor agonist.

[0033] In some embodiments, the apelin receptor agonist is an apelin receptor agonist described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the GIP receptor binding moiety is a GIP-1 receptor agonist.

[0034] Also provided herein is a method of inducing weight loss and increasing insulin sensitivity in a subject with obesity-induced insulin resistance, the method comprising: administering to a subject in need thereof: an effective amount of bifunctional compound described herein; or an effective amount of a trifunctional compound described herein, to induce fat and weight loss, and insulin sensitivity, in the subject.

[0035] Also provided herein is a method of inducing weight loss in a subject in need of weight loss, the method comprising: administering to a subject in need thereof: an effective amount of bifunctional compound described herein; or an effective amount of a trifunctional compound described herein, to induce fat and weight loss in the subject. 6 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)

[0036] Also provided herein is a method of inducing weight loss with maintenance of lean muscle mass in a subject in need of weight loss, the method comprising:

[0037] administering to a subject in need thereof: an effective amount of bifunctional compound described herein; or an effective amount of a trifunctional compound described herein, to maintain lean muscle mass while inducing fat and weight loss in the subject.

[0038] Also provided herein is a method of increasing total weight loss caused by administration of a pre-determined amount of a GLP-1 receptor agonist to a subject in need thereof, the method comprising: administering to a subject in need thereof: an effective amount of bifunctional compound described herein; or an effective amount of a trifunctional compound described herein, to increase total weight loss in the subject relative to weight loss caused by administration of a pre-determined amount of a GLP-1 receptor agonist alone.

[0039] Also provided herein is a method of treating or preventing further muscle mass decrease caused by administration of a GLP-1 receptor agonist to a subject in need thereof, the method comprising: administering to a subject in need thereof: an effective amount of bifunctional compound described herein; or an effective amount of a trifunctional compound described herein, to treat or prevent further lean muscle mass decrease in the subject.

[0040] Also provided herein is a method of increasing total weight loss to a subject in need thereof after prior treatment with a pre-determined amount of a GLP-1 receptor agonist alone caused weight loss in the subject to plateau, the method comprising: administering to a subject in need thereof: an effective amount of bifunctional compound described herein; or an effective amount of a trifunctional compound described herein,

[0041] to increase total weight loss in the subject relative to weight loss caused by administration of a pre-determined amount of a GLP-1 receptor agonist alone.

[0042] Also provided herein is a method of inducing weight loss in a subject in need thereof after prior treatment with a pre-determined amount of a GLP-1 receptor agonist alone caused weight loss in the subject to plateau, the method comprising: administering to a subject in need thereof: an effective amount of bifunctional compound described herein; or an effective amount of a trifunctional compound described herein, to induce fat and weight loss in the subject relative to prior treatment with a pre-determined amount of the GLP-1receptor agonist alone.

[0043] Also provided herein is a method of preventing or reducing rebound weight gain in a human subject who had prior treatment with a pre-determined amount of a GLP-1 receptor agonist alone that caused weight loss in the subject to plateau, the method comprising: 7 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) administering to a subject in need thereof: an effective amount of bifunctional compound described herein; or an effective amount of a trifunctional compound described herein; to prevent or reduce rebound weight gain in the subject. 3. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] These and other features, aspects, and advantages of the present invention will become better understood with regard to the following description, and accompanying drawings, where:

[0045] FIG.1 shows fat body mass (FBM) measurements of aged diet-induced obese (DIO) mice as measured using Echo-MRI for the various treatment groups in Example 1.

[0046] FIG.2 shows lean body mass (LBM) as a percentage of total body weight (BW) of aged diet-induced obese (DIO) mice as measured using Echo-MRI for the various treatment groups in Example 1.

[0047] FIGs.3A-3B show assessment of muscle function using grid hang tests of aged DIO mice for the various treatment groups of Example 1. FIG.3A shows analysis using One-Way ANOVA with Tukey’s multiple comparisons test, whereas FIG.3B shows analysis using One-Way ANOVA without multiple comparisons test (Fisher’s LSD)).

[0048] FIGs.4A-4B show measurements of perigonadal fat weight (FIG.4A) and quadriceps weight as a percentage of total body weight (FIG.4B) for aged DIO mice treatment groups in Example 1.

[0049] FIG.5 shows measurements of plasma neutrophil gelatinase-associated lipocalin (NGAL) level for the DIO-aged mice treatment groups in Example 1.

[0050] FIGs.6A-6B show lean body mass and body weight measurements of female vs male aged DIO mice of Example 2.

[0051] FIGs.7A-7D show measurements of body weight (FIG.7A), fat mass (FIG.7C), lean mass (FIG.7D), and fed glucose (FIG.7B) for both male and female mice groups used for randomization in Example 3.

[0052] FIGs.8A-8B show daily water intake measured for all treatment groups every 3 days throughout the duration of the study of Example 2.

[0053] FIGs.9A-9B show daily food intake measured for all treatment groups every 3 days throughout the duration of the study of Example 2. 8 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)

[0054] FIGs.10A-10B show cumulative water intake measured for all treatment groups every 3 days throughout the duration of the study of Example 2.

[0055] FIGs.11A-11B show cumulative food intake measured for all treatment groups every 3 days throughout the duration of the study of Example 2.

[0056] FIGs.12A-12C show body weight (BW) loss of treatment groups Example 2with tirzepatide at three different dosages (3 nmol / kg (FIG.12A), 10 nmol / kg (FIG.12B), or 30 nmol / kg (FIG.12C)) alone or in combination with BGE-105 (at 0.275 g / L or 1.1 g / L).

[0057] FIG.13 shows that BGE-105 treatment results in a significant, dose-dependent increase in overall weight loss compared to tirzepatide alone as measured by body weight loss (BWL) %. See Example 2.

[0058] FIGs.14A-14C show body composition of mice treated in the various treatment groups of Example 2. FIG.14A shows change of fat body mass over body weight (FBM / BW) %. FIG.14B shows change of lean body mass over body weight (LBM / BW) %. FIG.14C shows change of lean body mass over fat ratio (Lean / Fat Ratio).

[0059] FIG.15 shows fed glucose loss % of mice treated in the various treatment groups of Example 2.

[0060] FIGs.16A-16B illustrate overall weigh loss. BGE-105 in combination with tirzepatide significantly reduced body weight compared to BGE-105 or tirzepatide monotherapy in % change (FIG.16A) and absolute body weight (g) (FIG.16B). See Example 3.

[0061] FIG.17 shows daily food consumption (g / gBW / day) of mice treatment groups of Example 3. Tirzepatide monotherapy or BGE-105 combination with tirzepatide treatment reduced food daily food consumption compared to the DIO control group of Example 3.

[0062] FIGs.18A-18B illustrate percentage of lean mass and percentage fat mass assessed by echo-MRI. BGE-105 combination with tirzepatide treatment increased percentage of lean mass (FIG.18A) and reduced percentage of fat mass (FIG.18B) and restored the levels to that comparable to the lean control group at the end of the treatment (Day 21). See Example 3.

[0063] FIGs.19A-19B illustrate absolute lean mass and absolute fat mass assessed by Echo-MRI. BGE-105 combination with tirzepatide treatment dramatically decreased absolute (g) of fat body mass (FIG.19B). BGE-105 combination with tirzepatide treatment restored 9 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) absolute fat mass (FIG.19B) the level to that comparable to the lean control group at the end of the treatment (Day 21). See Example 3.

[0064] FIG.20 illustrates lean / fat ratio in mice treatment groups. BGE-105 with tirzepatide treated mice had increased lean / fat ratio as compared to tirzepatide alone. The mice treated with high dose of BGE-105 with tirzepatide combination showed comparable lean / fat ratio to the lean control group at the measurement on day 20.

[0065] FIG.21 shows addition of high dose BGE-105 lowered the fed glucose levels achieved with tirzepatide. The data demonstrates that a combination therapy may benefit patients with insulin resistance.

[0066] FIGs.22A-22C illustrate muscle function in mice treatment groups as assessed via grid hang tests. FIG.22C shows an image of the grid hang test. FIG.22A shows a graph of latency of fall (s), and FIG.22B shows graph of body weight x latency of fall (g*s). The results show that addition of BGE-105 to tirzepatide restored muscle function to that of lean controls.

[0067] FIGs.23A-23B shows that there were comparable effects on fat mass for BGE- 105 in combination with tirzepatide in obese mice, as for bimagrumab (Example 4).

[0068] FIGs.24A-24B shows that there were comparable effects on lean mass for BGE- 105 in combination with tirzepatide in obese mice as for bimagrumab (Example 4).

[0069] FIGs.25A-25B shows the monoclonal antibody bimagrumab in combination with tirzepatide provided a comparable lean / fat ratio (FIG.25B) as BGE-105 (1.1g / L) in combination with tirzepatide (FIG.25A). The data demonstrate comparable effects of BGE- 105 and bimagrumab on body composition when co-administered with tirzepatide.

[0070] FIGs.26A-26B illustrate BGE-105 and tirzepatide combination reduced body weight and body weight percentage in adult mice (Example 5).

[0071] FIGs.27A-27B show food and water consumption of adult mice in treatment groups of Example 5.

[0072] FIGs.28A-28E show lean mass (FIG.28A), fat mass (FIG.28B), lean mass percentage (FIG.28C), fat mass percentage (FIG.28D), and lean / fat mass ratio (FIG.28E) in treated adult mice of Example 5. BGE-105 and tirzepatide combination treatment showed significant reduction of absolute fat mass (FIG.28B).

[0073] FIG.29 shows blood glucose level in adult mice treatment groups of Example 5. 10 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)

[0074] FIGs.30A-31B illustrate that a BAL-1480 and tirzepatide combination treatment reduced body weight and body weight percentage.

[0075] FIGs.31A-31B show food and water consumption of mice in treatment groups of Example 6.

[0076] FIG.32 shows hydration ratio of mice in treatment groups of Example 6.

[0077] FIGs.33A-33B show lean mass and lean mass percentage of mice in treatment groups. BAL-1480 and tirzepatide combination restored lean mass percentage to lean control level.

[0078] FIGs.34A-34C illustrate fat mass, fat mass percentage and lean / fat ratio in mice treatment groups. BAL-1480 and tirzepatide combination restored fat mass (FIG.34A), fat mass percentage (FIG.34B), and lean / fat ratio (FIG.34C) to lean control level.

[0079] FIG.35 shows blood glucose level in mice treatment groups of Example 6.

[0080] FIG.36 shows rectal temperature of treated mice at Day 15.

[0081] FIGs.37A-37P illustrate fatty liver weight and fat tissue weights in tirzepatide treated mice. Shown are results of fatty liver (FIG.37A), fatty liver percentage (FIG.37B), inguinal fat (FIG.37C), inguinal fat percentage (FIG.37D), perigonadal fat (FIG.37E), perigonadal fat percentage (FIG.37F), brown fat (FIG.37G), brown fat percentage (FIG. 37H), tibialis anterior (TA) muscle (FIG.37I), TA percentage (FIG.37J), quadricep (quad) muscle (FIG.37K), quadricep muscle percentage (FIG.37L), gastrocnemius (gastric) muscle (FIG.37M), gastrocnemius muscle percentage (FIG.37N), total muscle (FIG.37O), and total muscle percentage (FIG.37P).

[0082] FIGs.38A-38B illustrate that a combination of BGE-105 and semaglutide reduced body weight and body weight percentage in a dose dependent fashion. See Example 7.

[0083] FIGs.39A-39B show food and water consumption of mice in semaglutide treatment groups of Example 7.

[0084] FIGs.40A-40B show lean mass and lean mass percentage in semaglutide treated mice. BGE-105 and semaglutide combination restored lean mass percentage to lean control level in a dose dependent fashion. 11 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)

[0085] FIGs.41A-41C illustrate fat mass, fat mass percentage and lean / fat ratio in semaglutide treated mice. BGE-105 and semaglutide combination restored fat mass (FIG. 41A), fat mass percentage (FIG.41B), and lean / fat ratio (FIG.41C) to lean control level in a dose dependent fashion.

[0086] FIG.42 shows semaglutide treated blood glucose level in mice treatment groups.

[0087] FIG.43 shows rectal temperature of semaglutide treated mice at Day 15.

[0088] FIGs.44A-44P illustrate fatty liver weight and fat tissue weights in semaglutide treated mice. Shown are results of fatty liver (FIG.44A), fatty liver percentage (FIG.44B), inguinal fat (FIG.44C), inguinal fat percentage (FIG.44D), perigonadal fat (FIG.44E), perigonadal fat percentage (FIG.44F), brown fat (FIG.44G), brown fat percentage (FIG. 44H), tibialis anterior (TA) muscle (FIG.44I), TA percentage (FIG.44J), quadricep (quad) muscle (FIG.44K), quadricep muscle percentage (FIG.44L), gastrocnemius (gastric) muscle (FIG.44M), gastrocnemius muscle percentage (FIG.44N), total muscle (FIG.44O), and total muscle percentage (FIG.44P). See Example 7.

[0089] FIG.45 provides a study dosing outline for BGE-105 in a Phase 1 clinical study with single ascending dose (SAD) cohorts 1-3, or multiple doses (MD) cohorts.

[0090] FIGs.46A-1B show the effect of BGE-105 in weight loss after tirzepatide dose adjustment. FIG.46A shows that BGE-105 broke the weight loss plateau on tirzepatide alone. In comparison with vehicle-treated DIO mice, adding BGE-105 to tirzepatide alone was able to increase 8.9% more weight loss on day 24 than on day 15. FIG.46B shows that BGE-105 reduced weight gain when tirzepatide dose was lowered. In the BGE-105 and tirzepatide combination group, when tirzepatide dose was changed from 10 nmol / kg to 3 nmol / kg, the DIO mice started to gain weight. The BGE-105 treated subgroup had 9.8% less weight gain in comparison to the subgroup without BGE-105 (overall p value < 0.0001).

[0091] FIG.47 shows the study design for each of the study groups of Example 9.

[0092] FIG.48 shows the effect of weight loss treatment with tirzepatide from Jastreboff et al., 2022 (N Engl J Med 2022;387:205-216; “SURMOUNT-1” Study), showing that weight loss with tirzepatide at 5 mg, 10 mg, or 15 mg only begins to emerge after 12 weeks of treatment. The dotted lines in FIG.48 show that, in the clinical study of Example 9, patients treated with the combination of tirzepatide and Azelaprag (AZP or “BGE-105”) via BID or QD, or Azelaprag alone started showing weight loss anywhere between 8-12 weeks as shown in FIG.49A. 12 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)

[0093] FIG.49A illustrates that there was no significant increase in weight loss in patients treated with the combination of Azelaprag and tirzepatide (Azelaprag 300 mg BID + Tirzepatide; Azelaprag 300 mg QD + tirzepatide) by week 12 as shown by the percent change in weight from baseline. The Azelaprag monotherapy arm (Azelaprag 300 mg BID monotherapy) showed higher weight loss compared to the placebo arm in the SURMOUNT-1 study of Jastreboff et al., 2022 (-3.13% in the study of Example 9 vs -1.7 in the SURMOUNT-1 study) at week 8 of treatment (p=0.08). FIG.49B illustrates the -1.7% change in body weight of the placebo in the SURMOUNT-1 study of Jastreboff et al., 2022.

[0094] FIG.50A shows a 40% greater decrease in the waist circumference (cm)in patients treated with the Azelaprag high-dose + tirzepatide combination arm (300 mg BID + tirzepatide) compared to tirzepatide treatment alone in the clinical study of Example 2 (-8.68 vs -6.29 cm, p=0.26). Patients treated with Azelaprag monotherapy showed a 60% greater decrease in waist circumference in the study of Example 9 compared to historical placebo in the SURMOUNT-1 study (-3.86 vs -2.35, p=0.18). FIG.50B illustrates the SURMOUNT-1 study change in wait circumference (cm) of tirzepatide treatment at different dosages compared to placebo.

[0095] FIG.51A shows the change in lean mass percentage from baseline of Example 9 when patients were treated with tirzepatide monotherapy, azelaprag QD plus tirzepatide, Azelaprag BID plus tirzepatide, or Azelaprag BID monotherapy, where the percentage is calculated as a sum of lean mass and total mass. The change is defined as: (% at Week 12) – (% at Baseline). FIG.51B shows the change in Appendicular lean mass percentage from baseline to week 12 of treatment in Example 9 for the tirzepatide monotherapy, azelaprag QD plus tirzepatide, azelaprag BID plus tirzepatide, or azelaprag BID monotherapy. The percentage is calculated as: the sum of appendicular lean mass and total mass. There was a significant and dose-dependent increase in the % appendicular lean mass when patients were treated with Azelaprag 300 mg BID + tirzepatide compared to Tirzepatide alone. The change is defined as: (% at Week 12) – (% at Baseline). FIG.51C shows the change in percent fat mass from baseline in patients treated with tirzepatide monotherapy, azelaprag QD plus tirzepatide, azelaprag BID plus tirzepatide, or azelaprag BID monotherapy, where the percentage is calculated as a sum of fat mass and total mass. The change is defined as: (% at Week 12) – (% at Baseline). FIG.51D shows the percent change in lean to fat mass ratio from baseline to week 12 in patients treated with tirzepatide monotherapy, azelaprag QD plus tirzepatide, azelaprag BID plus tirzepatide, or azelaprag BID monotherapy using lean mass 13 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) and total fat mass, where the change is defined as: (Lean / Fat Ratio at Week 12 - Lean / Fat Ratio at Baseline) / Lean / Fat Ratio at Baseline) x 100. FIG.51E shows the percent change in lean to fat mass ratio from baseline to week 12 for patients treated with tirzepatide monotherapy, azelaprag QD plus tirzepatide, azelaprag BID plus tirzepatide, or azelaprag BID monotherapy using appendicular lean mass and total fat mass, where the change is defined as: (Appendicular Lean / Fat Ratio at Week 12 - Appendicular Lean / Fat Ratio at Baseline) / Appendicular Lean / Fat Ratio at Baseline) x 100.

[0096] FIG.52 shows the study design for the effects of BGE-105 and tirzepatide alone or in combination in mice with diabetic obesity of Example 4.

[0097] FIG.53 shows that following 12 days of treatment, tirzepatide decreased DIO / STZ mice body weight by 11.2%. Combination of BGE-105 and tirzepatide (Group 6) reduced body weight by 26.2%, significantly more compared to tirzepatide alone (Group 4) (p<0.0001).

[0098] FIGs.54A-54B show that adding BGE-105 to tirzepatide (Group 6) significantly improved the body composition with increased lean mass to body weight percentage (FIG. 54A) and reduced fat mass to body weight percentage (FIG.54B) compared to tirzepatide alone (Group 4).

[0099] FIG.55 shows that compared to tirzepatide alone (Group 4), combination of BGE- 105 with tirzepatide (Group 6) significantly enhanced oral glucose tolerance in DIO / STZ mice.

[0100] FIGs.56A-56B show that BGE-105 monotherapy (Group 5) significantly reduced A1C% compared to VEH treated DIO / STZ mice (Group 3). In comparison to baseline A1C, combination of BGE-105 with tirzepatide (Group 6) reduced A1C% compared to tirzepatide alone (Group 4).

[0101] FIG.57 shows that compared to baseline fasting glucose, BGE-105 monotherapy (Group 5), and BGE-105 in combination with tirzepatide (Group 6) reduced blood glucose % significantly more than VEH (Group 3) or tirzepatide alone (Group 4) in DIO / STZ mice.

[0102] FIGs.58A-58B show homeostatic Model Assessment of Insulin Resistance (HOMA-IR): On day 12, after 6h of fasting, the blood samples were collected from mice to measure glucose and insulin levels (FIG.58A). HOMA-IR was calculated using multiplying insulin (μIU / ml) by glucose (mmol / l) and dividing by 22.5 (FIG.58B). As shown in FIG. 58A, in DIO mice, BGE-105 monotherapy (Group 2) significantly improved obesity-induced insulin resistance. In DIO / STZ mice, addition of BGE-105 to tirzepatide (Group 6) enhanced 14 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) insulin sensitivity significantly more than tirzepatide alone (Group 4) in comparison to the VEH group (Group 3).

[0103] FIGs.59A-59C show that on day 13, the inguinal fat (FIG.59A), tibialis anterior (TA) muscle (FIG.59B) and quadriceps muscle (FIG.59C) samples are harvested and weighed. Adding BGE-105 to tirzepatide (Group 6) improved DIO / STZ mice body composition by reducing fat to body weight percentage and increasing muscle to body weight percentage significantly more than tirzepatide alone compared to the VEH group (Group 3).

[0104] FIG.60 shows that BGE-105 in combination with tirzepatide for treatment of DIO mice significantly improved the effect of tirzepatide on reducing 6h fasting glucose during the entire study.

[0105] FIGs.61A-62B show that BGE-105 in combination with tirzepatide for treatment of DIO mice significantly improved the oral glucose tolerance and reduces the total glucose AUC.

[0106] FIGs.62A-62B show that BGE-105 treatment in combination with Danuglipron significantly reduced body weight compared to Danuglipron monotherapy alone in DIO mice.

[0107] FIGs.63A-63B show that BGE-105 in combination with Danuglipron significantly improved body weight loss compared to Danuglipron monotherapy alone in DIO mice.

[0108] FIGs.64A-64B show that Danuglipron showed mild but not significant effects on reduction in food intake at a dosage of 20 mpk, but significantly reduced food consumption at 60 mpk in DIO mice. The combination of BGE-105 with Danuglipron further reduced food consumption of Danuglipron at 20 mpk, but did not impact the food consumption of Danuglipron at 60 mpk.

[0109] FIGs.65A-65B show that the combination of BGE-105 and 20 mpk Danuglipron had a significant increase in lean mass percentage compared to VEH and compared to Danuglipron monotherapy in DIO mice. As shown in FIGs.65C-65D, the combination of BGE-105 and 60 mpk Danuglipron had a significant increase in lean mass percentage and reduced fat mass percentage compared to Danuglipron monotherapy in DIO mice.

[0110] FIGs.66A-66B show blood glucose levels after 6 h fasting in DIO mice after BGE- 105 treatment in combination with 20 mpk or 60 mpk danuglipron. The combination of BGE- 105 and 20 mpk danuglipron significantly reduced the fasting glucose compared to danuglipron alone at 20 mpk. 15 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)

[0111] FIGs.67A-67F shows that the combination of BGE-105 and 20 or 60 mpk Danuglipron dosages had a more significant effect on reducing liver weight and liver fat mass than Danuglipron alone in comparison to VEH in DIO mice.

[0112] FIGs.68A-68H show that the combination of BGE-105 and 60 mpk danuglipron significantly reduced the inguinal fat and perigonal fat weight compared to danuglipron at 60 mpk alone in treated DIO mice.

[0113] FIGs.69A-69H show that the combination of BGE-105 and 60 mpk danuglipron significantly improved the tibialis anterior and quadricep muscles to body weight percentage compared to danuglipron at 60 mpk alone in treated DIO mice.

[0114] FIG.70 shows a graph illustrating the changes in A1C levels from baseline to endpoint of the study of azelaprag in preclinical model of diabetic obesity in combination with tirzepatide. Low doses of streptozotocin treatment (DIO / STZ) impair β-cell function, mimicking late-stage type 2 diabetes in the DIO mice.

[0115] FIGs.71-77 show the results of assessments of azelaprag for cardioprotective effects either alone or with semaglutide in diet-induced obesity models of heart failure with preserved ejection fraction (HFpEF).

[0116] FIG.71 shows graphs of changes in body weight over time for various treatment groups in a HFpEF mouse model. In the HFpEF model, azelaprag results in increased weight loss as a monotherapy and in combination with semaglutide.

[0117] FIG.72 illustrates that azelaprag (BGE-105) reduces heart hypertrophy and heart injury marker (BNP).

[0118] FIGs.73A-73B illustrates that azelaprag (BGE-105) monotherapy or semaglutide combination suppressed heart pro-fibrotic gene expression.

[0119] FIG.74 shows the timeline of a BGE-105 monotherapy titration in female DIO HFpEF mouse model.

[0120] FIG.75 shows graphs of the body weight, body composition and food consumption of treatment groups of the female DIO HFpEF mouse model study.

[0121] FIG.76 shows graphs of heart rate and ECG indicating improvements with BGE- 105 monotherapy in the female DIO HFpEF mouse model study. HFpEF mice exhibited an increased P-R interval, along with prolonged R and P wave durations and elevated P wave amplitude. Treatment with BGE-105 partially mitigated these alterations. 16 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)

[0122] FIG.77 illustrates that BGE-105 monotherapy suppressed expression of pro-fibrotic and cardiac injury markers in the female DIO HFpEF mouse model study.

[0123] FIG.78 shows that AMG-8123 significantly increased DIO mice weight loss in combination with tirzepatide as assessed by body weight measurements.

[0124] FIG.79 shows that AMG-8123 significantly increased DIO mice weight loss in combination with tirzepatide as assessed by percentage body weight changes.

[0125] FIG.80 shows that AMG-8123 therapy did not significantly impact the normalized food consumption.

[0126] FIG.81 illustrates a study design of effect of BGE-105 on glucose regulation in DIO mice with higher basal A1C as described in Example 13.

[0127] FIGs.82A-C show DIO mice with higher basal A1C, body weight, and fasting glucose (preselection) compared to lean control mice at 5.4 months old.

[0128] FIGs.83A-I show the effects of BGE-105 on glucose regulation in DIO mice with higher basal A1C (randomization). Randomization was based on blood glucose, A1C, body weight (BW), and body composition.

[0129] FIG.84 shows that BGE-105 treatment significantly slowed down the body weight gain (in grams) of DIO mice.

[0130] FIG.85 shows that BGE-105 treatment significantly slowed down the body weight gain (as body weight % change) of DIO mice.

[0131] FIG.86 shows that BGE-105 treatment did not impact the food consumption of DIO mice.

[0132] FIGs.87A-87B shows that BGE-105 treatment significantly reduced the whole blood A1C level in comparison to VEH treated DIO mice, and restored it to the similar level as lean control mice.

[0133] FIGs.88A-88C show that BGE-105 significantly improved the oral glucose tolerance test and reduced the delta AUC of DIO mice after 60 days of treatment.

[0134] FIG.89 shows a study outline to measure the effect of BGE-105 monotherapy on weight loss in diet-induced obese mice in Example 16.

[0135] FIG.90 shows baseline measurements of body weight, rectal temperature, fat mass, and lean mass used for randomization in Example 16.

[0136] FIG.91 shows measurement of body weight of DIO mice treatment groups in Example 16.29-week old mice that were fed a HFD and treated with BGE-105 at 3.3 g / L in 17 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) drug water (Group 5) slowed down the body weight gain. At 29-weeks old, mice that were fed a HFD and treated with BGE-105 at 3.3 g / L (Group 5) had body weight of 52.7 g and mice that were fed a HFD and treated with VEH (Group 2) had body weight of 55.6 g. The body weight difference was 2.9 g.

[0137] FIG.92 shows measurement of body weight gain for DIO mice treatment groups in Example 16.29-week old mice that were fed a HFD and treated with 3.3 g / L BGE-105 (Group 5) showed significantly lower body weight gain than that of the mice that were fed a HFD and treated with vehicle (Group 2) (31.7 g vs.34.75 g, respectively; 3.05 g less, P<0.0001).

[0138] FIG.93 shows measurement of body weight change percentage for DIO mice treatment groups in Example 16.29-week old mice that were fed a HFD and treated with 3.3 g / L of BGE-105 in drug water (Group 5) slowed down body weight gain (17.5% less BW change %) compared to mice treated with vehicle and fed a HFD (Group 2) (BW change% of HFD+BGE-105 (3.3 g / L) was 154%; BW change% of HFD+VEH was 171.5%).

[0139] FIGs.94A-94C show daily food consumption (FIG.94A) and daily food intake (FIGs.94B-C) of DIO mice treatment groups over the 30-week study duration of Example 16. DIO mice fed a HFD (Groups 2-5) had no significant difference in food intake during the entire study.

[0140] FIG.95 shows rectal temperature measurements of DIO mice treatment groups in Example 16. Mice fed a HFD and treated with BGE-105 at 3.3 g / L in drug water (Group 5) had overall higher rectal temperature than other HFD groups (Groups 2-4). Temperature measurement was not pursued later due to operator changes. At 13 weeks, the rectal temperature of mice that were fed a HFD and treated with BGE-105 at 3.3 g / L (Group 5) was 0.5°C higher than mice that were fed a HFD and treated with VEH water (Group 2) (38.1°C vs.37.6 °C, p = 0.0003).

[0141] FIGs.96A-96C show measurements of lean body mass (LBM) as a percentage of total body weight (BW) of DIO mice of Example 16.29-week old mice that were fed a HFD and treated with BGE-105 (Groups 3-5) showed a dose-dependent improvement in body composition by increasing lean mass percentage. At 29-weeks old, lean mass % of mice that were fed a HFD and treated with BGE-105 at 3.3 g / L (Group 5) was 3.8% higher than mice that were fed a HFD and treated with VEH (Group 2) (58.5% vs.54.7%, respectively; p<0.0001). 18 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)

[0142] FIGs.97A-97C show measurements of fat body mass (FBM) and fat percentage for DIO mice treatment groups in Example 1.29-week old mice that were fed a HFD and treated with BGE-105 (Groups 3-5) showed a dose-dependent improvement in body composition by lowering fat mass percentage compared to mice that were fed with a HFD and treated with VEH. At 29-weeks old, mice that were fed a HFD and treated with BGE-105 at 3.3 g / L (Group 5) had 4.3% less fat mass% than mice that were fed a HFD and treated with VEH (Group 2) (37.8% vs.42.1%, respectively; p<0.0001).

[0143] FIG.98 shows lean / fat ratio in DIO mice treatment groups of Example 16.29-week old mice that were fed a HFD and treated with BGE-105 (Groups 3-5) showed dose- dependent improvement in body composition at 29-weeks with better lean / fat ratio (lean / fat ratio of HFD+BGE-105 (3.3 g / L) (Group 3) is 1.55; lean / fat ratio of HFD+VEH (Group 2) is 1.3).

[0144] FIGs.99A-99B show a measurement of total muscle % (quadricep, tibialis anterior, gastrocnemius) and inguinal fat tissue percentage of the DIO treatment groups of Example 16. Mice treated with BGE-105 (Groups 3-5) showed a dose-dependent effect on increasing muscle percentage (FIG.11A) and reducing inguinal fat percentage (FIG.11B).

[0145] FIGs.100A-100B show that the addition of BGE-105 to the calorie restriction therapy increased the body weight loss significantly (Combo -14.6% vs. CR alone -10.4% on day 44) with overall p value < 0.0001.

[0146] FIGs.101A-101B show that food consumption was calculated as grams of food consumed per gram of body weight per day. Absolute food consumption was expressed as grams of food consumed per mouse per day. There was no significant difference in food consumption or absolute food consumption between calorie restriction alone and calorie restriction / BGE-105 combination treatment.

[0147] FIG.102 shows the effects of liver enzyme levels and free fatty acid levels following treatment with BGE-105 on HFD mice. Treatment of BGE-105 on HFD mice reduced liver enzyme and free fatty acid levels as shown by the reduction of ALT, ALP, AST, and FFA levels compared to mice fed a HFD without BGE-105 treatment.

[0148] FIG.103 provides a study design of BGE-105 monotherapy in obese mice as described in Example 18.

[0149] FIGs.104A-104C show that, compared to VEH treated DIO mice, fasting caused more weight loss in BGE-105 treated mice. 19 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)

[0150] FIGs.105A-105B show that BGE-105 monotherapy did not change food consumption in DIO mice.

[0151] FIGs.106A-106D show that BGE-105 treated mice exhibited more volunteered activities in the home cage compared to veh-treated obese mice.

[0152] FIGs.107A-107B show that BGE-105 monotherapy increased energy expenditure and X-Y activity in obese mice especially in the dark cycle compared to obese mice fed a HFD without BGE-105 treatment.

[0153] FIGs.108A-108D show that BGE-105 monotherapy significant lowers Respiratory Exchange Ratio (RER) during ad libitum feeding, fasting, and refeeding, indicating a predominant utilization of fat than carbohydrate as the primary energy source, regardless of feeding status. BGE-105 monotherapy increased fat utilization in obese mice compared to obese mice fed a HFD without BGE-105 treatment.

[0154] FIGs.109A-109B show that BGE-105 monotherapy increased oxygen consumption and Carbon Dioxide (CO2) production in obese mice compared to obese mice fed a HFD without BGE-105 treatment. 4. DETAILED DESCRIPTION 4.1. Methods of Treating a Condition or Disorder Associated with Weight Gain

[0155] The present disclosure provides a method of treating a subject for a condition associated with weight gain, using a combination of an apelin receptor agonist and a GLP-1 receptor agonist. In some embodiments, the GLP-1 receptor agonist is referred to as a GLP-1 analog. In some embodiments, the method is a method of weight loss in a subject in need thereof. In some embodiments, the method includes co-administering to a subject a therapeutically effective amount of an apelin receptor agonist (e.g., as described herein), and a therapeutically effective amount GLP-1 receptor agonist (e.g., as described herein).

[0156] A receptor agonist is a compound that binds to a receptor and elicits a response typical of the natural ligand. A full agonist may be defined as one that elicits a response of the same magnitude as the natural ligand.

[0157] The “condition associated with weight gain” (referred to interchangeably herein as an “weight gain-related muscle condition” or “fat gain-related muscle condition”) refers to a disease or condition associated with weight gain in a mammalian subject, such as obesity- 20 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) associated comorbidities. In some embodiments, weight gain includes fat gain. In some embodiments, weight gain consists of fat gain.

[0158] Examples of conditions that can be targeted for treatment according to the methods of this disclosure include, but are not limited to, obesity, diabetes mellitus, insulin insensitivity, cardiovascular disease, cardiorenal disease, neurologic disease, obesity-linked gallbladder disease, obesity-induced sleep apnea, diabetes, excessive appetite, fatty liver disease, non-alcoholic fatty liver disease (NASH), metabolic dysfunction–associated steatohepatitis (MASH), dyslipidemia, metabolic syndrome, insufficient satiety, hyperinsulinemia, nighttime hypoglycemia, or a combination of treatments including obesity and sarcopenia, diabetes mellitus and sarcopenia, insulin insensitivity and sarcopenia, cardiovascular disease and sarcopenia, cardiorenal disease and sarcopenia, neurologic disease and sarcopenia, obesity-linked gallbladder disease and sarcopenia, obesity-induced sleep apnea and sarcopenia, diabetes and sarcopenia, excessive appetite and sarcopenia, fatty liver disease and sarcopenia, non-alcoholic fatty liver disease (NASH) and sarcopenia, dyslipidemia and sarcopenia, metabolic syndrome and sarcopenia, insufficient satiety and sarcopenia, hyperinsulinemia and sarcopenia, nighttime hypoglycemia and sarcopenia, obesity and frailty, diabetes mellitus and frailty, insulin insensitivity and frailty, cardiovascular disease and frailty, cardiorenal disease and frailty, neurologic disease and frailty, obesity-linked gallbladder disease and frailty, obesity-induced sleep apnea and frailty, diabetes and frailty, excessive appetite and frailty, fatty liver disease and frailty, non- alcoholic fatty liver disease (NASH) and frailty, dyslipidemia and frailty, metabolic syndrome and frailty, insufficient satiety and frailty, hyperinsulinemia and frailty, or nighttime hypoglycemia and frailty.

[0159] In some embodiments, the weight gain associated condition is obesity. In some embodiments, the weight gain associated condition is excessive weight gain. In some embodiments, the weight gain associated condition is diabetes mellitus. In some embodiments, the weight gain associated condition is insulin insensitivity. In some embodiments, the weight gain associated condition is cardiovascular disease. In some embodiments, the weight gain associated condition is neurologic disease. In some embodiments, the condition is obesity-linked gallbladder disease. In some embodiments, the weight gain associated condition is obesity-induced sleep apnea. In some embodiments, the condition is diabetes. In some embodiments, the weight gain associated condition is excessive appetite. In some embodiments, the weight gain associated condition is fatty liver disease. In 21 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) some embodiments, the weight gain associated condition is non-alcoholic fatty liver disease (NASH). In some embodiments, the weight gain associated condition is metabolic dysfunction–associated steatohepatitis (MASH). In some embodiments, the weight gain associated condition is dyslipidemia. In some embodiments, the condition is metabolic syndrome. In some embodiments, the condition is insufficient satiety. In some embodiments, the weight gain associated condition is hyperinsulinemia. In some embodiments, the weight gain associated condition is nighttime hypoglycemia.

[0160] In another aspect, the present disclosure provides methods of inducing weight loss in a subject while preserving or maintaining muscle mass and / or muscle function, using a combination therapy of apelin receptor agonist and GLP-1 receptor agonist.

[0161] Aspects of the present disclosure include methods of using a combination of the apelin receptor agonist and GLP-1 receptor agonist include use as an adjunct to a reduced- calorie diet and / or increased physical activity for chronic weight management in overweight or obese subjects, e.g., adults with an initial body mass index (BMI) of: 30 kg / m2or greater (obesity) or BMI of 27 kg / m2or greater (overweight). In some embodiments, the subject to be treated is overweight and in the presence of at least one weight-related comorbid condition (e.g., hypertension, dyslipidemia, type 2 diabetes mellitus, obstructive sleep apnea or cardiovascular disease).

[0162] Aspects of the present disclosure include methods of using of the apelin receptor agonist in combination with a GLP-1 receptor agonist and / or another drug that reduces caloric intake, as an adjunct to a reduced-calorie diet and / or increased physical activity for chronic weight management in overweight or obese subjects (e.g., adults with an initial body mass index (BMI) of: 30 kg / m2or greater (obesity) or BMI of 27 kg / m2or greater (overweight). In some embodiments, the subject to be treated is overweight and in the presence of at least one weight-related comorbid condition (e.g., hypertension, dyslipidemia, type 2 diabetes mellitus, obstructive sleep apnea or cardiovascular disease).

[0163] A drug that reduces caloric intake is a drug that can regulate appetite to make a subject feel less hungry and / or feel full faster after eating less food, resulting in fewer calories and less food being consumed by the subject. In some embodiments, a drug that reduces caloric intake is an appetite suppressant (e.g., as described herein). In some embodiments, the drug that reduces caloric intake is a cannabinoid receptor 1 (CB1r or CANN6 or CNR1) antagonist (e.g., as described herein). 22 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) 4.2. Methods of Increasing Weight Loss, or Inducing Weight Loss while Maintaining Muscle Mass or Muscle Strength

[0164] The present inventors demonstrated that co-administration of the apelin receptor agonist with the GLP-1 receptor agonist produced more weight loss, e.g., including more fat loss, than would have been expected from administration of GLP-1 receptor agonist alone. Accordingly, aspects of this disclosure include a method of increasing total weight loss caused by administration of a pre-determined amount of a GLP-1 receptor agonist to a subject in need thereof. In some embodiments, the method includes co-administering to a subject in need thereof an effective dose of an apelin receptor agonist and an effective dose of a GLP-1 receptor agonist, to increase total weight loss and / or fat loss in the subject. The increase in total weight loss or fat loss in the subject can be relative to weight loss that would be caused by administration of a pre-determined amount of a GLP-1 receptor agonist alone.

[0165] In some embodiments, the method includes adding an effective dose of an apelin receptor agonist to the GLP-1 receptor agonist treatment regimen of a subject in need thereof to increase total weight loss or fat loss caused by administration of a pre-determined amount of a GLP-1 receptor agonist to the subject.

[0166] In some embodiments, the increase in total weight loss is an increase of 5% or more over the weight loss that would be caused by, or expected for, administration of a pre- determined amount of a GLP-1 receptor agonist alone to the subject, such as an increase of 6% or more, 7% or more, 8% or more, 9% or more, 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, or 50% or more in total weight loss.

[0167] In some embodiments, the increase in fat loss is an increase of 5% or more over the fat loss that would be caused by, or expected for, administration of a pre-determined amount of a GLP-1 receptor agonist alone to the subject, such as an increase of 6% or more, 7% or more, 8% or more, 9% or more, 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, or 50% or more in fat loss.

[0168] Aspects of this disclosure include a method for inducing or increasing weight loss while maintaining and / or increasing muscle mass and / or muscle strength in a subject that has a condition or disease associated with weight gain. In some embodiments, the method is for maintenance of lean muscle mass. In some embodiments, the subject is undergoing weight loss therapy. 23 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)

[0169] In various embodiments, an apelin receptor agonist (e.g., as described herein) is administered to the subject to maintain or increase muscle mass (lean muscle) and / or muscle strength in skeletal muscle of the subject.

[0170] The muscle mass and / or muscle strength of a subject can be monitored during treatment and compared to a baseline level assessed prior to dosing with the apelin receptor agonist and the GLP-1 receptor agonist. In some embodiments, the muscle mass (e.g., lean muscle) or muscle strength of a subject is at least maintained at or near baseline levels during treatment, e.g., within 10% of baseline levels. In some embodiments, the subject is one who has suffered from declining muscle mass and / or muscle strength over time, and administration of the apelin receptor agonist according to methods of this disclosure reverses and / or ameliorates the decline.

[0171] Fat mass levels and lean muscle mass levels in a subject can be assessed prior to administration of either of the compounds (e.g., in a subject naïve to treatment with a GLP-1 receptor agonist). Baseline levels of fat mass and lean muscle mass in the subject can be assessed immediately prior to co-administration. In some embodiments, the subject exhibits loss of fat mass relative to baseline level but not a loss of lean muscle mass relative to baseline level after the co-administration. In some embodiments, the subject exhibits loss of fat mass relative to baseline level, an increase in lean to fat mass ratio, and / or increase in lean mass percentage, relative to baseline level in the subject (e.g., a baseline level in a subject naïve to treatment with a GLP-1 receptor agonist) after the co-administration of the apelin receptor agonist and the GLP-1 receptor agonist.

[0172] In some embodiments, a decrease of fat mass (or fat % of body weight BW) relative to baseline level is a decrease of 10% or more, such as a decrease of 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, or 50% or more. In some embodiments, a decrease of fat % of body weight (BW) relative to baseline level is a decrease of 10% or more, such as a decrease of 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, or 50% or more.

[0173] In some embodiments, the lean mass is maintained at a level that is within 10% of baseline level, such as within 5% of baseline level. In some embodiments, the increase in lean muscle % of body weight is an increase of 5% or more relative to baseline level, such as an increase of 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, or 50% or more. In some embodiments, the increase in lean to fat ratio is an increase of 5% or more relative to baseline level, such as an increase of 24 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, or 50% or more.

[0174] Aspects of this disclosure include methods of treating or preventing further muscle mass decrease caused by administration of a GLP-1 receptor agonist to a subject in need thereof. Thus, the method can include adding an effective dose of an apelin receptor agonist to the GLP-1 receptor agonist treatment regimen of a subject in need thereof. In some embodiments, the method treats or prevents lean muscle mass decrease in the subject after administration of the GLP-1 receptor agonist.

[0175] Fat mass levels and lean muscle mass levels in a subject undergoing GLP-1 receptor agonist therapy can be assessed prior to administration of the GLP-1 receptor agonist. A decrease in lean muscle mass caused by GLP-1 receptor agonist monotherapy over time can be assessed. Baseline levels of fat mass and lean muscle mass in the subject can be assessed immediately prior to administration of the apelin receptor agonist. Further decreases from baseline in lean muscle mass after administration of the apelin receptor agonist can be at least ameliorated and / or prevented using the methods of this disclosure. In some embodiments, the subject exhibits loss or decrease of fat mass relative to baseline level but not a loss of lean muscle mass relative to baseline level after the co-administration of the apelin receptor agonist. In some embodiments, the subject exhibits more fat mass loss relative to baseline level. In some embodiments, the subject exhibits an increase in lean to fat mass ratio relative to baseline level. In some embodiments, the subject exhibits an increase in lean mass percentage, relative to baseline level in the subject after the co-administration of the apelin receptor agonist.

[0176] In some embodiments, the subject exhibits an increased lean mass percentage, or increased lean / fat mass ratio after the co-administration, relative to a baseline level assessed before the co-administration.

[0177] In some embodiments, the subject exhibits a normal fed glucose level after the co- administration, e.g., within 20 days or less, such as 12 days or less, or 6 days or less of the co- administration, where baseline fed glucose levels were elevated above normal. A normal blood glucose level can be readily determined by the skilled artisan and can vary depending on, e.g., whether the patient has diabetes. 4.3. Apelin receptor agonists

[0178] Apelin is the endogenous peptide ligand for the apelin receptor (also referred to as APJ, or APLNR). The apelin receptor is a member of the rhodopsin-like G protein-coupled 25 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) receptor (GPCR) family. The apelin / APJ system is distributed in diverse periphery organ tissues and can play various roles in the physiology and pathophysiology of many organs. The apelin / APJ system participates in various cell activities such as proliferation, migration, apoptosis or inflammation. An apelin receptor agonist is any compound capable of promoting or activating the apelin / APJ system directly or indirectly, competitively, or non- competitively. Agonistic activities of a compound toward apelin receptor may be determined by any suitable method in the art. For example, the agonist can be assessed using the natural agonist of apelin receptor (i.e. apelin) and its receptor for promotion of the function of the receptor.

[0179] The apelin receptor can be activated by a variety of endogenous peptide isoforms of apelin and elabela. The apelin peptide isoforms can contain distinct structural features that aid in ligand recognition and activation of the receptor.

[0180] In some embodiments, the apelin receptor agonist is a polypeptide, such as an apelin polypeptide, e.g., one of several active isoforms ranging from 36 to 12 amino acids in length, or a fragment or analog thereof. Exemplary polypeptides that can be apelin receptor agonists include, but are not limited to, apelin-36, apelin-17, apelin-13, [Pyr1] apelin-13, and metabolically stable apelin analogs described in International Publication No. WO2016102648.

[0181] In some embodiments, the apelin receptor agonist is a polypeptide. In some embodiments, the apelin receptor agonist is a polypeptide that is an apelin peptide. An apelin peptide is a bioactive apelin receptor agonist that includes a polypeptide sequence derived from, or sharing 50% or greater sequence identity to, the preproapelin precursor protein (which is encoded by the APLN gene), or an isoform thereof, or a variant thereof, or an analog thereof. The apelin peptide may be connected to an additional moiety, such as a half- life extending moiety, or an additional active agent, via any convenient means such as via a covalent linker or a fusion polypeptide or protein.

[0182] In some embodiments, the apelin receptor agonist is a polypeptide that is an elabela peptide.

[0183] In some embodiments, the apelin peptide includes a polypeptide sequence of 12 to 36 amino acids in length. In some embodiments, the apelin peptide includes one of several active apelin isoforms ranging from 12 to 36 amino acids in length, or a fragment or analog thereof. Exemplary apelin peptides include, but are not limited to, apelin-36, apelin-17, 26 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) apelin-15, apelin-14, apelin-13, [Pyr1] apelin-13, and metabolically stable apelin analogs described in International Publication No. WO2016102648.

[0184] In some embodiments, the apelin peptide includes a polypeptide selected from apelin42-77 (apelin-36), apelin61-77 (apelin-17), apelin63-77 (apelin-15), apelin64-77 (apelin-14), apelin65-77 (apelin-13), apelin66-77 (apelin-12), apelin67-77 (apelin-11 ), apelin68-77 (apelin-10), apelin73-77 (apelin-5), apelin61-76 (apelin-K16P), apelin61-75 (apelin-K15M), apelin61-74 (apelin-K14P), apelin-F13A, apelin65-76, apelin65-75, apelin66-76, apelin67-76, apelin66-75, apelin 67-75, and [Pyr1]Apelin-13, or a fragment or derivative thereof.

[0185] In some embodiments, the apelin peptide is a variant that includes a polypeptide sequence having one or more D-amino acid residues. In some embodiments, the apelin peptide is a variant that includes a polypeptide sequence having one or more non-natural amino acid residues. It is understood that such sequence variations can be introduced at particular locations in an apelin peptide sequence without significantly adversely affecting the apelin receptor agonist activity of the compound.

[0186] In some embodiments, the apelin peptide includes an analog of apelin-13 or apelin- 17, such as a cyclic peptide analog. A cyclic peptide analog of an apelin can include a sequence of amino acids that align partially or completely with a parent apelin peptide sequence, and further include an intramolecular linkage, e.g., between the sidechains of two amino acid residues, or between the N-terminal or C-terminal of the peptide and a sidechain group of an amino acid. In some embodiments, the apelin peptide is AMG3054, an apelin-17 analog that includes a Glu10 to Lys13 sidechain to sidechain amide bond linkage. In some embodiments, the apelin peptide is a cyclic apelin-13 peptide analog. In some embodiments, the apelin peptide is CLR-325.

[0187] In some embodiments, the apelin peptide is a lanthipeptide. Lanthipeptides are polycyclic peptide that include thioether cross-linked amino acids, e.g., (2S, 6R)-lanthionine (Lan) or (2S, 3S, 6R)-3-methyllanthionine (MeLan). In some embodiments, the apelin peptide is a lanthipeptide analog or variant of an apelin peptide that includes thioether cross- linked amino acids.

[0188] In some embodiments, the apelin peptide is a long-acting apelin peptide. In some embodiments, an apelin peptide can be long acting (e.g., have a half-life of several hours to days) by including a half-life extending moiety such as a carrier protein or a moiety that 27 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) facilitates association with an endogenous carrier, such as albumin protein or an immunoglobulin.

[0189] In some embodiments, the apelin peptide is an apelin peptide conjugate that includes an apelin peptide conjugated to a half-life extending moiety via an optional linker or spacer moiety. The apelin peptide conjugate can include a polypeptide conjugated to a lipid, e.g., fatty acid, via an optional linker. The fatty acid can provide for association of the compound with endogenous carrier proteins in vivo such as albumin proteins. In some embodiments, the lipid or fatty acid is conjugated to the N-terminal of the apelin peptide via an optional linker.

[0190] In some embodiments, the apelin peptide is an apelin fusion protein. In some embodiments, the apelin fusion protein includes an apelin peptide fused to an Fc domain, a fragment of an Fc domain, or variant of an Fc domain. Exemplary apelin fusion proteins are described in WO 2014 / 152955. Similarly, elabela peptide is an elabela fusion protein. In some embodiments, the elabela fusion protein includes an elabela peptide fused to an Fc domain, a fragment of an Fc domain, or variant of an Fc domain. Exemplary elabela fusion proteins include, but are not limited to, Fc-ELA-32, and Fc-ELA-21.

[0191] Further exemplary apelin peptides include, but are not limited to, CLR-325 (Novartis), VS-364 (Vasa Therapeutics), VS-367, SBI-104 (ShiftBio), CB5064 (Cohbar), BIO 15529, Lanthi-apelin, APJ (PepLib), and apelin Fc-fusion polypeptide.

[0192] In some embodiments, the apelin receptor agonist is a small molecule. The term “small molecule” refers to an organic molecule of a size comparable to those organic molecules generally used in pharmaceuticals. The term excludes biological macromolecules (e.g., proteins, nucleic acids, etc.). Preferred small organic molecules range in size up to 5000 Da, more preferably up to 2000 Da, and most preferably up to 1000 Da.

[0193] Exemplary apelin receptor agonists of interest include, but are not limited to, E339- 3D6 (see, e.g., Iturrioz et al. (FASEB Journal, Volume24, Issue5, May 2010, Pages 1506- 1517), ML233, BMS-986224, ANPA-0073, AMG986, and the like.

[0194] As further described below, in some embodiments of the methods of this disclosure, the apelin receptor agonist is a compound described in US Patent No.9,573,936, US 9,868,721, International Publication No. WO2016196771, US 10,011,594, U.S. Patent No. RE49,594 E (a reissue of US 10,100,059) or Narayanan et al. (J. Med. Chem.2021, 64, 3006−3025), the disclosures of which are herein incorporated by reference in their entirety.

[0195] As known by those skilled in the art, certain compounds of this disclosure may exist in one or more tautomeric forms. Because one chemical structure may only be used to 28 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) represent one tautomeric form, it will be understood that for convenience, referral to a compound of a given structural formula includes tautomers of the structure represented by the structural formula.

[0196] In some embodiments, the apelin receptor agonist is an apelin receptor targeting moiety within a bifunctional or trifunctional compound. In some embodiments, the bifunctional compound comprises a fusion or conjugation of an apelin peptide with a GLP-1 receptor agonist. In some embodiments, the GLP-1 receptor agonist is an incretin / GLP-1 peptide. In some embodiments, the trifunctional compound comprises a fusion or conjugation of an apelin peptide with a GLP-1 receptor agonist and a GIP receptor agonist. In some embodiments, the GLP-1 receptor agonist is an incretin / GLP-1 peptide. In some embodiments, the GIP receptor agonist is a GIP peptide.

[0197] In some embodiments, the apelin receptor agonist is a compound of formula (I) or (II):or a pharmaceutically acceptable salt thereof, a tautomer thereof, a pharmaceutically acceptable salt of the tautomer, a stereoisomer of any of the foregoing, or a mixture thereof, wherein: R1is an unsubstituted pyridyl, pyridonyl, or pyridine N-oxide, or is a pyridyl, pyridonyl, or pyridine N-oxide substituted with 1, 2, 3, or 4 R1asubstituents; R1ain each instance is independently selected from —F, —Cl, —Br, —I, —CN, — C1-C6 alkyl, —C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —OH, —O—(C1-C6 alkyl), —O—(C1- C6haloalkyl), —O—(C1-C6perhaloalkyl), —C2-C6alkenyl, —O—(C1-C6alkyl)-OH, —O— (C1-C6alkyl)-O—(C1-C6alkyl), —O—(C1-C6haloalkyl)-OH, —O—(C1-C6haloalkyl)-O— (C1-C6 alkyl), —O—(C1-C6 perhaloalkyl)-OH, —O—(C1-C6 perhaloalkyl)-O—(C1-C6 alkyl), —NH2, —NH(C1-C6alkyl), —N(C1-C6alkyl)2, —C(═O)—(C1-C6alkyl), —C(═O)OH, — (C═O)—O—(C1-C6alkyl), —C(═O)NH2, —C(═O)NH(C1-C6alkyl), —C(═O)N(C1- C6 alkyl)2, phenyl, —C(═O)-(heterocyclyl), or a heterocyclyl group, wherein the heterocyclyl group of the —C(═O)-(heterocyclyl) or heterocyclyl group is a 3 to 7 membered ring containing 1, 2, or 3 heteroatoms selected from N, O, and S; 29 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) R2is selected from —H, and C1-C4 alkyl or is absent in the compounds of Formula II; R3is selected from an unsubstituted C1-C10 alkyl, a C1-C10 alkyl substituted with 1, 2, or 3 R1asubstituents, a group of formula —(CR3bR3c)-Q, a group of formula —NH— (CR3bR3c)-Q, a group of formula —(CR3bR3c)—C(═O)-Q, a group of formula —(CR3dR3e)— (CR3fR3g)-Q, a group of formula —(CR3b═CR3c)-Q, and a group of formula –(heterocyclyl)- Q, wherein the heterocyclyl of the –(heterocyclyl)-Q has 5 to 7 ring members of which 1, 2, or 3 are heteroatoms selected from N, O, and S and is unsubstituted or is substituted with 1, 2, or 3 R3hsubstituents; R1ain each instance is independently selected from —F, —Cl, —CN, —OH, —O— (C1-C6alkyl), —O—(C1-C6haloalkyl), —O—(C1-C6perhaloalkyl), —O—(C1-C6alkyl)-OH, —O—(C1-C6 alkyl)-O—(C1-C6 alkyl), C2-C6 alkenyl, C2-C6 alkynyl, —NH2, —NH(C1- C6 alkyl), and —N(C1-C6 alkyl)2; R3band R3care independently selected from —H, —F, —Cl, —CN, —C1-C6alkyl, — C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —OH, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —O—(C1-C6 perhaloalkyl), —O—(C1-C6 alkyl)-OH, —O—(C1-C6 alkyl)-O—(C1-C6 alkyl), —NH2, —NH(C1-C6alkyl), and —N(C1-C6alkyl)2; R3dand R3eare independently selected from —H, —F, —Cl, —CN, —C1-C6alkyl, — C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —OH, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —O—(C1-C6perhaloalkyl), —O—(C1-C6alkyl)-OH, —O—(C1-C6alkyl)-O—(C1-C6alkyl), —NH2, —NH(C1-C6alkyl), and —N(C1-C6alkyl)2; R3fand R3gare independently selected from —H, —F, —Cl, —CN, —C1-C6 alkyl, — C1-C6haloalkyl, —C1-C6perhaloalkyl, —OH, —O—(C1-C6alkyl), —O—(C1-C6haloalkyl), —O—(C1-C6perhaloalkyl), —O—(C1-C6alkyl)-OH, —O—(C1-C6alkyl)-O—(C1-C6alkyl), —NH2, —NH(C1-C6 alkyl), and —N(C1-C6 alkyl)2; R3hin each instance is independently selected from —F, —Cl, —CN, —C1-C6 alkyl, —C1-C6haloalkyl, —C1-C6perhaloalkyl, —OH, —O—(C1-C6alkyl), —O—(C1- C6 haloalkyl), —O—(C1-C6 perhaloalkyl), —O—(C1-C6 alkyl)-OH, —O—(C1-C6 alkyl)-O— (C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, and oxo; Q is a monocyclic or bicyclic C6-C10aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms selected from N, O, or S, a C3-C8 cycloalkyl group, or a 3 to 7 membered heterocyclyl group containing 1, 2, or 3 heteroatoms selected from N, O, or S, wherein the C6-C10aryl group, the heteroaryl group, the cycloalkyl group, and the heterocyclyl group are unsubstituted or are substituted with 1, 2, 3, or 4 RQsubstituent; 30 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) RQin each instance is independently selected from —F, —Cl, —Br, —I, —CN, —C1- C6 alkyl, —C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —OH, —O—(C1-C6alkyl), —O—(C1-C6haloalkyl), —O—(C1-C6perhaloalkyl), —NH2, —NH(C1- C6 alkyl), —N(C1-C6 alkyl)2, —C(═O)—(C1-C6 alkyl), —C(═O)OH, —C(═O)—O—(C1- C6 alkyl), —C(═O)NH2, —C(═O)NH(C1-C6 alkyl), —C(═O)N(C1-C6 alkyl)2, —S(═O)2— (C1-C6alkyl), phenyl, and a heteroaryl group, and the Q heterocyclyl group may be substituted with 1 oxo RQsubstituent; R4is selected from a monocyclic or bicyclic C6-C10 aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and a monocyclic or bicyclic heterocyclyl group with 5 to 10 ring members containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, wherein the C6-C10 aryl group, the heteroaryl group, or the heterocyclyl group are unsubstituted or are substituted with 1, 2, or 3 R4asubstituents; R4ain each instance is independently selected from —F, —Cl, —Br, —I, —CN, — C1-C6 alkyl, —C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —OH, —O—(C1-C6 alkyl), —O—(C1- C6haloalkyl), —O—(C1-C6perhaloalkyl), —NH2, —NH(C1-C6alkyl), —N(C1-C6alkyl)2, — C(═O)—(C1-C6alkyl), —C(═O)OH, —C(═O)—O—(C1-C6alkyl), —C(═O)NH2, — C(═O)NH(C1-C6 alkyl), and —C(═O)N(C1-C6 alkyl)2, and the heterocyclyl R4group may be further substituted with 1 oxo substituent; and further wherein: if R4is an unsubstituted or substituted phenyl ring and R3is a group of formula — (CR3b═CR3c)-Q, then at least one of the following is true: a) R4is substituted with at least one —O—(C1-C6alkyl) group; b) Q is not an oxadiazole; c) R3bis not —H; d) R3cis not —H; e) R1is not a 2-pyridyl group; or f) R4is substituted with two or more —O—(C1-C6 alkyl) groups.

[0198] In some embodiments, the apelin receptor agonist is a compound of formula (I) or (II): 31 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)(I) (II) or a pharmaceutically acceptable salt thereof, a tautomer thereof, a pharmaceutically acceptable salt of the tautomer, a stereoisomer of any of the foregoing, or a mixture thereof, wherein: R1is an unsubstituted pyridyl, pyridonyl, or pyridine N-oxide, or is a pyridyl, pyridonyl, or pyridine N-oxide substituted with 1, 2, 3, or 4 R1asubstituents; R1ain each instance is independently selected from —F, —Cl, —Br, —I, —CN, —C1- C6 alkyl, —C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —OH, —O—(C1-C6 alkyl), —O—(C1- C6haloalkyl), —O—(C1-C6perhaloalkyl), —C2-C6alkenyl, —O—(C1-C6alkyl)-OH, —O— (C1-C6alkyl)-O—(C1-C6alkyl), —O—(C1-C6haloalkyl)-OH, —O—(C1-C6haloalkyl)-O— (C1-C6 alkyl), —O—(C1-C6 perhaloalkyl)-OH, —O—(C1-C6 perhaloalkyl)-O—(C1-C6 alkyl), —NH2, —NH(C1-C6alkyl), —N(C1-C6alkyl)2, —C(═O)—(C1-C6alkyl), —C(═O)OH, — C(═O)—O—(C1-C6alkyl), —C(═O)NH2, —C(═O)NH(C1-C6alkyl), —C(═O)N(C1- C6 alkyl)2, phenyl, —C(═O)-(heterocyclyl), or a heterocyclyl group, wherein the heterocyclyl group of the —C(═O)-(heterocyclyl) or heterocyclyl group is a 3 to 7 membered ring containing 1, 2, or 3 heteroatoms selected from N, O, or S; R2is selected from —H, or C1-C4 alkyl or is absent in the compounds of Formula II; R3is a group of formula —(CR3dR3e)—(CR3fR3g)-Q; R3dand R3eare independently selected from —H, —F, —Cl, —CN, —C1-C6alkyl, — C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —OH, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —O—(C1-C6 perhaloalkyl), —O—(C1-C6 alkyl)-OH, —O—(C1-C6 alkyl)-O—(C1-C6 alkyl), —NH2, —NH(C1-C6alkyl), or —N(C1-C6alkyl)2; R3fand R3gare independently selected from —H, —F, —Cl, —CN, —C1-C6alkyl, — C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —OH, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —O—(C1-C6perhaloalkyl), —O—(C1-C6alkyl)-OH, —O—(C1-C6alkyl)-O—(C1-C6alkyl), —NH2, —NH(C1-C6alkyl), or —N(C1-C6alkyl)2; Q is a monocyclic or bicyclic C6-C10 aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms selected from N, O, or S, a C3-C8cycloalkyl group, or a 3 to 7 membered heterocyclyl group containing 1, 2, or 3 32 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) heteroatoms selected from N, O, or S, wherein the C6-C10 aryl group, the heteroaryl group, the cycloalkyl group, and the heterocyclyl group are unsubstituted or are substituted with 1, 2, 3, or 4 RQsubstituent; RQin each instance is independently selected from —F, —Cl, —Br, —I, —CN, —C1- C6 alkyl, —C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —OH, —O—(C1-C6alkyl), —O—(C1-C6haloalkyl), —O—(C1-C6perhaloalkyl), —NH2, —NH(C1- C6alkyl), —N(C1-C6alkyl)2, —C(═O)—(C1-C6alkyl), —C(═O)OH, —C(═O)—O—(C1- C6 alkyl), —C(═O)NH2, —C(═O)NH(C1-C6 alkyl), —C(═O)N(C1-C6 alkyl)2, —S(═O)2— (C1-C6alkyl), phenyl, or a heteroaryl group, and the Q heterocyclyl group may be substituted with 1 oxo substituent; R4is selected from a monocyclic or bicyclic C6-C10 aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, or a monocyclic or bicyclic heterocyclyl group with 5 to 10 ring members containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S, wherein the C6-C10 aryl group, the heteroaryl group, or the heterocyclyl group are unsubstituted or are substituted with 1, 2, or 3 R4asubstituents; and R4ain each instance is independently selected from —F, —Cl, —Br, —I, —CN, —C1- C6 alkyl, —C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —OH, —O—(C1-C6 alkyl), —O—(C1- C6haloalkyl), —O—(C1-C6perhaloalkyl), —NH2, —NH(C1-C6alkyl), —N(C1-C6alkyl)2, — C(═O)—(C1-C6alkyl), —C(═O)OH, —C(═O)—O—(C1-C6alkyl), —C(═O)NH2, — C(═O)NH(C1-C6 alkyl), or —C(═O)N(C1-C6 alkyl)2, and the heterocyclyl R4group may be further substituted with 1 oxo substituent.

[0199] As noted above, apelin receptor agonist compounds of this disclosure may exist in multiple tautomeric forms. This is particularly true in compounds of Formula I where R2is H. These forms are illustrated below as Tautomer A and Tautomer B:(Tautomer A) (Tautomer B).

[0200] Apelin receptor agonist compounds of this disclosure are depicted structurally and generally named as compounds in the “Tautomer A” form. However, it is specifically contemplated and known that the compounds exist in “Tautomer B” form and thus 33 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) compounds in “Tautomer B” form are expressly considered to be part of this disclosure. For this reason, the claims refer to compounds of Formula I and Formula II. Depending on the compound, some compounds may exist primarily in one form more than another. Also, depending on the compound and the energy required to convert one tautomer to the other, some compounds may exist as mixtures at room temperature whereas others may be isolated in one tautomeric form or the other.

[0201] In some embodiments of formula (I) and (II), R1is an unsubstituted pyridyl or is a pyridyl substituted with 1 or 2 R1asubstituents.

[0202] In some embodiments of formula (I) and (II), R1ain each instance is independently selected from —CH3, —CH2CH3, —F, —Cl, —Br, —CN, —CF3, —CH═CH2, — C(═O)NH2, —C(═O)NH(CH3), —C(═O)N(CH3)2, —C(═O)NH(CH2CH3), —OH, —OCH3, —OCHF2, —OCH2CH3, —OCH2CF3, —OCH2CH2OH, —OCH2C(CH3)2OH, — OCH2C(CF3)2OH, —OCH2CH2OCH3, —NH2, —NHCH3, —N(CH3)2, phenyl, and a group of formulawhen drawn across a bond, indicates the point of attachment to the rest of the molecule.

[0203] In some embodiments of formula (I) and (II), R1is selected from34 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)wherein the symbolwhen drawn across a bond, indicates the point of attachment to the rest of the molecule. 35 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)

[0204] In some embodiments of formula (I) and (II), R1is selected fromwherein the symbolwhen drawn across a bond, indicates the point of attachment to the rest of the molecule.

[0205] In some embodiments of formula (I) and (II), R2is —H.

[0206] In some embodiments of formula (I) and (II), R4is a phenyl, pyridyl, pyrimidinyl, isoxazolyl, indolyl, naphthyl, or pyridinyl any of which may be unsubstituted or substituted with 1, 2, or 3 R4asubstituents. In some embodiments of formula (I) and (II), R4is a phenyl substituted with 1 or 2 R4asubstituents. In some embodiments of formula (I) and (II), the 1 or 2 R4asubstituents are —O—(C1-C2alkyl) groups.

[0207] In some embodiments of formula (I) and (II), R4ais in each instance independently selected from —CH3, —F, —Cl, —Br, —CN, —CF3, —OCH3, —OCHF2, —OCH2CH3, — C(═O)OCH3, —C(═O)CH3, or —N(CH3)2.

[0208] In some embodiments of formula (I) and (II), R4is selected from: 36 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)37 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)wherein the symbolwhen drawn across a bond, indicates the point of attachment to the rest of the molecule.

[0209] In some embodiments of formula (I) and (II), R3is selected from a group of formula —(CR3bR3c)-Q, a group of formula —NH—(CR3bR3c)-Q, a group of formula —(CR3bR3c)— C(═O)-Q, a group of formula —(CR3dR3e)—(CR3fR3g)-Q, a group of formula — (CR3b═CR3c)-Q, or a group of formula –(heterocyclyl)-Q, wherein the heterocyclyl of the – (heterocyclyl)-Q has 5 to 7 ring members of which 1, 2, or 3 are heteroatoms selected from N, O, or S and is unsubstituted or is substituted with 1, 2, or 3 R3hsubstituents.

[0210] In some embodiments of formula (I) and (II), Q is selected from pyrimidinyl, pyridyl, isoxazolyl, thiazolyl, imidazolyl, phenyl, tetrahydropyrimidinonyl, cyclopropyl, cyclobutyl, cyclohexyl, morpholinyl, pyrrolidinyl, pyrazinyl, imidazo[1,2-a]pyridinyl, pyrazolyl, or oxetanyl any of which may be unsubstituted or substituted with 1, 2, or 3, RQsubstituents.

[0211] In some embodiments of formula (I) and (II), Q is a monocyclic heteroaryl group with 5 or 6 ring members containing 1 or 2 heteroatoms selected from N, O, or S and Q is unsubstituted or is substituted with 1 or 2 RQsubstituents.

[0212] In some embodiments of formula (I) and (II), Q is selected from 38 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)39 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)wherein the symbolwhen drawn across a bond, indicates the point of attachment to the rest of the molecule.

[0213] In some embodiments of formula (I) and (II), R3is a group of formula – (heterocyclyl)-Q, wherein the heterocyclyl of the –(heterocyclyl)-Q has 5 to 7 ring members of which 1, 2, or 3 are heteroatoms selected from N, O, or S and is unsubstituted or is substituted with 1, 2, or 3 R3hsubstituents.

[0214] In some embodiments of formula (I) and (II), R3is a group of formula — (CR3dR3e)—(CR3fR3g)-Q.

[0215] In some embodiments of formula (I) and (II), R3has one of the formula 40 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)41 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)wherein the symbolwhen drawn across a bond, indicates the point of attachment to the rest of the molecule. 42 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)

[0216] In some embodiments of formula (I) and (II), R3has one of the formulawherein the symbolwhen drawn across a bond, indicates the point of attachment to the rest of the molecule.

[0217] In particular embodiments of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxy-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5- methyl-2-pyrimidinyl)-2-butanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- hydroxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; (1S,2R)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)- 4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide; (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- hydroxy-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide; 43 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1- (5-methyl-2-pyrimidinyl)-2-propanesulfonamide; (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2- pyrimidinyl)-2-butanesulfonamide; (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4- triazol-3-yl)-1-ethoxy-2-propanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- ethoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1- (5-methyl-2-pyrazinyl)-2-propanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(6-methyl-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- hydroxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-ethoxy-1-(5- methyl-2-pyrimidinyl)-2-propanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-(5- fluoro-2-pyrimidinyl)-1-methoxy-2-propanesulfonamide; (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5- methyl-2-pyrazinyl)-2-butanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-ethoxy-1-(5- fluoro-2-pyrimidinyl)-2-propanesulfonamide; (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-(1- methylethoxy)-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-(1- methylethoxy)-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; (1S,2R)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4- triazol-3-yl)-1-methoxy-2-propanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methoxy-2-pyrazinyl)-2-propanesulfonamide; (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2- pyrazinyl)-2-butanesulfonamide; (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- ethoxy-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide; (1R,2S)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(6-methoxy-2-pyridinyl)-4H-1,2,4-triazol-3- yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide; 44 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) (1R,2R)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4- triazol-3-yl)-1-ethoxy-2-propanesulfonamide; or (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- ethoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide.

[0218] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxy-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide or the pharmaceutically acceptable salt thereof.

[0219] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide or the pharmaceutically acceptable salt thereof.

[0220] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- hydroxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide or the pharmaceutically acceptable salt thereof.

[0221] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1S,2R)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)- 4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide or the pharmaceutically acceptable salt thereof.

[0222] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide or the pharmaceutically acceptable salt thereof.

[0223] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- hydroxy-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide or the pharmaceutically acceptable salt thereof.

[0224] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1- (5-methyl-2-pyrimidinyl)-2-propanesulfonamide or the pharmaceutically acceptable salt thereof. 45 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)

[0225] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2- pyrimidinyl)-2-butanesulfonamide or the pharmaceutically acceptable salt thereof.

[0226] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4- triazol-3-yl)-1-ethoxy-2-propane sulfonamide or the pharmaceutically acceptable salt thereof.

[0227] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- ethoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide or the pharmaceutically acceptable salt thereof.

[0228] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1- (5-methyl-2-pyrazinyl)-2-propanesulfonamide or the pharmaceutically acceptable salt thereof.

[0229] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(6-methyl-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- hydroxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide or the pharmaceutically acceptable salt thereof.

[0230] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-ethoxy-1-(5- methyl-2-pyrimidinyl)-2-propanesulfonamide or the pharmaceutically acceptable salt thereof.

[0231] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-(5- fluoro-2-pyrimidinyl)-1-methoxy-2-propanesulfonamide or the pharmaceutically acceptable salt thereof.

[0232] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5- methyl-2-pyrazinyl)-2-butanesulfonamide or the pharmaceutically acceptable salt thereof.

[0233] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-ethoxy-1-(5- fluoro-2-pyrimidinyl)-2-propanesulfonamide or the pharmaceutically acceptable salt thereof. 46 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)

[0234] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-(1- methylethoxy)-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide or the pharmaceutically acceptable salt thereof.

[0235] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-(1- methylethoxy)-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide or the pharmaceutically acceptable salt thereof.

[0236] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1S,2R)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4- triazol-3-yl)-1-methoxy-2-propanesulfonamide or the pharmaceutically acceptable salt thereof.

[0237] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methoxy-2-pyrazinyl)-2-propanesulfonamide or the pharmaceutically acceptable salt thereof.

[0238] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2- pyrazinyl)-2-butanesulfonamide or the pharmaceutically acceptable salt thereof.

[0239] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- ethoxy-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide or the pharmaceutically acceptable salt thereof.

[0240] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(6-methoxy-2-pyridinyl)-4H-1,2,4-triazol- 3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide or the pharmaceutically acceptable salt thereof.

[0241] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2R)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4- triazol-3-yl)-1-ethoxy-2-propanesulfonamide or the pharmaceutically acceptable salt thereof.

[0242] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- 47 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) ethoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide or the pharmaceutically acceptable salt thereof.

[0243] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(6-methoxy-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0244] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0245] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- hydroxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0246] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1S,2R)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)- 4H-1,2,4-triazol-3-yl)-1-methoxy-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0247] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0248] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- hydroxy-1-(5-methyl-2-pyrazinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0249] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1- (5-methyl-2-pyrimidinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof. 48 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)

[0250] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2- pyrimidinyl)-2-butanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0251] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4- triazol-3-yl)-1-ethoxy-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0252] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2, 6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- ethoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0253] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1S,2R)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-methoxy-1- (5-methyl-2-pyrazinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0254] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2, 6-dimethoxyphenyl)-5-(6-methyl-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- hydroxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0255] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-ethoxy-1-(5- methyl-2-pyrimidinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0256] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-(5- fluoro-2-pyrimidinyl)-1-methoxy-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0257] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5- methyl-2-pyrazinyl)-2-butanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0258] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-ethoxy-1-(5- fluoro-2-pyrimidinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0259] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-(1- 49 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) methylethoxy)-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0260] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-(1- methylethoxy)-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0261] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1S,2R)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4- triazol-3-yl)-1-methoxy-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0262] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methoxy-2-pyrazinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0263] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2- pyrazinyl)-2-butanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0264] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- ethoxy-1-(5-fluoro-2-pyrimidinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0265] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(6-methoxy-2-pyridinyl)-4H-1,2,4-triazol- 3-yl)-1-methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0266] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2R)-1-(5-chloro-2-pyrimidinyl)-N-(4-(2,6-dimethoxyphenyl)-5-(3-pyridinyl)-4H-1,2,4- triazol-3-yl)-1-ethoxy-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0267] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- ethoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof. 50 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)

[0268] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(2,6-difluorophenyl)-5-(6-methoxy-2-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0269] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1R,2S)—N-(4-(4,6-dimethoxy-5-pyrimidinyl)-5-(2-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- methoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0270] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is N- (4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1-isopropoxy-1- (5-methyl-2-pyrimidinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0271] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (1S,2S)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-1- isopropoxy-1-(5-methyl-2-pyrimidinyl)-2-propanesulfonamide, or a pharmaceutically acceptable salt thereof.

[0272] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is N- (4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2- pyrimidinyl)-2-butanesulfonamide, or a pharmaceutically acceptable salt thereof, a tautomer thereof, a pharmaceutically acceptable salt of the tautomer, a stereoisomer of any of the foregoing, or a mixture thereof.

[0273] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5- methyl-2-pyrimidinyl)-2-butanesulfonamide (BGE-105) or a pharmaceutically acceptable salt thereof.

[0274] In a particular embodiment of formula (I) and (II), the apelin receptor agonist is(BGE-105) or a pharmaceutically acceptable salt thereof. 51 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)

[0275] U.S. Patents Nos.9,573,936, 9,868,721, 9,745,286, 9,656,997, 9,751,864, 9,656,998, 9,845,310, 10,058,550, 10,221,162, and 10,344,016, the disclosures of which are incorporated herein by reference in their entirety, describe apelin receptor agonists of formula (I) or (II), and methods of synthesizing such triazole agonists of the apelin receptor, including BGE-105. See e.g., Example 263.0 of U.S. Patent No.9,573,936.

[0276] In some embodiments, the apelin receptor agonist is a compound of Formula (XI)or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: alk is C1-6 alkyl substituted with 0-5 Re; ring A is independently selected from the group consisting of:52 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) ring B is independently selected from the group consisting of:and 6-membered heteroaryl; R1is independently selected from the group consisting of: H, halogen, NO2, — (CH2)nORb, (CH2)nS(O)pRc, —(CH2)nC(═O)Rb, —(CH2)nNRaRa, —(CH2)nCN, — (CH2)nC(═O)NRaRa, —(CH2)nNRaC(═O)Rb, —(CH2)nNRaC(═O)NRaRa, — (CH2)nNRaC(═O)ORb, —(CH2)nOC(═O)NRaRa, —(CH2)nC(═O)ORb, — (CH2)nS(O)pNRaRa, —(CH2)nNRaS(O)pNRaRa, —(CH2)nNRaS(O)pRc, C1-4 alkyl substituted with 0-3 Re, —(CH2)n—C3-6 carbocyclyl substituted with 0-3 Re, and — (CH2)n-heterocyclyl substituted with 0-3 Re; R2is independently selected from the group consisting of: C1-5alkyl substituted with 0-3 Re, C1-5 alkenyl substituted with 0-3 Re, and C1-6 cycloalkyl substituted with 0-3 Re; provided when R2is C1-5alkyl, the carbon atom except the one attached directly to the pyridine ring may be replaced by O, N, and S; R3is independently selected from the group consisting of: (1) —(CR4R4)rC(═O)OC1-4 alkyl substituted with 0-5 Re, (2) —(CR4R4)rNRaRa, (3) —(CR4R4)rC(═O)NRaRa, (4) —(CR4R4)rNRaC(═O)C1-4alkyl substituted with 0-5 Re, (5) —(CR4R4)rNRaC(═O)(CR4R4)nOC1-4alkyl substituted with 0-5 Re, (6) —(CR4R4)r—R5, (7) —(CR4R4)r—OR5, (8) —(CR4R4)rNRaC(═O)(CR4R4)nR5, and (9) (CR4R4)rC(═O)NRa(CR4R4)nR5; R4is independently selected from the group consisting of: H, halogen, NRaRa, OC1-4alkyl, and C1-4alkyl; or R4and R4together with the carbon atom to which they are both attached form C3-6cycloalkyl substituted with 0-5 Re; R5is independently selected from the group consisting of: —(CH2)n—C3-10 carbocycle and —(CH2)n-heterocycle, each substituted with 0-3 R6; 53 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) R6is independently selected from: H, halogen, ═O, —(CH2)nORb, (CH2)nS(O)pRc, — (CH2)nC(═O)Rb, —(CH2)nNRaRa, —(CH2)nCN, —(CH2)nC(═O)NRaRa, — (CH2)nNRaC(═O)Rb, —(CH2)nNRaC(═O)NRaRa, —(CH2)nNRaC(═O)ORb, — (CH2)nOC(═O)NRaRa, —(CH2)nC(═O)ORb, —(CH2)nS(O)pNRaRa, — (CH2)nNRaS(O)pNRaRa, —(CH2)nNRaS(O)pRc, C1-5 alkyl substituted with 0-3 Re, (CH2)n—C3-6carbocyclyl substituted with 0-3 Re, and —(CH2)n-heterocyclyl substituted with 0-3 Re; Rais independently selected from the group consisting of: H, C1-6 alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2-6alkynyl substituted with 0-5 Re, —(CH2)n—C3-10carbocyclyl substituted with 0-5 Re, and —(CH2)n-heterocyclyl substituted with 0-5 Re; or Raand Ratogether with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re; Rbis independently selected from the group consisting of: H, C1-6alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, —(CH2)n—C3-10carbocyclyl substituted with 0-5 Re, and —(CH2)n-heterocyclyl substituted with 0-5 Re; Rcis independently selected from the group consisting of: C1-6alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2-6alkynyl substituted with 0-5 Re, C3-6carbocyclyl, and heterocyclyl; Rdis independently selected from the group consisting of: H and C1-4alkyl substituted with 0-5 Re; Reis independently selected from the group consisting of: C1-6alkyl substituted with 0-5 Rf, C2-6alkenyl, C2-6alkynyl, —(CH2)n—C3-6cycloalkyl, —(CH2)n—C4-6 heterocyclyl, —(CH2)n-aryl, —(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, ═O, CO2H, —(CH2)nORf, S(O)pRf, C(═O)NRfRf, NRfC(═O)Rf, S(O)pNRfRf, NRfS(O)pRf, NRfC(═O)ORf, OC(═O)NRfRf, and —(CH2)nNRfRf; Rfis independently selected from the group consisting of: H, F, Cl, Br, CN, OH, C1- 5alkyl (optimally substituted with halogen and OH), C3-6 cycloalkyl, and phenyl, or Rfand Rftogether with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with C1-4alkyl; n is independently selected from zero, 1, 2, and 3; r is independently selected from zero, 1, 2, and 3; and 54 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) p is independently selected from zero, 1, and 2.

[0277] In some embodiments of the compound of Formula (XI), the compound is of Formula (XV):or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R1is independently selected from the group consisting of: —CH2OH, —OCH3, — OCF3, CH3, CH2CH3, CH(CH3)2, and cyclopropyl; R2is independently selected from the group consisting of: C1-4alkyl substituted with 0-3 Re, C2-4 alkenyl, C1-6 cycloalkyl, and CH2O(CH2)1-3CH3; R3is independently selected from the group consisting of: (1) —CH2C(═O)OC1-4alkyl substituted with 0-3 Re, (2) —CH2NRaRa, (3) —CH2C(═O)NRaRa, (4) —CH2NHC(═O)C1-4alkyl substituted with 0-3 Re, (5) —CH2NRaC(═O)(CH2)0-2OC1-4alkyl substituted with 0-3 Re, (6) —CH2—R5, (7) —CH2—OR5, (8) —CH2NRaC(═O)(CH2)0-2R5, and (9) —CH2C(═O)NRa(CH2)0-2R5; R5is independently selected from the group consisting of: aryl, C3-6cycloalkyl, and heterocycle, each substituted with 0-3 R6; R6is independently selected from the group consisting of: H, F, Cl, Br, —ORb, ═O, —(CH2)nC(═O)Rb, —(CH2)nC(═O)ORb, —(CH2)NRaRa, CN, —(CH2)nC(═O)NRaRa, 55 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) —S(O)2NH2, C1-4 alkyl substituted with 0-3 Re, (CH2)n—C3-6 carbocyclyl substituted with 0-3 Re, and —(CH2)n-heterocyclyl substituted with 0-3 Re; Rais independently selected from the group consisting of: H, C1-6alkyl substituted with 0-5 Re, —(CH2)n—C3-10carbocyclyl substituted with 0-5 Re, and —(CH2)n- heterocyclyl substituted with 0-5 Re; or Raand Ratogether with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re; Rbis independently selected from the group consisting of: H, C1-6alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, —(CH2)n—C3-10carbocyclyl substituted with 0-5 Re, and —(CH2)n-heterocyclyl substituted with 0-5 Re; Reis independently selected from the group consisting of: C1-6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, —(CH2)n—C3-6 cycloalkyl, —(CH2)n— C4-6heterocyclyl, —(CH2)n-aryl, —(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, ═O, and CO2H; and n is independently selected from zero, 1, 2, and 3.

[0278] In some embodiments, the apelin receptor agonist is a compound having the structure:or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof

[0279] In some embodiments, the apelin receptor agonist is a compound having the structure:or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof. 56 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)

[0280] In some embodiments, the apelin receptor agonist is a pyrazole agonist as described in U.S. Patent No. RE49,594 E (a reissue of US 10,100,059) or by Narayanan et al. (J. Med. Chem.2021, 64, 3006−3025). In some embodiments, the apelin receptor agonist is a compound of Formula (XXI):or a pharmaceutically acceptable salt thereof, a prodrug thereof, or a salt of a prodrug thereof, wherein R1is represented by the formula:is a monocyclic aryl or heteroaryl group; each A is independently fluoro substituted C1-C3alkoxy or fluoro substituted C1- C3 alkyl; n is 1, 2, 3, 4, or 5; R2is C3-8alkyl, C1-8alkyl (C3-8cycloalkyl), C3-8cycloalkyl, heteroaryl, or substituted aryl; R4 is adamantanyl, aryl, C1-8 alkyl, C1-8 alkyl alcohol, C1-8 alkyl amino, C1-8 alkyl amido, C2-8alkyl(aryl), C1-8alkyl (C3-8cycloalkyl), C1-8alkyl (C3-8cycloalkyl)—CO2R7, C1-8 alkyl guanidinyl, C1-8 alkyl heteroaryl, C1-8 alkyl tetrazol-5-one, C2-4 alkyl heterocycloalkyl, C1-8 alkyl thioether, C1-8 alkyl thiol, C2-8 alkenyl, C2-8 alkenyl(aryl), C2-8 alkenyl(heteroaryl), C3-8alkynyl, C3-8cycloalkyl, C3-8cycloalkyl—CO2R7, (CH2)xNR7R8, (CH2)xOR7, (CH2)xNR9COR7, (CH2)xNR9SO2R7, (CH2)xNR9CO2R7, (CH2)xNHCOR7, (CH2)xNHSO2R7, (CH2)xNHCO2R7, (CH2)xCONR7R8, (CH2)xCONR7(CH2)yCO2R9, (CH2)xCONR7(CH2)yCONR7R8, (CH2)xCONR7(CH2)yR9(CH2)xCOR7, (CH2)xCO2R7, (CH2)xSO2NR7(CH2)yR9, CHR7COR9, CHR7CONHCHR8COR9, CONR7R8, CONR7(CH2)xCO2R8, CONR7CHR8CO2R9, CO2R9, NHCO2R7, or (CH2)xSO2NR7R8; 57 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) R5 and R6 each are independently is adamantanyl, aryl, C1-8 alkyl, C1-8 alkyl alcohol, C1-8 alkyl amino, C1-8 alkyl amido, C2-8 alkyl(aryl), C1-8 alkyl (C3-8 cycloalkyl), C1-8 alkyl (C3-8cycloalkyl)—CO2R7, C1-8alkyl guanidinyl, C1-8alkyl heteroaryl, C1-8alkyl tetrazol-5-one, C2-4 alkyl heterocycloalkyl, C1-8 alkyl thioether, C1-8 alkyl thiol, C2-8 alkenyl, C2- 8 alkenyl(aryl), C2-8 alkenyl(heteroaryl), C3-8 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkyl-CO2R7, (CH2)xNR7R8, (CH2)xOR7, (CH2)xNR9COR7, (CH2)xNR9SO2R7, (CH2)xNR9CO2R7, (CH2)xNHCOR7, (CH2)xNHSO2R7, (CH2)xNHCO2R7, (CH2)xCONR7R8, (CH2)xCONR7(CH2)yCO2R9, (CH2)xCONR7(CH2)yCONR7R8, (CH2)xCONR7(CH2)yR9, (CH2)xCOR7, (CH2)xCO2R7, (CH2)xSO2NR7(CH2)yR9, CHR7COR9, CHR7CONHCHR8COR9, CONR7R8, CONR7(CH2)xCO2R8, CONR7CHR8CO2R9, CO2R9, NHCO2R7, or (CH2)x SO2NR7R8; or R4 and R5 together make a 4-8 member ring which may be substituted with one or more heteroatoms; or R4 and R5 together make a 5-8 nitrogen containing member ring with one or more carbonyl groups; wherein the group R4is substituted with one or more fluorine atoms; R6is H; R7 and R8 each are independently H, C1-8 alkoxy, aryl, C1-8 alkyl, C1-8 alkyl alcohol, C1-8alkyl amino, C1-8alkyl amido, C1-8alkyl(aryl), C1-8alkyl (C3-8cycloalkyl), C1-8alkyl tetrazol- 5-one, C1-8alkyl guanidinyl, C1-8alkyl heteroaryl, C1-8alkyl thioether, C1-8alkyl thiol, C1-8 alkenyl, C3-8 alkynyl, C3-8 cycloalkyl, (CH2)xCONHR9, (CH2)xCOR9, (CH2)xCO2R9, or heteroaryl; or R7and R8together make a 3-9 member ring which may contain one or more heteroatoms, wherein the ring is substituted with at least two fluorine atoms; or R7 and R8 together make a 5-8 nitrogen containing member ring with one or more carbonyl groups; R9 is aryl, C1-8 alkoxy, C1-8 alkyl, C1-8 alkyl(aryl), C3-8 cycloalkyl, H, heteroaryl, or hydroxyl; each x is independently 0-8; and each y is independently 1-8. 58 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)

[0281] In some embodiments of Formula (XXI), the apelin receptor agonist is a compound of the structure:or a pharmaceutically acceptable salt thereof, wherein R is selected from: ,, .

[0282] In some embodiments, the apelin receptor agonist is a compound of formula:or a pharmaceutically acceptable salt thereof. In some embodiments, the apelin receptor agonist is (S)-N-(1-(cyclobutylamino)-1-oxo-5-(piperidin-1-yl)pentan-3-yl)-5-(2,6- dimethoxyphenyl)-1-cyclopentyl-1H-pyrazole-3-carboxamide, or a pharmaceutically acceptable salt thereof, such as a hydrochloride salt of the compound.

[0283] In some embodiments, the apelin receptor agonist is a compound of formula: 59 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)or a pharmaceutically acceptable salt thereof. In some embodiments, the apelin receptor agonist is (1S,2S)-N-(4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3- yl)-1-isopropoxy-1-(5-methylpyrimidin-2-yl)propane-2-sulfonamide, or a pharmaceutically acceptable salt thereof, such as a hydrocholoride salt of the compound. 4.4. Glucagon-Like Peptide-1 Receptor Agonists

[0284] Glucagon-like peptide 1 receptor (GLP-1R) belongs to Family B1 of the seven- transmembrane G protein-coupled receptors, and its natural agonist ligand is the peptide hormone glucagon-like peptide-1 (GLP-1). GLP-1 is a peptide hormone arising by its alternative enzymatic cleavage from proglucagon, the prohormone precursor for GLP-1, which is highly expressed in enteroendocrine cells of the intestine, the alpha cells of the endocrine pancreas (islets of Langerhans), and the colon. GLP-1 acts through a G protein- coupled cell surface receptor (GLP-1R) and enhances nutrient-induced insulin synthesis and release. GLP-1 stimulates insulin secretion (insulinotropic action) and cAMP formation. GLP-1(7-36) amide stimulates insulin release, lowers glucagon secretion, and inhibits gastric secretion and emptying. These gastrointestinal effects of GLP-1 are not found in vagotomized subjects, pointing to a centrally-mediated effect. GLP-1 binds with high affinity to isolated rat adipocytes, activating cAMP production and stimulating lipogenesis or lipolysis. GLP-1 stimulates glycogen synthesis, glucose oxidation, and lactate formation in rat skeletal muscle.

[0285] On activation, GLP-1 receptors couple to the α-subunit of G protein, with subsequent activation of adenylate cyclase and increase of cAMP levels, thereby potentiating glucose-stimulated insulin secretion. Therefore, GLP-1 is also an attractive therapeutic target to lower blood glucose and preserve the β-cells of the pancreas of diabetic patients or patients diagnosed with obesity. The capability of activating the human GLP-1 receptor may be determined in a medium containing membrane expressing the GLP-1 receptor, and / or in an 60 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) assay with whole cells expressing the GLP-1 receptor. Alternatively, the response of the human GLP-1 receptor may be measured in a reporter gene assay.

[0286] A “GLP-1 receptor agonist” (GLP-1RA) is a compound which is capable of binding to the GLP-1 receptor (GLP-1R) and capable of activating it. In one embodiment the GLP-1 receptor is the human GLP-1 receptor. In some embodiments, the GLP-1RA is also capable of agonizing one or more additional receptors or functions. In some embodiments, the GLP- 1RA is also an agonist of GIP receptor. In some embodiments, the GLP-1RA is also an agonist of glucagon receptor. In some embodiments, the GLP-1RA is also an agonist of GIP receptor and glucagon receptor.

[0287] Aspects of the present disclosure include a method of treating a condition or disease associated with weight gain by co-administering to a subject an effective dose of an apelin receptor agonist and a GLP-1 receptor agonist. In some embodiments, the GLP-1RA is administered orally. In some embodiments, the GLP-1RA is administered via injection, e.g., subcutaneously.

[0288] A variety of compounds which are agonists of GLP-1R can be used in the methods of this disclosure. In some embodiments, the GLP-1 receptor agonist (GLP-1RA) is a polypeptide or polypeptide analog. A GLP-1RA can be an incretin mimetic, or GLP-1 analog. In some embodiments, the GLP-1RA is a fusion protein, or fusion of a protein and peptide. In some embodiments, the GLP-1RA is a recombinant polypeptide. In some embodiments, the GLP-1RA is a synthetic polypeptide.

[0289] In some embodiments, the GLP-1RA is a fusion protein to agonize GLP1R for Type 2 diabetes.

[0290] In some embodiments, the GLP-1RA has additional agonist activity at one or more receptors or relevant biological targets. In some embodiments, the GLP-1RA is a dual agonist (also referred to as a twincretin). In some embodiments, the dual agonist is an agonist of GLP-1R and glucose-dependent insulinotropic peptide (GIP) receptor. Tirzepatide is an exemplary dual agonist.

[0291] In some embodiments, the GLP-1RA is an agonist of GLP-1R, and GIP receptor and / or glucagon receptor. In some embodiments, the GLP-1RA is an agonist of GLP-1R and glucagon receptor (GL R or GCGR). In some embodiments, the GLP-1RA is an agonist of GLP-1R and GIP receptor.

[0292] In some embodiments, the GLP-1RA is a peptide drug for diabetes and / or obesity that agonizes GLP-1 and GCGR. 61 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)

[0293] In some embodiments, the GLP-1RA is a triple agonist (also referred to as a triple G agonist), e.g., an agonist of GLP-1R, GIP receptor and glucagon receptor. Retatrutide (LY3437943) is an exemplary triple G agonist. Other triple G agonists of interest include those described by Knerr et al. (Next generation GLP-1 / GIP / glucagon triple agonists normalize body weight in obese mice, Mol. Metab.2022 Sep; 63: 101533).

[0294] In some embodiments, the GLP-1RA is selected from: dulaglutide, exenatide, semaglutide, liraglutide, insulin degludec + liraglutide, insulin glargine + lixisenatide, tirzepatide, cagrilintide [INN] + semaglutide, albenatide [INN], cotadutide, CT-868, PF 06882961, efocipegtrutide, LY-3502970 (Orforglipron), NLY-001, pegapamodutide, pemvidutide, PF-07081532, retatrutide, RGT-075, TTP-273, vurolenatide, GZR-18, mazdutide, PB-119, AMG-133, dapiglutide, DD-01, DR-10627, ECC-5004, exenatide biobetter, GL-0034, GMA-105, HEC-88473, LY-3493269, NN-6177, NN-9847, NNC0519- 0130, PB-1023, Peptides to Agonize GLP-1 and GCGR for Diabetes and Obesity, Peptides to Agonize GLP-1 and GCGR for Diabetes and Obesity, SCO-094, semaglutide, VK-2735, YH- 25724, YN-012 (Supaglutide), NLY-02, ZP7570 (dapiglutide ), and YN-015.

[0295] In some embodiments, the GLP-1 receptor agonist is selected from albenatide, albiglutide, avexitide, cafraglutide, cotadutide, danuglipron, dapiglutide, diabegone, dulaglutide, ecnoglutide, efpeglenatide, efinopegdutide, efocipegtrutide, exenatide, exenatide biobetter, exenatide SR, froniglutide, liraglutide, liraglutide biobetter, lixisenatide, CT-868, efocipegtrutide, LY-3502970 (Orforglipron), maridebart, mazdutide, NLY-001, orforglipron, pegapamodutide, pemvidutide, retatrutide (LY-3437943), semaglutide, semaglutide injection, survodutide, vurolenatide, dapagliflozin + semaglutide, (cagrilintide + semaglutide), (LAI- 287 + semaglutide), (semaglutide + GIP analogue), 4P-004, AMG-133, AP-026, AZD-9550, BGM-0504, BMS-686117, Zn / BMS-686117 adduct, CT-388, CT-868, CT-996, DD-01, DR- 10624, DR-10627, ECC-5004, E-2HSA, GL-0034, GLP-06, GMA-105, GMA-106, GMA- 102, GSBR-1290, GXG-6, GZR-18, HEC-88473, HR-17031, HRS-7535, HRS-9531, HS- 20004, HS-20094, HB-1085, HDM-1002, HL-08, HZ-010, JY-09, KN-056, LY-3493269, MBX-1416, MDR-001, MWN-101, NLY-001, NN-9490, NNC0519-0130, NN-6177, NN- 9847, NN-9904, NN-6535 (semaglutide), NN-9932 (semaglutide), PF-06954522, PF- 07081532, PF-06882961 (Danuglipron), PB-1023, PB-119, PB-718, RGT-075, SAL-015, SAL-0112, SCO-094, TERN-601, TTP-273, Uni-E4, VK-2735, YH-25724, ecnoglutide (XW-004), XW-003, XW-014, YH-25724, YN-012 (Supaglutide), YN-015, ZP7570 (dapiglutide ), ZT-002, and pharmaceutically acceptable salts thereof. 62 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)

[0296] In some embodiments, the GLP-1 receptor agonist is danuglipron.

[0297] In some embodiments, the GLP-1RA is dulaglutide. Dulaglutide reduces fasting glucose concentrations and reduces postprandial glucose (PPG) concentrations in patients with type 2 diabetes mellitus through the agonism of the GLP-1 receptor. This drug primarily acts as an incretin mimetic hormone or analog of human glucagon-like peptide-1, which normally acts on the GLP-1 receptor. Dulaglutide activates the GLP-1 receptor found in pancreatic beta cells, increasing intracellular cyclic AMP (cAMP) in beta cells, leading to insulin release and subsequent reduction of blood glucose concentrations. Additionally, dulaglutide decreases glucagon secretion and slows gastric emptying.

[0298] In some embodiments, the GLP-1RA is exenatide. In some embodiments, the GLP- 1RA is Byetta. Exenatide binds to the intact human Glucagon-like peptide-1 receptor (GLP- 1R) in a similar way to the human peptide glucagon-like peptide-1 (GLP-1).

[0299] In some embodiments, the GLP-1RA is semaglutide. Semaglutide is a recombinant DNA produced polypeptide analogue of human glucagon-like peptide-1 (GLP-1) which is typically used in combination with diet and exercise in the therapy of type 2 diabetes, either alone or in combination with other antidiabetic agents. It is an agonist of glucagon-like peptide-1 receptors (GLP-1 AR) and used for the treatment of type 2 diabetes. semaglutide is a polypeptide that contains a linear sequence of 31 amino acids joined together by peptide linkages. It has a role as a hypoglycemic agent, a glucagon-like peptide-1 receptor agonist, an anti-obesity agent, a neuroprotective agent and an appetite depressant. It is a polypeptide and a lipopeptide.

[0300] In some embodiments, the GLP-1RA is liraglutide. Liraglutide is a lipopeptide that is an analogue of human GLP-1 in which the lysine residue at position 27 is replaced by arginine and a hexadecanoyl group attached to the remaining lysine via a glutamic acid spacer. Liraglutide is typically used as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. It has a role as a glucagon-like peptide-1 receptor agonist and a neuroprotective agent. It is a lipopeptide and a polypeptide.

[0301] In some embodiments, theGLP-1RA is liraglutide. In certain embodiments, the method further comprises administering an additional therapeutic agent. In certain embodiments, the additional therapeutic agent is insulin degludec. Insulin degludec is typically used with a proper diet and exercise program to control high blood sugar in people with diabetes. The combination therapy of insulin degludec and liraglutide gives a robust glycemic control with a low risk for hypoglycemia and less weight gain or even weight loss. 63 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)

[0302] In some embodiments, the GLP-1RA is lixisenatide. In some embodiments, the method further comprises administering GLP-1RA in combination with insulin glargine. In some embodiments, the method further comprises administering GLP-1RA in combination with glucose-dependent insulinotropic polypeptide (GIP). In some embodiments, the insulin glargine in combination with lixisenatide is Soliqua 100 / 33. Insulin glargine and lixisenatide is a combination medicine that is typically used together with diet and exercise to improve blood sugar control in adults with type 2 diabetes. Insulin glargine is a long-acting insulin that starts to work several hours after injection and keeps working evenly for 24 hours. Lixisenatide is a drug that helps the pancreas produce insulin more efficiently.

[0303] In some embodiments, the GLP-1RA is tirzepatide. tirzepatide is a dual glucose- dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist (RA). Tirzepatide works by activating both the GLP-1 and GIP receptors in the body. This triggers the release of insulin from the pancreas that blocks glucagon, a hormone that increases blood sugar levels.

[0304] In some embodiments, the GLP-1RA is semaglutide.

[0305] In some embodiments, the GLP-1RA is albenatide.

[0306] In some embodiments, the GLP-1RA is albiglutide.

[0307] In some embodiments, the GLP-1RA is cotadutide. Cotadutide (MEDI0382), a dual GLP-1 and glucagon receptor agonist, is currently under development for type 2 diabetes and NASH.

[0308] In some embodiments, the GLP-1RA is CT-868. CT-868 is a dual GLP-1 and GIP receptor modulator that is optimized for improved tolerability at the GLP-1 receptor. The combined action of GLP-1 and GIP result in greater body weight loss and glucose control.

[0309] In some embodiments, the GLP-1RA is efocipegtrutide. Efocipegtrutide is a glucagon, gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptors agonist. Efocipegtrutide shares sequence homology with glucagon, glucagon-like peptide 1 (GLP1) and gastric inhibitory polypeptide (GIP, glucose-dependent insulinotropic polypeptide, incretin hormone), where the gastric inhibitory peptide (GIP) and glucagon-like peptide-1 (GLP-1) triple full agonist is chemically conjugated with constant region of human immunoglobulin via non-peptidyl flexible linker. 64 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)

[0310] In some embodiments, the GLP-1RA is NLY-001. NLY-001 is a microglia-targeted GLP-1RA. NLY-001 is a pegylated exendin-4 analogue of Glucagon Like Peptide-1 Receptor (GLP-1R) agonist.

[0311] In some embodiments, the GLP-1RA is pegapamodutide.

[0312] In some embodiments, the GLP-1RA is pemvidutide. Pemvidutide is a peptide- based GLP-1 / glucagon dual receptor agonist developed for the treatment of obesity and non- alcoholic steatohepatitis (NASH). Pemvidutide has been shown to substantially decrease the amount of fat within the liver which could have beneficial effects on insulin resistance and cardiorenal risk, common problems in people with obesity. In clinical trials, pemvidutide demonstrated striking reductions in body weight, liver fat, serum lipids and markers of liver inflammation.

[0313] In some embodiments, the GLP-1RA is retatrutide. Retatrutide stimulates GIPR, GLP-1, and GLP-1 receptors .

[0314] In some embodiments, the GLP-1RA is TTP-273.

[0315] In some embodiments, the GLP-1RA is vurolenatide. Vurolenatide is a GLP-1 receptor agonist that is administered via injection.

[0316] In some embodiments, the GLP-1RA is GZR-18. GZR-18 is an analog of glucagon- like peptide-1 (GLP-1). In vitro pharmacology and activity of GZR18 were previously characterized by a binding assay of GZR18 using human serum albumin (HSA), an activation assay in human GLP-1 receptor-expressing cell lines, and its effect on glucose-stimulated insulin secretion (GSIS) in primary mice islets.

[0317] In some embodiments, the GLP-1RA is mazdutide. Mazdutide (IBI362) is a glucagon-like peptide-1 (GLP-1) and glucagon receptor dual agonist. Mazdutide is a long- acting synthetic peptide related to mammalian oxyntomodulin (OXM), which uses a fatty acid side chain to prolong the duration of action and allow once-weekly administration. Mazdutide is thought to exert its biological effects by activating GLP-1 receptor and glucagon receptor in human beings, which is estimated to improve glucose tolerance and induce weight loss, mimicking the effects of endogenous oxyntomodulin.

[0318] In some embodiments, the GLP-1RA is PB-119. PB-119 is a pegylated human glucagon-like peptide-1 (GLP-1) receptor agonist.

[0319] In some embodiments, the GLP-1RA is AMG-133. AMG 133 is a bispecific glucose-dependent insulinotropic polypeptide receptor (GIPR) antagonist and glucagon-like 65 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) peptide-1 (GLP-1) receptor agonist molecule. AMG 133 mimics the agonist effects of GLP-1 and antagonizes the effects of glucose-dependent insulinotropic polypeptide (GIP).

[0320] In some embodiments, the GLP-1RA is dapiglutide. Dapiglutide promotes significant intestinal growth, as indicated by significantly increased villus height as well as intestinal length. Dapiglutide reduces stool water losses, resulting in reduced plasma aldosterone. It has been shown that dapiglutide possesses specific and potent GLP-1R and GLP-2R agonist effects in rodents.

[0321] In some embodiments, the GLP-1RA is DD-01. DD-01 is a pegylated, long-acting, peptide based dual agonist of glucagon-like peptide 1 (GLP-1) receptor and glucagon receptor (GCGR).

[0322] In some embodiments, the GLP-1RA is DR-10627.

[0323] In some embodiments, the GLP-1RA is ECC-5004. ECC-5004 is an orally administered small-molecule GLP-1 RA.

[0324] In some embodiments, the GLP-1RA is exenatide biobetter.

[0325] In some embodiments, the GLP-1RA is GL-0034. GL0034 is a glucagon-like peptide-1 receptor (GLP-1R) agonist that has been shown to have glucose-lowering effects with increased insulin and C-peptide levels, reduced plasma glucagon levels, long-term reduction in HbA1C, and reduced body weight when tested in type 2 diabetic mice.

[0326] In some embodiments, the GLP-1RA is GMA-105. GMA-105 is a humanized anti- GLP-1R monoclonal antibody carrying a GLP-1 fragment.

[0327] In some embodiments, the GLP-1RA is HEC-88473. HEC88473 is a GLP-1 / FGF21 dual agonist.

[0328] In some embodiments, the GLP-1RA is LY-3493269. LY-3493269 is a GIP / GLP coagonist peptide.

[0329] In some embodiments, the GLP-1RA is NN-6177. NN-6177 acts by targeting glucagon receptor (GCGR) and glucagon like peptide 1 receptor (GLP1R).

[0330] In some embodiments, the GLP-1RA is NN-9847.

[0331] In some embodiments, the GLP-1RA is NNC0519-0130.

[0332] In some embodiments, the GLP-1RA is PB-1023. PB-1023 is a recombinant GLP-1 analogue used to treat sarcopenia-related diseases. 66 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)

[0333] In some embodiments, the GLP-1RA is SCO-094. SCO-094 is a dual agonist for GLP-1R and GIPR. Preclinical studies have shown that SCO-094 is more effective in improving diabetes and obesity than the GLP-1R mono-agonist.

[0334] In some embodiments, the GLP-1RA is semaglutide. semaglutide is a GLP-1 agonist and works by increasing insulin release, lowering the amount of glucagon released, delaying gastric emptying and reducing appetite.

[0335] In some embodiments, the GLP-1RA is VK-2735. VK-2735 is a dual agonist of the glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors for the potential treatment of various metabolic disorders such as diabetes, obesity and NASH.

[0336] In some embodiments, the GLP-1RA is YH-25724. YH-25724 is a long-acting GLP-1 / FGF21 dual agonist that lowers both non-alcoholic fatty liver disease activity score and fibrosis stage in a diet-induced obese mouse model of biopsy-confirmed non-alcoholic steatohepatitis.

[0337] In some embodiments, the GLP-1RA is YN-012 (Supaglutide).

[0338] In some embodiments, the GLP-1RA is and YN-015.

[0339] In some embodiments, the GLP-1RA is ZP7570 (dapiglutide).

[0340] In some embodiments, the GLP-1 receptor agonist (GLP-1RA) is a small molecule agonist of the GLP-1 receptor. In some embodiments, the GLP-1RA is PF-07081532. PF- 07081532 is an oral small molecule GLP-1 receptor agonist that is being developed for the treatment of Type 2 diabetes and obesity.

[0341] In some embodiments, the GLP-1RA is GSBR-1290, and orally delivered small molecule.

[0342] In some embodiments, the GLP-1RA is RGT-075. RGT-075 is an orally bioavailable, small-molecule GLP-1 RA.

[0343] In some embodiments, the GLP-1RA is orforglipron (LY-3502970). LY-3502970 is an orally active non-peptide agonist of glucagon-like peptide-1 (GLP-1) receptor. See Kawai et al., PNAS November 11, 2020, 117 (47) 29959-29967. In some embodiments, the GLP- 1RA is Danuglipron (PF-06882961).

[0344] GLP-1RA agents can include, but are not limited to, dapagliflozin + semaglutide, 4P-004, AP-026, BGM-0504, CT-996, DD-01, DR-10624, DR-10627, dulaglutide, ECC- 5004, exenatide, exenatide biobetter, GL-0034, GLP-06, GMA-106, HB-1085, HDM-1002, 67 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) HL-08, HZ-010, KN-056, liraglutide, MWN-101, NN-6177, NN-9847, NN-9904, PF- 06954522, SAL-0112, SCO-094, TERN-601, ecnoglutide (XW-004), XW003, XW-014, YH- 25724, YN-012 (Supaglutide), YN-015, ZP7570 (dapiglutide ), and ZT-002.

[0345] In some embodiments, the GLP-1RA is danuglipron (PF 06882961). Danuglipron activates the canonical G protein signaling activity only in the Glucagon-like peptide-1 (GLP- 1) receptor with Trp33ECD. Danuglipron has been shown to potentiate glucose-stimulated insulin release and reduces food intake in monkeys.

[0346] GLP-1RA agents of interest which can be utilized in the methods of this disclosure include, but are not limited to, dapagliflozin + semaglutide, 4P-004, AP-026, BGM-0504, CT-996, DD-01, DR-10624, DR-10627, dulaglutide, ECC-5004, exenatide, exenatide biobetter, GL-0034, GLP-06, GMA-106, HB-1085, HDM-1002, HL-08, HZ-010, KN-056, liraglutide, MWN-101, NN-6177, NN-9847, NN-9904, PF-06954522, SAL-0112, SCO-094, TERN-601, XW-004, XW-014, YH-25724, YN-012(Supaglutide),YN-015, and ZT-002.

[0347] Other GLP-1RA agents of interest, e.g., in clinical trials include, but are not limited to, (semaglutide + GIP analogue), AZD-9550, CT-388, CT-868, danuglipron tromethamine, dapiglutide, E-2HSA, efinopegdutide (HM12525A), efocipegtrutide, exenatide SR, froniglutide, GMA-105, GSBR-1290, GXG-6, GZR-18, HEC-88473, HR-17031, HRS-7535, HRS-9531, HS-20004, HS-20094, JY-09, liraglutide biobetter, maridebart cafraglutide, MBX-1416, MDR-001, NLY-001, NN-9490, NNC0519-0130, PB-718, pegapamodutide (OPK 88003 / TT401), pemvidutide (ALT-801), semaglutide injection, TTP-273, and VK- 2735.

[0348] Additional GLP-1RA agents of interest in clinical trials which can be utilized in the methods of this disclosure include, but are not limited to, (cagrilintide + semaglutide), retatrutide, (LAI-287 + semaglutide), albenatide, avexitide acetate, Diabegone, ecnoglutide, efpeglenatide LA, GMA-102, liraglutide, mazdutide, NN-6535 (semaglutide), NN-9932 (semaglutide), orforglipron calcium, PB-119, SAL-015, survodutide, Uni-E4, and vurolenatide.

[0349] Further GLP-1RA agents of interest which can be utilized in the methods of this disclosure include, but are not limited to, (dorzagliatin + GLP-1), (exenatide + insulin aspart), ACT-1003, Adogel Sema, AER-601, AGM-212, BEBT-808, BZ-043B, C-2816, DAJC-1, DD-02, DR-10625, DR-10628, DS-004, DS-005, DS-006, DS-012, E-6, efpeglenatide + HM- 12470, exenatide 2, exenatide LA, exenatide SR, Extendin-Fc, G-49, GB-7001, Gene Encoding GLP-1, GLP-1 Incretin Triagonist, GLP-1 Oral Preparation, GLP-1R Antagonist 68 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) for Hypoglycemia, glucagon, Glucagon-Like Peptide-1 + insulin human, GPCR-targeted Project 012, GPCR-targeted Project 013, GT-01123, HM-15275, HPG-5119, HSP-001, HSP- 004, HSP-005, HSP012-C, Hydrogel Exenatide, I2O-105S, I2O-110, KP-405, LA-EX, liraglutide biobetter, liraglutide LA, MK-1462, MLX-7000, MWN-105, MWN-109, NLY-12, NPM-115, OGB-21502, OXM, P-11, PB-2301, PB-2309, RGT-028, RGT-274, RPC-8844, RT-104, SHX-022, SL-209, synthetic peptides to agonize GLP-1R and CCKBR for diabetes, TB-013, TB-222023, TB-592, TE-8105, THDBH-111, UDS-003, VTCG-15, XL-110, XL- 310, XW-003 + XW-015, XW-003 + XW-017, Y-002, YGX-1, ZT-003, ZT-006, ZT-007, DA-1726, HDM-1005, (insulin degludec + liraglutide), DB-081, GW-002, HZCX-012, ID- 110521156, THDB-0211, THDBH-110, THDBH-120, THDBH-121, UBT-251, ATBB-22, BEM-012, CIN-209, CIN-210, DD-03, exenatide + ND-017, exenatide + Synthetic Peptide 2, glucagon, Insulin-GLP1, MD-02, OGB-21501, P-01, PAT-201, PF-1807, and PT-3.

[0350] Other GLP-1RA agents of interest include, but are not limited to: HMS-5678 BI- 3034701, DD-02S, DD-15, efpegerglucagon, I2O – 130, I2O-105S, MBX-4291, NA-931, RJVA-001, TERN-800, HZ-012, HS-10501, ZX-2010, ZX-2021, HYBR-014, PG-102, and VCT-220.

[0351] In some embodiments, the GLP-1RA is a GLP-1RA targeting moiety within a bifunctional or trifunctional compound. 4.5. Dual or Multi-function Agonist

[0352] Aspects of this disclosure include methods (e.g., as described herein) that make use of a dual or multi-function agonist agent that includes at least a GLP-1 receptor agonist portion and an apelin receptor agonist portion.

[0353] In some embodiments, the apelin receptor agonist portion is an apelin peptide or variant or analog thereof.

[0354] In some embodiments, the GLP-1RA and the apelin receptor agonist can both be incorporated into a single fusion polypeptide.

[0355] In some embodiments, the agent can include a further agonist portion, such as a polypeptide agonist of glucose-dependent insulinotropic polypeptide (GIP) receptor agonist and / or glucagon receptor agonist. In some embodiments, the GIP-RA is a GIP-RA within a bifunctional or trifunctional compound.

[0356] Any such multi-function agonist agents can be utilized in the methods and compositions of this disclosure. Accordingly, it is understood that any of the combination 69 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) methods described herein can be accomplished by co-administration of two discrete agents / agonists, or administration of a single agent / agonist with suitable dual agonist activity. 4.6. Additional therapeutic Agents

[0357] The methods of the present disclosure comprise co-administering an effective amount of an apelin receptor agonist and an effective amount of a GLP-1 receptor agonist to the subject. In some embodiments, the methods of the present disclosure further comprise co- administering an effective amount of one or more additional therapeutic agents, i.e., pharmacologically active substances.

[0358] In some embodiments, the methods of the present disclosure include administration of an additional therapeutic agent. In certain embodiments, the additional therapeutic agent is an incretin receptor agonist. In certain embodiments, the additional therapeutic agent is amylin. In some embodiments, the additional therapeutic agent is cagrilintide. In some embodiments, the additional therapeutic agent is insulin degludec. In some embodiments, the additional therapeutic agent is insulin glargine.

[0359] In some embodiments, the additional therapeutic agent is a drug that reduces caloric intake that is not a GLP-1 receptor agonist. In some embodiments, the additional therapeutic agent is a compound that regulates appetite, e.g., an appetite suppressant.

[0360] In some embodiments, the additional therapeutic agent is an incretin. In some embodiments, the additional therapeutic agent is an incretin receptor agonist. In some embodiments, the additional therapeutic agent is an incretin receptor ag that is not a GLP-1 receptor agonist.

[0361] In some embodiments, the additional therapeutic agent is a drug that reduces caloric intake selected from alpha amylase 2B (1,4-Alpha D-Glucan Glucanohydrolase 2B or Carcinoid Alpha Amylase or AMY2B or EC 3.2.1.1) inhibitor; gastric triacylglycerol lipase (Gastric Lipase or LIPF or EC 3.1.1.3) inhibitor; maltase glucoamylase (Alpha-14- Glucosidase or MGAM or EC 3.2.1.20) inhibitor; pancreatic alpha amylase (1,4 Alpha D Glucan Glucanohydrolase or AMY2A or EC 3.2.1.1) inhibitor; pancreatic triacylglycerol lipase (Pancreatic Lipase or Triacylglycerol Acylhydrolase or PNLIP or EC 3.1.1.3) inhibitor; and sucrase isomaltase intestinal (SI or EC 3.2.1.48 or EC 3.2.1.10) inhibitor. In some embodiments, the additional therapeutic agent is a drug that reduces caloric intake selected from TAS2R receptor agonist; bitter taste receptor agonist; Nutrient receptor agonist; Cannabinoid Receptor 1 (CB1 or CANN6 or CNR1) Antagonist; Alpha 1,6 Mannosyl Glycoprotein 2 Beta N Acetylglucosaminyltransferase (Beta 1,2 N 70 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) Acetylglucosaminyltransferase II or Mannoside Acetylglucosaminyltransferase 2 or N Glycosyl Oligosaccharide Glycoprotein N Acetylglucosaminyltransferase II or GlcNAc-T II or MGAT2 or EC 2.4.1.143) Inhibitor; Glabridin analog, Distal jejunal-release dextrose; and Mucin-complexing polymer. Drugs that reduce caloric intake which can be utilized in the methods of this disclosure include, but are not limited to, EMP-16, APH-012, ARD-101, GLY-200, K-757 + K-833, INV-202, S-309309, vutiglabridin, AMG-786, Amylin Agonist Long Acting, AZD-6234, CK-0045, ENT-03, ERX-1000, NO1820237, GUB-014295, CIN- 109, Dacra QW II, nimacimab, RAY-1225, XEN-101, ZP-8396, and LY-3971297. In some embodiments, the additional therapeutic agent is a cannabinoid receptor 1 (CB1r or CANN6 or CNR1) antagonist, such as INV-202, or INV-300.

[0362] Obesity related agents that reduce energy or caloric intake which can be utilized in the methods of this disclosure include, but are not limited to, CRB-913, DBPR-211, PB-722, (efpeglenatide + HM-15136), ACE-167, AD-9308, AGEX-BAT1, AvR-2V10, AZ- 12861903, AZ-13483342, AZD-3857, BEBT-809, BF-114, Cannabinoids, CKR-334, CLS-1, CNIO-PI3Ki, CV-08, CYTX-100, Era-107, ETBD-03, FM-801, Fusion Proteins to Activate GDF15 for Obesity, FZ-010, GCG-06, GMA-107, HM-15275, HTD-1804, HUM-234, I2O- 107, I2O-120, INHBE (Metabolic Disorders), CIN-110, KSB-10201, KY-19334, LR-19020, LR-19156, LY-3971297, M-43, MLX-0800, MLX-5000, MLX-7000, MNO-863, Monoclonal Antibody to Antagonize FSH Receptor for Obesity and Osteoporosis, MT-106, Myostatin antagonist, NM-136, NN-9056, NOVS-100, NPO-2237, OBE-2001, OLX-75016, orlistat, Peptide (PYY), Peptide to Antagonize MC3R for Obesity, Peptides for Non- Alcoholic Steatohepatitis and Obesity, Peptides to Agonize Oxytocin Receptor for Obesity, Peripheral CB1 Blockers, PF-06645849, PL-8905, PL-9610, psilocybin, PSYLO-3002, PYY- 1119, RB-014, Recombinant Protein to Agonize Leptin Receptor for Obesity, Rejuva, REMD-524, REP-003, RES-010, RES-020, RMD-1202, RP-1208, RSVI-301, RSVI-303, RT-210, SAL-0125, Gastrointestinal Hormones, SJT-4a, SJT-7a, sobetirome, SPN-007, SRK-439, TB-592, Tespria, TF-0062, TF-0103, ThermoStem, TLC-1235, VK-1430, XL-100, YH-34160, YN-103, YN-106, ZP-6590, ZYL-001, ADY-790011, ATC-601, AX-0601, BEBT-509, CBF-520, CYTA-002, DILOC-2, EB-012, ECN-0424, EMB-2, GM-60186, GPR75, GT-002, GUI-37, HLB-1007, HLB-1015, HMC-2073, and ICB-513.

[0363] Other drugs that reduce caloric intake which can be utilized in the methods of this disclosure include, but are not limited to, naltrexone-bupropion, phentermine-topiramate, benzphetamine, diethylpropion, phendimetrazine, phentermine, orlistat, and setmelanotide. 71 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)

[0364] It is understood that the following description, e.g., of isomers, salts, and other forms, etc., can apply to any classes of compounds and drugs within the scope of the specification.

[0365] If any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence. If the chemical structure and chemical name conflict, the chemical structure is determinative of the identity of the compound. The compounds of this disclosure may contain one or more chiral centers and / or double bonds and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers or diastereomers. Accordingly, any chemical structures within the scope of the specification depicted, in whole or in part, with a relative configuration encompass all possible enantiomers and stereoisomers of the illustrated compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can be resolved into the component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan.

[0366] Certain compounds of this disclosure may possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, enantiomers, diastereomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the invention. Furthermore, atropisomers and mixtures thereof such as those resulting from restricted rotation about two aromatic or heteroaromatic rings bonded to one another are intended to be encompassed within the scope of the invention. For example, when R4is a phenyl group and is substituted with two groups bonded to the C atoms adjacent to the point of attachment to the N atom of the triazole, then rotation of the phenyl may be restricted. In some instances, the barrier of rotation is high enough that the different atropisomers may be separated and isolated.

[0367] Unless otherwise indicated, the term “stereoisomer” or “stereomerically pure” means one stereoisomer of a compound that is substantially free of other stereoisomers of that compound. For example, a stereomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other 72 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) stereoisomers of the compound, more preferably greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, even more preferably greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, and most preferably greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound. If the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it. A bond drawn with a wavy line indicates that both stereoisomers are encompassed.

[0368] Various compounds of this disclosure contain one or more chiral centers, and can exist as racemic mixtures of enantiomers, mixtures of diastereomers or enantiomerically or optically pure compounds. This invention encompasses the use of stereoisomerically pure forms of such compounds, as well as the use of mixtures of those forms. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular compound of the invention may be used in methods and compositions of the invention. These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents.

[0369] Compounds of the present disclosure include, but are not limited to, apelin receptor agonist compounds, GLP-1 receptor agonist compounds, and all pharmaceutically acceptable forms thereof. Pharmaceutically acceptable forms of the compounds recited herein include pharmaceutically acceptable salts, solvates, crystal forms (including polymorphs and clathrates), chelates, non-covalent complexes, prodrugs, and mixtures thereof. In certain embodiments, the compounds described herein are in the form of pharmaceutically acceptable salts. The term “compound” encompasses not only the compound itself, but also a pharmaceutically acceptable salt thereof, a solvate thereof, a chelate thereof, a non-covalent complex thereof, a prodrug thereof, and mixtures of any of the foregoing. In some embodiments, the term “compound” encompasses the compound itself, pharmaceutically acceptable salts thereof, tautomers of the compound, pharmaceutically acceptable salts of the tautomers, and ester prodrugs such as (C1-C4)alkyl esters. In other embodiments, the term “compound” encompasses the compound itself, pharmaceutically acceptable salts thereof, tautomers of the compound, pharmaceutically acceptable salts of the tautomers. 73 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)

[0370] The term “solvate” refers to the compound formed by the interaction of a solvent and a compound. Suitable solvates are pharmaceutically acceptable solvates, such as hydrates, including monohydrates and hemi-hydrates.

[0371] The compounds of this disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I) or carbon-14 (14C). Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents, e.g., assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds of the invention, whether radioactive or not, are intended to be encompassed within the scope of the invention. For example, if a variable is said or shown to be H, this means that variable may also be deuterium (D) or tritium (T).

[0372] The term “pharmaceutically acceptable salt” refers to a salt that is acceptable for administration to a subject. Examples of pharmaceutically acceptable salts include, but are not limited to: mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate, and nitrate; sulfonic acid salts such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and trifluoromethanesulfonate; organic acid salts such as oxalate, tartrate, citrate, maleate, succinate, acetate, trifluoroacetate, benzoate, mandelate, ascorbate, lactate, gluconate, and malate; amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, and aspartate; inorganic salts such as lithium salt, sodium salt, potassium salt, calcium salt, and magnesium salt; and salts with organic bases such as ammonium salt, triethylamine salt, diisopropylamine salt, and cyclohexylamine salt. The term “salt(s)” as used herein encompass hydrate salt(s).

[0373] Other examples of pharmaceutically salts include anions of the compounds of the present disclosure compounded with a suitable cation. For therapeutic use, salts of the compounds of the present disclosure can be pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0374] Compounds included in the present compositions and methods that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to, malate, oxalate, chloride, 74 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p- toluenesulfonate and pamoate (i.e., 1,1’-methylene-bis-(2-hydroxy-3-naphthoate)) salts.

[0375] Compounds included in the present compositions and methods that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.

[0376] Furthermore, if the compounds of the present invention or salts thereof form hydrates or solvates, these are also included in the scope of the compounds of the present invention or salts thereof.

[0377] Compounds included in the present compositions and methods that include a basic or acidic moiety can also form pharmaceutically acceptable salts with various amino acids. The compounds of the disclosure can contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt. 4.7. Pharmaceutical Compositions

[0378] The pharmaceutical compositions can include the compound(s) or the pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, carrier or diluent. In some such embodiments, the compound or the pharmaceutically acceptable salt thereof, according to any one of the embodiments is present in an amount effective for the treatment of a condition or disease (e.g., as described herein).

[0379] The apelin receptor agonist compounds and / or GLP-1RA compounds used in the methods described herein can be formulated in any appropriate pharmaceutical composition for administration by any suitable route of administration.

[0380] The GLP-1 receptor agonists or GLP-1 analogs used in the methods described herein can be formulated in any appropriate pharmaceutical composition for administration by any suitable route of administration. The pharmaceutical compositions can include the GLP-1 receptor agonists or analogues thereof or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof according to any one of the embodiments described herein and at least one pharmaceutically acceptable excipient, carrier or diluent. In 75 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) some such embodiments, the GLP-1 receptor agonists or analogues thereof or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof according to any one of the embodiments is present in an amount effective for the treatment of a condition or disease (e.g., as described herein), for activating the GLP-1 receptor.

[0381] Suitable routes of administration for each of the apelin receptor agonists or GLP-1 receptor agonists include, but are not limited to, oral, topical, subcutaneous injection, and intravenous routes of administration. Suitable routes also include pulmonary administration, including by oral inhalation. In some embodiments, the route of administration is subcutaneous injection. The most suitable route may depend upon the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods known in the art of pharmacy.

[0382] In some embodiments, the pharmaceutical composition is formulated for oral delivery whereas in other embodiments, the pharmaceutical composition is formulated for subcutaneous or intravenous delivery. In some embodiments, the pharmaceutical composition is formulated for oral administration once a day or QD, and in some such formulations is a tablet where the effective amount of the active ingredient ranges from 5 mg to 60 mg, from 6 mg to 58 mg, from 10 mg to 40 mg, from 15 mg to 30 mg, from 16 mg to 25 mg, or from 17 mg to 20 mg. In some such compositions, the amount of active ingredient is 17 mg.

[0383] All methods include the step of bringing into association an apelin agonist, or a salt thereof, with the carrier which constitutes one or more excipients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

[0384] All methods include the step of bringing into association an GLP-1RA, or a salt thereof, with the carrier which constitutes one or more excipients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

[0385] In certain embodiments, the route of administration for use in the methods described herein can be different for the apelin receptor agonist and the GLP-1 receptor agonist or the 76 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) route of administration for the apelin receptor agonist and the GLP-1 receptor agonist is the same.

[0386] In some embodiments, the route of administration for the apelin receptor agonist is parenteral administration. In some embodiments, the route of administration for the apelin receptor agonist is intravenous administration (e.g., intravenous infusion). In some embodiments, the route of administration for the apelin receptor agonist is oral administration. In some embodiments, the route of administration for the apelin receptor agonist is constant intravenous infusion. In some embodiments, the route of administration for the apelin receptor agonist is subcutaneous injection.

[0387] In some embodiments, the route of administration for the GLP-1 receptor agonist is parenteral administration. In some embodiments, the route of administration for the GLP-1 receptor agonist is intravenous administration (e.g., intravenous infusion). In some embodiments, the route of administration for the GLP-1 receptor agonist is oral administration. In some embodiments, the route of administration for the GLP-1 receptor agonist is constant intravenous infusion. In some embodiments, the route of administration for the GLP-1 receptor agonist is subcutaneous injection.

[0388] Formulations of the present methods suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

[0389] Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient. Formulations for parenteral administration also include aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. The formulations may be presented in unit-dose of multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example saline, phosphate-buffered saline (PBS) or the like, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. 77 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)

[0390] The pharmaceutical composition may comprise one or more pharmaceutical excipients. The term “excipient” broadly refers to any component other than the active therapeutic ingredient(s). The excipient may be an inert substance, an inactive substance, and / or a not medicinally active substance.

[0391] Any suitable pharmaceutical excipient may be used, and one of ordinary skills in the art is capable of selecting suitable pharmaceutical excipients. The excipient may serve various purposes, e.g. as a carrier, vehicle, diluent, tablet aid, and / or to improve administration, and / or absorption of the active substance. Non-limiting examples of excipients are: Solvents, diluents, buffers, preservatives, tonicity regulating agents, chelating agents, and stabilizers.

[0392] Examples of formulations include liquid formulations, i.e. aqueous formulations comprising water. A liquid formulation may be a solution, or a suspension. An aqueous formulation typically comprises at least 50% w / w water, or at least 60%, 70%, 80%, or even at least 90% w / w of water.

[0393] Alternatively, a pharmaceutical composition may be a solid formulation, e.g. a freeze-dried or spray-dried composition, which may be used as is, or whereto the physician or the patient adds solvents, and / or diluents prior to use.

[0394] A pharmaceutical composition may comprise a buffer. A pharmaceutical composition may comprise a preservative. A pharmaceutical composition may comprise a chelating agent. A pharmaceutical composition may comprise a stabilizer. A pharmaceutical composition may comprise one or more surfactants. A pharmaceutical composition may comprise one or more protease inhibitors, e.g., when the active compound is a polypeptide.

[0395] A composition may be administered in several dosage forms, for example as a solution; a suspension; an emulsion; a microemulsion; multiple emulsions; an injection solution; an infusion solution.

[0396] Systemic or parenteral administration may be performed by subcutaneous, intramuscular, intraperitoneal, or intravenous injection by means of a syringe, optionally a pen-like syringe, or by means of an infusion pump. 4.8. Combination pharmaceutical products

[0397] Aspects of this disclosure include a pharmaceutical composition including a combination of an apelin receptor agonist and a GLP-1 receptor agonist in a single dosage form. In some embodiments, the pharmaceutical composition is formulated for oral 78 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) administration, where the apelin receptor agonist and the GLP-1 receptor agonist are both suitable for oral administration. In some embodiments, the apelin receptor agonist and the GLP-1 receptor agonist are both small molecule drugs (e.g., as described herein).

[0398] In some embodiments, the pharmaceutical composition is formulated for subcutaneous administration.

[0399] Aspects of this disclosure include kits that include an apelin receptor agonist and a GLP-1 receptor agonist, e.g., each present in a unit dosage form.

[0400] Aspects of this disclosure include a fixed dose combination pharmaceutical composition, comprising: a therapeutically effective dose of an apelin receptor agonist or a pharmaceutically acceptable salt thereof; and a therapeutically effective dose of a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof.

[0401] These compositions comprise a pharmaceutically acceptable excipient, carrier, buffer, stabilizer or other materials, such as those materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material can depend on the route of administration, e.g. oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, intraperitoneal routes.

[0402] In some embodiments, the pharmaceutical composition is formulated for oral administration. Pharmaceutical compositions for oral administration can be in tablet, capsule, pill, powder or liquid form. A tablet or pill can include a solid carrier such as gelatin or an adjuvant. Liquid pharmaceutical compositions generally include a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol can be included. In some embodiments, the pharmaceutically acceptable excipient is selected from filler / diluent, binder, disintegrant, lubricant, plasticizer, pH adjusting agent, pigment, opacifier, surfactant, and glidant.

[0403] In one aspect, combination pharmaceutical compositions of the present disclosure are created from one or more of the compounds disclosed herein and are in the form of a pill, tablet or capsule. 79 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)

[0404] In some embodiments, the pharmaceutical composition is formulated as an immediate release formulation. In some embodiments, the pharmaceutical composition is formulated as an extended-release formulation.

[0405] In some embodiments, the pharmaceutical composition, such as the fixed dose combination, includes a GLP-1 receptor agonist as described herein that is a dual-acting GLP-1 receptor agonist, a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, or glucagon receptor agonist. The GLP-1 receptor agonist can be a small-molecule GLP-1 receptor agonist suitable or oral formulation and administration.

[0406] Any suitable apelin receptor agonist described in this disclosure can be adapted for use in such a pharmaceutical composition, such as a fixed dose combination. In some embodiments, the pharmaceutical composition, such as the fixed dose combination, includes a compound of the structure:or a pharmaceutically acceptable salt thereof. 4.9. Dosage form

[0407] In some embodiments, an apelin receptor agonist or salt thereof is administered in a suspension. In other embodiments, an apelin receptor agonist or salt thereof is administered in a solution. In some embodiments, an apelin receptor agonist or salt thereof is administered in a solid dosage form. In some embodiments, the solid dosage form is a capsule. In some embodiments, the solid dosage form is a tablet. In specific embodiments, an apelin receptor agonist is in a crystalline or amorphous form. In some embodiments, an apelin receptor agonist is in amorphous form. In some embodiments, the apelin receptor agonist is an apelin receptor agonist.

[0408] In one aspect of the methods, the apelin receptor agonist, or the pharmaceutical composition including same, is administered intravenously, topically, orally, by inhalation, by infusion, by injection, intraperitoneally, intramuscularly, subcutaneously, intra-aurally, by intra-articular administration, by intra-mammary administration, by topical administration or by absorption through epithelial or mucocutaneous linings. In certain embodiments, the 80 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) apelin receptor agonist, or the pharmaceutical composition including same, is administered via intravenous infusion.

[0409] In some embodiments, an GLP-1 receptor agonist or salt thereof is administered in a suspension. In other embodiments, an GLP-1 receptor agonist or salt thereof is administered in a solution. In some embodiments, an GLP-1 receptor agonist or salt thereof is administered in a solid dosage form. In particular embodiments, the solid dosage form is a capsule. In particular embodiments, the solid dosage form is a tablet. In specific embodiments, a GLP-1 receptor agonist is in a crystalline or amorphous form. In particular embodiments, a GLP-1 receptor agonist is in amorphous form.

[0410] In one aspect of the methods, the GLP-1 receptor agonist, or the pharmaceutical composition including same, is administered intravenously, topically, orally, by inhalation, by infusion, by injection, intraperitoneally, intramuscularly, subcutaneously, intra-aurally, by intra-articular administration, by intra-mammary administration, by topical administration or by absorption through epithelial or mucocutaneous linings. In certain embodiments, the GLP- 1 receptor agonist, or the pharmaceutical composition including same, is administered via intravenous infusion. In certain embodiments, the GLP-1 receptor agonist, or the pharmaceutical composition including same, is administered via subcutaneous injection. 81 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) 4.10. Apelin receptor agonist dosing

[0411] In various embodiments, the dose of the apelin receptor agonist is at least 0.01 mg / kg, such as at least 0.5 mg / kg, or at least 1 mg / kg. In certain embodiments, the dose is 25 mg / kg to 1,000 mg / kg per day.

[0412] In some embodiments, the apelin receptor agonist is administered in a dose that is independent of patient weight or surface area (flat dose).

[0413] In various embodiments, the dose is 1-5000 mg. In various embodiments, the dose is 25-2000 mg. In some embodiments, the dose is at least 60 mg, at least 100 mg, at least 120 mg, at least 140 mg, at least 160 mg, at least 180 mg, at least 200 mg, at least 220 mg, at least 240 mg, at least 260 mg, at least 280 mg, at least 300 mg, at least 320 mg, at least 340 mg, at least 360 mg, at least 380 mg, at least 400 mg, at least 420 mg, at least 440 mg, at least 460 mg, at least 480 mg, at least 500 mg, at least 520 mg, at least 550 mg, at least 580 mg, at least 600 mg, at least 650 mg, at least 700 mg, at least 750 mg, at least 800 mg, at least 850 mg, at least 900 mg, at least 950 mg, at least 1000 mg, at least 1100 mg, at least 1200 mg, at least 1300 mg, at least 1400 mg, at least 1450 mg, or at least 1500 mg. In various embodiments, the dose is 25-2000 mg. In some embodiments, the dose is at least 200 mg. In various embodiments, the dose is 25-2000 mg. In some embodiments, the dose is at least 240 mg.

[0414] The apelin receptor agonist can be administered in a single dose or in multiple doses.

[0415] In some embodiments, the dose is administered daily.

[0416] In some embodiments, the dose is administered as a plurality of equally or unequally divided sub-doses.

[0417] In certain embodiments, the dose is administered continuously (e.g., IV infusion) for a period of time. In certain embodiments, the dose is administered as an intravenous infusion dose for a period of time (e.g., 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 2 hours, 3 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours). In certain embodiments, following the dose, the dose is administered as an intravenous infusion maintenance dose for a period of time (e.g., 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 2 hours, 3 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, or 48 hours). In certain embodiments, following a dose and a 24 hour or 48-hour washout period, the dose is administered as an intravenous infusion maintenance dose for a period of time (e.g., 10 minutes, 20 minutes, 30 82 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) minutes, 40 minutes, 50 minutes, 1 hour, 2 hours, 3 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, or 48 hours). In certain embodiments, following a first dose and a 24 hour or 48-hour washout period, the dose is administered as an intravenous infusion dose for a period of time (e.g., 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 2 hours, 3 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours), followed by a second dose for a period of time (e.g., 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 2 hours, 3 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, or 48 hours).

[0418] In some embodiments, the apelin receptor agonist is administered orally, intravenously, intranasally, or intramuscularly. In some embodiments, the apelin receptor agonist is administered orally. In some embodiments, the apelin receptor agonist is administered via enteral route of administration. In some embodiments, the apelin receptor agonist is administered via PO. In some embodiments, the apelin receptor agonist is administered via PO BID. In some embodiments, the apelin receptor agonist is administered via PO with a dose ranging from 25-2000 mg. In some embodiments, the dose is at least 60 mg, at least 100 mg, at least 120 mg, at least 140 mg, at least 160 mg, at least 180 mg, at least 200 mg, at least 220 mg, at least 240 mg, at least 260 mg, at least 280 mg, at least 300 mg, at least 320 mg, at least 340 mg, at least 360 mg, at least 380 mg, at least 400 mg, at least 420 mg, at least 440 mg, at least 460 mg, at least 480 mg, at least 500 mg, at least 520 mg, at least 550 mg, at least 580 mg, at least 600 mg, at least 650 mg, at least 700 mg, at least 750 mg, at least 800 mg, at least 850 mg, at least 900 mg, at least 950 mg, at least 1000 mg, at least 1100 mg, at least 1200 mg, at least 1300 mg, at least 1400 mg, at least 1450 mg, or at least 1500 mg.

[0419] In some embodiments, the apelin receptor agonist is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (qid), or three times a day (tid), over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to 83 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more. In some embodiments, the apelin receptor agonist is administered continuously for at least 10 minutes, at least 20 minutes, at least 30 minutes, at least 40 minutes, at least 50 minutes, at least 1 hour, at least 2 hours, at least 3 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 11 hours, at least 12 hours, at least 13 hours, at least 14 hours, at least 15 hours, at least 16 hours, at least 17 hours, at least 18 hours, at least 19 hours, at least 20 hours, at least 21 hours, at least 22 hours, at least 23 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 100 hours, at least 110 hours, at least 115 hours, at least 120 hours, or at least 125 hours. In some embodiments, the apelin receptor agonist is administered twice daily (bid). 4.11. GLP-1 receptor agonist dosing

[0420] In various embodiments, the dose of an GLP-1 receptor agonist is GLP-1 receptor agonist is adjusted according to the patient’s disease condition.

[0421] In various embodiments, the dose of the GLP-1 receptor agonist is at least 0.01 mg / kg, such as at least 0.5 mg / kg, or at least 1 mg / kg. In certain embodiments, the dose is 25 mg / kg to 1,000 mg / kg per day.

[0422] In some embodiments, the GLP-1 receptor agonist is administered in a dose that is independent of patient weight or surface area (flat dose).

[0423] In various embodiments, the dose is 0.01-5000 mg. In various embodiments, the dose is 0.05 -5 mg. In various embodiments, the dose is at least 0.1 mg, at least 0.2 mg, at least 0.25 mg, at least 0.3 mg, at least 0.4 mg, at least 0.5 mg, at least 0.7 mg, at least 0.6 mg, at least 0.75 mg, at least 0.8 mg, at least 0.9 mg, at least 1 mg, at least 1.2 mg, at least 1.25 mg, at least 1.3 mg, at least 1.4 mg, at least 1.5 mg, at least 1.6 mg, at least 1.75 mg, at least 1.8 mg, at least 1.9 mg, at least 2 mg, at least 2.1 mg, at least 2.2 mg, at least 2.25 mg, at least 2.3 mg, at least 2.4 mg, at least 2.5 mg, at least 2.6 mg, at least 2.75 mg, at least 2.8 mg, at least 2.9 mg, at least 3 mg, at least 3.1 mg, at least 3.2 mg, at least 3.25 mg, at least 3.3 mg, at least 3.4 mg, at least 3.5 mg, at least 3.6 mg, at least 3.75 mg, at least 3.8 mg, at least 3.9 mg, at least 4 mg, at least 4.1 mg, at least 4.2 mg, at least 4.25 mg, at least 4.3 mg, at least 4.4 mg, at least 4.5 mg, at least 4.6 mg, at least 4.75 mg, at least 4.8 mg, 4.9 mg, at least 5 mg, at least 5.25 mg, at least 5.5 mg, at least 5.75 mg, at least 6 mg, at least 6.25 mg, at least 6.5 mg, at least 6.75 mg, at least 7 mg, at least 7.25 mg, at least 7.5 mg, at least 7.75 mg, at least 8 mg, at least 8.25 mg, at least 8.5 mg, at least 8.75 mg, at least 9 mg, at least 9.25 mg, at least 9.5 84 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) mg, at least 9.75 mg, or at least 10 mg. In various doses, the dose is at least 10.5 mg, at least 11 mg, at least 11.5 mg, at least 12 mg, at least 12.5 mg, at least 13 mg, at least 13.5 mg, at least 14 mg, at least 14.5 mg, at least 15 mg, at least 15.5 mg, at least 16 mg, at least 16.5 mg, at least 17 mg, at least 17.5 mg, at least 18 mg, at least 18.5 mg, at least 19 mg, at least 19.5 mg, or at least 20 mg. In various embodiments, the dose is 25-2000 mg. In some embodiments, the dose is at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 100 mg, at least 120 mg, at least 140 mg, at least 160 mg, at least 180 mg, at least 200 mg, at least 220 mg, at least 240 mg, at least 260 mg, at least 280 mg, at least 300 mg, at least 320 mg, at least 340 mg, at least 360 mg, at least 380 mg, at least 400 mg, at least 420 mg, at least 440 mg, at least 460 mg, at least 480 mg, at least 500 mg, at least 520 mg, at least 550 mg, at least 580 mg, at least 600 mg, at least 650 mg, at least 700 mg, at least 750 mg, at least 800 mg, at least 850 mg, at least 900 mg, at least 950 mg, at least 1000 mg, at least 1100 mg, at least 1200 mg, at least 1300 mg, at least 1400 mg, at least 1450 mg, or at least 1500 mg. In various embodiments, the dose is 25-2000 mg. In some embodiments, the dose is at least 200 mg. In various embodiments, the dose is 25-2000 mg. In some embodiments, the dose is at least 240 mg.

[0424] In various embodiments, the dose of the GLP-1 receptor agonist is no more than 50 mg, no more than 45 mg, no more than 40 mg, no more than 35 mg, no more than 30 mg, no more than 25 mg, no more than 20 mg, or no more than 15 mg. In various embodiments, the dose of the GLP-1 receptor agonist is 15 mg, 10 mg, 5 mg, or 2.5 mg.

[0425] In various embodiments, the dose is 0.01-5000 mcg. In various embodiments, the dose is 0.05 -5 mcg. In various embodiments, the dose is at least 0.1 mcg, at least 0.2 mcg, at least 0.25 mcg, at least 0.3 mcg, at least 0.4 mcg, at least 0.5 mcg, at least 0.7 mcg, at least 0.6 mcg, at least 0.75 mcg, at least 0.8 mcg, at least 0.9 mcg, at least 1 mcg, at least 1.2 mcg, at least 1.25 mcg, at least 1.3 mcg, at least 1.4 mcg, at least 1.5 mcg, at least 1.6 mcg, at least 1.75 mcg, at least 1.8 mcg, at least 1.9 mcg, at least 2 mcg, at least 2.1 mcg, at least 2.2 mcg, at least 2.25 mcg, at least 2.3 mcg, at least 2.4 mcg, at least 2.5 mcg, at least 2.6 mcg, at least 2.75 mcg, at least 2.8 mcg, at least 2.9 mcg, at least 3 mcg, at least 3.1 mcg, at least 3.2 mcg, at least 3.25 mcg, at least 3.3 mcg, at least 3.4 mcg, at least 3.5 mcg, at least 3.6 mcg, at least 3.75 mcg, at least 3.8 mcg, at least 3.9 mcg, at least 4 mcg, at least 4.1 mcg, at least 4.2 mcg, at least 4.25 mcg, at least 4.3 mcg, at least 4.4 mcg, at least 4.5 mcg, at least 4.6 mcg, at least 4.75 mcg, at least 4.8 mcg, 4.9 mcg, at least 5 mcg, at least 5.25 mcg, at least 5.5 mcg, at least 5.75 mcg, at least 6 mcg, at least 6.25 mcg, at least 6.5 mcg, at least 6.75 mcg, at least 7 mcg, 85 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) at least 7.25 mcg, at least 7.5 mcg, at least 7.75 mcg, at least 8 mcg, at least 8.25 mcg, at least 8.5 mcg, at least 8.75 mcg, at least 9 mcg, at least 9.25 mcg, at least 9.5 mcg, at least 9.75 mcg, or at least 10 mcg. In various doses, the dose is at least 10.5 mcg, at least 11 mcg, at least 11.5 mcg, at least 12 mcg, at least 12.5 mcg, at least 13 mcg, at least 13.5 mcg, at least 14 mcg, at least 14.5 mcg, at least 15 mcg, at least 15.5 mcg, at least 16 mcg, at least 16.5 mcg, at least 17 mcg, at least 17.5 mcg, at least 18 mcg, at least 18.5 mcg, at least 19 mcg, at least 19.5 mcg, or at least 20 mcg. In various embodiments, the dose is 25-2000 mcg. In some embodiments, the dose is at least 25 mcg, at least 30 mcg, at least 35 mcg, at least 40 mcg, at least 45 mcg, at least 50 mcg, at least 55 mcg, at least 60 mcg, or at least 100 mcg.

[0426] The GLP-1 receptor agonist can be administered in a single dose or in multiple doses. In some embodiments, the GLP-1 receptor agonist is administered to a subject with a first dose. In certain embodiments, the effective amount of the GLP-1 receptor agonist is changed after a period of time. In some embodiments, the first dose is more than the second dose. In some embodiments, the first dose is less than the second dose. In some embodiments, the first dose is administered to the subject for a period of time sufficient to cause weight loss. In certain embodiments, the second dose is administered to the subject for a period of time sufficient to cause weight loss.

[0427] In some embodiments, the dose is administered daily. In some embodiments, the dose is administered once daily. In some embodiments, the dose is administered twice daily. In some embodiments, the dose is administered weekly. In some embodiments, the dose is administered monthly. In some embodiments, the dose is administered every 30 days. In some embodiments, the dose is administered weekly. In some embodiments, the dose is administered bimonthly. In some embodiments, the dose is administered once daily.

[0428] In some embodiments, the dose is administered as a plurality of equally or unequally divided sub-doses.

[0429] In some embodiments, the dose is administered as a single dose in the form of a pen. In some embodiments, the dose is administered at a single dose ranging from 0.5 – 6 mg once weekly. In some embodiments, the dose is administered at a single dose ranging from 0.75 – 4.5 mg once weekly.

[0430] In certain embodiments, the dose is administered continuously (e.g., IV infusion) for a period of time. In certain embodiments, the dose is administered as an intravenous infusion dose for a period of time (e.g., 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 2 hours, 3 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours). In certain 86 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) embodiments, following the dose, the dose is administered as an intravenous infusion maintenance dose for a period of time (e.g., 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 2 hours, 3 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, or 48 hours). In certain embodiments, following a dose and a 24 hour or 48-hour washout period, the dose is administered as an intravenous infusion maintenance dose for a period of time (e.g., 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 2 hours, 3 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, or 48 hours). In certain embodiments, following a first dose and a 24 hour or 48-hour washout period, the dose is administered as an intravenous infusion dose for a period of time (e.g., 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 2 hours, 3 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours), followed by a second dose for a period of time (e.g., 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 2 hours, 3 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, or 48 hours).

[0431] In some embodiments, the GLP-1 receptor agonist is administered orally, intravenously, intranasally, subcutaneously, or intramuscularly. In some embodiments, the GLP-1 receptor agonist is administered orally. In some embodiments, the GLP-1 receptor agonist is administered orally once daily. In some embodiments, the GLP-1 receptor agonist is administered orally twice daily.

[0432] In some embodiments, the GLP-1 receptor agonist is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (qid), or three times a day (tid), over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more. In some embodiments, the GLP-1 receptor agonist is administered continuously for at least 10 minutes, at least 20 minutes, at 87 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) least 30 minutes, at least 40 minutes, at least 50 minutes, at least 1 hour, at least 2 hours, at least 3 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 11 hours, at least 12 hours, at least 13 hours, at least 14 hours, at least 15 hours, at least 16 hours, at least 17 hours, at least 18 hours, at least 19 hours, at least 20 hours, at least 21 hours, at least 22 hours, at least 23 hours, at least 24 hours, at least 48 hours, at least 72 hours, at least 100 hours, at least 110 hours, at least 115 hours, at least 120 hours, or at least 125 hours.

[0433] In some embodiments, the GLP-1 receptor agonist is administered once weekly. In some embodiments, the GLP-1 receptor agonist is administered subcutaneously, once weekly. In some embodiments, the recommended starting dosage of the GLP-1 receptor agonist is 2.5 mg injected subcutaneously once weekly. In some embodiments, after an initial period (e.g., 4 weeks), dosage of the GLP-1 receptor is increased (e.g., in 2.5 mg increments to e.g., 5 mg) injected subcutaneously once weekly. In some embodiments, maintenance dosages of the GLP-1 receptor agonist of 5 mg, 10 mg, or 15 mg injected subcutaneously once weekly can be utilized. Treatment response and tolerability are considered when selecting a maintenance dosage. In some embodiments, the GLP-1 receptor agonist is tirzepatide or a pharmaceutically acceptable salt thereof.

[0434] In some embodiments, the GLP-1 receptor agonist is administered for a period of time prior to co-administration of the GLP-1 receptor agonist and the apelin receptor agonist. In some embodiments, co-administration comprises first administering an effective amount of the GLP-1 receptor agonist, followed by administration of the apelin receptor agonist.

[0435] In some embodiments, the GLP-1 receptor agonist and apelin receptor agonist are administered as a fixed dose combination. In certain embodiments, the GLP-1 receptor agonist and apelin receptor agonist are administered as a fixed dose oral combination. In some embodiments, the GLP-1 receptor agonist and apelin receptor agonist are co- administered as a single oral formulation. 4.12. Patients

[0436] In some embodiments of the methods of this disclosure, the subject is overweight or obese. In some embodiments, the subject has, is suspected of having, or is at risk of developing a metabolic disease. In some embodiments, the metabolic disease is weight gain or obesity. In some embodiments, the subject has, is suspected of having, or is at risk of developing weight gain. In some embodiments, the subject to be treated is overweight or obese and in the presence of at least one weight-related comorbid condition (e.g., 88 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) hypertension, dyslipidemia, type 2 diabetes mellitus, obstructive sleep apnea or cardiovascular disease).

[0437] In some embodiments, the subject is obese. In some embodiments, the subject is overweight. In some embodiments, the subject has, is suspected of having, or is at risk of developing a disease or condition associated with obesity. In some embodiments, the subject has a BMI of 25 to <30 kg / m2. In some embodiments, the subject has a BMI of 27 to <30 kg / m2. In some embodiments, the subject has a BMI of 27 kg / m2or greater, which is overweight. In some embodiments, the subject has a BMI of 30 kg / m2or higher, which is obese. In some embodiments, the subject is Class 1 obese (BMI of 30 to < 35), Class 2 obese (BMI of 35 to < 40), or Class 3 three obese (BMI of 40 or higher). Body Mass Index (BMI) is calculated by: BMI = weight (kg) / [height (m)]2.

[0438] In some embodiments, the subject can have, is suspected of having, is at risk of developing, or is diagnosed with diabetes type I, diabetes type II, diabetes type Illa, or a metabolic syndrome.

[0439] In some embodiments, the subject has a metabolic disorder or dysmetabolic disorder. In certain embodiments, the metabolic disorder is a glucose metabolic disorder. In certain embodiments, the dysmetabolic disorder is dysmetabolic syndrome X. In certain embodiments, the metabolic disorder is insulin resistance syndrome or syndrome X. In certain embodiments, the metabolic disorder is selected from the group consisting of diabetes, metabolic syndrome, obesity, hyperlipidemia, high cholesterol, arteriosclerosis, hypertension, non-alcoholic steatohepatitis, non-alcoholic fatty liver, NASH, MASH, hepatic steatosis, and any combination thereof.

[0440] In some embodiments, the subject has pancreatic beta-cell dysfunction. In some embodiments, the subject has a condition in which there is a lack of or diminished insulin production.

[0441] In some embodiments, the subject has, or is at risk of developing a metabolic disorder or dysmetabolic disorder. In some embodiments, the metabolic disorder is a glucose metabolic disorder. In some embodiments, the dysmetabolic disorder is dysmetabolic syndrome X. In some embodiments, the metabolic disorder is insulin resistance syndrome or syndrome X. In some embodiments, the metabolic disorder is selected from the group consisting of diabetes, metabolic syndrome, obesity, hyperlipidemia, hyperinsulinemia, high cholesterol, arteriosclerosis, hypertension, non-alcoholic steatohepatitis, non-alcoholic fatty liver, NASH, MASH, hepatic steatosis, and any combination thereof. In some embodiments, 89 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) the subject has, or is at risk of developing pancreatic beta-cell dysfunction. In some embodiments, the subject has, or is at risk of developing a condition in which there is a lack of or diminished insulin production.

[0442] In some embodiments, the weight gain associated condition is obesity. In some embodiments, the weight gain associated condition is excessive weight gain. In some embodiments, the weight gain associated condition is diabetes mellitus. In some embodiments, the weight gain associated condition is insulin insensitivity. In some embodiments, the weight gain associated condition is cardiovascular disease. In some embodiments, the weight gain associated condition is neurologic disease. In some embodiments, the condition is obesity-linked gallbladder disease. In some embodiments, the weight gain associated condition is obesity-induced sleep apnea. In some embodiments, the condition is diabetes. In some embodiments, the weight gain associated condition is excessive appetite. In some embodiments, the weight gain associated condition is fatty liver disease. In some embodiments, the weight gain associated condition is non-alcoholic fatty liver disease (NASH). In some embodiments, the weight gain associated condition is metabolic dysfunction–associated steatohepatitis (MASH). In some embodiments, the weight gain associated condition is dyslipidemia. In some embodiments, the condition is metabolic syndrome. In some embodiments, the condition is insufficient satiety. In some embodiments, the weight gain associated condition is hyperinsulinemia. In some embodiments, the weight gain associated condition is nighttime hypoglycemia.

[0443] It was previously demonstrated that aged mice (24-month-old) treated with BGE- 105 exhibit a statistically significant increase in voluntary motor activity (p=0.00228) and a statistically significant improvement in grip strength (p=0.04) as compared to age-matched controls, indicating improved physical health and increased muscle strength. It was also previously demonstrated that aged mice (18-month-old) first injected with a cardiotoxin and then treated with BGE-105 showed significantly higher levels of several mRNA transcripts which are indicative of muscle regeneration. It was also previously demonstrated that immortalized muscle precursor cells from human patients showed a dose-dependent relationship between cell growth and differentiation, and concentration of BGE-105. Lastly, immobilized aged mice (20-months-old) that were orally dosed with BGE-105 displayed significantly reduced muscle atrophy as compared to immobilized mice that were injected with the control vehicle. See, e.g., WO2024148104A1, which is hereby incorporated by reference in its entirety. 90 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)

[0444] Thus, an apelin receptor agonist can increase physical performance, counteract age- related frailty, and can reduce age-related muscle weakness.

[0445] Thus, an apelin receptor agonist can increase physical performance, counteract age- related frailty, prevent and can reduce age-related muscle weakness and treat muscle atrophy.

[0446] In some embodiments, the patient has, or is at risk of developing: sarcopenia, frailty, muscle weakness, reduction in risk of hip fracture, ICU associated muscle weakness, muscle atrophy, diaphragm disfunction, diaphragm atrophy, immobilization associated muscle weakness, immobility associated muscle weakness, recovery from muscle injury, or muscle wasting.

[0447] In some embodiments, the patient is on bedrest.

[0448] In some embodiments of the methods of this disclosure, the subject is human and has low muscle strength, low muscle force, low muscle mass, and / or low muscle volume due to disuse atrophy after immobilization.

[0449] In some embodiments, the patient is susceptible to, or at risk of having, sarcopenia. Sarcopenia is a condition characterized by loss of skeletal muscle mass and function. When this condition is associated with aging, it can also be referred to as age-related sarcopenia. Diagnosis of sarcopenia can be achieved via an assessment of low muscle mass plus the presence of low muscle function (low muscle strength / weakness or low physical performance) (see e.g., Cruz-Jentoft et al., (2010) Sarcopenia: European consensus on definition and diagnosis Report of the European Working Group on Sarcopenia in Older People. Age and Ageing; 39: 412-423; Muscaritoli et al., (2010) Consensus definition of sarcopenia, cachexia and pre-cachexia: joint document elaborated by Special Interest Groups (SIG) “cachexia- anorexia in chronic wasting diseases” and “nutrition in geriatrics”. Clin Nutr. Apr, 29(2):154-9; Fielding et al. (2011) Sarcopenia: An Undiagnosed Condition in Older Adults. Current Consensus Definition: Prevalence, Etiology, and Consequences. International Working Group on Sarcopenia. J Am Med Dir Assoc, 12: 249-256; and Studenski et al. (2014) The FNIH Sarcopenia Project: Rationale, study description, conference recommendations and final estimates. J Gerontol A Biol Sci Med Sci 69(5): 547- 558).

[0450] Frailty is a geriatric condition characterized by an increased vulnerability to external stressors. It is strongly linked to adverse outcomes, including mortality, nursing home admission, and falls. In some embodiments, the patient is susceptible to, or at risk of having, a condition associated with one or more characteristic measures of frailty. In some 91 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) embodiments, the subject is classified as frail. In some embodiments, the subject is classified as pre-frail, and is at a high risk or progression to being frail. Frailty can be diagnosed and / or characterized according to various indices of frailty that are composite measures of age- related changes indices of frailty, such as methods based on the Fried’s frailty scale (see e.g., Fried, et al., Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001, 56: M146-M156) and / or the Mitnitski’s Frailty Index (see e.g., Mitnitski et al., Frailty, fitness and late-life mortality in relation to chronological and biological age. BMC Geriatr. 2002, 2: 1-10).

[0451] In some embodiments, the patient is susceptible to, or at risk of having, muscle atrophy. Muscle atrophy refers to any wasting or loss of muscle tissue resulting from lack of use. Muscle atrophy can lead to muscle weakness and cause disability. In some embodiments, the patient is susceptible to, or at risk of having, immobilization-associated muscle weakness, which refers to any wasting or loss of muscle tissue resulting from immobilization, e.g., for medical reasons.

[0452] In some embodiments, the patient is susceptible to, or at risk of having, muscle weakness, also referred to as muscle fatigue, which refers to a condition characterized by the subject’s inability to exert force with skeletal muscles. Muscle weakness often follows muscle atrophy.

[0453] Muscle atrophy can be measured using various endpoints, such as skeletal muscle protein fractional synthetic rate (FSR) in a liquid biopsy. Other measurements of muscle atrophy include diaphragm thickness, echo-density (e.g. of vastus lateralis), muscle circumference (of muscles such as the thigh / vastus lateralis), muscle cross-sectional area, and the like. Detection of muscle circumference can be measured using ultrasound. Ultrasound can be used to assess muscle atrophy, diaphragm dysfunction, predict extubating success or failure, quantify respiratory effort, and detect atrophy in, for example, mechanically ventilated subjects or subjects on bedrest.

[0454] In some embodiments, the patient is susceptible to, or at risk of having, a skeletal muscle condition. In some embodiments, the condition is not a cardiovascular condition. In some embodiments, the subject is not suffering from, or identified as having, a cardiovascular disease or condition. In some embodiments, the subject is not suffering from, or at risk of, a heart failure. In some embodiments, the subject is suffering from, or identified as having, a cardiovascular disease or condition. In some embodiments, the subject is suffering from, or at risk of, a heart failure. 92 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)

[0455] In some embodiments the muscle condition is associated with the loss-of-function, decrease in the ability to regenerate, or heal after injury of skeletal muscle. In some embodiments the condition is associated with the loss-of-function of muscle stem cells.

[0456] In some embodiments, the patient is susceptible to, or at risk of having, insulin insensitivity associated with muscle atrophy. Type 2 diabetes mellitus can be associated with an accelerated muscle loss during aging, decreased muscle function, and increased disability. 4.12.1. Patient Age

[0457] In some embodiments of the method of treating a subject for a condition, the subject has, or is suspected of having, a condition associated with weight gain. In some embodiments of the method of inducing weight loss and preserving muscle function, the subject has, or is suspected of having, a condition associated with weight gain.

[0458] In some embodiments, the subject is human. The subject can be a human patient suffering from, or a risk of, an age-related muscle condition. In some embodiments, the patient is at least 30-years-old. In some embodiments, the patient is at least 40-years-old. In some embodiments, the patient is at least 50-years-old. In some embodiments, the patient is at least 60-years-old. In some embodiments, the patient is at least 65-years-old. In some embodiments, the patient is at least 70-years-old. In some embodiments, the patient is at least 75-years-old. In some embodiments, the patient is at least 80-years-old. In some embodiments, the patient is at least 85-years-old. In some embodiments, the patient is at least 90-years-old. In certain embodiments, the patient is 40-50 years old, 50-60 years old, 60-70 years old, 70-80 years old, or 80-90 years old. 4.12.2. Assessment of patients

[0459] A subject can be being susceptible of having a condition or disease, at risk of having a condition or disease, or having a condition or disease and identified as in need of treatment according to the methods of this disclosure, using a variety of different assessment methods.

[0460] For example, in some embodiments, the subject is susceptible of having, or at risk of having or developing, a muscle condition such as sarcopenia or frailty. In certain embodiments, the subject is at risk of developing sarcopenia or frailty due to weight loss therapy. In alternative embodiments, the subject has a muscle condition such as sarcopenia or frailty in addition to a condition or disease associated with weight gain (e.g., obesity). In certain embodiments, the subject that has a muscle condition such as sarcopenia or frailty in addition to a condition or disease associated with weight gain (e.g., such as obesity) has the muscle condition prior to undergoing weight loss therapy. 93 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)

[0461] In some embodiments, the human subject has, is susceptible of having, is at risk of having, sarcopenia. In some embodiments, the human subject is identified as having sarcopenia. In some embodiments, the human subject is susceptible of having sarcopenia. In some embodiments, the human subject is at risk of having or developing sarcopenia. In some embodiments, the human subject is identified as having frailty. In some embodiments, the human subject is susceptible of having frailty. In some embodiments, the human subject is at risk of having or developing frailty.

[0462] In some embodiments, the patient has a BMI of at least 25. In some embodiments, the patient has a BMI of at least 30. In some embodiments, the patient has a BMI of at least 35, at least 40, at least 45, at least 50, at least 55, or at least 60. In some embodiments, the patient has a BMI of at 25 or more. In some embodiments, the patient has a BMI of 30 or more, 35 or more, 40 or more, 45 or more, 50 or more, 55 or more, or 60 or more. In some embodiments, a patient with a BMI of 25 or more is considered overweight. In certain embodiments, a patient with a BMI 25 or more is considered obese. In certain embodiments, a patient with a BMI 30 or more is considered obese.

[0463] A sarcopenia diagnosis can be determined or confirmed by the presence of low muscle quantity or quality. When low muscle strength or force, low muscle quantity / quality and low physical performance are all detected, sarcopenia is considered severe. In some embodiments, the patient has low muscle quantity or quality as compared to criteria representative of a healthy human subject, e.g., a subject of the same age or younger.

[0464] Low muscle mass can be assessed using appendicular lean body mass (ALBM). In some embodiments, low muscle mass is indicated by an ALBM adjusted for body mass index (BMI) of < 0.789 kg for men or < 0.512 kg for women, where ALBM can be measured by dual energy X-ray absorptiometry (DXA) or echoMRI. Additional muscle mass measurements include DEXA, total body potassium (TBK), MRI, total body electrical conductivity (TOBEC), and CT.

[0465] Low muscle mass can be assessed by the appendicular skeletal muscle index (ASMI). In some low muscle mass is indicated by an appendicular skeletal muscle index (ASMI) of less than 7.26 kg / m2for men, or less than 5.5 kg / m2for women, said ASMI being defined as appendicular skeletal muscle mass divided by the square of height, said ASMI being measured by dual energy X-ray absorptiometry (DXA).

[0466] Low muscle strength can include low grip strength, and be determined using a handgrip strength test. In some embodiments, low grip strength is assessed by measuring the 94 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) amount of static force that the hand can squeeze around a handgrip dynamometer, e.g., as indicated by a value of less than 30 kg, such as less than 26 kg for men, or less than 20 kg for women, such as less than 16 kg, in the handgrip strength test.

[0467] In some embodiments, the human subject has, or is identified as having, low muscle strength. In some embodiments, the human subject has, or is identified as having, low muscle force. In some embodiments of the methods of this disclosure, the subject is human and has, or is identified as having or is at risk of having, one or more of low muscle strength, low muscle force, low muscle mass, low muscle volume. In some embodiments, the muscle is skeletal muscle. In some embodiments, the muscle is the diaphragm, tibialis anterior, tibialis posterior, gastrocnemius, sartorius, quadriceps femoris (rectus femoris, vastus intermedius, vastus lateralis, and vastus medialis), soleus, or extensor digitorum longus.

[0468] In some embodiments, the human subject has, is susceptible of having, is at risk of having, low lower limb muscle mass. In some embodiments, the human subject has, or is identified as having, low upper limb muscle mass. In some embodiments, the human subject has, or is identified as having, after undergoing weight loss therapy, low lower limb muscle mass. In some embodiments, the human subject has, or is identified as having, after undergoing weight loss therapy, low upper limb muscle mass.

[0469] In some embodiments, the human subject has, is susceptible or having, or is at risk of having, low muscle volume. In some embodiments, the muscle volume is skeletal muscle volume. In some embodiments, the muscle is a skeletal muscle. In some embodiments, the skeletal muscle is a diaphragm. In some embodiments, the muscle is diaphragm, tibialis anterior, tibialis posterior, gastrocnemius, sartorius, vastus intermedius, vastus lateralis, vastus medialis, soleus, or extensor digitorum longus. In some embodiments, the muscle is diaphragm, tibialis anterior, tibialis posterior, sartorius, soleus, or extensor digitorum longus. In some embodiments, the muscle is diaphragm muscle.

[0470] In some embodiments, the muscle volume is the muscle volume of one or more upper limb muscles selected from the group consisting of: shoulder abductors, shoulder adductors, elbow flexors, elbow extensors, wrist flexors, and wrist extensors.

[0471] In some embodiments, muscle mass is assessed after the dosing. In some embodiments, muscle mass is assessed at least one day after dosing. In some embodiments, the muscle mass is assessed at least one week after dosing. In some embodiments, the muscle mass is assessed at least one month after dosing. 95 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)

[0472] In some embodiments, the subject has, susceptible of having, or is at risk of having, a muscle condition. In some embodiments, the muscle condition is a skeletal muscle condition. In some embodiments, the skeletal muscle expresses the apelin receptor and administration of the apelin receptor agonist activates the apelin / APJ system (APLNR gene) in the muscle tissue of the subject. The muscle of interest expresses the apelin receptor, and in some embodiments, the level of expression of the apelin receptor can be assessed or determined in a muscle tissue of the subject prior to and / or after treatment. In some embodiments, the subject has, or is identified as having, a low circulating level of apelin. Apelin circulating levels can be assessed in a biological sample obtained from the subject, e.g., using a quantitative assay (e.g., ELISA assay, or LC / MS) for determining the amount of an apelin peptide in a sample.

[0473] In some embodiments, the muscle condition is a diaphragmatic muscle condition. In some embodiments, the diaphragmatic muscle condition is diaphragm atrophy. In some embodiments, the diaphragmatic muscle condition is diaphragm dysfunction. Dysfunction of the diaphragm ranges from a partial loss of the ability to generate pressure (weakness) to a complete loss of diaphragmatic function (paralysis). Patients with bilateral diaphragmatic paralysis or severe diaphragmatic weakness are likely to have dyspnea or recurrent respiratory failure. They can have considerable dyspnea at rest, when supine, with exertion, or when immersed in water above their waist. Further, patients with bilateral diaphragmatic paralysis are at an increased risk for sleep fragmentation and hypoventilation during sleep.

[0474] In some embodiments of the methods of this disclosure, the subject is human and has, is identified as having, or is at risk of having, one or more of diabetes mellitus, insulin insensitivity, and cardiovascular disease.

[0475] Muscle atrophy can be measured using various endpoints, such as skeletal muscle protein fractional synthetic rate (FSR) in a liquid biopsy. Other measurements of muscle atrophy include muscle thickness, echo-density (e.g. of vastus lateralis), muscle circumference (of muscles such as the thigh / vastus lateralis), muscle cross-sectional area, and the like. Detection of muscle circumference can be measured using ultrasound.

[0476] In some embodiments, the patient is diagnosed as obese. In some embodiments, the patient is diagnosed with diabetes mellitus. In some embodiments, the patient is diagnosed with insulin insensitivity. In some embodiments, the patient is diagnosed with cardiovascular disease. In some embodiments, the patient is diagnosed with obesity-linked gallbladder disease. In some embodiments, the patient is diagnosed with is obesity-induced sleep apnea. 96 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) In some embodiments, the patient is diagnosed with diabetes. In some embodiments, the patient is diagnosed with excessive appetite. In some embodiments, the patient is diagnosed with fatty liver disease. In some embodiments, the patient is diagnosed with non-alcoholic fatty liver disease (NASH). In some embodiments, the patient is diagnosed with metabolic dysfunction–associated steatohepatitis (MASH). In some embodiments, the patient is diagnosed with dyslipidemia. In some embodiments, the patient is diagnosed with insufficient satiety. In some embodiments, the patient is diagnosed with hyperinsulinemia. In some embodiments, the patient is diagnosed with nighttime hypoglycemia.

[0477] In some embodiments, the patient is diagnosed as obese and as having sarcopenia. In some embodiments, the patient is diagnosed with diabetes mellitus and sarcopenia. In some embodiments, the patient is diagnosed with insulin insensitivity and sarcopenia. In some embodiments, the patient is diagnosed with cardiovascular disease and sarcopenia. In some embodiments, the patient is diagnosed with obesity-linked gallbladder disease and sarcopenia. In some embodiments, the patient is diagnosed with is obesity-induced sleep apnea and sarcopenia. In some embodiments, the patient is diagnosed with diabetes and sarcopenia. In some embodiments, the patient is diagnosed with excessive appetite and sarcopenia. In some embodiments, the patient is diagnosed with fatty liver disease and sarcopenia. In some embodiments, the patient is diagnosed with non-alcoholic fatty liver disease (NASH) and sarcopenia. In some embodiments, the patient is diagnosed with dyslipidemia and sarcopenia. In some embodiments, the patient is diagnosed with insufficient satiety and sarcopenia. In some embodiments, the patient is diagnosed with hyperinsulinemia and sarcopenia. In some embodiments, the patient is diagnosed with nighttime hypoglycemia and sarcopenia.

[0478] In some embodiments, the patient is diagnosed as obese and as having frailty. In some embodiments, the patient is diagnosed with diabetes mellitus and frailty. In some embodiments, the patient is diagnosed with insulin insensitivity and frailty. In some embodiments, the patient is diagnosed with cardiovascular disease and frailty. In some embodiments, the patient is diagnosed with obesity-linked gallbladder disease and frailty. In some embodiments, the patient is diagnosed with is obesity-induced sleep apnea and frailty. In some embodiments, the patient is diagnosed with diabetes and frailty. In some embodiments, the patient is diagnosed with excessive appetite and frailty. In some embodiments, the patient is diagnosed with fatty liver disease and frailty. In some embodiments, the patient is diagnosed with non-alcoholic fatty liver disease (NASH) and 97 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) frailty. In some embodiments, the patient is diagnosed with dyslipidemia and frailty. In some embodiments, the patient is diagnosed with insufficient satiety and frailty. In some embodiments, the patient is diagnosed with hyperinsulinemia and frailty. In some embodiments, the patient is diagnosed with nighttime hypoglycemia and frailty. 4.13. Additional embodiments

[0479] The followed numbered embodiments are also included within the present disclosure. 1. A method of inducing weight loss with maintenance of lean muscle mass in a subject in need of weight loss, the method comprising: co-administering to a subject in need thereof: an effective dose of an apelin receptor agonist; and an effective dose of a GLP-1 receptor agonist, to maintain lean muscle mass while inducing fat and weight loss in the subject. 2. A method of increasing total weight loss caused by administration of a pre-determined amount of a GLP-1 receptor agonist to a subject in need thereof, the method comprising: co-administering to a subject in need thereof: an effective dose of an apelin receptor agonist; and an effective dose of a GLP-1 receptor agonist, to increase total weight loss in the subject relative to weight loss caused by administration of a pre-determined amount of a GLP-1 receptor agonist alone. 3. A method of treating or preventing further muscle mass decrease caused by administration of a GLP-1 receptor agonist to a subject in need thereof, the method comprising: adding an effective dose of an apelin receptor agonist to the GLP-1 receptor agonist treatment regimen of a subject in need thereof, to treat or prevent further lean muscle mass decrease in the subject. 4. The method of any one of embodiments 1 to 3, wherein the co-administering stimulates muscle mass preservation, or stimulates an increase in muscle mass in the subject relative to a baseline level. 5. The method of any one of embodiments 1 to 4, wherein the subject exhibits after the co-administration: loss of fat but not lean muscle; increased lean mass percentage; 98 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) increased lean / fat mass ratio; and / or reduced or normal fed glucose level, relative to a baseline level immediately before administration. 6. The method of any one of embodiments 1 to 6, wherein the subject is overweight or obese. 7. The method of any one of embodiments 1 to 6, wherein the subject has a disease or condition associated with weight gain. 8. The method of any one of embodiment 7, wherein the disease or condition associated with weight gain is selected from obesity, obesity-linked gallbladder disease, obesity-induced sleep apnea, diabetes, excessive appetite, fatty liver disease, non-alcoholic fatty liver disease (NASH), metabolic dysfunction–associated steatohepatitis (MASH), dyslipidemia, metabolic syndrome, insufficient satiety, hyperinsulinemia, and nighttime hypoglycemia. 9. The method of any one of embodiments 1 to 8, wherein the subject has a metabolic disorder. 10. The method of embodiment 9, wherein the subject has diabetic obesity. 11. The method of embodiment 9 or 10, wherein the subject has type 1 diabetes, type 2 diabetes, or gestational diabetes. 12. The method of any one of embodiments 1 to 11, wherein the subject has one or more of hypertension, dyslipidemia, obstructive sleep apnea, and cardiovascular disease. 13. The method of any one of embodiments 1 to 12, wherein the GLP-1 receptor agonist is selected from albiglutide, exenatide, liraglutide, lixisenatide, semaglutide, and tirzepatide. 14. The method of embodiment 14, wherein the GLP-1 receptor agonist is semaglutide. 15. The method of any one of embodiments 1 to 12, wherein the GLP-1 receptor agonist is a dual-acting GLP-1 receptor agonist, and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist or glucagon receptor agonist. 16. The method of embodiment 15, wherein the GLP-1 receptor agonist is tirzepatide. 17. The method of any one of embodiments 1 to 12, wherein the GLP-1 receptor agonist is a triple-acting GLP-1 receptor agonist, GIP receptor agonist, and glucagon receptor agonist. 18. The method of embodiment 17, wherein the GLP-1 receptor agonist is retatrutide. 19. The method of any one of embodiments 1 to 12, wherein the GLP-1 receptor agonist is selected from albenatide, albiglutide, avexitide, cafraglutide, cotadutide, danuglipron, dapiglutide, diabegone, dulaglutide, ecnoglutide, efpeglenatide, efinopegdutide, efocipegtrutide, exenatide, exenatide biobetter, exenatide SR, froniglutide, liraglutide, 99 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) liraglutide biobetter, lixisenatide, CT-868, efocipegtrutide, LY-3502970 (Orforglipron), maridebart, mazdutide, NLY-001, orforglipron, pegapamodutide, pemvidutide, retatrutide (LY-3437943), semaglutide, semaglutide injection, survodutide, vurolenatide, dapagliflozin + semaglutide, (cagrilintide + semaglutide), (LAI-287 + semaglutide), (semaglutide + GIP analogue), 4P-004, AMG-133, AP-026, AZD-9550, BGM-0504, BMS-686117, Zn / BMS- 686117 adduct, CT-388, CT-868, CT-996, DD-01, DR-10624, DR-10627, ECC-5004, E- 2HSA, GL-0034, GLP-06, GMA-105, GMA-106, GMA-102, GSBR-1290, GXG-6, GZR-18, HEC-88473, HR-17031, HRS-7535, HRS-9531, HS-20004, HS-20094, HB-1085, HDM- 1002, HL-08, HZ-010, JY-09, KN-056, LY-3493269, MBX-1416, MDR-001, MWN-101, NLY-001, NN-9490, NNC0519-0130, NN-6177, NN-9847, NN-9904, NN-6535 (semaglutide), NN-9932 (semaglutide), PF-06954522, PF-07081532, PF-06882961, PB- 1023, PB-119, PB-718, RGT-075, SAL-015, SAL-0112, SCO-094, TERN-601, TTP-273, Uni-E4, VK-2735, YH-25724, XW-004, XW-014, YH-25724, YN-012 (Supaglutide), YN- 015, ZT-002, and pharmaceutically acceptable salts thereof. 20. The method of any one of embodiments 1 to 12, wherein the GLP-1 receptor agonist is selected from (dorzagliatin + GLP-1), (exenatide + insulin aspart), ACT-1003, Adogel Sema, AER-601, AGM-212, BEBT-808, BZ-043B, C-2816, DAJC-1, DD-02, DR-10625, DR-10628, DS-004, DS-005, DS-006, DS-012, E-6, efpeglenatide + HM-12470, exenatide 2, exenatide LA, exenatide SR, Extendin-Fc, G-49, GB-7001, Gene Encoding GLP-1, GLP-1 Incretin Triagonist, GLP-1 Oral Preparation, GLP-1R Antagonist for Hypoglycemia, glucagon, Glucagon-Like Peptide-1 + insulin human, GPCR-targeted Project 012, GPCR- targeted Project 013, GT-01123, HM-15275, HPG-5119, HSP-001, HSP-004, HSP-005, HSP012-C, Hydrogel Exenatide, I2O-105S, I2O-110, KP-405, LA-EX, liraglutide biobetter, liraglutide LA, MK-1462, MLX-7000, MWN-105, MWN-109, NLY-12, NPM-115, OGB- 21502, OXM, P-11, PB-2301, PB-2309, RGT-028, RGT-274, RPC-8844, RT-104, SHX-022, SL-209, synthetic peptides to agonize GLP-1R and CCKBR for diabetes, TB-013, TB- 222023, TB-592, TE-8105, THDBH-111, UDS-003, VTCG-15, XL-110, XL-310, XW-003 + XW-015, XW-003 + XW-017, Y-002, YGX-1, ZT-003, ZT-006, ZT-007, DA-1726, HDM- 1005, (insulin degludec + liraglutide), DB-081, GW-002, HZCX-012, ID-110521156, THDB-0211, THDBH-110, THDBH-120, THDBH-121, UBT-251, ATBB-22, BEM-012, CIN-209, CIN-210, DD-03, exenatide + ND-017, exenatide + Synthetic Peptide 2, glucagon, Insulin-GLP1, MD-02, OGB-21501, P-01, PAT-201, PF-1807, PT-3, and pharmaceutically acceptable salts thereof. 100 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) 21. The method of any one of embodiments 1 to 20, wherein the apelin receptor agonist is selected from BAL-1480, BMS-986224, ANPA-0073, apelin-13, [Pyr1]apelin-13, E339-3D6, (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5- methyl-2-pyrimidinyl)-2-butanesulfonamide, (S)-N-(1-(cyclobutylamino)-1-oxo-5-(piperidin- 1-yl)pentan-3-yl)-5-(2,6-dimethoxyphenyl)-1-cyclopentyl-1H-pyrazole-3-carboxamide, and pharmaceutically acceptable salts thereof. 22. The method of any one of embodiments 1 to 20, wherein the apelin receptor agonist is of formula (I) or (II):or a pharmaceutically acceptable salt thereof, a tautomer thereof, a pharmaceutically acceptable salt of the tautomer, a stereoisomer of any of the foregoing, or a mixture thereof, wherein: R1is an unsubstituted pyridyl, pyridonyl, or pyridine N-oxide, or is a pyridyl, pyridonyl, or pyridine N-oxide substituted with 1, 2, 3, or 4 R1asubstituents; R1ain each instance is independently selected from —F, —Cl, —Br, —I, —CN, — C1-C6alkyl, —C1-C6haloalkyl, —C1-C6perhaloalkyl, —OH, —O—(C1-C6alkyl), —O—(C1- C6 haloalkyl), —O—(C1-C6 perhaloalkyl), —C2-C6 alkenyl, —O—(C1-C6 alkyl)-OH, —O— (C1-C6 alkyl)-O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl)-OH, —O—(C1-C6 haloalkyl)-O— (C1-C6alkyl), —O—(C1-C6perhaloalkyl)-OH, —O—(C1-C6perhaloalkyl)-O—(C1-C6alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —C(═O)—(C1-C6 alkyl), —C(═O)OH, — (C═O)—O—(C1-C6 alkyl), —C(═O)NH2, —C(═O)NH(C1-C6 alkyl), —C(═O)N(C1- C6alkyl)2, phenyl, —C(═O)-(heterocyclyl), or a heterocyclyl group, wherein the heterocyclyl group of the —C(═O)-(heterocyclyl) or heterocyclyl group is a 3 to 7 membered ring containing 1, 2, or 3 heteroatoms selected from N, O, and S; R2is selected from —H, and C1-C4alkyl or is absent in the compounds of Formula II; R3is selected from an unsubstituted C1-C10alkyl, a C1-C10alkyl substituted with 1, 2, or 3 R1asubstituents, a group of formula —(CR3bR3c)-Q, a group of formula —NH— (CR3bR3c)-Q, a group of formula —(CR3bR3c)—C(═O)-Q, a group of formula —(CR3dR3e)— (CR3fR3g)-Q, a group of formula —(CR3b═CR3c)-Q, and a group of formula -(heterocyclyl)- 101 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) Q, wherein the heterocyclyl of the -(heterocyclyl)-Q has 5 to 7 ring members of which 1, 2, or 3 are heteroatoms selected from N, O, and S and is unsubstituted or is substituted with 1, 2, or 3 R3hsubstituents; R1ain each instance is independently selected from —F, —Cl, —CN, —OH, —O— (C1-C6 alkyl), —O—(C1-C6 haloalkyl), —O—(C1-C6 perhaloalkyl), —O—(C1-C6 alkyl)-OH, —O—(C1-C6alkyl)-O—(C1-C6alkyl), C2-C6alkenyl, C2-C6alkynyl, —NH2, —NH(C1- C6alkyl), and —N(C1-C6alkyl)2; R3band R3care independently selected from —H, —F, —Cl, —CN, —C1-C6 alkyl, — C1-C6haloalkyl, —C1-C6perhaloalkyl, —OH, —O—(C1-C6alkyl), —O—(C1-C6haloalkyl), —O—(C1-C6perhaloalkyl), —O—(C1-C6alkyl)-OH, —O—(C1-C6alkyl)-O—(C1-C6alkyl), —NH2, —NH(C1-C6 alkyl), and —N(C1-C6 alkyl)2; R3dand R3eare independently selected from —H, —F, —Cl, —CN, —C1-C6 alkyl, — C1-C6haloalkyl, —C1-C6perhaloalkyl, —OH, —O—(C1-C6alkyl), —O—(C1-C6haloalkyl), —O—(C1-C6 perhaloalkyl), —O—(C1-C6 alkyl)-OH, —O—(C1-C6 alkyl)-O—(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), and —N(C1-C6 alkyl)2; R3fand R3gare independently selected from —H, —F, —Cl, —CN, —C1-C6alkyl, — C1-C6haloalkyl, —C1-C6perhaloalkyl, —OH, —O—(C1-C6alkyl), —O—(C1-C6haloalkyl), —O—(C1-C6 perhaloalkyl), —O—(C1-C6 alkyl)-OH, —O—(C1-C6 alkyl)-O—(C1-C6 alkyl), —NH2, —NH(C1-C6alkyl), and —N(C1-C6alkyl)2; R3hin each instance is independently selected from —F, —Cl, —CN, —C1-C6alkyl, —C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —OH, —O—(C1-C6 alkyl), —O—(C1- C6haloalkyl), —O—(C1-C6perhaloalkyl), —O—(C1-C6alkyl)-OH, —O—(C1-C6alkyl)-O— (C1-C6alkyl), —NH2, —NH(C1-C6alkyl), —N(C1-C6alkyl)2, and oxo; Q is a monocyclic or bicyclic C6-C10 aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms selected from N, O, or S, a C3-C8cycloalkyl group, or a 3 to 7 membered heterocyclyl group containing 1, 2, or 3 heteroatoms selected from N, O, or S, wherein the C6-C10 aryl group, the heteroaryl group, the cycloalkyl group, and the heterocyclyl group are unsubstituted or are substituted with 1, 2, 3, or 4 RQsubstituent; RQin each instance is independently selected from —F, —Cl, —Br, —I, —CN, —C1- C6 alkyl, —C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —OH, —O—(C1-C6alkyl), —O—(C1-C6haloalkyl), —O—(C1-C6perhaloalkyl), —NH2, —NH(C1- C6alkyl), —N(C1-C6alkyl)2, —C(═O)—(C1-C6alkyl), —C(═O)OH, —C(═O)—O—(C1- C6 alkyl), —C(═O)NH2, —C(═O)NH(C1-C6 alkyl), —C(═O)N(C1-C6 alkyl)2, —S(═O)2— 102 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) (C1-C6 alkyl), phenyl, and a heteroaryl group, and the Q heterocyclyl group may be substituted with 1 oxo RQsubstituent; R4is selected from a monocyclic or bicyclic C6-C10aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and a monocyclic or bicyclic heterocyclyl group with 5 to 10 ring members containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, wherein the C6-C10aryl group, the heteroaryl group, or the heterocyclyl group are unsubstituted or are substituted with 1, 2, or 3 R4asubstituents; R4ain each instance is independently selected from —F, —Cl, —Br, —I, —CN, — C1-C6alkyl, —C1-C6haloalkyl, —C1-C6perhaloalkyl, —OH, —O—(C1-C6alkyl), —O—(C1- C6 haloalkyl), —O—(C1-C6 perhaloalkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, — C(═O)—(C1-C6 alkyl), —C(═O)OH, —C(═O)—O—(C1-C6 alkyl), —C(═O)NH2, — C(═O)NH(C1-C6alkyl), and —C(═O)N(C1-C6alkyl)2, and the heterocyclyl R4group may be further substituted with 1 oxo substituent; and further wherein: if R4is an unsubstituted or substituted phenyl ring and R3is a group of formula — (CR3b═CR3c)-Q, then at least one of the following is true: a) R4is substituted with at least one —O—(C1-C6 alkyl) group; b) Q is not an oxadiazole; c) R3bis not —H; d) R3cis not —H; e) R1is not a 2-pyridyl group; or f) R4is substituted with two or more —O—(C1-C6alkyl) groups. 23. The method of any one of embodiments 1 to 22, wherein the apelin receptor agonist is a compound of the structureor a pharmaceutically acceptable salt thereof. 103 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) 24. The method of embodiment 23, wherein the apelin receptor agonist is (2S,3R)—N-(4- (2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2- pyrimidinyl)-2-butanesulfonamide. 25. The method of embodiment 23, wherein the apelin receptor agonist is a pharmaceutically acceptable salt of (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3- pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide. 26. The method of any one of embodiments 1 to 20, wherein the apelin receptor agonist is of Formula (XXI):or a pharmaceutically acceptable salt thereof, wherein R1is represented by the formula:whereinis a monocyclic aryl or heteroaryl group; each A is independently fluoro substituted C1-C3alkoxy or fluoro substituted C1- C3 alkyl; n is 1, 2, 3, 4, or 5; R2is C3-8alkyl, C1-8alkyl (C3-8cycloalkyl), C3-8cycloalkyl, heteroaryl, or substituted aryl; R4 is adamantanyl, aryl, C1-8 alkyl, C1-8 alkyl alcohol, C1-8 alkyl amino, C1-8 alkyl amido, C2-8alkyl(aryl), C1-8alkyl (C3-8cycloalkyl), C1-8alkyl (C3-8cycloalkyl)—CO2R7, C1-8alkyl guanidinyl, C1-8alkyl heteroaryl, C1-8alkyl tetrazol-5-one, C2-4alkyl heterocycloalkyl, C1-8 alkyl thioether, C1-8 alkyl thiol, C2-8 alkenyl, C2-8 alkenyl(aryl), C2-8 alkenyl(heteroaryl), C3-8alkynyl, C3-8cycloalkyl, C3-8cycloalkyl—CO2R7, (CH2)xNR7R8, (CH2)xOR7, (CH2)xNR9COR7, (CH2)xNR9SO2R7, (CH2)xNR9CO2R7, (CH2)xNHCOR7, (CH2)xNHSO2R7, (CH2)xNHCO2R7, (CH2)xCONR7R8, (CH2)xCONR7(CH2)yCO2R9, 104 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) (CH2)xCONR7(CH2)yCONR7R8, (CH2)xCONR7(CH2)yR9 (CH2)xCOR7, (CH2)xCO2R7, (CH2)xSO2NR7(CH2)yR9, CHR7COR9, CHR7CONHCHR8COR9, CONR7R8, CONR7(CH2)xCO2R8, CONR7CHR8CO2R9, CO2R9, NHCO2R7, or (CH2)xSO2NR7R8; R5 and R6 each are independently is adamantanyl, aryl, C1-8 alkyl, C1-8 alkyl alcohol, C1-8 alkyl amino, C1-8 alkyl amido, C2-8 alkyl(aryl), C1-8 alkyl (C3-8 cycloalkyl), C1-8 alkyl (C3-8cycloalkyl)—CO2R7, C1-8alkyl guanidinyl, C1-8alkyl heteroaryl, C1-8alkyl tetrazol-5-one, C2-4alkyl heterocycloalkyl, C1-8alkyl thioether, C1-8alkyl thiol, C2-8alkenyl, C2-8 alkenyl(aryl), C2-8 alkenyl(heteroaryl), C3-8 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkyl-CO2R7, (CH2)xNR7R8, (CH2)xOR7, (CH2)xNR9COR7, (CH2)xNR9SO2R7, (CH2)xNR9CO2R7, (CH2)xNHCOR7, (CH2)xNHSO2R7, (CH2)xNHCO2R7, (CH2)xCONR7R8, (CH2)xCONR7(CH2)yCO2R9, (CH2)xCONR7(CH2)yCONR7R8, (CH2)xCONR7(CH2)yR9, (CH2)xCOR7, (CH2)xCO2R7, (CH2)xSO2NR7(CH2)yR9, CHR7COR9, CHR7CONHCHR8COR9, CONR7R8, CONR7(CH2)xCO2R8, CONR7CHR8CO2R9, CO2R9, NHCO2R7, or (CH2)x SO2NR7R8; or R4 and R5 together make a 4-8 member ring which may be substituted with one or more heteroatoms; or and R5together make a 5-8 nitrogen containing member ring with one or more carbonyl groups; wherein the group R4is substituted with one or more fluorine atoms; R7 and R8 each are independently H, C1-8 alkoxy, aryl, C1-8 alkyl, C1-8 alkyl alcohol, C1-8alkyl amino, C1-8alkyl amido, C1-8alkyl(aryl), C1-8alkyl (C3-8cycloalkyl), C1-8alkyl tetrazol- 5-one, C1-8alkyl guanidinyl, C1-8alkyl heteroaryl, C1-8alkyl thioether, C1-8alkyl thiol, C1-8 alkenyl, C3-8 alkynyl, C3-8 cycloalkyl, (CH2)xCONHR9, (CH2)xCOR9, (CH2)xCO2R9, or heteroaryl; or R7and R8together make a 3-9 member ring which may contain one or more heteroatoms, wherein the ring is substituted with at least two fluorine atoms; or R7 and R8 together make a 5-8 nitrogen containing member ring with one or more carbonyl groups; R9is aryl, C1-8alkoxy, C1-8alkyl, C1-8alkyl(aryl), C3-8cycloalkyl, H, heteroaryl, or hydroxyl; each x is independently 0-8; and each y is independently 1-8. 105 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) 27. The method of embodiment 26, wherein the apelin receptor agonist is a compound of the structure(BAL-1480) or a pharmaceutically acceptable salt thereof. 28. The method of any one of embodiments 1 to 20, wherein the apelin receptor agonist is a compound of Formula (XV):or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R1is independently selected from the group consisting of: —CH2OH, —OCH3, — OCF3, CH3, CH2CH3, CH(CH3)2, and cyclopropyl; R2is independently selected from the group consisting of: C1-4 alkyl substituted with 0-3 Re, C2-4 alkenyl, C1-6 cycloalkyl, and CH2O(CH2)1-3CH3; R3is independently selected from the group consisting of: (1) —CH2C(═O)OC1-4 alkyl substituted with 0-3 Re, (2) —CH2NRaRa, (3) —CH2C(═O)NRaRa, 106 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) (4) —CH2NHC(═O)C1-4alkyl substituted with 0-3 Re, (5) —CH2NRaC(═O)(CH2)0-2OC1-4alkyl substituted with 0-3 Re, (6) —CH2—R5, (7) —CH2—OR5, (8) —CH2NRaC(═O)(CH2)0-2R5, and (9) —CH2C(═O)NRa(CH2)0-2R5; R5is independently selected from the group consisting of: aryl, C3-6cycloalkyl, and heterocycle, each substituted with 0-3 R6; R6is independently selected from the group consisting of: H, F, Cl, Br, —ORb, ═O, —(CH2)nC(═O)Rb, —(CH2)nC(═O)ORb, —(CH2)NRaRa, CN, —(CH2)nC(═O)NRaRa, —S(O)2NH2, C1-4 alkyl substituted with 0-3 Re, (CH2)n—C3-6 carbocyclyl substituted with 0-3 Re, and —(CH2)n-heterocyclyl substituted with 0-3 Re; Rais independently selected from the group consisting of: H, C1-6alkyl substituted with 0-5 Re, —(CH2)n—C3-10carbocyclyl substituted with 0-5 Re, and —(CH2)n- heterocyclyl substituted with 0-5 Re; or Raand Ratogether with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re; Rbis independently selected from the group consisting of: H, C1-6alkyl substituted with 0-5 Re, C2-6 alkenyl substituted with 0-5 Re, C2-6 alkynyl substituted with 0-5 Re, —(CH2)n—C3-10carbocyclyl substituted with 0-5 Re, and —(CH2)n-heterocyclyl substituted with 0-5 Re; Reis independently selected from the group consisting of: C1-6 alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, —(CH2)n—C3-6cycloalkyl, —(CH2)n— C4-6heterocyclyl, —(CH2)n-aryl, —(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, ═O, and CO2H; and n is independently selected from zero, 1, 2, and 3. 107 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) 29. The method of embodiment 28, wherein the apelin receptor agonist is a compound having one of the following structures:or a pharmaceutically acceptable salt thereof. 30. The method of any one of embodiments 1 to 29, wherein the method further comprises co-administering an additional therapeutic agent. 31. The method of embodiment 30, wherein the additional therapeutic agent is selected from insulin glargine, insulin degludec, cagrilintide, naltrexone-bupropion, phentermine- topiramate, benzphetamine, diethylpropion, phendimetrazine, phentermine, orlistat, and setmelanotide. 32. The method of any one of embodiments 1 to 31, wherein the GLP-1 receptor agonist is administered orally, intravenously, subcutaneously, intranasally, or intramuscularly. 33. The method of embodiment 32, wherein the GLP-1 receptor agonist is administered orally. 34. The method of embodiment 32 or 33, wherein the effective dose of the GLP-1 receptor agonist is administered daily. 35. The method of any one of embodiments 1 to 34, wherein the apelin receptor agonist is administered orally, intravenously, subcutaneously, intranasally, or intramuscularly. 36. The method of embodiment 35, wherein the apelin receptor agonist is administered orally. 37. The method of embodiment 35 or 36, wherein the effective dose of the apelin receptor agonist is administered daily. 108 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) 38. The method of embodiment one of embodiments 1 to 33, further comprising, assessing lean muscle mass after the dosing. 39. A method for inducing weight loss that is adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in subjects with an initial body mass index (BMI), the method comprising co-administering to a subject in need thereof: an effective dose of an apelin receptor agonist; and an effective dose of a drug that reduces caloric intake. wherein the subject (e.g., adult) is overweight or obese. 40. The method of embodiment 39, wherein the subject has a metabolic disorder. 41. The method of embodiment 40, wherein the subject has diabetic obesity. 42. The method of embodiment 40 or 41, wherein the subject has type 1 diabetes, type 2 diabetes, or gestational diabetes. 43. The method of any one of embodiments 39 to 42, wherein the subject has one or more of hypertension, dyslipidemia, obstructive sleep apnea, and cardiovascular disease. 44. The method of any one of embodiments 39 to 42, wherein the drug that reduces caloric intake is an appetite suppressor. 45. The method of any one of embodiments 39 to 44, wherein the drug that reduces caloric intake is selected from naltrexone-bupropion, phentermine-topiramate, benzphetamine, diethylpropion, phendimetrazine, phentermine, orlistat, setmelanotide, and pharmaceutically acceptable salts thereof. 46. The method of any one of embodiments 39 to 44, wherein the drug that reduces caloric intake is a GLP-1 receptor agonist. 47. The method of embodiment 46, wherein the GLP-1 receptor agonist is selected from albiglutide, exenatide, liraglutide, lixisenatide, semaglutide, and tirzepatide. 48. The method of embodiment 46, wherein the GLP-1 receptor agonist is selected from albenatide, albiglutide, avexitide, cafraglutide, cotadutide, danuglipron, dapiglutide, diabegone, dulaglutide, ecnoglutide, efpeglenatide, efinopegdutide, efocipegtrutide, exenatide, exenatide biobetter, exenatide SR, froniglutide, liraglutide, liraglutide biobetter, lixisenatide, CT-868, efocipegtrutide, LY-3502970 (Orforglipron), maridebart, mazdutide, NLY-001, orforglipron, pegapamodutide, pemvidutide, retatrutide (LY-3437943), semaglutide, semaglutide injection, survodutide, vurolenatide, dapagliflozin + semaglutide, (cagrilintide + semaglutide), (LAI-287 + semaglutide), (semaglutide + GIP analogue), 4P- 004, AMG-133, AP-026, AZD-9550, BGM-0504, BMS-686117, Zn / BMS-686117 adduct, 109 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) CT-388, CT-868, CT-996, DD-01, DR-10624, DR-10627, ECC-5004, E-2HSA, GL-0034, GLP-06, GMA-105, GMA-106, GMA-102, GSBR-1290, GXG-6, GZR-18, HEC-88473, HR- 17031, HRS-7535, HRS-9531, HS-20004, HS-20094, HB-1085, HDM-1002, HL-08, HZ- 010, JY-09, KN-056, LY-3493269, MBX-1416, MDR-001, MWN-101, NLY-001, NN-9490, NNC0519-0130, NN-6177, NN-9847, NN-9904, NN-6535 (semaglutide), NN-9932 (semaglutide), PF-06954522, PF-07081532, PF-06882961, PB-1023, PB-119, PB-718, RGT- 075, SAL-015, SAL-0112, SCO-094, TERN-601, TTP-273, Uni-E4, VK-2735, YH-25724, XW-004, XW-014, YH-25724, YN-012(Supaglutide), YN-015, ZT-002, and pharmaceutically acceptable salts thereof. 49. The method of embodiment 46, wherein the GLP-1 receptor agonist is selected from (dorzagliatin + GLP-1), (exenatide + insulin aspart), ACT-1003, Adogel Sema, AER-601, AGM-212, BEBT-808, BZ-043B, C-2816, DAJC-1, DD-02, DR-10625, DR-10628, DS-004, DS-005, DS-006, DS-012, E-6, efpeglenatide + HM-12470, exenatide 2, exenatide LA, exenatide SR, Extendin-Fc, G-49, GB-7001, Gene Encoding GLP-1, GLP-1 Incretin Triagonist, GLP-1 Oral Preparation, GLP-1R Antagonist for Hypoglycemia, glucagon, Glucagon-Like Peptide-1 + insulin human, GPCR-targeted Project 012, GPCR-targeted Project 013, GT-01123, HM-15275, HPG-5119, HSP-001, HSP-004, HSP-005, HSP012-C, Hydrogel Exenatide, I2O-105S, I2O-110, KP-405, LA-EX, liraglutide biobetter, liraglutide LA, MK-1462, MLX-7000, MWN-105, MWN-109, NLY-12, NPM-115, OGB-21502, OXM, P-11, PB-2301, PB-2309, RGT-028, RGT-274, RPC-8844, RT-104, SHX-022, SL-209, synthetic peptides to agonize GLP-1R and CCKBR for diabetes, TB-013, TB-222023, TB- 592, TE-8105, THDBH-111, UDS-003, VTCG-15, XL-110, XL-310, XW-003 + XW-015, XW-003 + XW-017, Y-002, YGX-1, ZT-003, ZT-006, ZT-007, DA-1726, HDM-1005, (insulin degludec + liraglutide), DB-081, GW-002, HZCX-012, ID-110521156, THDB-0211, THDBH-110, THDBH-120, THDBH-121, UBT-251, ATBB-22, BEM-012, CIN-209, CIN- 210, DD-03, exenatide + ND-017, exenatide + Synthetic Peptide 2, glucagon, Insulin-GLP1, MD-02, OGB-21501, P-01, PAT-201, PF-1807, PT-3, and pharmaceutically acceptable salts thereof. 50. The method of any one of embodiments 39 to 49, wherein the apelin receptor agonist is selected from BAL-1480, BMS-986224, ANPA-0073, apelin-13, [Pyr1]apelin-13, E339- 3D6, (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)- 3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide, (S)-N-(1-(cyclobutylamino)-1-oxo-5- (piperidin-1-yl)pentan-3-yl)-5-(2,6-dimethoxyphenyl)-1-cyclopentyl-1H-pyrazole-3- carboxamide, and pharmaceutically acceptable salts thereof. 110 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) 51. The method of any one of embodiments 39 to 49, wherein the apelin receptor agonist is a compound of the structureor a pharmaceutically acceptable salt thereof. 52. The method of any one of embodiments 39 to 49, wherein the apelin receptor agonist is a compound of the structure(BAL-1480) or a pharmaceutically acceptable salt thereof. 53. The method of any one of embodiments 39 to 49, wherein the apelin receptor agonist is a compound having one of the following structures:111 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)or a pharmaceutically acceptable salt thereof.

[0480] The followed series of numbered embodiments are also included within the present disclosure. 1. A method of treating a disease or condition associated with weight gain in a subject, the method comprising: co-administering to a subject in need thereof: an effective dose of an apelin receptor agonist; and an effective dose of a glucagon-like peptide 1 receptor agonist (GLP-1RA) or analog thereof. 2. The method of embodiment 1, wherein the apelin receptor agonist is of formula (I) or (II):or a pharmaceutically acceptable salt thereof, a tautomer thereof, a pharmaceutically acceptable salt of the tautomer, a stereoisomer of any of the foregoing, or a mixture thereof, wherein: R1is an unsubstituted pyridyl, pyridonyl, or pyridine N-oxide, or is a pyridyl, pyridonyl, or pyridine N-oxide substituted with 1, 2, 3, or 4 R1asubstituents; R1ain each instance is independently selected from —F, —Cl, —Br, —I, —CN, — C1-C6alkyl, —C1-C6haloalkyl, —C1-C6perhaloalkyl, —OH, —O—(C1-C6alkyl), —O—(C1- C6 haloalkyl), —O—(C1-C6 perhaloalkyl), —C2-C6 alkenyl, —O—(C1-C6 alkyl)-OH, —O— (C1-C6 alkyl)-O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl)-OH, —O—(C1-C6 haloalkyl)-O— 112 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) (C1-C6 alkyl), —O—(C1-C6 perhaloalkyl)-OH, —O—(C1-C6 perhaloalkyl)-O—(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —C(═O)—(C1-C6 alkyl), —C(═O)OH, — (C═O)—O—(C1-C6alkyl), —C(═O)NH2, —C(═O)NH(C1-C6alkyl), —C(═O)N(C1- C6 alkyl)2, phenyl, —C(═O)-(heterocyclyl), or a heterocyclyl group, wherein the heterocyclyl group of the —C(═O)-(heterocyclyl) or heterocyclyl group is a 3 to 7 membered ring containing 1, 2, or 3 heteroatoms selected from N, O, and S; R2is selected from —H, and C1-C4alkyl or is absent in the compounds of Formula II; R3is selected from an unsubstituted C1-C10 alkyl, a C1-C10 alkyl substituted with 1, 2, or 3 R1asubstituents, a group of formula —(CR3bR3c)-Q, a group of formula —NH— (CR3bR3c)-Q, a group of formula —(CR3bR3c)—C(═O)-Q, a group of formula —(CR3dR3e)— (CR3fR3g)-Q, a group of formula —(CR3b═CR3c)-Q, and a group of formula -(heterocyclyl)- Q, wherein the heterocyclyl of the -(heterocyclyl)-Q has 5 to 7 ring members of which 1, 2, or 3 are heteroatoms selected from N, O, and S and is unsubstituted or is substituted with 1, 2, or 3 R3hsubstituents; R1ain each instance is independently selected from —F, —Cl, —CN, —OH, —O— (C1-C6alkyl), —O—(C1-C6haloalkyl), —O—(C1-C6perhaloalkyl), —O—(C1-C6alkyl)-OH, —O—(C1-C6alkyl)-O—(C1-C6alkyl), C2-C6alkenyl, C2-C6alkynyl, —NH2, —NH(C1- C6 alkyl), and —N(C1-C6 alkyl)2; R3band R3care independently selected from —H, —F, —Cl, —CN, —C1-C6alkyl, — C1-C6haloalkyl, —C1-C6perhaloalkyl, —OH, —O—(C1-C6alkyl), —O—(C1-C6haloalkyl), —O—(C1-C6 perhaloalkyl), —O—(C1-C6 alkyl)-OH, —O—(C1-C6 alkyl)-O—(C1-C6 alkyl), —NH2, —NH(C1-C6alkyl), and —N(C1-C6alkyl)2; R3dand R3eare independently selected from —H, —F, —Cl, —CN, —C1-C6alkyl, — C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —OH, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —O—(C1-C6 perhaloalkyl), —O—(C1-C6 alkyl)-OH, —O—(C1-C6 alkyl)-O—(C1-C6 alkyl), —NH2, —NH(C1-C6alkyl), and —N(C1-C6alkyl)2; R3fand R3gare independently selected from —H, —F, —Cl, —CN, —C1-C6 alkyl, — C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —OH, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —O—(C1-C6perhaloalkyl), —O—(C1-C6alkyl)-OH, —O—(C1-C6alkyl)-O—(C1-C6alkyl), —NH2, —NH(C1-C6alkyl), and —N(C1-C6alkyl)2; R3hin each instance is independently selected from —F, —Cl, —CN, —C1-C6 alkyl, —C1-C6haloalkyl, —C1-C6perhaloalkyl, —OH, —O—(C1-C6alkyl), —O—(C1- C6haloalkyl), —O—(C1-C6perhaloalkyl), —O—(C1-C6alkyl)-OH, —O—(C1-C6alkyl)-O— (C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, and oxo; 113 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) Q is a monocyclic or bicyclic C6-C10 aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms selected from N, O, or S, a C3-C8cycloalkyl group, or a 3 to 7 membered heterocyclyl group containing 1, 2, or 3 heteroatoms selected from N, O, or S, wherein the C6-C10 aryl group, the heteroaryl group, the cycloalkyl group, and the heterocyclyl group are unsubstituted or are substituted with 1, 2, 3, or 4 RQsubstituent; RQin each instance is independently selected from —F, —Cl, —Br, —I, —CN, —C1- C6 alkyl, —C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —OH, —O—(C1-C6alkyl), —O—(C1-C6haloalkyl), —O—(C1-C6perhaloalkyl), —NH2, —NH(C1- C6alkyl), —N(C1-C6alkyl)2, —C(═O)—(C1-C6alkyl), —C(═O)OH, —C(═O)—O—(C1- C6 alkyl), —C(═O)NH2, —C(═O)NH(C1-C6 alkyl), —C(═O)N(C1-C6 alkyl)2, —S(═O)2— (C1-C6 alkyl), phenyl, and a heteroaryl group, and the Q heterocyclyl group may be substituted with 1 oxo RQsubstituent; R4is selected from a monocyclic or bicyclic C6-C10 aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and a monocyclic or bicyclic heterocyclyl group with 5 to 10 ring members containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, wherein the C6-C10 aryl group, the heteroaryl group, or the heterocyclyl group are unsubstituted or are substituted with 1, 2, or 3 R4asubstituents; R4ain each instance is independently selected from —F, —Cl, —Br, —I, —CN, — C1-C6 alkyl, —C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —OH, —O—(C1-C6 alkyl), —O—(C1- C6haloalkyl), —O—(C1-C6perhaloalkyl), —NH2, —NH(C1-C6alkyl), —N(C1-C6alkyl)2, — C(═O)—(C1-C6alkyl), —C(═O)OH, —C(═O)—O—(C1-C6alkyl), —C(═O)NH2, — C(═O)NH(C1-C6 alkyl), and —C(═O)N(C1-C6 alkyl)2, and the heterocyclyl R4group may be further substituted with 1 oxo substituent; and further wherein: if R4is an unsubstituted or substituted phenyl ring and R3is a group of formula — (CR3b═CR3c)-Q, then at least one of the following is true: a) R4is substituted with at least one —O—(C1-C6alkyl) group; b) Q is not an oxadiazole; c) R3bis not —H; d) R3cis not —H; e) R1is not a 2-pyridyl group; or f) R4is substituted with two or more —O—(C1-C6 alkyl) groups. 114 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) 3. The method of any one of embodiments 1 to 2, wherein the condition or disorder is obesity, obesity-linked gallbladder disease, obesity-induced sleep apnea, diabetes, excessive appetite, fatty liver disease, non-alcoholic fatty liver disease (NASH), dyslipidemia, metabolic syndrome, insufficient satiety, hyperinsulinemia, or hypoglycemia. 4. The method of embodiment 3, wherein the diabetes is type 1 diabetes, type 2 diabetes, or gestational diabetes. 5. The method of embodiment 4, wherein the subject exhibits lower fed glucose levels after treatment (e.g., within 20 days or less, such as 12 days or less, or 6 days or less of treatment). 6. The method of any one of embodiments 1 to 4, wherein the subject is human and at least 40-years-old. 7. The method of embodiment 6, wherein the subject is at least 50-years-old. 8. The method of embodiment 7, wherein the subject is at least 60-years-old. 9. The method of embodiment 8, wherein the subject is at least 65-years-old. 10. The method of embodiment 9, wherein the subject is at least 70-years-old or at least 75-years-old. 11. The method of embodiment 10, wherein the subject is at least 80-years-old. 12. The method of any one of embodiments 1 to 11, wherein the human subject has, or is at risk of having, low muscle strength or low muscle force. 13. The method of any one of embodiments 1 to 12, wherein the human subject has, or is at risk of having a muscle condition selected from: sarcopenia, frailty, muscle weakness, reduction in risk of hip fracture, ICU associated muscle weakness, muscle atrophy, diaphragm disfunction, diaphragm atrophy, immobilization associated muscle weakness, immobility associated muscle weakness, recovery from muscle injury, and muscle wasting. 14. The method of any one of embodiments 1 to 13, wherein the human subject has, or is or is at risk of having, low lower limb muscle mass. 15. The method of any one of embodiments 1 to 14, wherein the human subject has, or is at risk of having, low upper limb muscle mass. 16. The method of any one of embodiments 1 to 15, wherein the human subject has, or is at risk of having, low muscle volume. 115 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) 17. The method of embodiment 16, wherein the muscle volume is skeletal muscle volume. 18. The method of embodiment 16, wherein the muscle is tibialis anterior, tibialis posterior, gastrocnemius, sartorius, vastus intermedius, vastus lateralis, vastus medialis, soleus, or extensor digitorum longus. 19. The method of any one of embodiments 1 to 18, wherein the apelin receptor agonist is administered orally, intravenously, subcutaneously, intranasally, or intramuscularly. 20. The method of any one of embodiments 1 to 19, wherein the effective dose of the apelin receptor agonist is administered daily. 21. The method of any one of embodiments 1 to 20, wherein the of the apelin receptor agonist is administered as a plurality of equally or unequally divided sub-doses. 22. The method of any one of embodiments 1 to 21, wherein the effective dose of the apelin receptor agonist is administered at varying dosing intervals. 23. The method of any one of embodiments 1 to 22, wherein the effective dose of the apelin receptor agonist is 200 mg. 24. The method of any one of embodiments 1 to 23, wherein the GLP-1RA or analog thereof is selected from: dulaglutide, exenatide, semaglutide, liraglutide, lixisenatide, tirzepatide, albenatide [INN], cotadutide, CT-868, PF 06882961, efocipegtrutide, LY- 3502970 (Orforglipron), NLY-001, pegapamodutide, pemvidutide, PF-07081532, retatrutide, RGT-075, TTP-273, vurolenatide, GZR-18, mazdutide, PB-119, AMG-133, dapiglutide, DD- 01, DR-10627, ECC-5004, exenatide biobetter, GL-0034, GMA-105, HEC-88473, LY- 3493269, NN-6177, NN-9847, NNC0519-0130, PB-1023, SCO-094, VK-2735, YH-25724, YN-012, and YN-015. 25. The method of any one of embodiments 1 to 24 wherein the GLP-1RA or analog thereof is administered orally, intravenously, intranasally, or intramuscularly. 26. The method of any one of embodiments 1 to 25, wherein the effective dose of the GLP-1RA or analog thereof is administered daily. 27. The method of any one of embodiments 1 to 26, wherein the of the GLP-1RA or analog thereof is administered as a plurality of equally or unequally divided sub-doses. 116 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) 28. The method of any one of embodiments 1 to 27, wherein the of the GLP-1RA or analog thereof is administered at varying dosing intervals. 29. The method of embodiment one of embodiments 1 to 28, further comprising, assessing muscle mass after the dosing. 30. The method of embodiment 29, wherein the muscle mass is assessed at least one day after dosing. 31. The method of embodiment 30, wherein the muscle mass is assessed at least one week after dosing. 32. The method of embodiment 30, wherein the muscle mass is assessed at least one month after dosing. 33. The method of any of embodiments 1-32, wherein the subject has a low circulating levels of apelin. 34. The method of any one of embodiments 1-33, wherein the subject has had surgery. 35. The method of any one of embodiments 1-34, wherein the subject has had weight loss surgery. 36. The method of any one of embodiments 1-35, further comprising co-administering an effective dose of an additional therapeutic agent. 37. The method of embodiment 36, wherein the additional therapeutic agent is an incretin receptor agonist. 38. The method of embodiment 36, wherein the additional therapeutic agent is selected from: cagrilintide [INN], insulin glargine, and insulin degludec. 39. A method of inducing weight loss in a subject in need thereof, the method comprising: co-administering to a subject in need thereof: an effective dose of an apelin receptor agonist; and an effective dose of a glucagon-like peptide 1 (GLP-1) receptor agonist or analog thereof. 117 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) 40. The method of embodiment 39, wherein the apelin receptor agonist is of formula (I) or (II):(I) (II) or a pharmaceutically acceptable salt thereof, a tautomer thereof, a pharmaceutically acceptable salt of the tautomer, a stereoisomer of any of the foregoing, or a mixture thereof, wherein: R1is an unsubstituted pyridyl, pyridonyl, or pyridine N-oxide, or is a pyridyl, pyridonyl, or pyridine N-oxide substituted with 1, 2, 3, or 4 R1asubstituents; R1ain each instance is independently selected from —F, —Cl, —Br, —I, —CN, — C1-C6alkyl, —C1-C6haloalkyl, —C1-C6perhaloalkyl, —OH, —O—(C1-C6alkyl), —O—(C1- C6 haloalkyl), —O—(C1-C6 perhaloalkyl), —C2-C6 alkenyl, —O—(C1-C6 alkyl)-OH, —O— (C1-C6alkyl)-O—(C1-C6alkyl), —O—(C1-C6haloalkyl)-OH, —O—(C1-C6haloalkyl)-O— (C1-C6alkyl), —O—(C1-C6perhaloalkyl)-OH, —O—(C1-C6perhaloalkyl)-O—(C1-C6alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —C(═O)—(C1-C6 alkyl), —C(═O)OH, — (C═O)—O—(C1-C6 alkyl), —C(═O)NH2, —C(═O)NH(C1-C6 alkyl), —C(═O)N(C1- C6alkyl)2, phenyl, —C(═O)-(heterocyclyl), or a heterocyclyl group, wherein the heterocyclyl group of the —C(═O)-(heterocyclyl) or heterocyclyl group is a 3 to 7 membered ring containing 1, 2, or 3 heteroatoms selected from N, O, and S; R2is selected from —H, and C1-C4alkyl or is absent in the compounds of Formula II; R3is selected from an unsubstituted C1-C10 alkyl, a C1-C10 alkyl substituted with 1, 2, or 3 R3asubstituents, a group of formula —(CR3bR3c)-Q, a group of formula —NH— (CR3bR3c)-Q, a group of formula —(CR3bR3c)—C(═O)-Q, a group of formula —(CR3dR3e)— (CR3fR3g)-Q, a group of formula —(CR3b═CR3c)-Q, and a group of formula -(heterocyclyl)- Q, wherein the heterocyclyl of the -(heterocyclyl)-Q has 5 to 7 ring members of which 1, 2, or 3 are heteroatoms selected from N, O, and S and is unsubstituted or is substituted with 1, 2, or 3 R3hsubstituents; R3ain each instance is independently selected from —F, —Cl, —CN, —OH, —O— (C1-C6 alkyl), —O—(C1-C6 haloalkyl), —O—(C1-C6 perhaloalkyl), —O—(C1-C6 alkyl)-OH, 118 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) —O—(C1-C6 alkyl)-O—(C1-C6 alkyl), C2-C6 alkenyl, C2-C6 alkynyl, —NH2, —NH(C1- C6 alkyl), and —N(C1-C6 alkyl)2; R3band R3care independently selected from —H, —F, —Cl, —CN, —C1-C6alkyl, — C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —OH, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —O—(C1-C6 perhaloalkyl), —O—(C1-C6 alkyl)-OH, —O—(C1-C6 alkyl)-O—(C1-C6 alkyl), —NH2, —NH(C1-C6alkyl), and —N(C1-C6alkyl)2; R3dand R3eare independently selected from —H, —F, —Cl, —CN, —C1-C6alkyl, — C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —OH, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —O—(C1-C6perhaloalkyl), —O—(C1-C6alkyl)-OH, —O—(C1-C6alkyl)-O—(C1-C6alkyl), —NH2, —NH(C1-C6alkyl), and —N(C1-C6alkyl)2; R3fand R3gare independently selected from —H, —F, —Cl, —CN, —C1-C6 alkyl, — C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —OH, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —O—(C1-C6perhaloalkyl), —O—(C1-C6alkyl)-OH, —O—(C1-C6alkyl)-O—(C1-C6alkyl), —NH2, —NH(C1-C6 alkyl), and —N(C1-C6 alkyl)2; R3hin each instance is independently selected from —F, —Cl, —CN, —C1-C6 alkyl, —C1-C6haloalkyl, —C1-C6perhaloalkyl, —OH, —O—(C1-C6alkyl), —O—(C1- C6haloalkyl), —O—(C1-C6perhaloalkyl), —O—(C1-C6alkyl)-OH, —O—(C1-C6alkyl)-O— (C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, and oxo; Q is a monocyclic or bicyclic C6-C10aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms selected from N, O, or S, a C3-C8 cycloalkyl group, or a 3 to 7 membered heterocyclyl group containing 1, 2, or 3 heteroatoms selected from N, O, or S, wherein the C6-C10aryl group, the heteroaryl group, the cycloalkyl group, and the heterocyclyl group are unsubstituted or are substituted with 1, 2, 3, or 4 RQsubstituent; RQin each instance is independently selected from —F, —Cl, —Br, —I, —CN, —C1- C6alkyl, —C1-C6haloalkyl, —C1-C6perhaloalkyl, —C2-C6alkenyl, —C2-C6alkynyl, —OH, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —O—(C1-C6 perhaloalkyl), —NH2, —NH(C1- C6 alkyl), —N(C1-C6 alkyl)2, —C(═O)—(C1-C6 alkyl), —C(═O)OH, —C(═O)—O—(C1- C6alkyl), —C(═O)NH2, —C(═O)NH(C1-C6alkyl), —C(═O)N(C1-C6alkyl)2, —S(═O)2— (C1-C6alkyl), phenyl, and a heteroaryl group, and the Q heterocyclyl group may be substituted with 1 oxo substituent; R4is selected from a monocyclic or bicyclic C6-C10aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and a monocyclic or bicyclic heterocyclyl group 119 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) with 5 to 10 ring members containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, wherein the C6-C10 aryl group, the heteroaryl group, or the heterocyclyl group are unsubstituted or are substituted with 1, 2, or 3 R4asubstituents; R4ain each instance is independently selected from —F, —Cl, —Br, —I, —CN, — C1-C6 alkyl, —C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —OH, —O—(C1-C6 alkyl), —O—(C1- C6haloalkyl), —O—(C1-C6perhaloalkyl), —NH2, —NH(C1-C6alkyl), —N(C1-C6alkyl)2, — C(═O)—(C1-C6alkyl), —C(═O)OH, —C(═O)—O—(C1-C6alkyl), —C(═O)NH2, — C(═O)NH(C1-C6 alkyl), and —C(═O)N(C1-C6 alkyl)2, and the heterocyclyl R4group may be further substituted with 1 oxo substituent; and further wherein: if R4is an unsubstituted or substituted phenyl ring and R3is a group of formula — (CR3b═CR3c)-Q, then at least one of the following is true: a) R4is substituted with at least one —O—(C1-C6alkyl) group; b) Q is not an oxadiazole; c) R3bis not —H; d) R3cis not —H; e) R1is not a 2-pyridyl group; or f) R4is substituted with two or more —O—(C1-C6 alkyl) groups. 41. The method of any one of embodiments 39-40, wherein the subject is at least 60- years-old. 42. The method of embodiment 41, wherein the subject is at least 65-years-old. 43. The method of embodiment 42, wherein the subject is at least 70-years-old. 44. The method of embodiment 43, wherein the subject is at least 75-years-old. 45. The method of embodiment 44, wherein the subject is at least 80-years-old. 46. The method of any one of embodiments 39 to 45, wherein the human subject has, or is identified as having, low muscle strength. 47. The method of any one of embodiments 39 to 46, wherein the human subject has, or is identified as having, low muscle force. 48. The method of any one of embodiments 39 to 47, wherein the human subject has, or is identified as having, low lower limb muscle mass. 120 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) 49. The method of any one of embodiments 39 to 48, wherein the human subject has, or is identified as having, low upper limb muscle mass. 50. The method of any one of embodiments 39 to 49, wherein the human subject has, or is identified as having, low muscle volume. 51. The method of embodiment 50, wherein the muscle volume is skeletal muscle volume. 52. The method of embodiment 51, wherein the muscle is the tibialis anterior, tibialis posterior, gastrocnemius, sartorius, vastus intermedius, vastus laterals, vastus medialis, soleus, or extensor digitorum longus. 53. The method of any one of embodiments 51 to 52, wherein the muscle is a skeletal muscle. 54. The method of any of embodiments 39 to 53, wherein the human subject has a low circulating apelin level. 55. The method of any one of embodiments 39 to 54, wherein the apelin receptor agonist is administered orally, intravenously, intranasally, or intramuscularly. 56. The method of any one of embodiments 39 to 55, wherein the dose is administered daily. 57. The method of any one of embodiments 39 to 56, wherein the dose is administered as a plurality of equally or unequally divided sub-doses. 58. The method of any one of embodiments 39 to 57, wherein the dose is administrated intravenously. 59. The method of any one of embodiments 39 to 58, wherein the GLP-1RA or analog thereof is selected from: dulaglutide, exenatide, semaglutide, liraglutide, liraglutide, lixisenatide, tirzepatide, semaglutide, albenatide [INN], cotadutide, CT-868, PF 06882961, efocipegtrutide, LY-3502970 (Orforglipron), NLY-001, pegapamodutide, pemvidutide, PF- 07081532, retatrutide, RGT-075, TTP-273, vurolenatide, GZR-18, mazdutide, PB-119, AMG-133, dapiglutide, DD-01, DR-10627, ECC-5004, exenatide biobetter, GL-0034, GMA- 105, HEC-88473, LY-3493269, NN-6177, NN-9847, NNC0519-0130, PB-1023, SCO-094, VK-2735, YH-25724, YN-012(Supaglutide), and YN-015, preferably wherein the GLP-1RA or analog thereof is semaglutide, liraglutide, or tirzepatide. 121 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) 60. The method of any one of embodiments 39 to 59, wherein the GLP-1RA is administered orally, subcutaneously, intravenously, intranasally, or intramuscularly. 61. The method of any one of embodiments 39 to 60, wherein the dose is administered daily. 62. The method of any one of embodiments 39 to 61, wherein the dose is administered as a plurality of equally or unequally divided sub-doses. 63. The method of any one of embodiments 39 to 62, wherein the dose is administered at varying dosing intervals. 64. The method of any one of embodiments 39 to 63, wherein R1is an unsubstituted pyridyl or is a pyridyl substituted with 1 or 2 R1asubstituents. 65. The method of any one of embodiments 39 to 64, wherein R1ain each instance is independently selected from —CH3, —CH2CH3, —F, —Cl, —Br, —CN, —CF3, — CH═CH2, —C(═O)NH2, —C(═O)NH(CH3), —C(═O)N(CH3)2, —C(═O)NH(CH2CH3), — OH, —OCH3, —OCHF2, —OCH2CH3, —OCH2CF3, —OCH2CH2OH, —OCH2C(CH3)2OH, —OCH2C(CF3)2OH, —OCH2CH2OCH3, —NH2, —NHCH3, —N(CH3)2, phenyl, and a group of formulawherein the symbol when drawn across a bond, indicates the point of attachment to the rest of the molecule. 66. The method of any one of embodiments 38 to 62, wherein R1is selected from122 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)wherein the symbolwhen drawn across a bond, indicates the point of attachment to the rest of the molecule. 67. The method of any one of embodiments 39 to 66, wherein R2is —H. 68. The method of any one of embodiments 39 to 67, wherein R4is a phenyl, pyridyl, pyrimidinyl, isoxazolyl, indolyl, naphthyl, or pyridinyl any of which may be unsubstituted or substituted with 1, 2, or 3 R4asubstituents. 69. The method of embodiment 68, wherein R4is a phenyl substituted with 1 or 2 R4asubstituents. 70. The method of embodiment 69, wherein the 1 or 2 R4asubstituents are —O—(C1-C2 alkyl) groups. 71. The method of any one of embodiments 39 to 70, wherein R4ais in each instance independently selected from —CH3, —F, —Cl, —Br, —CN, —CF3, —OCH3, —OCHF2, — OCH2CH3, —C(═O)OCH3, —C(═O)CH3, or —N(CH3)2. 72. The method of any one of embodiments 39 to 71, wherein R3is selected from a group of formula —(CR3bR3c)-Q, a group of formula —NH—(CR3bR3c)-Q, a group of formula — (CR3bR3c)—C(═O)-Q, a group of formula —(CR3dR3e)—(CR3fR3g)-Q, a group of formula — (CR3b═CR3c)-Q, or a group of formula -(heterocyclyl)-Q, wherein the heterocyclyl of the - (heterocyclyl)-Q has 5 to 7 ring members of which 1, 2, or 3 are heteroatoms selected from N, O, or S and is unsubstituted or is substituted with 1, 2, or 3 R3hsubstituents. 73. The method of any one of embodiments 39 to 72, wherein Q is selected from pyrimidinyl, pyridyl, isoxazolyl, thiazolyl, imidazolyl, phenyl, tetrahydropyrimidinonyl, cyclopropyl, cyclobutyl, cyclohexyl, morpholinyl, pyrrolidinyl, pyrazinyl, imidazo[1,2- a]pyridinyl, pyrazolyl, or oxetanyl any of which may be unsubstituted or substituted with 1, 2, or 3, RQsubstituents. 123 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) 74. The method of any one of embodiments 39 to 70, wherein Q is a monocyclic heteroaryl group with 5 or 6 ring members containing 1 or 2 heteroatoms selected from N, O, or S and Q is unsubstituted or is substituted with 1 or 2 RQsubstituents. 75. The method of any one of embodiments 39 to 74, wherein R3is a group of formula — (CR3dR3e)—(CR3fR3g)-Q. 76. The method of any one of embodiments 39 to 75, wherein R3has the formulawherein the symbolwhen drawn across a bond, indicates the point of attachment to the rest of the molecule. 124 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) 77. The method of any one of embodiments 1 to 76, wherein the apelin receptor agonist is (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5- methyl-2-pyrimidinyl)-2-butanesulfonamide, or a pharmaceutically acceptable salt thereof, a tautomer thereof, a pharmaceutically acceptable salt of the tautomer, a stereoisomer of any of the foregoing, or a mixture thereof. 78. The method of embodiment 77, wherein the apelin receptor agonist is (2S,3R)—N-(4- (2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2- pyrimidinyl)-2-butanesulfonamide or a pharmaceutically acceptable salt thereof. 79. The method of any one of embodiments 39 to 78, wherein the method further comprises co-administering an additional therapeutic agent. 80. The method of embodiment 79, wherein the additional therapeutic agent is an incretin receptor agonist. 81. The method of embodiment 79, wherein the additional therapeutic agent is selected from: insulin glargine, insulin degludec, and cagrilintide [INN]. 82. The method of any one of embodiments 1 to 81, wherein the apelin receptor agonist is BGE-105 or a pharmaceutically acceptable salt thereof, and the glucagon-like peptide 1 receptor agonist (GLP-1RA) or analog thereof is semaglutide or a pharmaceutically acceptable salt thereof. 83. The method of any one of embodiments 1 to 81, wherein the apelin receptor agonist is BGE-105 or a pharmaceutically acceptable salt thereof, and the glucagon-like peptide 1 receptor agonist (GLP-1RA) or analog thereof is liraglutide or a pharmaceutically acceptable salt thereof. 84. The method of any one of embodiments 1 to 81, wherein the apelin receptor agonist is BGE-105 or a pharmaceutically acceptable salt thereof, and the glucagon-like peptide 1 receptor agonist (GLP-1RA) or analog thereof is tirzepatide or a pharmaceutically acceptable salt thereof. 4.14. Definitions

[0481] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this invention belongs.

[0482] The terms “individual,” “host,” and “subject” are used interchangeably, and refer to an animal to be treated, including but not limited to humans and non-human primates; 125 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) rodents, including rats and mice; bovines; equines; ovines; felines; and canines. “Mammal” means a member or members of any mammalian species. Non-human animal models, i.e., mammals, non-human primates, murines, lagomorpha, etc. may be used for experimental investigations. The term “patient” refers to a human subject.

[0483] The term “modulator” refers to a compound or composition that modulates the level of a target, or the activity or function of a target, which may be, but is not limited to, apelin receptor. In some embodiments, the modulator compound can agonize or activate the target, such as apelin receptor. An agonist or activator of a target can increase the level of activity or signaling associated with the target.

[0484] The terms “treating,” “treatment,” and grammatical variations thereof are used in the broadest sense understood in the clinical arts. Accordingly, the terms do not require cure or complete remission of disease, and the terms encompass obtaining any clinically desired pharmacologic and / or physiologic effect, including improvement in physiologic measures associated with “normal”, non-pathologic, aging. Unless otherwise specified, “treating” and “treatment” do not encompass prophylaxis.

[0485] The phrase “therapeutically effective amount” refers to the amount of a compound that, when administered to a mammal or other subject for treating a disease, condition, or disorder, is sufficient to effect treatment of the disease, condition, or disorder. The “therapeutically effective amount” may vary depending on the compound, the disease and its severity and the age, weight, etc., of the subject to be treated.

[0486] Ranges: throughout this disclosure, various aspects of the invention are presented in a range format. Ranges include the recited endpoints. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6, should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc. as well as individual number within that range, for example, 1, 2, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0487] Unless specifically stated or apparent from context, as used herein the term “or” is understood to be inclusive. 126 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)

[0488] Unless specifically stated or apparent from context, as used herein, the terms “a”, “an”, and “the” are understood to be singular or plural. That is, the articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0489] Unless specifically stated or otherwise apparent from context, as used herein the term “about” is understood as within range of normal tolerance in the art, for example within 2 standard deviations of the mean, and is meant to encompass variations of ± 20% or ± 10%, more preferably ± 5%, even more preferably ± 1%, and still more preferably ± 0.1% from the stated value. Where a percentage is provided with respect to an amount of a component or material in a composition, the percentage should be understood to be a percentage based on weight, unless otherwise stated or understood from the context.

[0490] It should be understood that the order of steps or order for performing certain actions is immaterial so long as the present disclosure remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0491] The terms “pharmaceutically acceptable excipient,” “pharmaceutically acceptable diluent,” “pharmaceutically acceptable carrier,” and “pharmaceutically acceptable adjuvant” are used interchangeably and refer to an excipient, diluent, carrier, or adjuvant that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and include an excipient, diluent, carrier, and adjuvant that is acceptable for veterinary use as well as human pharmaceutical use. The phrase “pharmaceutically acceptable excipient” includes both one and more than one such excipient, diluent, carrier, and / or adjuvant.

[0492] “Alkyl” refers to a saturated branched or straight-chain monovalent hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyls such as propan-1-yl and propan-2-yl, butyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2- methyl-propan-2-yl, tert-butyl, and the like. In certain embodiments, an alkyl group comprises 1 to 20 carbon atoms. In some embodiments, alkyl groups include 1 to 10 carbon atoms or 1 to 6 carbon atoms whereas in other embodiments, alkyl groups include 1 to 4 carbon atoms. In still other embodiments, an alkyl group includes 1 or 2 carbon atoms. Branched chain alkyl groups include at least 3 carbon atoms and typically include 3 to 7, or in some embodiments, 3 to 6 carbon atoms. An alkyl group having 1 to 6 carbon atoms may be 127 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) referred to as a (C1-C6)alkyl group and an alkyl group having 1 to 4 carbon atoms may be referred to as a (C1-C4)alkyl. This nomenclature may also be used for alkyl groups with differing numbers of carbon atoms. The term “alkyl may also be used when an alkyl group is a substituent that is further substituted in which case a bond between a second hydrogen atom and a C atom of the alkyl substituent is replaced with a bond to another atom such as, but not limited to, a halogen, or an O, N, or S atom. For example, a group —O—(C1-C6alkyl)-OH will be recognized as a group where an —O atom is bonded to a C1-C6alkyl group and one of the H atoms bonded to a C atom of the C1-C6 alkyl group is replaced with a bond to the O atom of an —OH group. As another example, a group —O—(C1-C6alkyl)-O—(C1-C6alkyl) will be recognized as a group where an —O atom is bonded to a first C1-C6alkyl group and one of the H atoms bonded to a C atom of the first C1-C6 alkyl group is replaced with a bond to a second O atom that is bonded to a second C1-C6 alkyl group.

[0493] “Alkenyl” refers to an unsaturated branched or straight-chain hydrocarbon group having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene. The group may be in either the Z- or E-form (cis or trans) about the double bond(s). Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), and prop-2- en-2-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1- yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, and buta-1,3-dien-2-yl; and the like. In certain embodiments, an alkenyl group has 2 to 20 carbon atoms and in other embodiments, has 2 to 6 carbon atoms. An alkenyl group having 2 to 6 carbon atoms may be referred to as a (C2-C6)alkenyl group.

[0494] “Alkynyl” refers to an unsaturated branched or straight-chain hydrocarbon having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne. Typical alkynyl groups include, but are not limited to, ethynyl; propynyl; butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl and the like. In certain embodiments, an alkynyl group has 2 to 20 carbon atoms and in other embodiments, has 2 to 6 carbon atoms. An alkynyl group having 2 to 6 carbon atoms may be referred to as a —(C2-C6)alkynyl group.

[0495] “Alkoxy” refers to a radical —OR where R represents an alkyl group as defined herein. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy, and the like. Typical alkoxy groups include 1 to 10 carbon atoms, 1 to 6 carbon atoms or 1 to 4 carbon atoms in the R group. Alkoxy groups that include 1 to 6 128 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) carbon atoms may be designated as —O—(C1-C6) alkyl or as —O—(C1-C6 alkyl) groups. In some embodiments, an alkoxy group may include 1 to 4 carbon atoms and may be designated as —O—(C1-C4) alkyl or as —O—(C1-C4alkyl) groups group.

[0496] “Aryl” refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Aryl encompasses monocyclic carbocyclic aromatic rings, for example, benzene. Aryl also encompasses bicyclic carbocyclic aromatic ring systems where each of the rings is aromatic, for example, naphthalene. Aryl groups may thus include fused ring systems where each ring is a carbocyclic aromatic ring. In certain embodiments, an aryl group includes 6 to 10 carbon atoms. Such groups may be referred to as C6-C10aryl groups. Aryl, however, does not encompass or overlap in any way with heteroaryl as separately defined below. Hence, if one or more carbocyclic aromatic rings is fused with an aromatic ring that includes at least one heteroatom, the resulting ring system is a heteroaryl group, not an aryl group, as defined herein.

[0497] “Carbonyl” refers to the radical —C(O) or —C(═O) group.

[0498] “Carboxy” refers to the radical —C(O)OH.

[0499] “Cyano” refers to the radical —CN.

[0500] “Cycloalkyl” refers to a saturated cyclic alkyl group derived by the removal of one hydrogen atom from a single carbon atom of a parent cycloalkane. Typical cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, 129astric129idi, cyclopentane, cyclohexane, cycloheptane, cyclooctane, and the like. Cycloalkyl groups may be described by the number of carbon atoms in the ring. For example a cycloalkyl group having 3 to 7 ring members may be referred to as a (C3-C7)cycloalkyl and a cycloalkyl group having 4 to 7 ring members may be referred to as a (C4-C7)cycloalkyl. In certain embodiments, the cycloalkyl group can be a (C3-C10)cycloalkyl, a (C3-C8)cycloalkyl, a (C3- C7)cycloalkyl, a (C3-C6)cycloalkyl, or a (C4-C7)cycloalkyl group and these may be referred to as C3-C10 cycloalkyl, C3-C8 cycloalkyl, C3-C7 cycloalkyl, C3-C6 cycloalkyl, or C4- C7 cycloalkyl groups using alternative language.

[0501] “Heterocyclyl” refers to a cyclic group that includes at least one saturated or unsaturated, but non-aromatic, cyclic ring. Heterocyclyl groups include at least one heteroatom as a ring member. Typical heteroatoms include O, S and N and are independently chosen. Heterocyclyl groups include monocyclic ring systems and bicyclic ring systems. Bicyclic heterocyclyl groups include at least one non-aromatic ring with at least one 129 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) heteroatom ring member that may be fused to a cycloalkyl ring or may be fused to an aromatic ring where the aromatic ring may be carbocyclic or may include one or more heteroatoms. The point of attachment of a bicyclic heterocyclyl group may be at the non- aromatic cyclic ring that includes at least one heteroatom or at another ring of the heterocyclyl group. For example, a heterocyclyl group derived by removal of a hydrogen atom from one of the 9 membered heterocyclic compounds shown below may be attached to the rest of the molecule at the 5-membered ring or at the 6-membered ring.

[0502] In some embodiments, a heterocyclyl group includes 5 to 10 ring members of which 1, 2, 3 or 4 or 1, 2, or 3 are heteroatoms independently selected from O, S, or N. In other embodiments, a heterocyclyl group includes 3 to 7 ring members of which 1, 2, or 3 heteroatoms are independently selected from O, S, or N. In such 3-7 membered heterocyclyl groups, only 1 of the ring atoms is a heteroatom when the ring includes only 3 members and includes 1 or 2 heteroatoms when the ring includes 4 members. In some embodiments, a heterocyclyl group includes 3 or 4 ring members of which 1 is a heteroatom selected from O, S, or N. In other embodiments, a heterocyclyl group includes 5 to 7 ring members of which 1, 2, or 3 are heteroatoms independently selected from O, S, or N. Typical heterocyclyl groups include, but are not limited to, groups derived from epoxides, aziridine, azetidine, imidazolidine, morpholine, piperazine, piperidine, hexahydropyrimidine, 1,4,5,6- tetrahydropyrimidine, pyrazolidine, pyrrolidine, quinuclidine, tetrahydrofuran, tetrahydropyran, benzimidazolone, pyridinone, and the like. Substituted heterocyclyl also includes ring systems substituted with one or more oxo (═O) or oxide (—O−) substituents, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl, pyridinonyl, benzimidazolonyl, benzo[d]oxazol-2(3H)-onyl, 3,4-dihydroisoquinolin-1(2H)-onyl, indolin- onyl, 1H-imidazo[4,5-c]pyridin-2(3H)-onyl, 7H-purin-8(9H)-onyl, imidazolidin-2-onyl, 1H- imidazol-2(3H)-onyl, 1,1-dioxo-1-thiomorpholinyl, and the like.

[0503] “Halo” or “halogen” refers to a fluoro, chloro, bromo, or iodo group.

[0504] “Haloalkyl” refers to an alkyl group in which at least one hydrogen is replaced with a halogen. Thus, the term “haloalkyl” includes monohaloalkyl (alkyl substituted with one halogen atom) and polyhaloalkyl (alkyl substituted with two or more halogen atoms). 130 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) Representative “haloalkyl” groups include difluoromethyl, 2,2,2-trifluoroethyl, 2,2,2- trichloroethyl, and the like. The term “perhaloalkyl” means, unless otherwise stated, an alkyl group in which each of the hydrogen atoms is replaced with a halogen atom. For example, the term “perhaloalkyl”, includes, but is not limited to, trifluoromethyl, pentachloroethyl, 1,1,1- trifluoro-2-bromo-2-chloroethyl, and the like.

[0505] “Heteroaryl” refers to a monovalent heteroaromatic group derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system. Heteroaryl groups typically include 5- to 14-membered, but more typically include 5- to 10-membered aromatic, monocyclic, bicyclic, and tricyclic rings containing one or more, for example, 1, 2, 3, or 4, or in certain embodiments, 1, 2, or 3, heteroatoms chosen from O, S, or N, with the remaining ring atoms being carbon. In monocyclic heteroaryl groups, the single ring is aromatic and includes at least one heteroatom. In some embodiments, a monocyclic heteroaryl group may include 5 or 6 ring members and may include 1, 2, 3, or 4 heteroatoms, 1, 2, or 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom where the heteroatom(s) are independently selected from O, S, or N. In bicyclic aromatic rings, both rings are aromatic. In bicyclic heteroaryl groups, at least one of the rings must include a heteroatom, but it is not necessary that both rings include a heteroatom although it is permitted for them to do so. For example, the term “heteroaryl” includes a 5- to 7-membered heteroaromatic ring fused to a carbocyclic aromatic ring or fused to another heteroaromatic ring. In tricyclic aromatic rings, all three of the rings are aromatic and at least one of the rings includes at least one heteroatom. For fused, bicyclic and tricyclic heteroaryl ring systems where only one of the rings contains one or more heteroatoms, the point of attachment may be at the ring including at least one heteroatom or at a carbocyclic ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In certain embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2 In certain embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1 Heteroaryl does not encompass or overlap with aryl as defined above. Examples of heteroaryl groups include, but are not limited to, groups derived from acridine, carbazole, cinnoline, furan, imidazole, indazole, indole, indolizine, isobenzofuran, isochromene, isoindole, isoquinoline, isothiazole, 2H-benzo[d][1,2,3]triazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, 131 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) triazole, and the like. In certain embodiments, the heteroaryl group can be between 5 to 20 membered heteroaryl, such as, for example, a 5 to 14 membered or 5 to 10 membered heteroaryl. In certain embodiments, heteroaryl groups can be those derived from thiophene, pyrrole, benzothiophene, 2H-benzo[d][1,2,3]triazole benzofuran, indole, pyridine, quinoline, imidazole, benzimidazole, oxazole, tetrazole, and pyrazine.

[0506] As described herein, the text refers to various embodiments of the present compounds, compositions, and methods. The various embodiments described are meant to provide a variety of illustrative examples and should not be construed as descriptions of alternative species. Rather, it should be noted that the descriptions of various embodiments provided herein may be of overlapping scope. The embodiments discussed herein are merely illustrative and are not meant to limit the scope of the present technology. 5. EXAMPLES OF NON-LIMITING ASPECTS OF THE DISCLOSURE

[0507] Aspects, including embodiments, of the present subject matter described above may be beneficial alone or in combination, with one or more other aspects or embodiments. Without limiting the foregoing description, certain non-limiting aspects of the disclosure numbered 1-131 are provided below. As will be apparent to those of skill in the art upon reading this disclosure, each of the individually numbered aspects may be used or combined with any of the preceding or following individually numbered aspects. This is intended to provide support for all such combinations of aspects and is not limited to combinations of aspects explicitly provided below:

[0508] Aspect 1. A method of inducing weight loss and increasing insulin sensitivity in a subject with obesity-induced insulin resistance, the method comprising: co-administering to a subject in need thereof: an effective dose of an apelin receptor agonist; and an effective dose of a GLP-1 receptor agonist, to induce fat and weight loss, and insulin sensitivity, in the subject.

[0509] Aspect 2. A method of inducing weight loss in a subject in need of weight loss, the method comprising: co-administering to a subject in need thereof: an effective dose of an apelin receptor agonist; and an effective dose of a GLP-1 receptor agonist, to induce fat and weight loss in the subject.

[0510] Aspect 3. A method of inducing weight loss with maintenance of lean muscle mass in a subject in need of weight loss, the method comprising: co-administering to a subject in 132 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) need thereof: an effective dose of an apelin receptor agonist; and an effective dose of a GLP- 1 receptor agonist, to maintain lean muscle mass while inducing fat and weight loss in the subject.

[0511] Aspect 4. A method of increasing total weight loss caused by administration of a pre-determined amount of a GLP-1 receptor agonist to a subject in need thereof, the method comprising: co-administering to a subject in need thereof: an effective dose of an apelin receptor agonist; and an effective dose of a GLP-1 receptor agonist, to increase total weight loss in the subject relative to weight loss caused by administration of a pre-determined amount of a GLP-1 receptor agonist alone.

[0512] Aspect 5. A method of treating or preventing further muscle mass decrease caused by administration of a GLP-1 receptor agonist to a subject in need thereof, the method comprising: adding an effective dose of an apelin receptor agonist to the GLP-1 receptor agonist treatment regimen of a subject in need thereof, to treat or prevent further lean muscle mass decrease in the subject.

[0513] Aspect 6. A method of increasing total weight loss to a subject in need thereof after prior treatment with a pre-determined amount of a GLP-1 receptor agonist alone caused weight loss in the subject to plateau, the method comprising: co-administering to a subject in need thereof: an effective dose of an apelin receptor agonist; and an effective dose of the GLP-1 receptor agonist, to increase total weight loss in the subject relative to weight loss caused by administration of a pre-determined amount of a GLP-1 receptor agonist alone.

[0514] Aspect 7. A method of inducing weight loss in a subject in need thereof after prior treatment with a pre-determined amount of a GLP-1 receptor agonist alone caused weight loss in the subject to plateau, the method comprising: co-administering to a subject in need thereof: an effective dose of an apelin receptor agonist; and an effective dose of a GLP-1 receptor agonist, to induce fat and weight loss in the subject relative to prior treatment with a pre-determined amount of the GLP-1receptor agonist alone.

[0515] Aspect 8. A method of preventing or reducing rebound weight gain in a human subject who had prior treatment with a pre-determined amount of a GLP-1 receptor agonist alone that caused weight loss in the subject to plateau, the method comprising: co- administering to a subject in need thereof: an effective dose of an apelin receptor agonist;

[0516] to prevent or reduce rebound weight gain in the subject.

[0517] Aspect 9. The method of any one of aspects 1 to 7, wherein the subject is overweight or obese. 133 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)

[0518] Aspect 10. The method of any one of aspects 1 to 9, wherein the subject has a disease or condition associated with weight gain.

[0519] Aspect 11. The method of any one of aspect 10, wherein the disease or condition associated with weight gain is selected from obesity, obesity-linked gallbladder disease, obesity-induced sleep apnea, diabetes, excessive appetite, fatty liver disease, non-alcoholic fatty liver disease (NASH), metabolic dysfunction–associated steatohepatitis (MASH), dyslipidemia, metabolic syndrome, insufficient satiety, hyperinsulinemia, and hypoglycemia.

[0520] Aspect 12. The method of any one of aspects 1 to 11, wherein the subject has, or is at risk of developing a metabolic disorder or dysmetabolic disorder.

[0521] Aspect 13. The method of aspect 12, wherein the metabolic disorder is a glucose metabolic disorder.

[0522] Aspect 14. The method of aspect 12, wherein the dysmetabolic disorder is dysmetabolic syndrome X.

[0523] Aspect 15. The method of aspect 12, wherein the metabolic disorder is insulin resistance syndrome or syndrome X.

[0524] Aspect 16. The method of aspect 12, wherein the metabolic disorder is selected from the group consisting of diabetes, metabolic syndrome, obesity, hyperlipidemia, hyperinsulinemia, high cholesterol, arteriosclerosis, hypertension, non-alcoholic steatohepatitis, non-alcoholic fatty liver, NASH, MASH, hepatic steatosis, and any combination thereof.

[0525] Aspect 17. The method of any one of aspects 1 to 16, wherein the subject has, or is at risk of developing pancreatic beta-cell dysfunction.

[0526] Aspect 18. The method of any one of aspects 1-17, wherein the subject has, or is at risk of developing a condition in which there is a lack of or diminished insulin production.

[0527]

[0528] Aspect 19. The method of any one of aspects 12-18, wherein the subject has, or is at risk of developing diabetic obesity.

[0529] Aspect 20. The method of any one of aspects 12-19, wherein the subject has, or is at risk of developing type 1 diabetes, type 2 diabetes, or gestational diabetes.

[0530] Aspect 21. The method of any one of aspects 1 to 20, wherein the subject has, or is at risk of developing one or more of hypertension, dyslipidemia, obstructive sleep apnea, and cardiovascular disease. 134 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)

[0531] Aspect 22. The method of any one of aspects 1 to 21, wherein the co- administering stimulates muscle mass preservation, or stimulates an increase in muscle mass in the subject relative to a baseline level.

[0532] Aspect 23. The method of any one of aspects 1 to 22, wherein the subject exhibits, after the co-administration: loss of fat but not lean muscle; increased lean mass percentage; increased lean / fat mass ratio; reduced or normal fed glucose level, reduced lipid accumulation, increased fat oxidation, increased insulin sensitivity, decrease in waist circumference; increase in percent appendicular lean mass; and / or increased glucose utilization, relative to a baseline level immediately before administration.

[0533] Aspect 24. The method of any one of aspects 1 to 23, wherein the subject exhibits, after the co-administration: a decrease in waist circumference, and / or a decrease in triglycerides and LDL-C.

[0534] Aspect 25. The method of...

Claims

Attorney Docket No.: 32554- 61700 (022USP7) WHAT IS CLAIMED IS:

1. A method of inducing weight loss and increasing insulin sensitivity in a subject with obesity-induced insulin resistance, the method comprising: co-administering to a subject in need thereof: an effective dose of an apelin receptor agonist; and an effective dose of a GLP-1 receptor agonist, to induce fat and weight loss, and insulin sensitivity, in the subject.

2. A method of inducing weight loss in a subject in need of weight loss, the method comprising: co-administering to a subject in need thereof: an effective dose of an apelin receptor agonist; and an effective dose of a GLP-1 receptor agonist, to induce fat and weight loss in the subject.

3. A method of inducing weight loss with maintenance of lean muscle mass in a subject in need of weight loss, the method comprising: co-administering to a subject in need thereof: an effective dose of an apelin receptor agonist; and an effective dose of a GLP-1 receptor agonist, to maintain lean muscle mass while inducing fat and weight loss in the subject.

4. A method of increasing total weight loss caused by administration of a pre-determined amount of a GLP-1 receptor agonist to a subject in need thereof, the method comprising: co-administering to a subject in need thereof: an effective dose of an apelin receptor agonist; and an effective dose of a GLP-1 receptor agonist, to increase total weight loss in the subject relative to weight loss caused by administration of a pre-determined amount of a GLP-1 receptor agonist alone. 249 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) 5. A method of treating or preventing further muscle mass decrease caused by administration of a GLP-1 receptor agonist to a subject in need thereof, the method comprising: adding an effective dose of an apelin receptor agonist to the GLP-1 receptor agonist treatment regimen of a subject in need thereof, to treat or prevent further lean muscle mass decrease in the subject.

6. A method of increasing total weight loss to a subject in need thereof after prior treatment with a pre-determined amount of a GLP-1 receptor agonist alone caused weight loss in the subject to plateau, the method comprising: co-administering to a subject in need thereof: an effective dose of an apelin receptor agonist; and an effective dose of the GLP-1 receptor agonist, to increase total weight loss in the subject relative to weight loss caused by administration of a pre-determined amount of a GLP-1 receptor agonist alone.

7. A method of inducing weight loss in a subject in need thereof after prior treatment with a pre-determined amount of a GLP-1 receptor agonist alone caused weight loss in the subject to plateau, the method comprising: co-administering to a subject in need thereof: an effective dose of an apelin receptor agonist; and an effective dose of a GLP-1 receptor agonist, to induce fat and weight loss in the subject relative to prior treatment with a pre- determined amount of the GLP-1receptor agonist alone.

8. A method of preventing or reducing rebound weight gain in a human subject who had prior treatment with a pre-determined amount of a GLP-1 receptor agonist alone that caused weight loss in the subject to plateau, the method comprising: co-administering to a subject in need thereof: an effective dose of an apelin receptor agonist; to prevent or reduce rebound weight gain in the subject.

9. A method of inhibiting weight gain in a human subject having a condition caused or characterized by excess body weight, the method comprising: 250 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) administering to the subject in need thereof a dose of an apelin receptor agonist effective to inhibit weight gain in the subject.

10. A method of preventing or reducing rebound weight gain in a human subject who has previously lost weight, the method comprising: administering to the subject in need thereof a dose of an apelin receptor agonist effective to prevent or reduce rebound weight gain in the subject.

11. A method of increasing total weight loss in a human subject having a condition caused or characterized by excess body weight, the method comprising: administering to the subject in need thereof a dose of an apelin receptor agonist effective to inhibit weight gain in the subject.

12. A method of preventing or inhibiting decrease of lean muscle mass caused by administration of a pre-determined dose of GLP-1 receptor agonist to a human subject in need thereof, the method comprising: administering to the subject in need thereof a dose of an apelin receptor agonist effective to treat or prevent lean muscle mass decrease in the subject.

13. A method of preventing or treating type-2 diabetes, the method comprising: administering to the subject in need thereof a dose of an apelin receptor agonist effective to enhance glycemic control in the subject.

14. The method of any one of claims 1 to 13, wherein the subject is overweight or obese.

15. The method of any one of claims 1 to 14, wherein the subject has a disease or condition associated with weight gain.

16. The method of any one of claim 15, wherein the disease or condition associated with weight gain is selected from obesity, obesity-linked gallbladder disease, obesity- induced sleep apnea, diabetes, diabetic obesity, excessive appetite, fatty liver disease, non-alcoholic fatty liver disease (NASH), metabolic dysfunction–associated steatohepatitis (MASH), dyslipidemia, metabolic syndrome, insufficient satiety, hyperinsulinemia, and hypoglycemia. 251 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) 17. The method of any one of claims 1 to 16, wherein the subject has, or is at risk of developing a metabolic disorder or dysmetabolic disorder.

18. The method of claim 17, wherein the metabolic disorder is a glucose metabolic disorder.

19. The method of claim 17, wherein the dysmetabolic disorder is dysmetabolic syndrome X.

20. The method of claim 17, wherein the metabolic disorder is insulin resistance syndrome or syndrome X.

21. The method of claim 17, wherein the metabolic disorder is selected from the group consisting of diabetes, metabolic syndrome, obesity, hyperlipidemia, hyperinsulinemia, high cholesterol, arteriosclerosis, hypertension, non-alcoholic steatohepatitis, non-alcoholic fatty liver, NASH, MASH, hepatic steatosis, and any combination thereof.

22. The method of any one of claims 1 to 21, wherein the subject has, or is at risk of developing pancreatic beta-cell dysfunction.

23. The method of any one of claims 1-22, wherein the subject has, or is at risk of developing a condition in which there is a lack of or diminished insulin production.

24. The method of any one of claims 17-23, wherein the subject has, or is at risk of developing diabetic obesity.

25. The method of any one of claims 17-24, wherein the subject has, or is at risk of developing type 1 diabetes, type 2 diabetes, or gestational diabetes.

26. The method of any one of claims 1 to 25, wherein the subject has, or is at risk of developing one or more of hypertension, dyslipidemia, obstructive sleep apnea, and cardiovascular disease. 252 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) 27. The method of any one of claims 1 to 26, wherein the co-administering stimulates muscle mass preservation, or stimulates an increase in muscle mass in the subject relative to a baseline level.

28. The method of any one of claims 1 to 8 and 14-27, wherein the subject exhibits, after the co-administration: loss of fat but not lean muscle; increased lean mass percentage; increased lean / fat mass ratio; reduced or normal fed glucose level, reduced lipid accumulation, increased fat oxidation, increased insulin sensitivity, decrease in waist circumference; increase in percent appendicular lean mass; and / or increased glucose utilization, relative to a baseline level immediately before administration.

29. The method of any one of claims 9-27, wherein the subject exhibits, after the administration: reduced A1c levels, improved glucose tolerance, reduced body weight without impact on food consumption, decreased inguinal fat percentage, and / or reduced or normal fed glucose level, relative to a baseline level immediately before administration.

30. The method of any one of claims 1-29, wherein the subject is on a: calorie-restricted diet or a low fat diet. 253 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) 31. The method of any one of claims 1 to 8 and 14-28, wherein the subject exhibits, after the co-administration: a decrease in waist circumference, and / or a decrease in triglycerides and LDL-C.

32. The method of any one of claims 1 to 8, 14-28, and 30, wherein the GLP-1 receptor agonist is selected from albiglutide, exenatide, liraglutide, lixisenatide, semaglutide, and tirzepatide.

33. The method of any one of claims 1 to 8 and 14-28, wherein the GLP-1 receptor agonist is a dual-acting GLP-1 receptor agonist, a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist or glucagon receptor agonist.

34. The method of claim 33, wherein the GLP-1 receptor agonist is tirzepatide.

35. The method of any one of claims 1 to 8 and 14-28, wherein the GLP-1 receptor agonist is a triple-acting GLP-1 receptor agonist, GIP receptor agonist, and glucagon receptor agonist.

36. The method of claim 35, wherein the GLP-1 receptor agonist is retatrutide.

37. The method of any one of claims 1 to 8 and 14-28, wherein the GLP-1 receptor agonist is selected from albenatide, albiglutide, avexitide, cafraglutide, cotadutide, danuglipron, dapiglutide, diabegone, dulaglutide, ecnoglutide, efpeglenatide, efinopegdutide, efocipegtrutide, exenatide, exenatide biobetter, exenatide SR, froniglutide, liraglutide, liraglutide biobetter, lixisenatide, CT-868, efocipegtrutide, LY-3502970 (Orforglipron), maridebart, mazdutide, NLY-001, orforglipron, pegapamodutide, pemvidutide, retatrutide (LY-3437943), semaglutide, semaglutide injection, survodutide, vurolenatide, dapagliflozin + semaglutide, (cagrilintide + semaglutide), (LAI-287 + semaglutide), (semaglutide + GIP analogue), 4P-004, AMG-133, AP-026, AZD-9550, BGM-0504, BMS-686117, Zn / BMS-686117 adduct, CT-388, CT-868, CT-996, DD-01, DR-10624, DR-10627, ECC-5004, E-2HSA, GL- 0034, GLP-06, GMA-105, GMA-106, GMA-102, GSBR-1290, GXG-6, GZR-18, HEC-88473, HR-17031, HRS-7535, HRS-9531, HS-20004, HS-20094, HB-1085, 254 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) HDM-1002, HL-08, HZ-010, JY-09, KN-056, LY-3493269, MBX-1416, MDR-001, MWN-101, NLY-001, NN-9490, NNC0519-0130, NN-6177, NN-9847, NN-9904, NN-6535 (semaglutide), NN-9932 (semaglutide), PF-06954522, PF-07081532, PF- 06882961, PB-1023, PB-119, PB-718, RGT-075, SAL-015, SAL-0112, SCO-094, TERN-601, TTP-273, Uni-E4, VK-2735, YH-25724, XW-004, XW-014, YH-25724, YN-012 (Supaglutide), YN-015, ZT-002, and pharmaceutically acceptable salts thereof.

38. The method of claim 38, wherein the GLP-1 receptor agonist is danuglipron.

39. The method of any one of claims 1 to 8 and 14-28, wherein the GLP-1 receptor agonist is selected from (dorzagliatin + GLP-1), (exenatide + insulin aspart), ACT- 1003, Adogel Sema, AER-601, AGM-212, BEBT-808, BZ-043B, C-2816, DAJC-1, DD-02, DR-10625, DR-10628, DS-004, DS-005, DS-006, DS-012, E-6, efpeglenatide + HM-12470, exenatide 2, exenatide LA, exenatide SR, Extendin-Fc, G-49, GB-7001, Gene Encoding GLP-1, GLP-1 Incretin Triagonist, GLP-1 Oral Preparation, GLP-1R Antagonist for Hypoglycemia, glucagon, Glucagon-Like Peptide-1 + insulin human, GPCR-targeted Project 012, GPCR-targeted Project 013, GT-01123, HM-15275, HPG-5119, HSP-001, HSP-004, HSP-005, HSP012-C, Hydrogel Exenatide, I2O- 105S, I2O-110, KP-405, LA-EX, liraglutide biobetter, liraglutide LA, MK-1462, MLX-7000, MWN-105, MWN-109, NLY-12, NPM-115, OGB-21502, OXM, P-11, PB-2301, PB-2309, RGT-028, RGT-274, RPC-8844, RT-104, SHX-022, SL-209, synthetic peptides to agonize GLP-1R and CCKBR for diabetes, TB-013, TB-222023, TB-592, TE-8105, THDBH-111, UDS-003, VTCG-15, XL-110, XL-310, XW-003 + XW-015, XW-003 + XW-017, Y-002, YGX-1, ZT-003, ZT-006, ZT-007, DA-1726, HDM-1005, (insulin degludec + liraglutide), DB-081, GW-002, HZCX-012, ID- 110521156, THDB-0211, THDBH-110, THDBH-120, THDBH-121, UBT-251, ATBB-22, BEM-012, CIN-209, CIN-210, DD-03, exenatide + ND-017, exenatide + Synthetic Peptide 2, glucagon, Insulin-GLP1, MD-02, OGB-21501, P-01, PAT-201, PF-1807, PT-3, and pharmaceutically acceptable salts thereof.

40. The method of any one of claims 1 to 39, wherein the apelin receptor agonist is selected from BAL-1480, BMS-986224, ANPA-0073, apelin-13, [Pyr1]apelin-13, E339-3D6, (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H- 255 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) 1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide, (S)-N-(1- (cyclobutylamino)-1-oxo-5-(piperidin-1-yl)pentan-3-yl)-5-(2,6-dimethoxyphenyl)-1- cyclopentyl-1H-pyrazole-3-carboxamide, and pharmaceutically acceptable salts thereof.

41. The method of any one of claims 1 to 40, wherein the apelin receptor agonist is of formula (I) or (II):or a pharmaceutically acceptable salt thereof, a tautomer thereof, a pharmaceutically acceptable salt of the tautomer, a stereoisomer of any of the foregoing, or a mixture thereof, wherein: R1is an unsubstituted pyridyl, pyridonyl, or pyridine N-oxide, or is a pyridyl, pyridonyl, or pyridine N-oxide substituted with 1, 2, 3, or 4 R1asubstituents; R1ain each instance is independently selected from —F, —Cl, —Br, —I, —CN, — C1-C6 alkyl, —C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —OH, —O—(C1-C6 alkyl), —O—(C1- C6haloalkyl), —O—(C1-C6perhaloalkyl), —C2-C6alkenyl, —O—(C1-C6alkyl)-OH, —O— (C1-C6 alkyl)-O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl)-OH, —O—(C1-C6 haloalkyl)-O— (C1-C6 alkyl), —O—(C1-C6 perhaloalkyl)-OH, —O—(C1-C6 perhaloalkyl)-O—(C1-C6 alkyl), —NH2, —NH(C1-C6alkyl), —N(C1-C6alkyl)2, —C(═O)—(C1-C6alkyl), —C(═O)OH, — (C═O)—O—(C1-C6 alkyl), —C(═O)NH2, —C(═O)NH(C1-C6 alkyl), —C(═O)N(C1- C6 alkyl)2, phenyl, —C(═O)-(heterocyclyl), or a heterocyclyl group, wherein the heterocyclyl group of the —C(═O)-(heterocyclyl) or heterocyclyl group is a 3 to 7 membered ring containing 1, 2, or 3 heteroatoms selected from N, O, and S; R2is selected from —H, and C1-C4 alkyl or is absent in the compounds of Formula II; R3is selected from an unsubstituted C1-C10alkyl, a C1-C10alkyl substituted with 1, 2, or 3 R1asubstituents, a group of formula —(CR3bR3c)-Q, a group of formula —NH— (CR3bR3c)-Q, a group of formula —(CR3bR3c)—C(═O)-Q, a group of formula —(CR3dR3e)— (CR3fR3g)-Q, a group of formula —(CR3b═CR3c)-Q, and a group of formula -(heterocyclyl)- Q, wherein the heterocyclyl of the -(heterocyclyl)-Q has 5 to 7 ring members of which 1, 2, 256 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) or 3 are heteroatoms selected from N, O, and S and is unsubstituted or is substituted with 1, 2, or 3 R3hsubstituents; R1ain each instance is independently selected from —F, —Cl, —CN, —OH, —O— (C1-C6 alkyl), —O—(C1-C6 haloalkyl), —O—(C1-C6 perhaloalkyl), —O—(C1-C6 alkyl)-OH, —O—(C1-C6 alkyl)-O—(C1-C6 alkyl), C2-C6 alkenyl, C2-C6 alkynyl, —NH2, —NH(C1- C6alkyl), and —N(C1-C6alkyl)2; R3band R3care independently selected from —H, —F, —Cl, —CN, —C1-C6alkyl, — C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —OH, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —O—(C1-C6perhaloalkyl), —O—(C1-C6alkyl)-OH, —O—(C1-C6alkyl)-O—(C1-C6alkyl), —NH2, —NH(C1-C6alkyl), and —N(C1-C6alkyl)2; R3dand R3eare independently selected from —H, —F, —Cl, —CN, —C1-C6 alkyl, — C1-C6 haloalkyl, —C1-C6 perhaloalkyl, —OH, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —O—(C1-C6perhaloalkyl), —O—(C1-C6alkyl)-OH, —O—(C1-C6alkyl)-O—(C1-C6alkyl), —NH2, —NH(C1-C6 alkyl), and —N(C1-C6 alkyl)2; R3fand R3gare independently selected from —H, —F, —Cl, —CN, —C1-C6 alkyl, — C1-C6haloalkyl, —C1-C6perhaloalkyl, —OH, —O—(C1-C6alkyl), —O—(C1-C6haloalkyl), —O—(C1-C6perhaloalkyl), —O—(C1-C6alkyl)-OH, —O—(C1-C6alkyl)-O—(C1-C6alkyl), —NH2, —NH(C1-C6 alkyl), and —N(C1-C6 alkyl)2; R3hin each instance is independently selected from —F, —Cl, —CN, —C1-C6alkyl, —C1-C6haloalkyl, —C1-C6perhaloalkyl, —OH, —O—(C1-C6alkyl), —O—(C1- C6 haloalkyl), —O—(C1-C6 perhaloalkyl), —O—(C1-C6 alkyl)-OH, —O—(C1-C6 alkyl)-O— (C1-C6alkyl), —NH2, —NH(C1-C6alkyl), —N(C1-C6alkyl)2, and oxo; Q is a monocyclic or bicyclic C6-C10aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms selected from N, O, or S, a C3-C8 cycloalkyl group, or a 3 to 7 membered heterocyclyl group containing 1, 2, or 3 heteroatoms selected from N, O, or S, wherein the C6-C10aryl group, the heteroaryl group, the cycloalkyl group, and the heterocyclyl group are unsubstituted or are substituted with 1, 2, 3, or 4 RQsubstituent; RQin each instance is independently selected from —F, —Cl, —Br, —I, —CN, —C1- C6alkyl, —C1-C6haloalkyl, —C1-C6perhaloalkyl, —C2-C6alkenyl, —C2-C6alkynyl, —OH, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —O—(C1-C6 perhaloalkyl), —NH2, —NH(C1- C6alkyl), —N(C1-C6alkyl)2, —C(═O)—(C1-C6alkyl), —C(═O)OH, —C(═O)—O—(C1- C6alkyl), —C(═O)NH2, —C(═O)NH(C1-C6alkyl), —C(═O)N(C1-C6alkyl)2, —S(═O)2— 257 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) (C1-C6 alkyl), phenyl, and a heteroaryl group, and the Q heterocyclyl group may be substituted with 1 oxo RQsubstituent; R4is selected from a monocyclic or bicyclic C6-C10aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and a monocyclic or bicyclic heterocyclyl group with 5 to 10 ring members containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, wherein the C6-C10aryl group, the heteroaryl group, or the heterocyclyl group are unsubstituted or are substituted with 1, 2, or 3 R4asubstituents; R4ain each instance is independently selected from —F, —Cl, —Br, —I, —CN, — C1-C6alkyl, —C1-C6haloalkyl, —C1-C6perhaloalkyl, —OH, —O—(C1-C6alkyl), —O—(C1- C6 haloalkyl), —O—(C1-C6 perhaloalkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, — C(═O)—(C1-C6 alkyl), —C(═O)OH, —C(═O)—O—(C1-C6 alkyl), —C(═O)NH2, — C(═O)NH(C1-C6alkyl), and —C(═O)N(C1-C6alkyl)2, and the heterocyclyl R4group may be further substituted with 1 oxo substituent; and further wherein: if R4is an unsubstituted or substituted phenyl ring and R3is a group of formula — (CR3b═CR3c)-Q, then at least one of the following is true: a) R4is substituted with at least one —O—(C1-C6 alkyl) group; b) Q is not an oxadiazole; c) R3bis not —H; d) R3cis not —H; e) R1is not a 2-pyridyl group; or f) R4is substituted with two or more —O—(C1-C6alkyl) groups.

42. The method of any one of claims 1 to 39, wherein the apelin receptor agonist is a compound of the structureor a pharmaceutically acceptable salt thereof. 258 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) 43. The method of claim 42, wherein the apelin receptor agonist is (2S,3R)—N-(4-(2,6- dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazol-3-yl)-3-(5-methyl-2- pyrimidinyl)-2-butanesulfonamide.

44. The method of claim 42, wherein the apelin receptor agonist is a pharmaceutically acceptable salt of (2S,3R)—N-(4-(2,6-dimethoxyphenyl)-5-(5-methyl-3-pyridinyl)- 4H-1,2,4-triazol-3-yl)-3-(5-methyl-2-pyrimidinyl)-2-butanesulfonamide.

45. The method of any one of claims 1 to 39, wherein the apelin receptor agonist is of Formula (XXI):or a pharmaceutically acceptable salt thereof, wherein R1 is represented by the formula: whereinis a monocyclic aryl or heteroaryl group; each A is independently fluoro substituted C1-C3 alkoxy or fluoro substituted C1- C3alkyl; n is 1, 2, 3, 4, or 5; R2 is C3-8 alkyl, C1-8 alkyl (C3-8 cycloalkyl), C3-8 cycloalkyl, heteroaryl, or substituted aryl; R4is adamantanyl, aryl, C1-8alkyl, C1-8alkyl alcohol, C1-8alkyl amino, C1-8alkyl amido, C2-8 alkyl(aryl), C1-8 alkyl (C3-8 cycloalkyl), C1-8 alkyl (C3-8 cycloalkyl)—CO2R7, C1-8alkyl guanidinyl, C1-8alkyl heteroaryl, C1-8alkyl tetrazol-5-one, C2-4alkyl heterocycloalkyl, C1-8alkyl thioether, C1-8alkyl thiol, C2-8alkenyl, C2-8alkenyl(aryl), C2-8alkenyl(heteroaryl), C3-8 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkyl—CO2R7, (CH2)xNR7R8, (CH2)xOR7, 259 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) (CH2)xNR9COR7, (CH2)xNR9SO2R7, (CH2)xNR9CO2R7, (CH2)xNHCOR7, (CH2)xNHSO2R7, (CH2)xNHCO2R7, (CH2)xCONR7R8, (CH2)xCONR7(CH2)yCO2R9, (CH2)xCONR7(CH2)yCONR7R8, (CH2)xCONR7(CH2)yR9(CH2)xCOR7, (CH2)xCO2R7, (CH2)xSO2NR7(CH2)yR9, CHR7COR9, CHR7CONHCHR8COR9, CONR7R8, CONR7(CH2)xCO2R8, CONR7CHR8CO2R9, CO2R9, NHCO2R7, or (CH2)xSO2NR7R8; R5and R6each are independently is adamantanyl, aryl, C1-8alkyl, C1-8alkyl alcohol, C1-8alkyl amino, C1-8alkyl amido, C2-8alkyl(aryl), C1-8alkyl (C3-8cycloalkyl), C1-8alkyl (C3-8 cycloalkyl)—CO2R7, C1-8 alkyl guanidinyl, C1-8 alkyl heteroaryl, C1-8 alkyl tetrazol-5-one, C2-4alkyl heterocycloalkyl, C1-8alkyl thioether, C1-8alkyl thiol, C2-8alkenyl, C2-8alkenyl(aryl), C2-8alkenyl(heteroaryl), C3-8alkynyl, C3-8cycloalkyl, C3-8cycloalkyl-CO2R7, (CH2)xNR7R8, (CH2)xOR7, (CH2)xNR9COR7, (CH2)xNR9SO2R7, (CH2)xNR9CO2R7, (CH2)xNHCOR7, (CH2)xNHSO2R7, (CH2)xNHCO2R7, (CH2)xCONR7R8, (CH2)xCONR7(CH2)yCO2R9, (CH2)xCONR7(CH2)yCONR7R8, (CH2)xCONR7(CH2)yR9, (CH2)xCOR7, (CH2)xCO2R7, (CH2)xSO2NR7(CH2)yR9, CHR7COR9, CHR7CONHCHR8COR9, CONR7R8, CONR7(CH2)xCO2R8, CONR7CHR8CO2R9, CO2R9, NHCO2R7, or (CH2)xSO2NR7R8; or and R5together make a 4-8 member ring which may be substituted with one or more heteroatoms; or R4and R5together make a 5-8 nitrogen containing member ring with one or more carbonyl groups; wherein the group R4 is substituted with one or more fluorine atoms; R6is H; R7and R8each are independently H, C1-8alkoxy, aryl, C1-8alkyl, C1-8alkyl alcohol, C1-8 alkyl amino, C1-8 alkyl amido, C1-8 alkyl(aryl), C1-8 alkyl (C3-8 cycloalkyl), C1-8 alkyl tetrazol- 5-one, C1-8 alkyl guanidinyl, C1-8 alkyl heteroaryl, C1-8 alkyl thioether, C1-8 alkyl thiol, C1-8alkenyl, C3-8alkynyl, C3-8cycloalkyl, (CH2)xCONHR9, (CH2)xCOR9, (CH2)xCO2R9, or heteroaryl; or R7 and R8 together make a 3-9 member ring which may contain one or more heteroatoms, wherein the ring is substituted with at least two fluorine atoms; or R7and R8together make a 5-8 nitrogen containing member ring with one or more carbonyl groups; R9is aryl, C1-8alkoxy, C1-8alkyl, C1-8alkyl(aryl), C3-8cycloalkyl, H, heteroaryl, or hydroxyl; each x is independently 0-8; and 260 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) each y is independently 1-8.

46. The method of any one of claims 1 to 39, wherein the apelin receptor agonist is a compound of the structure(BAL-1480) or a pharmaceutically acceptable salt thereof.

47. The method of any one of claims 1 to 39, wherein the apelin receptor agonist is a compound of Formula (XV):or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: R1is independently selected from the group consisting of: —CH2OH, —OCH3, — OCF3, CH3, CH2CH3, CH(CH3)2, and cyclopropyl; R2is independently selected from the group consisting of: C1-4 alkyl substituted with 0-3 Re, C2-4 alkenyl, C1-6 cycloalkyl, and CH2O(CH2)1-3CH3; R3is independently selected from the group consisting of: (1) —CH2C(═O)OC1-4alkyl substituted with 0-3 Re, 261 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) (2) —CH2NRaRa, (3) —CH2C(═O)NRaRa, (4) —CH2NHC(═O)C1-4alkyl substituted with 0-3 Re, (5) —CH2NRaC(═O)(CH2)0-2OC1-4alkyl substituted with 0-3 Re, (6) —CH2—R5, (7) —CH2—OR5, (8) —CH2NRaC(═O)(CH2)0-2R5, and (9) —CH2C(═O)NRa(CH2)0-2R5; R5is independently selected from the group consisting of: aryl, C3-6cycloalkyl, and heterocycle, each substituted with 0-3 R6; R6is independently selected from the group consisting of: H, F, Cl, Br, —ORb, ═O, —(CH2)nC(═O)Rb, —(CH2)nC(═O)ORb, —(CH2)NRaRa, CN, —(CH2)nC(═O)NRaRa, —S(O)2NH2, C1-4alkyl substituted with 0-3 Re, (CH2)n—C3-6carbocyclyl substituted with 0-3 Re, and —(CH2)n-heterocyclyl substituted with 0-3 Re; Rais independently selected from the group consisting of: H, C1-6 alkyl substituted with 0-5 Re, —(CH2)n—C3-10carbocyclyl substituted with 0-5 Re, and —(CH2)n- heterocyclyl substituted with 0-5 Re; or Raand Ratogether with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 Re; Rbis independently selected from the group consisting of: H, C1-6alkyl substituted with 0-5 Re, C2-6alkenyl substituted with 0-5 Re, C2-6alkynyl substituted with 0-5 Re, —(CH2)n—C3-10carbocyclyl substituted with 0-5 Re, and —(CH2)n-heterocyclyl substituted with 0-5 Re; Reis independently selected from the group consisting of: C1-6alkyl (optionally substituted with F and Cl), OH, OCH3, OCF3, —(CH2)n—C3-6 cycloalkyl, —(CH2)n— C4-6 heterocyclyl, —(CH2)n-aryl, —(CH2)n-heteroaryl, F, Cl, Br, CN, NO2, ═O, and CO2H; and n is independently selected from zero, 1, 2, and 3.

48. The method of any one of claims 1 to 39, wherein the apelin receptor agonist is a compound having one of the following structures: 262 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7)or a pharmaceutically acceptable salt thereof.

49. The method of any one of claims 1 to 39, wherein the apelin receptor agonist is a compound of formula:or a pharmaceutically acceptable salt thereof.

50. The method of claim 49, wherein the apelin receptor agonist is (1S,2S)-N-(4-(2,6- dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-4H-1,2,4-triazol-3-yl)-1-isopropoxy-1- (5-methylpyrimidin-2-yl)propane-2-sulfonamide, or a pharmaceutically acceptable salt thereof, such as a hydrocholoride salt of the compound.

51. The method of any one of claims 1 to 50, wherein the method further comprises co- administering an additional therapeutic agent.

52. The method of claim 51, wherein the additional therapeutic agent is selected from insulin glargine, insulin degludec, cagrilintide, naltrexone-bupropion, phentermine- 263 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) topiramate, benzphetamine, diethylpropion, phendimetrazine, phentermine, orlistat, and setmelanotide.

53. The method of any one of claims 1 to 8, 14-27, 28, and 30-39, wherein the GLP-1 receptor agonist is administered orally, intravenously, subcutaneously, intranasally, or intramuscularly.

54. The method of claim 53, wherein the GLP-1 receptor agonist is administered orally.

55. The method of claim 53 or 54, wherein the effective dose of the GLP-1 receptor agonist is administered daily.

56. The method of any one of claims 1 to 55, wherein the apelin receptor agonist is administered orally, intravenously, subcutaneously, intranasally, or intramuscularly.

57. The method of claim 56, wherein the apelin receptor agonist is administered orally.

58. The method of claim 56 or 57, wherein the effective dose of the apelin receptor agonist is administered daily.

59. The method of claim 58, wherein the effective dose of the apelin receptor agonist is administered twice daily (bid).

60. The method of any one of claims 56-59, wherein the effective dose of the apelin receptor agonist is in the range from 150 mg to 400 mg.

61. The method of any one of claims 54-55, wherein the GLP-1 receptor agonist is administered intravenously or subcutaneously.

62. The method of claim 61, wherein the effective dose of the GLP-1 receptor agonist is less than 15 mg or less than 10 mg. 264 32554 / 61636 / FW / 20310346.1Attorney Docket No.: 32554- 61700 (022USP7) 63. The method of any one of claims 54-55, wherein the effective dose of the GLP-1 receptor agonist is less than the pre-determined dose of the prior treatment with the GLP-1 receptor agonist alone.

64. The method of any one of claims 54-55, wherein the effective dose of the GLP-1 receptor agonist is the same as the pre-determined dose of the prior treatment with the GLP-1 receptor agonist alone.

65. The method of any one of claims 1-64, wherein the subject is at least 55 years old.

66. A fixed dose combination pharmaceutical composition, comprising: a therapeutically effective dose of an apelin receptor agonist or a pharmaceutically acceptable salt thereof; a therapeutically effective dose of a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

67. The pharmaceutical composition of claim 66, wherein the pharmaceutical composition is a solid single dosage unit selected from tablets, pellets, caplets, granules, lozenges, pills, and capsules.

68. A bifunctional compound comprising: (a) an apelin receptor binding moiety; and (b) a GLP-1 receptor binding moiety.

69. A trifunctional compound comprising: (a) an apelin receptor binding moiety; (b) a GLP-1 receptor binding moiety; and (c) a gastric inhibitory polypeptide receptor (GIP-R) binding moiety. 265 32554 / 61636 / FW / 20310346.1

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