Compounds for modulating energy expenditure

Abstract

The present disclosure relates to a method of preventing or treating a disease or disorder in a subject in need thereof, wherein administration of a composition of the present disclosure is effective to result in an increase of energy expenditure in the subject. The present disclosure provides a method of reducing fat mass and / or improving glycemic control in a subject in need thereof. The present disclosure provides a method of promoting weight loss and weight maintenance. The present disclosure provides a method of maintaining lean mass. Compositions for use in the methods include a compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof, or in combination with a compound selected from the group consisting of an ACC2 inhibitor and an incretin mimetic.

Description

COMPOUNDS FOR MODULATING ENERGY EXPENDITURECROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 63 / 659,817, filed June 13, 2024, which is incorporated herein by reference in its entirety.TECHNICAL FIELD

[0002] The present disclosure relates to a method of preventing or treating a disease or disorder in a subject in need thereof, wherein administration of a composition of the present disclosure is effective to result in an increase of energy expenditure in the subject. An increase of energy expenditure can provide benefits or effects to a subject, thereby treating or preventing a condition, disease, or disorder. The present disclosure provides a method of reducing fat mass and / or improving glycemic control in a subject in need thereof. The present disclosure provides a method of inducing weight loss. The present disclosure provides a method of sustaining weight loss. The present disclosure provides a method of maintaining lean mass. Compositions for use in the methods include a compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof, or in combination with a compound selected from the group consisting of an ACC2 inhibitor and an incretin mimetic.BACKGROUND

[0003] Control of excess body fat is a healthcare challenge. Excess body fat causes human diseases, disabilities, and cosmetic disturbances. Excess body fat may be diffuse or concentrated on particular portion(s) of the body. A number of methods have been developed to reduce or remove excess body fat, which include extractive, metabolic, or adipolytic methods. Extractive methods, such as lipoplasty (e.g., liposuction) or local excision, are methods whereby fat is physically removed from areas of interest.

[0004] Metabolic methods include systemic medications, nutritional supplements, devices, and exercise or other body treatment, which seek to modify the subject's metabolism (e.g., whether caloric consumption, expenditure, or both) such that thesubject incurs a net loss of fat. A disadvantage of metabolic methods is that it is difficult to target a particular part of the body. Another drawback is potential concomitant loss of water, carbohydrates, protein, vitamins, minerals, and other nutrients. Furthermore, some medications may have undesired side effects, for example palpitations, tremor, insomnia, and / or irritability.

[0005] Adipolytic methods cause the breakdown of adipocytes and / or their lipid contents. For example, fat deposits can be reduced by exposure to cold temperature or to deoxycholate, a solubilizer which lyses cell membranes and results in local necrosis. Drawbacks of adipolytic methods include poor discrimination between adipose and other nearby tissues, barriers to delivery that require hypodermic needles or special equipment, and adverse effects such as necrosis, inflammation, and pain.

[0006] Benefits of glycemic control are well-established. Glycemic control can help with certain conditions, such as prevention of diabetes complications and weight loss.

[0007] There is an unmet need for methods and pharmaceutical compositions or combinations that exhibit good efficacy with respect to reduction of fat mass and achieving glycemic control, while at the same time exhibiting an acceptable safety profile.SUMMARY

[0008] The present disclosure relates to a method of treating or preventing a condition in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0009] The present disclosure relates to a method of treating or preventing a condition in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (I):or a pharmaceutically acceptable salt thereof, in a dose ranging from 30-380 mg; wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0010] The present disclosure relates to a method of treating or preventing a condition in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (II):or a pharmaceutically acceptable salt thereof, wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0011] The present disclosure relates to a method of treating or preventing a condition in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (II):or a pharmaceutically acceptable salt thereof, in a dose ranging from 0.5-350 mg; wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0012] The present disclosure relates to a method of treating or preventing a condition in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (III):or a pharmaceutically acceptable salt thereof, wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0013] The present disclosure relates to a method of treating or preventing a condition in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (III):or a pharmaceutically acceptable salt thereof, in a dose ranging from 0.5-350wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0014] In certain embodiments, the administration of the compound is effective to result in an increase of energy expenditure in the subject without causing hyperthermia. In certain embodiments, the compound is administered orally to the subject. In certain embodiments, the compound is administered once daily to the subject.

[0015] In certain embodiments, the administration results in a reduction of fat mass. In certain embodiments, the administration results in a reduction of fat mass in the subject by at least about 5%. In certain embodiments, the administration results in reduction of fat mass while substantially maintaining lean body mass.

[0016] In certain embodiments, the administration results in inducing weight loss or sustaining weight loss. In certain embodiments, the weight loss is at least about 5% over a period of 48 or 52 weeks. In certain embodiments, the weight loss is at least 3% over 36 weeks. In certain embodiments, the weight loss is at least 2% over 24 weeks. In certain embodiments, the weight loss is at least 1% over 12 weeks. In certain embodiments, at least 80-90% of the weight loss is from fat mass.

[0017] In certain embodiments, the administration results in improving glycemic control. In certain embodiments, the administration lowers fasted blood glucose of the subject. In certain embodiments, the administration lowers HbAlc level in the subject.

[0018] The present disclosure relates to a method of treating or preventing a condition in a subject undergoing treatment with an incretin mimetic, comprising administering to the subject in need thereof an effective amount of a compound of formula (I):or a pharmaceutically acceptable salt thereof,wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0019] The present disclosure relates to a method of treating or preventing a condition in a subject undergoing treatment with an incretin mimetic, comprising administering to the subject in need thereof an effective amount of a compound of formula (II):or a pharmaceutically acceptable salt thereof, wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0020] The present disclosure relates to a method of treating or preventing a condition in a subject undergoing treatment with an incretin mimetic, comprising administering to the subject in need thereof an effective amount of a compound of formula (III):or a pharmaceutically acceptable salt thereof, wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0021] In certain embodiments, the amount of the incretin mimetic administered is reduced after the initiation of administration of the compound of formula (I), (II), or (III). In certain embodiments, the incretin mimetic is discontinued after the initiation of administration of the compound of formula (I), (II), or (III). In certainembodiments, the incretin mimetic is discontinued about 4 weeks after the initiation of administration of the compound of formula (I), (II), or (III). In certain embodiments, the incretin mimetic is discontinued about 8 weeks after the initiation of administration of the compound of formula (I), (II), or (III). In certain embodiments, the incretin mimetic is discontinued about 12 weeks after the initiation of administration of the compound of formula (I), (II), or (III). In certain embodiments, the incretin mimetic is discontinued about 24 weeks after the initiation of administration of the compound of formula (I), (II), or (III).

[0022] The present disclosure relates to a method of treating or preventing a condition in a subject, comprising administering to the subject in need thereof a compound of formula (I):pharmaceutically acceptable salt thereof, in combination with an incretin mimetic; wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0023] The present disclosure relates to a method of treating or preventing a condition in a subject, comprising administering to the subject in need thereof a compound of formula (II):pharmaceutically acceptable salt thereof, in combination with an incretin mimetic; wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0024] The present disclosure relates to a method of treating or preventing a condition in a subject, comprising administering to the subject in need thereof a compound of formula (III):pharmaceutically acceptable salt thereof, in combination with an incretin mimetic; wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0025] In certain embodiments, the incretin mimetic is semaglutide or tirzepatide. In certain embodiments, semaglutide is administered orally at about 1.5-15 mg per day or subcutaneously at about 0.25-2.4 mg per week. In certain embodiments, semaglutide is administered orally at a dose of less than about 15 mg per day. In certain embodiments, the incretin mimetic is tirzepatide administered as a subcutaneous dose of about 2.5-15 mg per week. In certain embodiments, tirzepatide is administered as a subcutaneous dose of less than about 15 mg per week. In certain embodiments, tirzepatide is administered at a dose of less than 10 mg per week.

[0026] In certain embodiments, the compound of formula (I) is administered at about 180-380 mg per day. In certain embodiments, the compound of formula (I) is administered at about 30-180 mg per day. In certain embodiments, the compound of formula (II) is administered at about 0.5 to 350 mg per day. In certain embodiments, the compound of formula (II) is administered at about 2.5 to 350 mg per week. In certain embodiments, the compound of formula (III) is administered at about 0.5 to 350 mg per day. In certain embodiments, the compound of formula (III) is administered at about 2.5 to 350 mg per week.

[0027] The present disclosure relates to a method of inducing or sustaining weight loss in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein the administration of the compound is effective to result in an increase of energy expenditure in the subject without thermogenesis.

[0028] The present disclosure relates to a method of inducing or sustaining weight loss in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (I):or a pharmaceutically acceptable salt thereof, in a dose ranging from 30-380 mg.

[0029] The present disclosure relates to a method of inducing or sustaining weight loss in a subject undergoing treatment with an incretin mimetic, comprising administering to the subject in need thereof an effective amount of a compound of formula (I):or a pharmaceutically acceptable salt thereof.

[0030] The present disclosure relates to a method of inducing or sustaining weight loss in a subject, comprising administering to the subject in need thereofan effective amount of a compound of formula (I):pharmaceutically acceptable salt thereof, in combination with an incretin mimetic; wherein the subject is not administered the compound of formula (I), or a pharmaceutically acceptable salt thereof, or the incretin mimetic prior the administration of the combination of the compound of formula (I), or pharmaceutically acceptable salts thereof, and the incretin mimetic.

[0031] The present disclosure relates to a method of inducing or sustaining weight loss in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (II):or a pharmaceutically acceptable salt thereof, wherein the administration of the compound is effective to result in an increase of energy expenditure in the subject without thermogenesis.

[0032] The present disclosure relates to a method of inducing or sustaining weight loss in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (II):or a pharmaceutically acceptable salt thereof, in a dose ranging from 0.5-350 mg.

[0033] The present disclosure relates to a method of inducing or sustaining weight loss in a subject undergoing treatment with an incretin mimetic, comprising administering to the subject in need thereof an effective amount of a compound of formula (II):or a pharmaceutically acceptable salt thereof.

[0034] The present disclosure relates to a method of inducing or sustaining weight loss in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (II):pharmaceutically acceptable salt thereof, in combination with an incretin mimetic; wherein the subject is not administered the compound of formula (II), or a pharmaceutically acceptable salt thereof, or the incretin mimetic prior the administration of the combination of the compound of formula (II), or pharmaceutically acceptable salts thereof, and the incretin mimetic.

[0035] The present disclosure relates to a method of inducing or sustaining weight loss in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (III):or a pharmaceutically acceptable salt thereof, wherein the administration of the compound is effective to result in an increase of energy expenditure in the subject without thermogenesis.

[0036] The present disclosure relates to a method of inducing or sustaining weight loss in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (III):or a pharmaceutically acceptable salt thereof, in a dose ranging from 0.5-350 mg.

[0037] The present disclosure relates to a method of inducing or sustaining weight loss in a subject undergoing treatment with an incretin mimetic, comprising administering to the subject in need thereof an effective amount of a compound of formula (III):or a pharmaceutically acceptable salt thereof.

[0038] The present disclosure relates to a method of inducing or sustaining weight loss in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (III):pharmaceutically acceptable salt thereof, in combination with an incretin mimetic; wherein the subject is not administered the compound of formula (III), or a pharmaceutically acceptable salt thereof, or the incretin mimetic prior the administration of the combination of the compound of formula (III), or pharmaceutically acceptable salts thereof, and the incretin mimetic.

[0039] The present disclosure relates to a method of treating or preventing a condition in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein the administration of the compound is effective to result in an increase of energy expenditure in the subject; thereby treating or preventing the condition.

[0040] The present disclosure relates to a method of treating or preventing a condition in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (II):or a pharmaceutically acceptable salt thereof, wherein the administration of the compound is effective to result in an increase of energy expenditure in the subject; thereby treating or preventing the condition.

[0041] In certain embodiments, the treatment or prevention of a condition is reduction of fat mass. In certain embodiments, the administration results in reduction of fat mass while substantially maintaining lean body mass.

[0042] In certain embodiments, the treatment or prevention of a condition is improving glycemic control. In certain embodiments, the administration lowers fasted blood glucose of the subject. In certain embodiments, the administration lowers HbAlc level in the subject.

[0043] The present disclosure provides a composition comprising a compound of formula (I):or a pharmaceutically acceptable salt thereof; and a compound selected from the group consisting of an ACC2 inhibitor, and an incretin mimetic.

[0044] The present disclosure provides a composition comprising a compound of formula (II):or a pharmaceutically acceptable salt thereof; and a compound selected from the group consisting of an ACC2 inhibitor and an incretin mimetic.

[0045] The present disclosure provides a composition comprising a compound of formula (III):or a pharmaceutically acceptable salt thereof; and a compound selected from the group consisting of an ACC2 inhibitor and an incretin mimetic.

[0046] All of the documents cited herein are incorporated herein by reference in their entireties.BRIEF DESCRIPTION OF THE DRAWINGS

[0047] FIG. 1 A shows energy expenditure in DIO mice, measured by indirect calorimetry, on Day 6, 2 hours post the administration of vehicle (0.5% methylcellulose) or Compound 1 (6 mg / kg, low; 20 mg / kg, mid; 60 mg / kg, high) twice daily by oral gavage to DIO mice. Baseline was defined as the 2 hour period with lowest values in the 24-hour energy expenditure curve. FIG. IB shows the change in energy expenditure in the dark phase of DIO mice, 2 hours post vehicle (0.5% methylcellulose) or Compound 1 (6 mg / kg (low), 20 mg / kg (mid), 60 mg / kg (high)) administered twice daily by oral gavage to DIO mice. FIG. 1C shows relative body weight in diet-induced obese (DIO) mice treated with vehicle (0.5% methylcellulose) or Compound 1 (6 mg / kg (low), 20 mg / kg (mid), 60 mg / kg (high)) twice daily by oral gavage for 8 days.

[0048] FIG. 2A and FIG. 2B show relative body weight for DIO mice dosed with Compound 1 either in the high-fat diet (HFD) or via oral gavage (PO) over 10 days. Briefly, DIO mice were treated with Compound 1 either dosed in HFD (60 and 120 mg / kg / day) or via oral gavage (60 mg / kg twice daily) for 10 days. A separate group of animals were used as controls / vehicles (HFD or vehicle (PO, twice daily), respectively.

[0049] FIG. 3 shows energy balance (derived by subtracting energy expenditure from energy / food intake) in DIO mice dosed with HFD alone or Compound 1 formulated in HFD (60 and 120 mg / kg / day). A positive energy balance is indicative of excesscalories, resulting in weight gain and a negative energy balance is indicative of calorie deficit, resulting in weight loss.

[0050] FIG. 4 shows results for energy expenditure in DIO mice prior to dosing (baseline) or immediately post dosing with Compound 1 twice daily (60 mg / kg / dose) by oral gavage.

[0051] FIG. 5 shows energy balance in DIO mice at baseline and for 2 days after initiation of vehicle or Compound 1 (60 mg / kg twice daily) administration.

[0052] FIG. 6 shows the relationship between energy balance and weight gain for DIO mice dosed with vehicle or Compound 1, either formulated in HFD or via oral gavage.

[0053] FIG. 7 shows RER for DIO mice at baseline (prior to dosing) or immediately post administration of Compound 1 formulated in HFD during the light phase and dark phase.

[0054] FIG. 8 shows RER for DIO mice at baseline (prior to dosing) or immediately post dosing with vehicle or Compound 1 by oral gavage, twice daily, during the light phase and dark phase.

[0055] FIGS. 9A and 9B show plasma concentration time profiles during the SAD and MAD components of the Phase 1 study of Compound 1 in healthy volunteers.

[0056] FIG. 10 shows that subjects treated with Compound 1 tended to show a dosedependent increase in energy expenditure.

[0057] FIG. 11 shows that increases in REE with Compound 1 were inversely correlated with baseline REE and exposure dependent.

[0058] FIG. 12 shows the change in RQ from day 1 to day 10 in relation to dose of Compound 1 administered.

[0059] FIG. 13 shows the relationship between increase in REE and decrease in LDL- C.

[0060] FIG. 14A shows respiratory quotient with relation to dose of Compound 1 on day 1 and day 10. FIG. 14B shows relative change in respiratory quotient from day 1 to day 10 with relation to dose of Compound 1.

[0061] FIG. 15A shows relative body weight for DIO mice dosed subcutaneously with vehicle (40% PEG300, 60% lOmM phosphate buffer, pH 8) or Compound 2 (3 mg / kg, low; 10 mg / kg, mid; 30 mg / kg, high) twice weekly. FIG. 15B shows fasted blood glucose at day 7 for DIO mice in various dose groups.

[0062] FIG. 16 shows energy expenditure, measured by indirect calorimetry, in DIO mice at baseline (prior to Compound 2 dosing), and for 48 hours immediately after subcutaneous administration of vehicle (40% PEG300, 60% lOmM phosphate buffer, pH 8) or Compound 2 (3 mg / kg, low; 10 mg / kg, mid; 30 mg / kg, high).

[0063] FIG. 17A shows RER in dark phase for mice in various dose groups. FIG. 17B shows RER in light phase for mice in various dose groups.

[0064] FIG. 18 shows results of fasting glucose, HbAlc, and OGTT iAUC in obese and diabetic db / <Xo mice in various dose groups after 3-4 weeks.

[0065] FIGS. 19A and 19B shows relative body weight in DIO mice housed at thermoneutrality (28°C) treated subcutaneously with Compound 2 monotherapy (10 mg / kg, low; 30 mg / kg, high, twice weekly), semaglutide monotherapy (SEMA, 10 nmol / kg, daily) or a combination of Compound 2 (30 mg / kg twice weekly) and SEMA for 4 weeks.

[0066] FIG. 20A shows fat mass loss and FIG. 20B shows lean body mass in DIO mice housed at thermoneutrality (28°C) treated subcutaneously with Compound 2 monotherapy (10 mg / kg, low; 30 mg / kg, high, twice weekly) for 4 weeks. FIG. 20C shows fat mass loss and FIG. 20D shows lean body mass in DIO mice housed at thermoneutrality (28°C) treated subcutaneously with Compound 2 monotherapy (30 mg / kg, twice weekly), semaglutide monotherapy (SEMA, 10 nmol / kg, daily) or a combination of Compound 2 (30 mg / kg twice weekly) and SEMA for 4 weeks.

[0067] FIGS. 21A and 21B shows HOMA-IR score in DIO mice housed at thermoneutrality (28°C) treated subcutaneously with Compound 2 monotherapy (10mg / kg, low; 30 mg / kg, high, twice weekly), semaglutide monotherapy (SEMA, 10 nmol / kg, daily) or a combination of Compound 2 (30 mg / kg twice weekly) and SEMA for 4 weeks.

[0068] FIG. 22A shows body weight and FIG. 22B shows fat mass loss in DIO mice housed at thermoneutrality (28°C) treated subcutaneously with Compound 2 monotherapy (30 mg / kg, twice weekly), semaglutide monotherapy (SEMA, 10 nmol / kg, daily) or a combination of Compound 2 (30 mg / kg twice weekly) and SEMA for 4 weeks, followed by discontinuation of SEMA with continued Compound 2 treatment for 2 additional weeks.

[0069] FIG. 23 A shows fasting plasma insulin and FIG. 23B shows HOMA-IR in DIO mice housed at thermoneutrality (28°C) treated subcutaneously with Compound 2 monotherapy (30 mg / kg, twice weekly), semaglutide monotherapy (SEMA, 10 nmol / kg, daily) or a combination of Compound 2 (30 mg / kg twice weekly) and SEMA for 4 weeks, followed by discontinuation of SEMA with continued Compound 2 treatment for 2 additional weeks.

[0070] FIG. 24 shows serum ALT levels in DIO mice housed at thermoneutrality (28°C) treated subcutaneously with Compound 2 monotherapy (30 mg / kg, twice weekly), semaglutide monotherapy (SEMA, 10 nmol / kg, daily) or a combination of Compound 2 (30 mg / kg twice weekly) and SEMA for 4 weeks, followed by discontinuation of SEMA with continued Compound 2 treatment for 2 additional weeks.

[0071] FIGS. 25A-25B show relative body weight results in an experiment where DIO mice were treated with vehicle, Compound 1 (120 mg / kg in HFD), or SEMAhigh (10 nmol / kg, QD, subcutaneously) monotherapy for 6 weeks and then after 3 weeks of treatment, SEMAiow (3 nmol / kg, QD, subcutaneously) was initiated in half the vehicle or Compound 1 cohorts through the end of the study. FIG. 25C shows fat mass results. FIG. 25D shows fasted blood glucose results. FIG. 25E shows HOMA- IR results.

[0072] FIG. 26A shows relative body weight results in an experiment where DIO mice were treated with vehicle or SEMA (10 nmol / kg, QD, subcutaneously) monotherapy for 3 weeks and then after 3 weeks of treatment, SEMA-treated animalswere randomized to 3 cohorts for an additional 3 weeks: continued SEMA treatment (SEMA— > SEMA), SEMA discontinuation (SEMA— ehicle) or SEMA replacement with Compound 1 (120 mg / kg in HFD; SEMA^ Compound 1). FIG. 26B shows fat mass results. FIG. 26C shows fasted blood glucose results. FIG. 26D shows HOMA- IR results.

[0073] FIGS. 27A-27H show results in an experiment for the groups discussed herein where —> indicates a transition to a therapy with a different composition: (1) vehicle;(2) vehicle —> SEMAi0W; (3) Compound 2; (4) Compound 2 —> Compound 2 + SEMAiow; (5) SEMAhigh. FIG. 27A shows relative body weight results for the groups. FIG. 27B shows fat mass results for the groups. FIG. 27C shows fat free mass results for the groups. FIG. 27D shows ALT (alanine aminotransferase) results for the groups. FIG. 27E shows liver triglycerides results for the groups. FIG. 27F shows muscle triglycerides results for the groups. FIG. 27G shows plasma insulin results for the groups. FIG. 27H shows plasma insulin-15 min. post glucose results for the groups.

[0074] FIG. 28 shows body weight results of subcutaneous administration of Compound 2 to non-human primates.

[0075] FIG. 29 shows body weight results of once-daily oral administration of Compound 2 to cynos.

[0076] FIG. 30A shows relative body weight results for the test groups, including groups receiving TLC-3595 or Compound 2. FIG. 30B shows body composition results for the test groups, including groups receiving TLC-3595 or Compound 2.

[0077] FIG. 31 shows a schematic diagram of a clinical trial study protocol to explore the safety, tolerability, PK, and efficacy of Compound 1.

[0078] FIG. 32 shows a schematic diagram of a clinical trial protocol to explore the safety, tolerability, PK and efficacy of a combination of Compound 1 and Tirzepatide.

[0079] FIG. 33 shows change in body weight following a single subcutaneous administration of Compound 3 at 7.5 mg / kg to male cynomolgus monkeys.

[0080] FIG. 34 shows pharmacokinetics of Compound 3 following a single subcutaneous administration at 7.5 mg / kg to male cynomolgus monkeys.

[0081] FIG. 35 shows plasma pharmacokinetics of Compound 3 following a single subcutaneous administration at 7.5 mg / kg to male C57B1 / 6 mice.

[0082] FIG. 36 shows tissue pharmacokinetics of Compound 3 following a single subcutaneous administration at 7.5 mg / kg to male C57B1 / 6 mice.

[0083] FIG. 37 shows plasma pharmacokinetics of Compound 3 following a single oral administration at 10, 50, and 100 mg / kg to male C57B1 / 6 mice.

[0084] FIG. 38A-38C shows tissue and plasma concentrations of Compound 3 following a single oral administration at 10, 50, and 100 mg / kg to male C57B1 / 6 mice at 24 h post dose. FIG. 38A shows results for liver exposure. FIG. 38B shows results for adipose exposure. FIG. 38C shows results for plasma exposure.DETAILED DESCRIPTION

[0085] The present disclosure relates to a method of preventing or treating a disease or disorder in a subject in need thereof, wherein administration of a composition of the present disclosure is effective to result in an increase of energy expenditure in the subject. An increase of energy expenditure can provide benefits or effects to a subject, thereby treating or preventing a condition, disease, or disorder. The present disclosure provides a method of reducing fat mass and / or improving glycemic control in a subject in need thereof. In certain embodiments, the administration results in reduction of fat mass while substantially maintaining lean body mass. The present disclosure provides a method of inducing weight loss. The present disclosure provides a method of sustaining weight loss. As a result of the benefits or effects from an increase in energy expenditure, a subject can be treated for diseases, such as obesity and obesity-related comorbidities, such as type 2 diabetes, sleep apnea, dyslipidemia, coronary artery disease, heart failure, or cardiovascular disease. The present disclosure provides a method, where the administration results in an increase of energy expenditure in the subject without causing undesirable side effects, such as hyperthermia.

[0086] Compositions for use in the methods include a compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof, or in combination with a compound selected from the group consisting of an ACC2 inhibitor and an incretin mimetic.

[0087] As used above, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings. If a term is missing, the conventional term as known to one skilled in the art controls.

[0088] As used herein, the terms “including,” “containing,” and “comprising” are used in their open, non-limiting sense.

[0089] The articles “a” and “an” are used in this disclosure to refer to one or more than one (z.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.

[0090] The term “and / or”, as used herein, refers to either “and” or “or”, or both.

[0091] To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term “about”. It is understood that, whether the term “about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including equivalents and approximations due to the experimental and / or measurement conditions for such given value.

[0092] The term “disorder” is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0093] The term “treatment” or “treating” with regard to a subject, as used herein, refers to improving at least one symptom, pathology or marker of the subject’s disease or disorder, either directly or by enhancing the effect of another treatment. Treating includes curing, improving, or at least partially ameliorating the disorder, and may include even minimal changes or improvements in one or more measurable markers of the disease or condition being treated. “Treatment” or “treating” does notnecessarily indicate complete eradication or cure of the disease or condition, or associated symptoms thereof. The subject receiving this treatment is any subject in need thereof. Exemplary markers of clinical improvement will be apparent to persons skilled in the art.Compounds and Compositions

[0094] The present disclosure relates to a method of treating or preventing a condition in subject, comprising administering to the subject in need thereof an effective amount of a composition of the present disclosure. Administration of the composition is effective to result in an increase of energy expenditure in the subject; thereby treating or preventing the condition. In certain embodiments, administration of the composition is effective to result in reduction in fat mass in the subject. In certain embodiments, the administration results in reduction of fat mass while substantially maintaining lean body mass. In certain embodiments, the administration of the compound is effective to induce weight loss in the subject. In certain embodiments, the administration of the compound is effective to sustain weight loss in the subject. In certain embodiments, administration of the composition is effective to improve glycemic control in the subject.

[0095] The present disclosure relates to a method comprising administering a compound of formula (I):or a pharmaceutically acceptable salt thereof.

[0096] The present disclosure relates to a method comprising administering a compound of formula (II):or a pharmaceutically acceptable salt thereof.

[0097] The present disclosure relates to a method comprising administering a compound of formula (III):or a pharmaceutically acceptable salt thereof.

[0098] Provided are also pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, and polymorphs of the compounds described herein. “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.

[0099] The term “pharmaceutically acceptable salt” of a given compound refers to salts that retain the biological effectiveness and properties of the given compound, and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptableaddition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines (i.e., NH2(alkyl)), dialkyl amines (i.e., HN(alkyl)2), trialkyl amines (i.e., N(alkyl)s), substituted alkyl amines (i.e., NH2(substituted alkyl)), di(substituted alkyl) amines (i.e., HN(substituted alkyl)2), tri (substituted alkyl) amines (i.e., N(substituted alkyl)s), alkenyl amines (i.e., NH2(alkenyl)), dialkenyl amines (i.e., HN(alkenyl)2), trialkenyl amines (i.e., N(alkenyl)3), substituted alkenyl amines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl) amines (i.e., HN(substituted alkenyl^), tri (substituted alkenyl) amines (i.e., N(substituted alkenyl)3, mono-, di- or tri- cycloalkyl amines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di- or tri- arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)s), or mixed amines, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri (iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2- dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0100] Also disclosed herein are compositions comprising more than one compound to result in an increase of energy expenditure, a reduction of fat mass, a maintenance of lean body mass, an inducement of weight loss, a sustainment of weight loss, or an improvement of glycemic control in a subject. The present disclosure provides a composition comprising a compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof; and a compound selected from the group consisting of an Acetyl-CoA carboxylase 2 (ACC2) inhibitor and an incretinmimetic. The different compounds can act on complementarity of modes of action to yield synergistic therapeutic effects.

[0101] Acetyl-CoA carboxylase (ACC) is an enzyme that converts malonyl-CoA by carboxylation of acetyl-CoA. It is involved in the metabolism of fatty acids. The ACC has two isoforms called acetyl-CoA carboxylase 1 (ACC1) and ACC2. ACC2 is mainly expressed in heart and skeletal muscle, and malonyl-CoA produced by ACC2 inhibits the oxidation of fatty acids by inhibiting carnitine palmitoyl transferase I (CPT-I). ACC2 deficient mice reduce the amount of malonyl-CoA in heart and skeletal muscle. As a result, fatty acids in the mice continuously are oxidized, and the mice lose their weight regardless of the increase in food intake.

[0102] In certain embodiments, a composition comprises an acetyl-CoA carboxylase 2 (ACC2) inhibitor. In certain embodiments, the ACC2 inhibitor is TLC- 3595. In certain embodiments, the ACC2 inhibitor is a compound disclosed in W02023 / 090411.

[0103] An incretin mimetic mimics the actions of one or more incretin hormones. Examples of incretin mimetics include Glucagon-like peptide 1 (GLP-1) receptor agonists and dipeptidyl peptidase 4 inhibitors (DPP -4 inhibitors or gliptins).

[0104] Glucagon-like peptide 1 (GLP-1) receptor agonists can selectively bind to and activate the GLP-1 receptor, which is the target for native GLP-1. GLP-1 receptor agonist can stimulate insulin secretion, lower glucagon secretion, and provide minor delay in gastric emptying. Examples of GLP-1 receptor agonists include exenatide, liraglutide, dulaglutide, semaglutide, danuglipron, orforglipron, aneliglipron, CT-996, VRB-101, AZD-5004 and AC-3174. In some cases, GLP-1 receptor agonists also interact with other receptors such as that for glucose-dependent insulinotropic peptide (GIP) or glucagon. Examples of GLP-1 receptor agonists that interact with these other receptors include tirzepatide, CT-388, VK-2735, KAI-9531, maritide and retatrutide.

[0105] In certain embodiments, the composition comprises an incretin mimetic. In certain embodiments, the incretin mimetic is a GLP-1 receptor agonist. In certain embodiments, the GLP-1 receptor agonist is semaglutide. In certain embodiments, the GLP-1 receptor agonist is tirzepatide or orforglipron.

[0106] The present disclosure provides a composition comprising a compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof; and a compound selected from the group consisting of an ACC2 inhibitor and an incretin mimetic. In certain embodiments, the ACC2 inhibitor is TLC-3595. In certain embodiments, the incretin mimetic is a GLP-1 receptor agonist. In certain embodiments, the GLP-1 receptor agonist is semaglutide. In certain embodiments, the GLP-1 receptor agonist is tirzepatide or orforglipron.

[0107] In certain embodiments, the composition comprises a compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof, and an ACC2 inhibitor. In certain embodiments, the composition comprises a compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof, and an incretin mimetic. In certain embodiments, the composition comprises a compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof, an ACC2 inhibitor, and an incretin mimetic. In certain embodiments, the ACC2 inhibitor is TLC-3595. In certain embodiments, the incretin mimetic is a GLP-1 receptor agonist. In certain embodiments, the GLP-1 receptor agonist is semaglutide. In certain embodiments, the GLP-1 receptor agonist is tirzepatide or orforglipron.

[0108] In some embodiments, the compounds are co-formulated in a single dosage form. In some embodiments, the compounds are administered in separate dosage forms. In some embodiments, the compounds are administered at approximately the same time, in a separate dosage form. In some embodiments, the compounds are administered separately at different times in relation to the other compounds.Pharmaceutical compositions

[0109] One or more compounds of the compositions described herein can be administered as a pharmaceutical composition orally or parenterally. In certain embodiments, the compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof, is administered orally. In the case of oral administration, it may be in any usual form such as tablets, granules, powders, capsules and the like. In certain embodiments, the administration of the compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof, is parenterally. When the compound is parenterally administered, any usual form is preferable injections and the like.

[0110] One or more compounds of the compositions described herein may be orally administered as a pharmaceutical composition in any orally acceptable dosage form including, but not limited to, tablets, granules, powders, capsules, sprinkles, aqueous suspensions or solutions. In certain embodiments, the pharmaceutical composition is in form of a tablet or capsule. In certain embodiments, the pharmaceutical composition is in form of a suspension.

[0111] Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

[0112] One or more compounds may be administered as a pharmaceutical composition in parenteral dosage form.

[0113] In certain embodiments, pharmaceutical compositions of the present disclosure are solutions. In certain embodiments, pharmaceutical compositions of the present disclosure are solids. In certain embodiments, pharmaceutical compositions of the present disclosure are to be reconstituted with an aqueous solution such as a buffer or water for injection.

[0114] In certain embodiments, pharmaceutical compositions of the present disclosure are suitable for administration by injection or infusion. In certainembodiments, pharmaceutical compositions of the present disclosure are suitable for subcutaneous administration. In certain embodiments, pharmaceutical compositions of the present disclosure are suitable for intramuscular administration. In certain embodiments, pharmaceutical compositions of the present disclosure are suitable for intravenous administration.

[0115] The present disclosure provides for a pharmaceutical composition that is safe and well tolerated after single or multiple doses. In certain embodiments the administration of the pharmaceutical composition results in a prolonged half-life, supporting dosing once-daily, or at longer intervals. In certain embodiments, administration of the pharmaceutical composition results in a low ratio of plasma to liver concentration due to liver targeting, thereby minimizing systemic exposures associated with toxicity (e.g., hyperthermia). Also, the pharmaceutical composition results in plasma and liver concentrations such that the compound reaches concentrations associated with efficacy in preclinical models (e.g., weight loss, improvements in hepatic and plasma triglycerides).

[0116] In some embodiments, the administration comprises about 3-120 mg of the compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof. In some embodiments, the administration comprises about 3, 6, 15, 30, 60, or 120 mg of the compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof. In some embodiments, the administration of the compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof, is once daily.

[0117] In some embodiments, the administration comprises about 3-380 mg of the compound of formula (I), or pharmaceutically acceptable salts thereof. In some embodiments, the administration comprises about 30-380 mg or 90-380 mg of the compound of formula (I), or pharmaceutically acceptable salts thereof. In some embodiments, the administration comprises about 30-360 mg or 90-360 mg of the compound of formula (I), or pharmaceutically acceptable salts thereof. In some embodiments, the administration of the compound of formula (I), or pharmaceutically acceptable salts thereof, is oral. In some embodiments, the administration of the compound of formula (I), or pharmaceutically acceptable salts thereof, is once daily.

[0118] In some embodiments, the administration comprises about 30-360 mg of the compound of formula (I), or pharmaceutically acceptable salts thereof. In some embodiments, the administration comprises about 30-135 mg of the compound of formula (I), or pharmaceutically acceptable salts thereof. In some embodiments, the administration comprises about 135-360 mg, 135-380 mg, 180-380 mg, or 270-380 mg of the compound of formula (I), or pharmaceutically acceptable salts thereof. In some embodiments, the administration comprises about 3, 6, 15, 30, 60, 90, 120, 135, 180, 240, 270, 360, or 380 mg of the compound of formula (I), or pharmaceutically acceptable salts thereof. In some embodiments, the administration of the compound of formula (I), or pharmaceutically acceptable salts thereof, is oral. In some embodiments, the administration of the compound of formula (I), or pharmaceutically acceptable salts thereof, is once daily.

[0119] In some embodiments, the administration comprises about 0.5-350 mg of the compound of formula (II), or pharmaceutically acceptable salts thereof. In some embodiments, the administration comprises about 0.5-300; 0.5-250; 0.5-200; 0.5-150; or 0.5-100 mg of compound of formula (II), or pharmaceutically acceptable salts thereof. In some embodiments, the administration comprises about 0.5-50 mg of compound of formula (II), or pharmaceutically acceptable salts thereof. In some embodiments, the administration of the compound of formula (II), or pharmaceutically acceptable salts thereof, is oral. In some embodiments, the administration of the compound of formula (II), or pharmaceutically acceptable salts thereof, is once daily.

[0120] In some embodiments, the administration comprises about 2.5-350 mg of the compound of formula (II), or pharmaceutically acceptable salts thereof. In some embodiments, the administration comprises about 2.5-300; 2.5-250; 2.5-200; 2.5-150; 2.5-100; or 2.5-50 mg of the compound of formula (II), or pharmaceutically acceptable salts thereof. In some embodiments, the compound of formula (II), or pharmaceutically acceptable salts thereof, is administered by subcutaneous injection. In some embodiments, the administration of the compound of formula (II), or pharmaceutically acceptable salts thereof, is once weekly.

[0121] In some embodiments, the administration comprises about 0.5-350 mg of the compound of formula (III), or pharmaceutically acceptable salts thereof. In someembodiments, the administration comprises about 0.5-300; 0.5-250; 0.5-200; 0.5-150; or 0.5-100 mg of compound of formula (III), or pharmaceutically acceptable salts thereof. In some embodiments, the administration comprises about 0.5-50 mg of compound of formula (III), or pharmaceutically acceptable salts thereof. In some embodiments, the administration of the compound of formula (III), or pharmaceutically acceptable salts thereof, is oral. In some embodiments, the administration of the compound of formula (III), or pharmaceutically acceptable salts thereof, is once daily.

[0122] In some embodiments, the administration comprises about 2.5-350 mg of the compound of formula (III), or pharmaceutically acceptable salts thereof. In some embodiments, the administration comprises about 2.5-300; 2.5-250; 2.5-200; 2.5-150; 2.5-100; or 2.5-50 mg of the compound of formula (III), or pharmaceutically acceptable salts thereof. In some embodiments, the compound of formula (III), or pharmaceutically acceptable salts thereof, is administered by subcutaneous injection. In some embodiments, the administration of the compound of formula (III), or pharmaceutically acceptable salts thereof, is once weekly.Co-adininistration

[0123] It is contemplated that the compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof, could be used in a desirable combination product with an additional compound, co-administered with an additional compound, or administered to a subject already on an additional compound.

[0124] In some embodiments, the compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof, is co-formulated with one or more additional compounds. In some embodiments, the compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof, and the one or more additional compounds are co-formulated in a single dosage form. In some embodiments, the compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof, and the one or more additional compounds are administered in separate dosage forms. In some embodiments, the compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof, and the one or more additional compounds are administered at approximately the same time, in a separate dosage form. In some embodiments, the compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof,and the one or more additional compounds are administered separately at different times in relation to each other.

[0125] One or more compounds of the present disclosure can be administered as a pharmaceutical composition orally or parenterally. In certain embodiments, the compounds of the present disclosure (if more than one compound) can be administered as a pharmaceutical composition in the same route, orally or parenterally. In certain embodiments, the compounds of the present disclosure (if more than one compound) can be administered as a pharmaceutical composition in different routes, e.g., one is administered orally and the other is administered parenterally.

[0126] In some embodiments, the administration comprises administration of a compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof, with an additional compound. In some embodiments, the additional compound is an ACC2 inhibitor. In some embodiments, the additional compound is an incretin mimetic, such as a GLP-1 receptor agonist.

[0127] In some embodiments, the method comprises administration of a compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof, and an incretin mimic. In certain instances, the administration of the incretin mimic is discontinued before the administration of the compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof, is discontinued.

[0128] In certain embodiments, the compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof, is administered to a subject, wherein the subject is undergoing treatment with an incretin mimetic. In some instances, the subject is already being administered an incretin mimetic at the recommended dosage of the incretin mimetic.

[0129] In certain embodiments, the amount of the incretin mimetic is reduced after the initiation of administration of the compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof.

[0130] In certain embodiments, the amount of the incretin mimetic is reduced prior to, or concurrent with, the initiation of administration of the compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof.

[0131] In certain embodiments, the dose of the incretin mimetic is reduced after about 2-52 weeks (e.g., 2, 4, 8, 12, 24, 36, 48 or 52 weeks) after the initiation of administration of the compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof.

[0132] In certain embodiments, the incretin mimetic is discontinued after the initiation of administration of the compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof.

[0133] In certain embodiments the administration of the incretin mimetic is discontinued prior to, or concurrent with the initiation of administration of the compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof.

[0134] In certain embodiments the administration of the incretin mimetic is discontinued about 2-52 weeks (e.g., 2, 4, 8, 12, 24, 48 or 52 weeks) after the initiation of administration of the compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof.

[0135] In certain embodiments, the method comprises administration to a subject of the compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof, in combination with an incretin mimetic. In some instances, the subject is administered the compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof, prior to the start of administration of the incretin mimetic. In certain embodiments, the administration of the compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof, is initiated about 4-24 weeks (e.g., 4, 8, 12, or 24 weeks) prior to the initiation of administration of the incretin mimetic.

[0136] In certain embodiments, the method comprises administering to the subject an incretin mimetic, such as dulaglutide, liraglutide, semaglutide, tirzepatide, or orforglipron in combination with a compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof.

[0137] In certain embodiments, the method comprises orally administering to the subject an incretin mimetic at 1.5-45, 1.5-15, 3-15, 3.5-15, or 5-15 mg / day. In certain embodiments, the method comprises subcutaneously administering to the subject an incretin mimetic at 0.25-15, 0.25-2.4, 0.25-7.2, or 2.5-15 mg / week.

[0138] In certain embodiments, the incretin mimetic is semaglutide. In certain embodiments, the semaglutide is administered orally at about 1.5-15, 3-15, or 5-15 mg / day. In certain embodiments, semaglutide is administered orally at about 1.5-15 mg per day. In certain embodiments, semaglutide is administered orally at a dose of less than about 15 mg per day. In certain embodiments, semaglutide is administered by subcutaneous injection at a dose of 0.25-2.4 or 0.25-7.2 mg / week. In certain embodiments, semaglutide is administered subcutaneously at about 0.25-2.4 mg per week.

[0139] In certain embodiments, the incretin mimetic is tirzepatide. In certain embodiments, tirzepatide is administered subcutaneously at a dose of about 2.5-15 mg per week. In certain embodiments, tirzepatide is administered as a subcutaneous dose of less than about 15 mg per week. In certain embodiments, tirzepatide is administered at a dose of less than 10 mg per week. In certain embodiments, tirzepatide is administered at a dose of less than 7.5, 5, or 2.5 mg per week.

[0140] In certain embodiments, the incretin mimetic is semaglutide. In certain embodiments, the dose of semaglutide changes over a regimen. In certain embodiments the patient is administered a combination regimen comprising a dose of semaglutide and the compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof. In certain embodiments, the dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, is about 30-270, 135-270, or 180- 380 mg / day.

[0141] In certain embodiments, the incretin mimetic is tirzepatide. In certain embodiments, the dose of tirzepatide changes over a regimen. For example, in certain embodiments, the dose of tirzepatide administered is 2.5 mg / week for about 4 weeks, and 5 mg / week thereafter. In certain embodiments, the dose of tirzepatide is further increased to 10 mg / week after 8 weeks of treatment. In certain embodiments the patient is administered a combination regimen comprising a dose of tirzepatide of lessthan 15 mg / week and the compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof. In certain embodiments, the dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, is about 30-270, 135-270, or 180- 380 mg / day. In certain embodiments, the dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, is about 135-270 mg / day.

[0142] In certain embodiments, the compound of formula (I), or a pharmaceutical salt thereof, is administered at about 180 mg per day. In certain embodiments, the compound of formula (I), or pharmaceutical salt thereof, is administered at a dose of 180-380 mg or 270-380 mg per day. In certain embodiments, when administered with an incretin mimetic, the compound of formula (I), or pharmaceutical salt thereof, is administered at about 30-180 mg or 30-270 mg per day.

[0143] In certain embodiments, when administered with an incretin mimetic, the compound of formula (II), or a pharmaceutical salt thereof, is administered at a dose of about 0.5-50 mg per day. In certain embodiments, the compound of formula (II), or a pharmaceutical salt thereof, is administered at a dose of 5-30 mg per day. In certain embodiments, the compound of formula (II), or a pharmaceutical salt thereof, is administered orally, once daily. In certain embodiments the compound of formula (II), or pharmaceutical salt thereof, is administered as a weekly subcutaneous dose of about 2.5-350 mg per week. In certain embodiments, when administered with an oral incretin mimetic, the compound of formula (II), or pharmaceutical salts thereof, is administered as an oral dose of about 0.5-50 mg per day. In certain embodiments, when administered with an injectable incretin mimetic, the compound of formula (II), or a pharmaceutical salt thereof, is administered at a subcutaneous dose of about 2.5- 350 mg per week.

[0144] In certain embodiments, when administered with an incretin mimetic, the compound of formula (III), or a pharmaceutical salt thereof, is administered at a dose of about 0.5-50 mg per day. In certain embodiments, the compound of formula (III), or a pharmaceutical salt thereof, is administered at a dose of 5-30 mg per day. In certain embodiments, the compound of formula (III), or a pharmaceutical salt thereof, is administered orally, once daily. In certain embodiments the compound of formula (III), or pharmaceutical salt thereof, is administered as a weekly subcutaneous dose of about 2.5-350 mg per week. In certain embodiments, when administered with an oralincretin mimetic, the compound of formula (III), or pharmaceutical salts thereof, is administered as an oral dose of about 0.5-50 mg per day. In certain embodiments, when administered with an injectable incretin mimetic, the compound of formula (III), or a pharmaceutical salt thereof, is administered at a subcutaneous dose of about 2.5-350 mg per week.Conditions

[0145] Obesity is a complex disease that reflects interactions between environmental influences and genetic variants that impact the behaviors and metabolism affecting weight gain, and the responses to fluctuations in energy balance. Excess fat mass typically evolves slowly due to positive energy balance over the longterm. With progressive weight gain, excess lipids — mainly triglycerides — accumulate in adipose tissue and many additional body compartments, a phenomenon linked with many of the metabolic disturbances and adverse outcomes associated with obesity. Adipocytes and macrophages within the adipose tissue synthesize proinflammatory adipokines and cytokines, which cause a low-grade systemic inflammatory state and contribute to insulin resistance (IR). The ectopic accumulation of lipid in organs beyond adipose has important pathophysiological consequences. Ectopic lipid accumulation in insulin-target tissues (e.g., skeletal muscle, liver, adipose tissue) have been shown to trigger whole-body IR. Similarly, accumulation of lipid in the liver causes the steatosis characteristic of MASLD / MASH, where lipotoxic intermediates drive cellular injury, apoptosis, inflammation, and progressive hepatic fibrosis. These data highlight the deleterious consequences of excess fat mass and the unmet need for novel therapeutics that can reduce fat mass for patients with obesity, diabetes and other metabolic disorders.

[0146] While the efficacy of incretin mimetics has heralded a new era in the pharmacotherapy of obesity, these therapies require subcutaneous administration and are limited by adverse effects (e.g., nausea, vomiting, diarrhea, constipation, abdominal pain), and the potential for serious complications (e.g., pancreatitis, gallbladder disease, hypoglycemia). These factors limit the ability of some patients to achieve their target dose and / or to maintain long-term adherence. Moreover, reductions in energy expenditure (EE) occur in response to GLP-1 receptor agonists that serve to limit the magnitude of initial weight loss and the subsequent ability tomaintain it. In this regard, weight regain invariably occurs upon cessation of GLP-1 receptor agonist therapy. Finally, incretin therapies are associated with substantial loss of lean body mass, which accounts for 15 to 40% of lost weight. This loss of lean, highly thermogenic tissue, particularly muscle, contributes to the reductions in EE observed with these therapies and may be associated with other complications (e.g., frailty). The present disclosure provides a method, where the administration results in reduction of fat mass while substantially maintaining lean body mass.

[0147] In certain embodiments, the present disclosure provides for methods of treating or preventing obesity or obesity related comorbidities. Obesity is associated with other conditions known as comorbidities. Examples of obesity related comorbidities include metabolic disorder (e.g., diabetes, insulin resistance, hypertension), hyperlipidemia (e.g., dyslipidemia), liver disease, cirrhosis, metabolic liver disease, liver fibrosis, cardiovascular disease (e.g., coronary artery disease, heart failure), and obstructive sleep apnea.

[0148] In certain embodiments, the present disclosure provides for methods and pharmaceutical compositions of therapeutics that can be used as monotherapy, or in combinations with incretin mimetics, to exhibit efficacy with respect to reduction of fat mass, induction of weight loss, maintenance of weight loss and while at the same time exhibiting an acceptable safety profile. The present disclosure provides a method, where the administration results in an increase of energy expenditure in the subject without causing hyperthermia.

[0149] The present disclosure provides methods of treating or preventing a condition in a subject, comprising administering to the subject in need thereof an effective amount of a composition of the present disclosure, wherein administration of the composition is effective to result in an increase of energy expenditure in the subject; thereby treating or preventing the condition. The administration of the compound in the subject results in an increase of energy expenditure without causing hyperthermia in the subject.

[0150] The term “energy expenditure” refers to the amount of energy (calories), that a subject uses, for example, to breathe, circulate blood, digest food, support routinephysiological functions and be physically active. To prevent weight gain, energy intake (caloric intake) should be balanced with energy expenditure.

[0151] Daily energy expenditure has four components: 1) sleeping metabolic rate, 2) the energy cost of arousal, 3) the thermic effect of food (or diet-induced energy expenditure (DEE)), and 4) the energy cost of physical activity or activity-induced energy expenditure (AEE). Resting energy expenditure (REE) is the metabolic rate for maintaining vital physiological functions of a subject that is in rest, awake, in a fasted state, and in a thermoneutral environment. Sleeping metabolic rate and the energy cost of arousal are combined and referred to as resting energy expenditure.

[0152] The metabolism of a subject requires energy production by consumption of fuel. In the process, oxygen is consumed and carbon dioxide is produced. Measuring energy expenditure can be accomplished by measuring heat production or heat loss, via direct calorimetry. The measurement of heat production by measuring oxygen consumption and / or carbon dioxide production can be accomplished via indirect calorimetry or DLW (doubly labeled water) technique. The DLW technique can be used as a method for measurement of free-living energy expenditure in animals.

[0153] In certain embodiments, the subject has a below average or average energy expenditure. In certain embodiments, the subject has a below average energy expenditure. In certain embodiments, the subject has an average energy expenditure.

[0154] In certain embodiments, the energy expenditure in the subject is increased by at least about 5%, wherein the energy expenditure is measured by an indirect calorimeter or DLW technique. In certain embodiments, the energy expenditure in the subject is increased by at least about 5, 10, 15, 20, 25, 30, 35, or 40%, wherein the energy expenditure is measured by an indirect calorimeter or DLW technique. In certain embodiments, the energy expenditure is measured after a single dose. In certain embodiments, the energy expenditure is measured over 1-10 days, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days. In certain embodiments, the energy expenditure is a resting energy expenditure.

[0155] The Respiratory Exchange Ratio (RER) or respiratory quotient (RQ) is the proportion of CO2 produced by the body to the quantity of O2 consumed by the body. The RER or RQ, which typically ranges between 0.7 and 1.0, is an indicator ofmetabolic fuel or substrate use in tissues; it should be calculated under resting or steady-state exercise conditions. A ratio of about 0.7 is indicative of mixed fat use, whereas a ratio of 1.0 indicates mainly the use of carbohydrates. In certain embodiments, the administration of a composition of the present disclosure to the subject results in a RER or RQ of about 0.7. In certain embodiments, administration of a composition of the present disclosure to the subject decreases the respiratory quotient in the subject. In certain embodiments, administration of a composition of the present disclosure to the subject decreases the respiratory quotient in the subject by at least about 1%, wherein the respiratory quotient is measured by an indirect calorimeter. In certain embodiments, administration of a composition of the present disclosure to the subject decreases the respiratory quotient in the subject by at least about 1, 2, 3, 4, 5, or 6%, wherein the respiratory quotient is measured by an indirect calorimeter. In certain embodiments, the respiratory quotient is measured after a single dose. In certain embodiments, the respiratory quotient is measured over 1-10 days, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days.

[0156] Energy expenditure relates to energy balance. When energy expenditure exceeds energy intake, energy balance is negative and leads to weight loss. When intake equals expenditure, equilibrium results and body fat is maintained, regardless of whether the body weight is at, above, or below normal. The present disclosure provides methods to increase energy expenditure and affect energy balance. Fat, as a substrate for energy metabolism, is at the bottom of the oxidation hierarchy that determines fuel selection and studies show a link between macronutrient balance for fat and energy balance.

[0157] Fat oxidation is the process by which a body breaks down fats (such as triglycerides) into smaller molecules, such as free fatty acids and glycerol, which can then be used as a source of energy. This process occurs primarily in the mitochondria of cells and is part of the body’s energy metabolism. There is a relation of fat oxidation with the body fat content. Usually, there is an observed reduction in fat oxidation in subjects with greater body fat, which may play a role in maintenance of obesity. A low fat oxidation may make a subject prone to weight gain. The present disclosure provides methods to increase fat oxidation.

[0158] The present disclosure provides methods of treating or preventing a condition in subject, comprising administering to the subject in need thereof an effective amount of a composition of the present disclosure, wherein administration of the composition is effective to result in reduction of fat mass in the subject. In certain embodiments, the compositions of the disclosure reduce fat mass and improve metabolism in subjects.

[0159] Adipose tissue, or adiposity, body fat, fat, or fat mass, is connective tissue comprising adipocytes. Adipose tissue includes white adipose tissue (WAT), which stores energy, and brown adipose tissue (BAT), which generates body heat. Body mass can be divided into two components: adipose tissue and lean body mass (or lean mass; e.g., including muscle, organs, and bones).

[0160] In subjects, adipose tissue can be located beneath the skin (subcutaneous fat), around internal organs (visceral fat), in bone marrow (yellow bone marrow), intermuscular (muscular system), and in the breast (breast tissue).

[0161] In certain embodiments, the fat mass is visceral fat. In certain embodiments, fat mass is central adiposity, which is also abdominal fat or truncal fat. Central fat is a condition of excessive concentration of visceral fat around the stomach and abdomen. Abdominal adipose tissue in a subject can be measured by magnetic resonance imaging (MRI) and computed tomography (CT) and a range of other techniques, such as BMI, waist circumference (WC), bioelectrical impedance (BIA) devices, and dual X-ray absorptiometry (DXA).

[0162] In certain embodiments, the fat mass is subcutaneous fat. Subcutaneous fat can be found below the skin in the hypodermis. Excessive levels of subcutaneous fat can lead to serious health issues. Subcutaneous fat in a subject can be measured by caliper and ultrasound. Calipometry is an easy and well-tested method that measures the subcutaneous fat tissue depth (SFT) through skinfold thickness and can be used to determine total body fat by applying a specific skinfold equation, which calculates total body fat on the basis of body density manifested through regression analysis. Ultrasound device can be used to differentiate subcutaneous from visceral fat and has been applied for skinfold measurements as well.

[0163] In certain embodiments, the reduction in fat mass occurs while substantially maintaining lean body mass. In certain embodiments, the reduction in fat mass is at least about 5% over a period of time. In certain embodiments, the reduction in fat mass is at least about 5, 10, 15, 20, or 25% over a period of time. In certain embodiments, the reduction in fat mass is at least about 1, 2, 3, 4, or 5% over a period of time. In certain embodiments, the reduction in fat mass is at least about 6, 7, 8, 9, or 10% over a period of time. In certain embodiments, the reduction in fat mass is at least about 11, 12, 13, 14, or 15% over a period of time. In certain embodiments, the reduction in fat mass is at least about 16, 17, 18, 19, or 20% over a period of time. In certain embodiments, the reduction in fat mass is at least about 21, 22, 23, 24, or 25% over a period of time. In certain embodiments, the period time is 3 months, 6 months, or 12 months. In certain embodiments, the period time is 4-12 weeks, 4-24 weeks, 4- 36 weeks, or 4-52 weeks. In certain embodiments, the period time is 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, or 52 weeks.

[0164] In certain embodiments, the administration results in weight loss, where a majority of the weight loss is from reduction of fat mass. In certain embodiments, the administration results in greater than about 1-5% (e.g., 1, 2, 3, 4, or 5 %) reduction in a subject’s body fat mass percentage, which is a percentage of fat mass of the total body mass. In certain embodiments, the administration results in greater than about 1- 5% (e.g., 1, 2, 3, 4, or 5 %) reduction in total body weight, and at least about 80-100% of the weight loss is fat mass loss. In certain embodiments, at least about 80-90% of the weight loss is fat mass loss. In certain embodiments, at least about 80, 85, 90, 95, or 100% of the weight loss is fat mass loss. In certain embodiments, the period time for the change in body fat mass percentage and total body weight percentage is 3 months, 6 months, or 12 months. In certain embodiments, the period time is 4-12 weeks, 4-24 weeks, 4-36 weeks, or 4-52 weeks. In certain embodiments, the period time is 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, or 52 weeks.

[0165] In certain embodiments, fat mass is reduced, while maintaining lean body mass. In certain embodiments, there is no substantial loss in lean body mass. In certain embodiments, there is a loss of less than about 15% of lean body mass over a period of time. In certain embodiments, there is a loss of less than about 5%, 10%, or 15% of lean body mass over a period of time. In certain embodiments, the reductionin lean body mass is less than about 1, 2, 3, 4, or 5% over a period of time. In certain embodiments, the reduction in lean body mass is less than about 6, 7, 8, 9, or 10% over a period of time. In certain embodiments, the reduction in learn mass is less than about 11, 12, 13, 14, or 15% over a period of time. In certain embodiments, the period time is 3 months, 6 months, or 12 months. In certain embodiments, the period time is 4-12 weeks, 4-24 weeks, 4-36 weeks, or 4-52 weeks. In certain embodiments, the period time is 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, or 52 weeks.

[0166] In certain embodiments, the administration of a composition of the present disclosure is directed to the liver.

[0167] In certain embodiments, the administration of a composition of the present disclosure is effective to induce weight loss. In certain embodiments, the administration of a composition of the present disclosure is effective to sustain weight loss. In certain embodiments, a composition for inducing weight loss comprises a compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof. In certain embodiments, a composition for sustaining weight loss comprises a compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof.

[0168] In certain embodiments, the subject can be obese, overweight, or of normal body mass index (“BMI”). In certain embodiments, the subject is obese, determined by a BMI of over about 30 kg / m2. In certain embodiments, the subject is overweight, determined by a BMI of between about 25 kg / m2and 30 kg / m2. In certain embodiments, the subject is of normal BMI, which is less that about 25 kg / m2.

[0169] In certain embodiments, subject has a body mass index of more than about 30.0 kg / m2. In certain embodiments, subject has a body mass index of less than about any of 30.0 kg / m2, 29.0 kg / m2, 28.0 kg / m2, 27.0 kg / m2, 26.0 kg / m2, and 25.0 kg / m2.In certain embodiments, the subject has a body mass index of less than about any of 25.0 kg / m2, 24.0 kg / m2, 23.0 kg / m2, 22.0 kg / m2, 21.0 kg / m2, 20 kg / m2, 19.0 kg / m2, and 18.5 kg / m2.

[0170] In certain embodiments, the present disclosure provides methods for inducing weight loss in a subject, comprising administering to the subject in need thereof an effective amount of a composition of the present disclosure. In certain embodiments, the weight loss is about 5, 10, or 15% over a time period. In certainembodiments, the weight loss is about 1, 2, 3, 4, or 5% over a time period. In certain embodiments, the weight loss is about 6, 7, 8, 9, or 10% over a time period. In certain embodiments, the weight loss is about 11, 12, 13, 14, or 15% over a time period. In certain embodiments, the period time is 3 months, 6 months, or 12 months. In certain embodiments, the period time is 4-12 weeks, 4-24 weeks, 4-36 weeks, or 4-52 weeks. In certain embodiments, the period time is 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, or 52 weeks.

[0171] In certain embodiments, the weight loss is at least about 5% over a period of 12, 24, 36, 48, or 52 weeks. In certain embodiments, the weight loss is at least about 4% over a period of 12, 24, 36, 48, or 52 weeks. In certain embodiments, the weight loss is at least 3% over 12, 24, 36, 48, or 52 weeks. In certain embodiments, the weight loss is at least 2% over 12, 24, 36, 48, or 52 weeks. In certain embodiments, the weight loss is at least 1% over 12, 24, 36, 48, or 52 weeks.

[0172] In certain embodiments, the weight loss is at least about 5% over a period of 52 weeks. In certain embodiments, the weight loss is at least about 4% over a period of 52 weeks. In certain embodiments, the weight loss is at least 3% over 36 weeks. In certain embodiments, the weight loss is at least 2% over 24 weeks. In certain embodiments, the weight loss is at least 1% over 12 weeks.

[0173] In certain embodiments, the present disclosure provides methods of sustaining weight loss in subject, comprising administering to the subject in need thereof an effective amount of a composition of the present disclosure. Weight maintenance or sustaining weight loss refers to any manner of preventing, reducing, or controlling weight gain. This can include after an initial weight loss (e.g., in a subject taking a weight loss medication), but need not. For example, sustaining weight loss in a subject can include preventing weight gain after an initial weight loss, reducing the amount of weight gained after an initial weight loss, controlling weight gain after an initial weight loss or slowing the rate of weight gain after an initial weight loss.

[0174] In certain embodiments, a subject does not gain substantial weight after an initial weight loss. An initial weight loss can apply to a regimen where a subject is administered an incretin mimetic and the initial weight loss results from prior to thereduction in dose or discontinuation of the incretin mimetic. For example, weight maintenance or sustaining weight loss refers to continued weight loss after an initial weight loss; no weight gain after an initial weight loss; or weight gain after an initial weight loss of less than about 1-15% during administration of a composition of the present disclosure. In certain embodiments, the weight gain after an initial weight loss is less than about 5, 10, or 15%. In certain embodiments, the weight gain after an initial weight loss is less than about 1, 2, 3, 4, or 5%. In certain embodiments, the weight gain after an initial weight loss is less than about 6, 7, 8, 9, or 10%. In certain embodiments, the weight gain after an initial weight loss is less than about 11, 12, 13, 14, or 15%.

[0175] In certain embodiments, a composition for promoting weight loss or weight maintenance comprises a compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof, in combination with at least one additional compound, wherein the administration of the at least one additional compound is discontinued before the administration of the compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof, is discontinued. In some embodiments, the additional compound is an incretin mimetic, such as a GLP-1 receptor agonist, such as semaglutide.

[0176] In certain embodiments, the present disclosure provides a method where the compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof, is administered to a subject, wherein the subject is undergoing treatment with an incretin mimetic. In some instances, the subject is already being administered an incretin mimetic at the recommended dosage of the incretin mimetic. In certain embodiments, the administration of the compound of formula (I), (II), or (III) or pharmaceutically acceptable salts thereof, in combination with the incretin mimetic, can induce more weight loss in such subjects, relative to subjects who continue treatment with the incretin mimetic alone.

[0177] In certain embodiments of the method, the amount of the incretin mimetic is reduced after the initiation of administration of the compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof. After the reduction of the amount of incretin mimetic in the method, continued administration of the compound offormula (I), (II), or (III), or pharmaceutically acceptable salts thereof, can sustain weight loss.

[0178] In certain embodiments of the method, the incretin mimetic is discontinued about 4-52 weeks (e.g., 4, 8, 12, 24, 36, 48, or 52 weeks) after the initiation of administration of the compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof. After the discontinuation of the incretin mimetic, continued administration of the compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof, can sustain weight loss.

[0179] In certain embodiments, the method comprises administration to a subject of an effective amount of the compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof, in combination with an incretin mimetic. In some instances, the subject is not administered the compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof, or the incretin mimetic prior the administration of the combination of the compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof, and the incretin mimetic.

[0180] The present disclosure provides methods of treating or preventing a condition in subject, comprising administering to the subject in need thereof an effective amount of a composition of the present disclosure, wherein administration of the composition is effective to improve glycemic control in the subject.

[0181] Glycemic control can be determined by levels of plasma glucose concentration or HbAlc. In the present disclosure, “improvement of glycemic control” or “glycemic control” refers to improvement of postprandial plasma glucose concentration, improvement of fasting plasma glucose concentration, or / and improvement of the HbAlc (hemoglobin Ale) value.

[0182] In certain embodiments, the present disclosure provides methods of treating or preventing a condition in subject, comprising administering to the subject in need thereof an effective amount of a composition of the present disclosure, wherein administration of the composition is effective to reduce blood glucose level in the subject.

[0183] In certain embodiments, the administration of a composition of the present disclosure lowers the fasted blood glucose of the subject, where the fasted blood glucose is measured by a standard blood glucose meter, continuous glucose meter, or other glucose measuring device.

[0184] In certain embodiments, the administration of a composition of the present disclosure lowers the fasted blood glucose of the subject by at least about 5% over seven days, where the fasted blood glucose is measured by a standard blood glucose meter, continuous glucose meter, or other glucose measuring device. In certain embodiments, the administration of a composition of the present disclosure lowers the fasted blood glucose of the subject by at least about 5, 10, 15, or 20% over seven days, where the fasted blood glucose is measured by a standard blood glucose meter, continuous glucose meter, or other glucose measuring device. In certain embodiments, the fasted blood glucose of the subject is lowered over the time period while the subject is administered a composition of the present disclosure with a dosing regimen.

[0185] In certain embodiments, the subject exhibits a reduction in blood glucose level as measured prior to administration compared to a vehicle. In certain embodiments, the improvement in glucose tolerance during an oral glucose tolerance test is about 25-40% over a period of 6 weeks. In certain embodiments, the improvement in glucose tolerance during an oral glucose tolerance test is about 25- 30% over a period of 6 weeks. In certain embodiments, the improvement in glucose tolerance during an oral glucose tolerance test is about 30-40% over a period of 6 weeks.

[0186] Glucose tolerance refers to a subject’s capacity to manage blood sugar levels after consuming glucose. For example, glucose tolerance can refer to a subject’s ability to remove glucose from the bloodstream and store it for energy. Thus, an improvement in glucose tolerance can result in maintenance of a glucose level in a healthy range. In certain embodiments, administration of a composition of the present disclosure results in maintaining blood glucose level of a subject during the time period of administration.

[0187] In certain embodiments, the present disclosure provides methods of treating or preventing a condition in subject, comprising administering to the subject in need thereof an effective amount of a composition of the present disclosure, wherein administration of the composition is effective to reduce HbAlc in the subject.

[0188] Ale is a minor component of hemoglobin to which glucose is bound. Ale also is referred to as glycosylated or glucosylated hemoglobin. Ale may be separated by charge and size from the other hemoglobin A components in blood using high performance liquid chromatography (HPLC). Because Ale is not affected by shortterm fluctuations in blood glucose concentrations, for example, due to meals, blood can be drawn for Ale testing without regard to when food was eaten. In healthy, nondiabetic patients the Ale level is less than 7% of total hemoglobin. The normal range is 4-5.9%. In poorly controlled diabetes, it can be 8.0% or above. It has been demonstrated that the complications of diabetes can be delayed or prevented if the Ale level can be kept close to 7%. In certain embodiments, the subject has an HbAlc value above 6.5%, 7.0%, 7.5%, or 8%.

[0189] In certain embodiments, the administration of a composition of the present disclosure lowers HbAlc in a subject. In certain embodiments, the administration of a composition of the present disclosure lowers HbAlc in a subject, where HbAlc is measured by a blood test.Comorbidities

[0190] In certain embodiments, the subject to be treated may have at least one additional disease or disorder. In certain embodiments, the subject may have an additional disease or disorder selected from the group consisting of a metabolic disorder, hyperlipidemia, liver disease, cirrhosis, metabolic liver disease, liver fibrosis, cardiovascular disease, or combinations thereof.

[0191] In certain instances, the subject has a metabolic disorder, such as diabetes, including type I and type II diabetes, prediabetes, metabolic syndrome, dyslipidemia, obesity, insulin resistance, hyperglycemia, lipodystrophy, hypertension, elevated serum cholesterol, elevated triglycerides, or combinations thereof.

[0192] In certain instances, the subject has hyperlipidemia. Hyperlipidemia includes, for example, primary (inherited) dyslipidemias, such as familialhypercholesterolemia, Wolman Disease, and Cholesteryl ester storage disease, as well as secondary (acquired) dyslipidemias, such as hyperlipidemia associated with diabetes mellitus, elevated cholesterol (particularly elevated LDL cholesterol), combined hyperlipidemia / type lib, elevated triglycerides alcohol overuse, chronic kidney disease, hypothyroidism, and primary biliary cholangitis (PBC).

[0193] In certain instances, the subject has liver disease. The presence of active liver disease can be detected by the existence of elevated enzyme levels in the blood. Specifically, blood levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) above clinically accepted normal ranges are known to be indicative of on-going liver damage. Routine monitoring of liver disease subjects for blood levels of ALT and AST is used clinically to measure progress of the liver disease while on medical treatment. Reduction of elevated ALT and AST to within the accepted normal range is taken as clinical evidence reflecting a reduction in the severity of the subject’s on-going liver damage.

[0194] In certain embodiments, the liver disease is a chronic liver disease. Chronic liver diseases involve the progressive destruction and regeneration of the liver parenchyma, leading to fibrosis and cirrhosis. In general, chronic liver diseases can be caused by viruses (such as hepatitis B, hepatitis C, cytomegalovirus (CMV), or Epstein Barr Virus (EBV)), toxic agents or drugs (such as alcohol, methotrexate, or nitrofurantoin), a metabolic disease (such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), haemochromatosis, or Wilson's Disease), an autoimmune disease (such as autoimmune chronic hepatitis, primary biliary cholangitis (formerly known as primary biliary cirrhosis), or primary sclerosing cholangitis), or other causes (such as right heart failure).

[0195] In certain instances, the subject has cirrhosis. In certain embodiments, cirrhosis is characterized pathologically by loss of the normal microscopic lobular architecture, with fibrosis and nodular regeneration. Methods for measuring the extent of cirrhosis are well known in the art.

[0196] In certain embodiments, the liver disease is a metabolic liver disease. In one embodiment, the liver disease is non-alcoholic fatty liver disease (NAFLD). NAFLD is associated with insulin resistance and metabolic syndrome (obesity, combinedhyperlipidemia, diabetes mellitus (type II) and high blood pressure). NAFLD is considered to cover a spectrum of disease activity and begins as fatty accumulation in the liver (hepatic steatosis).

[0197] It has been shown that both obesity and insulin resistance probably play a strong role in the disease process of NAFLD. In addition to a poor diet, NAFLD has several other known causes. For example, NAFLD can be caused by certain medications, such as amiodarone, antiviral drugs (e.g., nucleoside analogues), aspirin (rarely as part of Reye's syndrome in children), corticosteroids, methotrexate, tamoxifen, or tetracycline. NAFLD has also been linked to the consumption of soft drinks through the presence of high fructose com syrup which may cause increased deposition of fat in the abdomen, although the consumption of sucrose shows a similar effect (likely due to its breakdown into fructose). Genetics have also been known to play a role, as two genetic mutations for this susceptibility have been identified.

[0198] If left untreated, NAFLD can develop into non-alcoholic steatohepatitis (NASH), which is the most extreme form of NAFLD, a state in which steatosis is combined with inflammation and fibrosis. NASH is regarded as a major cause of cirrhosis of the liver. Accordingly, provided herein is a method of treating and / or preventing nonalcoholic steatohepatitis (NASH) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising the compound of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof.

[0199] In certain instances, the subject has liver fibrosis. Liver fibrosis is the excessive accumulation of extracellular matrix proteins including collagen that occurs in most types of chronic liver diseases. In certain embodiments, advanced liver fibrosis results in cirrhosis and liver failure. Methods for measuring liver histologies, such as changes in the extent of fibrosis, lobular hepatitis, and periportal bridging necrosis, are well known in the art. In certain embodiments, treatment as described herein may improve a subject’s fibrosis from baseline, for example, improving from F4 to F3, F3 to F2, or F2 to FL In certain embodiments, a subject’s fibrosis score is improved by one or more following 24 weeks of daily treatment.

[0200] In certain embodiments, the compositions provided herein reduce the level of fibrogenesis in the liver. Liver fibrogenesis is the process leading to the deposition of an excess of extracellular matrix components in the liver known as fibrosis. It is observed in a number of conditions such as chronic viral hepatitis B and C, alcoholic liver disease, drug-induced liver disease, hemochromatosis, auto-immune hepatitis, Wilson disease, Primary Biliary Cholangitis (formerly known as Primary Biliary Cirrhosis), sclerosing cholangitis, liver schistosomiasis and others.

[0201] In certain instances, the subject has cardiovascular disorder. Cardiovascular diseases refer to any one or more than one of, for example, heart failure (including congestive heart failure, diastolic heart failure, systolic heart failure, heart failure with preserved ejection fraction), acute heart failure, ischemia, recurrent ischemia, myocardial infarction, arrhythmias, angina (including exercise-induced angina, variant angina, stable angina, unstable angina), acute coronary syndrome, diabetes, intermittent claudication, and idiopathic pulmonary fibrosis.

[0202] In certain instances, the subject has a pathological consequence or outcome associated with oxidative stress.Exemplary Embodiments

[0203] Embodiment 1-1. A method of treating or preventing a condition in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein the administration of the compound is effective to result in an increase of energy expenditure in the subject; thereby treating or preventing the condition.

[0204] Embodiment 1-2. The method of Embodiment 1-1, wherein the administration further comprises administration of an additional compound.

[0205] Embodiment 1-3. The method of Embodiment 1-2, wherein the additional compound is an ACC2 inhibitor.

[0206] Embodiment 1-4. The method of Embodiment 1-3, wherein the ACC2 inhibitor is TLC-3595.

[0207] Embodiment 1-5. The method of Embodiment 1-2, wherein the additional compound is an incretin mimetic.

[0208] Embodiment 1-6. The method of Embodiment 1-5, wherein the incretin mimetic is a GLP-1 receptor agonist.

[0209] Embodiment 1-7. The method of Embodiment 1-6, wherein the GLP-1 receptor agonist is semaglutide.

[0210] Embodiment 1-8. The method of Embodiment 1-2, wherein the additional compounds are an ACC2 inhibitor and a GLP-1 receptor agonist.

[0211] Embodiment 1-9. The method of Embodiment 1-8, wherein the ACC2 inhibitor is TLC-3595 and the GLP-1 receptor agonist is semaglutide.

[0212] Embodiment I- 10. The method of any one of Embodiments 1-1 to 1-9, wherein the treatment or prevention of a condition is reduction of adiposity.

[0213] Embodiment 1-11. The method of Embodiment I- 10, wherein the administration results in reduction of adiposity while substantially maintaining lean body mass.

[0214] Embodiment 1-12. The method of any one of Embodiments 1-1 to 1-11, wherein the administration results in 5, 10, 15, 20, or 25% reduction of fat mass over a period of time selected from 3 months, 6 months, and 12 months.

[0215] Embodiment 1-13. The method of any one of Embodiments 1-1 to 1-12, wherein the administration results in a loss of lean mass of less than about 15% over a period of time selected from 3 months, 6 months, and 12 months.

[0216] Embodiment 1-14. The method of any one of Embodiments 1-1 to 1-9, wherein the treatment or prevention of a condition is improving glycemic control.

[0217] Embodiment 1-15. The method of any one of Embodiments 1-1 to 1-9 and 1-14, wherein the administration lowers fasted blood glucose of the subject by at least about 5, 10, 15, or 20 %.

[0218] Embodiment 1-16. The method of any one of Embodiments 1-1 to 1-9 and 1-14, wherein the administration lowers HbAlc level in the subject.

[0219] Embodiment 1-17. The method of any one of Embodiments 1-1 to 1-16, wherein the energy expenditure in the subject is increased by at least about 5%, wherein the energy expenditure is measured by an indirect calorimeter or DLW technique.

[0220] Embodiment 1-18. The method of any one of Embodiments 1-1 to 1-16, wherein administration of the compound to the subject decreases the respiratory quotient in the subject by at least about 1%, wherein the respiratory quotient is measured by an indirect calorimeter.

[0221] Embodiment 1-19. The method of any one of Embodiments 1-1 to 1-18, wherein the subject has below average or normal energy expenditure, as measured by an indirect calorimetry.

[0222] Embodiment 1-20. The method of any one of Embodiments 1-1 to 1-19, wherein the subject has another disease or disorder selected from the group consisting of a metabolic disorder, hyperlipidemia, liver disease, cirrhosis, metabolic liver disease, liver fibrosis, and cardiovascular disease.

[0223] Embodiment 1-21. The method of any one of Embodiments 1-5 to 1-7, wherein the administration of the incretin mimetic is discontinued after the start of the administration of the compound of formula (I).

[0224] Embodiment 1-22. A method of treating or preventing a condition in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein the administration of the compound is effective to result in an increase of energy expenditure in the subject; thereby treating or preventing the condition.

[0225] Embodiment 1-23. The method of Embodiment 1-22, wherein the administration further comprises administration of an additional compound.

[0226] Embodiment 1-24. The method of Embodiment 1-23, wherein the additional compound is an ACC2 inhibitor.

[0227] Embodiment 1-25. The method of Embodiment 1-24, wherein the ACC2 inhibitor is TLC-3595.

[0228] Embodiment 1-26. The method of Embodiment 1-22, wherein the additional compound is an incretin mimetic.

[0229] Embodiment 1-27. The method of Embodiment 1-26, wherein the incretin mimetic is a GLP-1 receptor agonist.

[0230] Embodiment 1-28. The method of Embodiment 1-27, wherein the GLP-1 receptor agonist is semaglutide.

[0231] Embodiment 1-29. The method of Embodiment 1-23, wherein the additional compounds are an ACC2 inhibitor and a GLP-1 receptor agonist.

[0232] Embodiment 1-30. The method of Embodiment 1-29, wherein the ACC2 inhibitor is TLC-3595 and the GLP-1 receptor agonist is semaglutide.

[0233] Embodiment 1-31. The method of any one of Embodiments 1-22 to 1-30, wherein the treatment or prevention of a condition is reduction of adiposity.

[0234] Embodiment 1-32. The method of Embodiment 1-31, wherein the administration results in reduction of adiposity while substantially maintaining lean body mass.

[0235] Embodiment 1-33. The method of any one of Embodiments 1-22 to 1-32, wherein the administration results in 5, 10, 15, 20, or 25% reduction of fat mass over a period of time selected from 3 months, 6 months, and 12 months.

[0236] Embodiment 1-34. The method of any one of Embodiments 1-22 to 1-33, wherein the administration results in a loss of lean mass of less than about 15% over a period of time selected from 3 months, 6 months, and 12 months.

[0237] Embodiment 1-35. The method of any one of Embodiments 1-22 to 1-30, wherein the treatment or prevention of a condition is improving glycemic control.

[0238] Embodiment 1-36. The method of any one of Embodiments 1-22 to 1-30 and 1-35, wherein the administration lowers fasted blood glucose of the subject by at least about 5, 10, 15, or 20 % over seven days.

[0239] Embodiment 1-37. The method of any one of Embodiments 1-22 to 1-30 and 1-35, wherein the administration lowers HbAlc level in the subject.

[0240] Embodiment 1-38. The method of any one of Embodiments 1-22 to 1-37, wherein the energy expenditure in the subject is increased by at least about 5%, wherein the energy expenditure is measured by an indirect calorimeter or DLW technique.

[0241] Embodiment 1-39. The method of any one of Embodiment 1-22 to 1-37, wherein administration of the compound to the subject decreases the respiratory quotient in the subject by at least about 1%, wherein the respiratory quotient is measured by an indirect calorimeter.

[0242] Embodiment 1-40. The method of any one of Embodiments 1-22 to 1-39, wherein the subject has below average or normal energy expenditure, as measured by an indirect calorimetry.

[0243] Embodiment 1-41. The method of any one of Embodiment 1-22 to 1-40, wherein the subject has another disease or disorder selected from the group consisting of a metabolic disorder, hyperlipidemia, liver disease, cirrhosis, metabolic liver disease, liver fibrosis, and cardiovascular disease.

[0244] Embodiment 1-42. The method of any one of Embodiment 1-26 to 1-28, wherein the administration of the incretin mimetic is discontinued after the start of the administration of the compound of formula (II).

[0245] Embodiment 1-43. A composition comprising a compound of formula (I):or a pharmaceutically acceptable salt thereof; and a compound selected from the group consisting of an ACC2 inhibitor and an incretin mimetic.

[0246] Embodiment 1-44. A composition comprising a compound of formula (II)or a pharmaceutically acceptable salt thereof; and a compound selected from the group consisting of an ACC2 inhibitor, and an incretin mimetic.

[0247] Embodiment 1-45. The composition of any one of Embodiments 1-43 to I- 44, wherein the ACC2 inhibitor is TLC-3595.

[0248] Embodiment 1-46. The composition of any one of Embodiments 1-43 to I- 44, wherein the incretin mimetic is GLP-1 receptor agonist.

[0249] Embodiment 1-47. The composition of Embodiment 1-46, wherein the GLP-1 receptor agonist is semaglutide.

[0250] Embodiment II- E A method of treating or preventing a condition in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0251] Embodiment II-2. A method of treating or preventing a condition in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (I):or a pharmaceutically acceptable salt thereof, in a dose ranging from 30-380 mg; wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0252] Embodiment II-3. The method of Embodiment II- 1 or II-2, wherein the administration of the compound is effective to result in an increase of energy expenditure in the subject without causing hyperthermia.

[0253] Embodiment II-4. The method of any one of Embodiments II- 1 to II-3, wherein the compound is administered orally to the subject.

[0254] Embodiment II-5. The method of any one of Embodiments II- 1 to II-4, wherein the compound is administered once daily to the subject.

[0255] Embodiment II-6. The method of any one of Embodiments II- 1 to II-5, wherein the compound is administered at about 90-360 mg per day.

[0256] Embodiment II-7. The method of any one of Embodiments II- 1 to II-6, wherein the compound is administered at about 90 mg per day.

[0257] Embodiment II-8. The method of any one of Embodiments II- 1 to II-6, wherein the compound is administered at about 180 mg per day.

[0258] Embodiment II-9. The method of any one of Embodiments II- 1 to II-6, wherein the compound is administered at about 270 mg per day.

[0259] Embodiment II- 10. The method of any one of Embodiments II- 1 to II-9, wherein the administration results in a reduction of fat mass.

[0260] Embodiment II- 11. The method of Embodiment II- 10, wherein the administration results in a reduction of fat mass in the subject by at least about 5%.

[0261] Embodiment 11-12. The method of any one of Embodiments II- 10 to II- 11, wherein the administration results in reduction of fat mass while substantially maintaining lean body mass.

[0262] Embodiment 11-13. The method of any one of Embodiments II- 1 to 11-12, wherein the administration results in inducing weight loss or sustaining weight loss.

[0263] Embodiment 11-14. The method of any one of Embodiments II- 1 to 11-13, wherein the weight loss is at least about 5% over a period of 52 weeks.

[0264] Embodiment 11-15. The method of any one of Embodiments II- 1 to 11-13, wherein the weight loss is at least about 3% over 36 weeks.

[0265] Embodiment 11-16. The method of any one of Embodiments II- 1 to 11-13, wherein the weight loss is at least about 2% over 24 weeks.

[0266] Embodiment 11-17. The method of any one of Embodiments II- 1 to 11-13, wherein the weight loss is at least about 1% over 12 weeks.

[0267] Embodiment 11-18. The method of any one of Embodiments II- 1 to 11-17, wherein at least 80-90% of the weight loss is from fat mass.

[0268] Embodiment 11-19. The method of any one of Embodiments II- 1 to 11-18, wherein the administration results in improving glycemic control.

[0269] Embodiment 11-20. The method of any one of Embodiments II- 1 to 11-19, wherein the administration lowers fasted blood glucose of the subject.

[0270] Embodiment 11-21. The method of any one of Embodiments II- 1 to 11-20, wherein the administration lowers HbAlc level in the subject.

[0271] Embodiment 11-22. A method of treating or preventing a condition in a subject undergoing treatment with an incretin mimetic, comprising administering to the subject in need thereof an effective amount of a compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0272] Embodiment 11-23. The method of Embodiment 11-22, wherein the amount of the incretin mimetic is reduced after the initiation of administration of the compound of formula (I).

[0273] Embodiment 11-24. The method of Embodiments 11-22 or 11-23, wherein the incretin mimetic is discontinued after the initiation of administration of the compound of formula (I).

[0274] Embodiment 11-25. The method of Embodiment 11-24, wherein the incretin mimetic is discontinued about 4 weeks after the initiation of administration of the compound of formula (I).

[0275] Embodiment 11-26. The method of Embodiment 11-24, wherein the incretin mimetic is discontinued about 8 weeks after the initiation of administration of the compound of formula (I).

[0276] Embodiment 11-27. The method of Embodiment 11-24, wherein the incretin mimetic is discontinued about 12 weeks after the initiation of administration of the compound of formula (I).

[0277] Embodiment 11-28. The method of Embodiment 11-24, wherein the incretin mimetic is discontinued about 24 weeks after the initiation of administration of the compound of formula (I).

[0278] Embodiment 11-29. A method of treating or preventing a condition in a subject, comprising administering to the subject in need thereof a compound of formula (I):pharmaceutically acceptable salt thereof, in combination with an incretin mimetic; wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0279] Embodiment 11-30. The method of any one of Embodiments 11-22 to 11-29, wherein the incretin mimetic is semaglutide or tirzepatide.

[0280] Embodiment II-31. The method of Embodiment 11-30, wherein semaglutide is administered orally at about 1.5-15 mg per day or subcutaneously at about 0.25-2.4 mg per week.

[0281] Embodiment 11-32. The method of Embodiment 11-30, wherein tirzepatide is administered subcutaneously at about 2.5-15 mg per week.

[0282] Embodiment 11-33. The method of any one of Embodiment 11-22 to 11-32, wherein the compound of formula (I) is administered at about 180-380 mg per day.

[0283] Embodiment 11-34. The method of any one of Embodiments 11-22 to 11-32, wherein the compound of formula (I) is administered at about 30-180 mg per day.

[0284] Embodiment 11-35. A method of inducing or sustaining weight loss in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein the administration of the compound is effective to result in an increase of energy expenditure in the subject without thermogenesis.

[0285] Embodiment 11-36. A method of inducing or sustaining weight loss in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (I):or a pharmaceutically acceptable salt thereof, in a dose ranging from 30-380 mg.

[0286] Embodiment 11-37. The method of any one of Embodiments 11-35 to 11-36, wherein the compound is administered orally to the subject.

[0287] Embodiment 11-38. The method of any one of Embodiments 11-35 to 11-37, wherein the compound is administered once daily to the subject.

[0288] Embodiment 11-39. The method of any one of Embodiments 11-34 to 11-37, wherein the compound is administered at about 90-360 mg per day.

[0289] Embodiment 11-40. The method of any one of Embodiments 11-35 to 11-39, wherein the compound is administered at about 90 mg per day.

[0290] Embodiment 11-41. The method of any one of Embodiments 11-35 to 11-39, wherein the compound is administered at about 180 mg per day.

[0291] Embodiment 11-42. The method of any one of Embodiments 11-35 to 11-39, wherein the compound is administered at about 270 mg per day.

[0292] Embodiment 11-43. A method of inducing or sustaining weight loss in a subject undergoing treatment with an incretin mimetic, comprising administering to the subject in need thereof an effective amount of a compound of formula (I):or a pharmaceutically acceptable salt thereof.

[0293] Embodiment 11-44. The method of Embodiment 11-43, wherein the amount of the incretin mimetic is reduced after the initiation of administration of the compound of formula (I).

[0294] Embodiment 11-45. The method of Embodiment 11-43 or 11-44, wherein the incretin mimetic is discontinued after the initiation of administration of the compound of formula (I).

[0295] Embodiment 11-46. The method of Embodiment 11-45, wherein the incretin mimetic is discontinued about 4 weeks after the initiation of administration of the compound of formula (I).

[0296] Embodiment 11-47. The method of Embodiment 11-45, wherein the incretin mimetic is discontinued about 8 weeks after the initiation of administration of the compound of formula (I).

[0297] Embodiment 11-48. The method of Embodiment 11-45, wherein the incretin mimetic is discontinued about 12 weeks after the initiation of administration of the compound of formula (I).

[0298] Embodiment 11-49. The method of Embodiment 11-45, wherein the incretin mimetic is discontinued about 24 weeks after the initiation of administration of the compound of formula (I).

[0299] Embodiment 11-50. A method of inducing or sustaining weight loss in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (I):pharmaceutically acceptable salt thereof, in combination with an incretin mimetic; wherein the subject is not administered the compound of formula (I), or a pharmaceutically acceptable salt thereof, or the incretin mimetic prior the administration of the combination of the compound of formula (I), or pharmaceutically acceptable salts thereof, and the incretin mimetic.

[0300] Embodiment II-51. The method of any one of Embodiments 11-43 to 11-50, wherein the incretin mimetic is semaglutide or tirzepatide.

[0301] Embodiment 11-52. The method of Embodiment II-51, wherein semaglutide is administered orally at about 1.5-15 mg per day or subcutaneously at about 0.25-2.4 mg per week.

[0302] Embodiment 11-53. The method of Embodiment 11-51, wherein tirzepatide is administered subcutaneously at about 2.5-15 mg per week.

[0303] Embodiment 11-54. The method of any one of Embodiment 11-43 to 11-53, wherein the compound of formula (I) is administered at about 135-270 mg per day.

[0304] Embodiment 11-55. The method of any one of Embodiments 11-43 to 11-53, wherein the compound of formula (I) is administered at about 30-135 mg per day.

[0305] Embodiment 11-56. A method of treating or preventing a condition in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (II):or a pharmaceutically acceptable salt thereof, wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0306] Embodiment 11-57. A method of treating or preventing a condition in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (II):or a pharmaceutically acceptable salt thereof, in a dose ranging from 0.5-350 mg; wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0307] Embodiment 11-58. The method of Embodiment 11-56 or 11-57, wherein the administration of the compound is effective to result in an increase of energy expenditure in the subject without causing hyperthermia.

[0308] Embodiment 11-59. The method of any one of Embodiments 11-56 to 11-58, wherein the compound is administered orally to the subject.

[0309] Embodiment 11-60. The method of any one of Embodiments 11-56 to 11-58, wherein the compound is administered once daily to the subject.

[0310] Embodiment II-61. The method of Embodiment 11-60, wherein the compound is administered at about 0.5 to 350 mg per day.

[0311] Embodiment 11-62. The method of Embodiment 11-60, wherein the compound is administered at about 0.5 to 50 mg per day.

[0312] Embodiment 11-63. The method of any one of Embodiments 11-56 to 11-58, wherein the compound is administered parenterally to the subject.

[0313] Embodiment 11-64. The method of any one of Embodiments 11-56 to 11-58, wherein the compound is administered subcutaneously to the subject.

[0314] Embodiment 11-65. The method of Embodiments 11-63 or 11-64, wherein the compound is administered at about 2.5 to 350 mg per week.

[0315] Embodiment 11-66. The method of any one of Embodiments 11-56 to 11-65, wherein the administration results in a reduction of fat mass.

[0316] Embodiment 11-67. The method of Embodiment 11-66, wherein the administration results in a reduction of fat mass in the subject by at least about 5%.

[0317] Embodiment 11-68. The method of any one of Embodiments 11-66 to 11-67, wherein the administration results in reduction of fat mass while substantially maintaining lean body mass.

[0318] Embodiment 11-69. The method of any one of Embodiments 11-56 to 11-68, wherein the administration results in inducing weight loss or sustaining weight loss.

[0319] Embodiment 11-70. The method of any one of Embodiments 11-56 to 11-69, wherein the weight loss is at least about 5% over a period of 52 weeks.

[0320] Embodiment 11-71. The method of any one of Embodiments 11-56 to 11-69, wherein the weight loss is at least about 3% over 36 weeks.

[0321] Embodiment 11-72. The method of any one of Embodiments 11-56 to 11-69, wherein the weight loss is at least about 2% over 24 weeks.

[0322] Embodiment 11-73. The method of any one of Embodiments 11-56 to 11-69, wherein the weight loss is at least about 1% over 12 weeks.

[0323] Embodiment 11-74. The method of any one of Embodiments 11-56 to 11-73, wherein at least 80-90% of the weight loss is from fat mass.

[0324] Embodiment 11-75. The method of any one of Embodiments 11-56 to 11-74, wherein the administration results in improving glycemic control.

[0325] Embodiment 11-76. The method of any one of Embodiments 11-56 to 11-75, wherein the administration lowers fasted blood glucose of the subject.

[0326] Embodiment 11-77. The method of any one of Embodiments 11-56 to 11-76, wherein the administration lowers 14b Ale level in the subject.

[0327] Embodiment 11-78. A method of treating or preventing a condition in a subject undergoing treatment with an incretin mimetic, comprising administering to the subject in need thereof an effective amount of a compound of formula (II):or a pharmaceutically acceptable salt thereof, wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0328] Embodiment 11-79. The method of Embodiment 11-78, wherein the amount of the incretin mimetic is reduced after the initiation of administration of the compound of formula (II).

[0329] Embodiment 11-80. The method of Embodiment 11-78 or 11-79, wherein the incretin mimetic is discontinued after the initiation of administration of the compound of formula (II).

[0330] Embodiment II-81. The method of Embodiment 11-80, wherein the incretin mimetic is discontinued about 4 weeks after the initiation of administration of the compound of formula (II).

[0331] Embodiment 11-82. The method of Embodiment 11-80, wherein the incretin mimetic is discontinued about 8 weeks after the initiation of administration of the compound of formula (II).

[0332] Embodiment 11-83. The method of Embodiment 11-80, wherein the incretin mimetic is discontinued about 12 weeks after the initiation of administration of the compound of formula (II).

[0333] Embodiment 11-84. The method of Embodiment 11-80, wherein the incretin mimetic is discontinued about 24 weeks after the initiation of administration of the compound of formula (II).

[0334] Embodiment 11-85. A method of treating or preventing a condition in a subject, comprising administering to the subject in need thereof a compound of formula (II):pharmaceutically acceptable salt thereof, in combination with an incretin mimetic; wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0335] Embodiment 11-86. The method of any one of Embodiments 11-78-85, wherein the incretin mimetic is semaglutide or tirzepatide.

[0336] Embodiment 11-87. The method of Embodiment 11-86, wherein semaglutide is administered orally at about 1.5-15 mg per day or subcutaneously at about 0.25-2.4 mg per week.

[0337] Embodiment 11-88. The method of Embodiment 11-86, wherein tirzepatide is administered subcutaneously at about 2.5-15 mg per week.

[0338] Embodiment 11-89. The method of any one of Embodiments 11-78 to 11-88, wherein the compound of formula (II) is administered at about 0.5-350 mg per day.

[0339] Embodiment 11-90. The method of any one of Embodiments 11-78 to 11-88, wherein the compound of formula (II) is administered at about 2.5-350 mg per day.

[0340] Embodiment 11-91. A method of inducing or sustaining weight loss in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (II):or a pharmaceutically acceptable salt thereof, wherein the administration of the compound is effective to result in an increase of energy expenditure in the subject without thermogenesis.

[0341] Embodiment 11-92. A method of inducing or sustaining weight loss in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (II):or a pharmaceutically acceptable salt thereof, in a dose ranging from 0.5 to 350 mg.

[0342] Embodiment 11-93. The method of any one of Embodiments 11-91 to 11-92, wherein the compound is administered orally to the subject.

[0343] Embodiment 11-94. The method of any one of Embodiment 11-91 to 11-93, wherein the compound is administered once daily to the subject.

[0344] Embodiment 11-95. The method of any one of Embodiments 11-91 to 11-92, wherein the compound is administered parenterally to the subject.

[0345] Embodiment 11-96. The method of any one of Embodiments 11-91 or 11-92, wherein the compound is administered subcutaneously to the subject.

[0346] Embodiment 11-97. The method of any one of Embodiments 11-95 to 11-96, wherein the compound is administered at about 2.5 to 350 mg per week.

[0347] Embodiment 11-98. A method of inducing or sustaining weight loss in a subject undergoing treatment with an incretin mimetic, comprising administering to the subject in need thereof an effective amount of a compound of formula (II):or a pharmaceutically acceptable salt thereof.

[0348] Embodiment 11-99. The method of Embodiment 11-98, wherein the amount of the incretin mimetic is reduced after the initiation of administration of the compound of formula (II).

[0349] Embodiment II- 100. The method of Embodiment 11-98 or 11-99, wherein the incretin mimetic is discontinued after the initiation of administration of the compound of formula (II).

[0350] Embodiment II-101. The method of Embodiment 11-100, wherein the incretin mimetic is discontinued about 4 weeks after the initiation of administration of the compound of formula (II).

[0351] Embodiment 11-102. The method of Embodiment II- 100, wherein the incretin mimetic is discontinued about 8 weeks after the initiation of administration of the compound of formula (II).

[0352] Embodiment 11-103. The method of Embodiment II- 100, wherein the incretin mimetic is discontinued about 12 weeks after the initiation of administration of the compound of formula (II).

[0353] Embodiment 11-104. The method of Embodiment II- 100, wherein the incretin mimetic is discontinued about 24 weeks after the initiation of administration of the compound of formula (II).

[0354] Embodiment 11-105. A method of inducing or sustaining weight loss in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (II):pharmaceutically acceptable salt thereof, in combination with an incretin mimetic; wherein the subject is not administered the compound of formula (II), or a pharmaceutically acceptable salt thereof, or the incretin mimetic prior the administration of the combination of the compound of formula (II), or pharmaceutically acceptable salts thereof, and the incretin mimetic.

[0355] Embodiment 11-106. The method of any one of Embodiments 11-98 to 11-105, wherein the incretin mimetic is semaglutide or tirzepatide.

[0356] Embodiment 11-107. The method of Embodiment 11-106, wherein semaglutide is administered orally at about 1.5-15 mg per day or subcutaneously at about 0.25-2.4 mg per week.

[0357] Embodiment 11-108. The method of Embodiment 11-106, wherein tirzepatide is administered subcutaneously at about 2.5-15 mg per week.

[0358] Embodiment 11-109. The method of any one of Embodiments 11-98 to 11-108, wherein the compound of formula (II) is administered at about 0.5 to 350 mg per day.

[0359] Embodiment II- 110. The method of any one of Embodiments 11-98 to 11-108, wherein the compound of formula (II) is administered at about 2.5 to 350 mg per week.

[0360] Embodiment II- 111. A method of treating or preventing a condition in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (III):or a pharmaceutically acceptable salt thereof, wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0361] Embodiment II- 112. A method of treating or preventing a condition in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (III):or a pharmaceutically acceptable salt thereof, in a dose ranging from 0.5-350 mg; wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0362] Embodiment II- 113. The method of Embodiment II- 111 or II- 112, wherein the administration of the compound is effective to result in an increase of energy expenditure in the subject without hyperthermia.

[0363] Embodiment II- 114. The method of any one of Embodiments II- 111 to II-113, wherein the compound is administered orally to the subject.

[0364] Embodiment II- 115. The method of any one of Embodiments II- 111 to II-114, wherein the compound is administered once daily to the subject.

[0365] Embodiment II- 116. The method of Embodiment II- 115, wherein the compound is administered at about 0.5 to 350 mg per day.

[0366] Embodiment II- 117. The method of any one of Embodiments II- 111 to II- 113, wherein the compound is administered parenterally to the subject.

[0367] Embodiment II- 118. The method of any one of Embodiments II- 111 to II- 113, wherein the compound is administered subcutaneously to the subject.

[0368] Embodiment II- 119. The method of Embodiment II- 117 or II- 118, wherein the compound is administered at about 2.5 to 350 mg per week.

[0369] Embodiment 11-120. The method of any one of Embodiments II- 111 to II- 119, wherein the administration results in a reduction of fat mass.

[0370] Embodiment 11-121. The method of Embodiment 11-120, wherein the administration results in a reduction of fat mass in the subject by at least about 5%.

[0371] Embodiment 11-122. The method of any one of Embodiments 11-120 to II-121, wherein the administration results in reduction of fat mass while substantially maintaining lean body mass.

[0372] Embodiment 11-123. The method of any one of Embodiments II- 111 to II-122, wherein the administration results in inducing weight loss or sustaining weight loss.

[0373] Embodiment 11-124. The method of any one of Embodiments II- 111 to II- 123, wherein the weight loss is at least about 5% over a period of 52 weeks.

[0374] Embodiment 11-125. The method of any one of Embodiments II- 111 to II- 123, wherein the weight loss is at least about 3% over 36 weeks.

[0375] Embodiment 11-126. The method of any one of Embodiments II- 111 to II- 123, wherein the weight loss is at least about 2% over 24 weeks.

[0376] Embodiment 11-127. The method of any one of Embodiments II- 111 to II- 123, wherein the weight loss is at least about 1% over 12 weeks.

[0377] Embodiment 11-128. The method of any one of Embodiments II- 111 to II-127, wherein at least 80-90% of the weight loss is from fat mass.

[0378] Embodiment 11-129. The method of any one of Embodiments II- 111 to II-128, wherein the administration results in improving glycemic control.

[0379] Embodiment 11-130. The method of any one of Embodiments II- 111 to II-129, wherein the administration lowers fasted blood glucose of the subject.

[0380] Embodiment 11-131. The method of any one of Embodiments II- 111 to II-130, wherein the administration lowers HbAlc level in the subject.

[0381] Embodiment 11-132. A method of treating or preventing a condition in a subject undergoing treatment with an incretin mimetic, comprising administering to the subject in need thereof an effective amount of a compound of formula (III):or a pharmaceutically acceptable salt thereof, wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0382] Embodiment 11-133. The method of Embodiment 11-132, wherein the amount of the incretin mimetic is reduced after the initiation of administration of the compound of formula (III).

[0383] Embodiment 11-134. The method of Embodiment 11-132 or 11-133, wherein the incretin mimetic is discontinued after the initiation of administration of the compound of formula (III).

[0384] Embodiment 11-135. The method of Embodiment 11-134, wherein the incretin mimetic is discontinued about 4 weeks after the initiation of administration of the compound of formula (III).

[0385] Embodiment 11-136. The method of Embodiment 11-134, wherein the incretin mimetic is discontinued about 8 weeks after the initiation of administration of the compound of formula (III).

[0386] Embodiment 11-137. The method of Embodiment 11-134, wherein the incretin mimetic is discontinued about 12 weeks after the initiation of administration of the compound of formula (III).

[0387] Embodiment 11-138. The method of Embodiment 11-134, wherein the incretin mimetic is discontinued about 24 weeks after the initiation of administration of the compound of formula (III).

[0388] Embodiment 11-139. A method of treating or preventing a condition in a subject, comprising administering to the subject in need thereof a compound of formula (III):pharmaceutically acceptable salt thereof, in combination with an incretin mimetic; wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0389] Embodiment 11-140. The method of any one of Embodiments 11-132 to II- 139, wherein the incretin mimetic is semaglutide or tirzepatide.

[0390] Embodiment 11-141. The method of Embodiment 11-140, wherein semaglutide is administered orally at about 1.5-15 mg per day or subcutaneously at about 0.25-2.4 mg per week.

[0391] Embodiment 11-142. The method of Embodiment 11-140, wherein tirzepatide is administered subcutaneously at about 2.5-15 mg per week.

[0392] Embodiment 11-143. The method of any one of Embodiments 11-132 to II- 142, wherein the compound of formula (III) is administered at about 0.5-350 mg per day.

[0393] Embodiment 11-144. The method of any one of Embodiments 11-132 to II- 142, wherein the compound of formula (III) is administered at about 2.5-350 mg per week.

[0394] Embodiment 11-145. A method of inducing or sustaining weight loss in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (III):or a pharmaceutically acceptable salt thereof, wherein the administration of the compound is effective to result in an increase of energy expenditure in the subject without thermogenesis.

[0395] Embodiment 11-146. A method of inducing or sustaining weight loss in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (III):or a pharmaceutically acceptable salt thereof, in a dose ranging from 0.5 to 350 mg.

[0396] Embodiment 11-147. The method of any one of Embodiments 11-145 to II-146, wherein the compound is administered orally to the subject.

[0397] Embodiment 11-148. The method of any one of Embodiments 11-145 to II-147, wherein the compound is administered once daily to the subject.

[0398] Embodiment 11-149. The method of any one of Embodiments 11-145 to II- 146, wherein the compound is administered parenterally to the subject.

[0399] Embodiment 11-150. The method of any one of Embodiments 11-145 or II- 146, wherein the compound is administered subcutaneously to the subject.

[0400] Embodiment II- 151. The method of any one of Embodiments 11-149 to II- 150, wherein the compound is administered at about 2.5 to 350 mg per week.

[0401] Embodiment 11-152. A method of inducing or sustaining weight loss in a subject undergoing treatment with an incretin mimetic, comprising administering to the subject in need thereof an effective amount of a compound of formula (III):or a pharmaceutically acceptable salt thereof.

[0402] Embodiment 11-153. The method of Embodiment 11-152, wherein the amount of the incretin mimetic is reduced after the initiation of administration of the compound of formula (III).

[0403] Embodiment 11-154. The method of Embodiment 11-152 or 11-153, wherein the incretin mimetic is discontinued after the initiation of administration of the compound of formula (III).

[0404] Embodiment 11-155. The method of Embodiment 11-154, wherein the incretin mimetic is discontinued about 4 weeks after the initiation of administration of the compound of formula (III).

[0405] Embodiment 11-156. The method of Embodiment 11-154, wherein the incretin mimetic is discontinued about 8 weeks after the initiation of administration of the compound of formula (III).

[0406] Embodiment 11-157. The method of Embodiment 11-154, wherein the incretin mimetic is discontinued about 12 weeks after the initiation of administration of the compound of formula (III).

[0407] Embodiment 11-158. The method of Embodiment 11-154, wherein the incretin mimetic is discontinued about 24 weeks after the initiation of administration of the compound of formula (III).

[0408] Embodiment 11-159. A method of inducing or sustaining weight loss in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (III):pharmaceutically acceptable salt thereof, in combination with an incretin mimetic; wherein the subject is not administered the compound of formula (III), or a pharmaceutically acceptable salt thereof, or the incretin mimetic prior the administration of the combination of the compound of formula (III), or pharmaceutically acceptable salts thereof, and the incretin mimetic.

[0409] Embodiment 11-160. The method of any one of Embodiments 11-152 to II- 159, wherein the incretin mimetic is semaglutide or tirzepatide.

[0410] Embodiment 11-161. The method of Embodiment 11-160, wherein semaglutide is administered orally at about 1.5-15 mg per day or subcutaneously at about 0.25-2.4 mg per week.

[0411] Embodiment 11-162. The method of Embodiment 11-160, wherein tirzepatide is administered subcutaneously at about 2.5-15 mg per week.

[0412] Embodiment 11-163. The method of any one of Embodiments 11-152 to II- 162, wherein the compound of formula (III) is administered at about 0.5 to 350 mg per day.

[0413] Embodiment 11-164. The method of any one of Embodiments 11-152 to II- 162, wherein the compound of formula (III) is administered at about 2.5 to 350 mg per week.

[0414] Embodiment 11-165. A composition comprising a compound of formula (I):or a pharmaceutically acceptable salt thereof; and a compound selected from the group consisting of an ACC2 inhibitor and an incretin mimetic.

[0415] Embodiment 11-166. A composition comprising a compound of formula (II)or a pharmaceutically acceptable salt thereof; and a compound selected from the group consisting of an ACC2 inhibitor, and an incretin mimetic.

[0416] Embodiment 11-167. A composition comprising a compound of formula (III)or a pharmaceutically acceptable salt thereof; and a compound selected from the group consisting of an ACC2 inhibitor, and an incretin mimetic.

[0417] Embodiment 11-168. The composition of any one of Embodiments 11-165 to 11-167, wherein the ACC2 inhibitor is TLC-3595.

[0418] Embodiment 11-169. The composition of any one of Embodiments 11-165 to 11-167, wherein the incretin mimetic is GLP-1 receptor agonist.

[0419] Embodiment 11-170. The composition of Embodiment 11-169, wherein the GLP-1 receptor agonist is semaglutide.

[0420] Embodiment 11-171. The composition of Embodiment 11-169, wherein the GLP-1 receptor agonist is tirzepatide.

[0421] Embodiment III- 1. Use of a compound of formula (I):or a pharmaceutically acceptable salt thereof, for treating or preventing a condition in a subject, wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0422] Embodiment III-2. Use of a compound of formula (I):or a pharmaceutically acceptable salt thereof, for treating or preventing a condition in a subject, wherein the compound is administered in a dose ranging from 30-380 mg;wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0423] Embodiment III-3. Use of a compound of formula (I):or a pharmaceutically acceptable salt thereof, for treating or preventing a condition in a subject undergoing treatment with an incretin mimetic, wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0424] Embodiment III-4. The use of Embodiment HI-4, wherein the amount of the incretin mimetic is reduced after the initiation of administration of the compound of formula (I).

[0425] Embodiment III-5. The use of Embodiments III-3 or III-4, wherein the incretin mimetic is discontinued after the initiation of administration of the compound of formula (I).

[0426] Embodiment III-6. Use of a compound of formula (I):or a pharmaceutically acceptable salt thereof, in combination with an incretin mimetic; for treating or preventing a condition in a subject, wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0427] Embodiment III-7. Use of a compound of formula (I):or a pharmaceutically acceptable salt thereof, for inducing or sustaining weight loss in a subject, wherein the administration of the compound is effective to result in an increase of energy expenditure in the subject without thermogenesis.

[0428] Embodiment III-8. Use of a compound of formula (I):or a pharmaceutically acceptable salt thereof, for inducing or sustaining weight loss in a subject; wherein the compound is administered in a dose ranging from 30-380 mg.

[0429] Embodiment HI-9. Use of a compound of formula (I):or a pharmaceutically acceptable salt thereof, for inducing or sustaining weight loss in a subject undergoing treatment with an incretin mimetic.

[0430] Embodiment III- 10. The use of Embodiment III-9, wherein the amount of the incretin mimetic is reduced after the initiation of administration of the compound of formula (I).

[0431] Embodiment III- 11. The use of Embodiment III- 9 or III- 10, wherein the incretin mimetic is discontinued after the initiation of administration of the compound of formula (I).

[0432] Embodiment III- 12. Use of a compound of formula (I):pharmaceutically acceptable salt thereof, in combination with an incretin mimetic; for inducing or sustaining weight loss in a subject, wherein the subject is not administered the compound of formula (I), or a pharmaceutically acceptable salt thereof, or the incretin mimetic prior the administration of the combination of the compound of formula (I), or pharmaceutically acceptable salts thereof, and the incretin mimetic.

[0433] Embodiment III- 13. Use of a compound of formula (II):or a pharmaceutically acceptable salt thereof, for treating or preventing a condition in a subject, wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0434] Embodiment III- 14. Use of a compound of formula (II):or a pharmaceutically acceptable salt thereof, for treating or preventing a condition in a subject, wherein the compound is administered in a dose ranging from 0.5-350 mg; wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0435] Embodiment III- 15. Use of a compound of formula (II):or a pharmaceutically acceptable salt thereof, for treating or preventing a condition in a subject undergoing treatment with an incretin mimetic, wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0436] Embodiment III- 16. The use of Embodiment III- 15, wherein the amount of the incretin mimetic is reduced after the initiation of administration of the compound of formula (II).

[0437] Embodiment III- 17. The use of Embodiments III-15 or III- 16, wherein the incretin mimetic is discontinued after the initiation of administration of the compound of formula (II).

[0438] Embodiment III- 18. Use of a compound of formula (II):or a pharmaceutically acceptable salt thereof, in combination with an incretin mimetic; for treating or preventing a condition in a subject,wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0439] Embodiment III- 19. Use of a compound of formula (II):or a pharmaceutically acceptable salt thereof, for inducing or sustaining weight loss in a subject, wherein the administration of the compound is effective to result in an increase of energy expenditure in the subject without thermogenesis.

[0440] Embodiment III-20. Use of a compound of formula (II):or a pharmaceutically acceptable salt thereof, for inducing or sustaining weight loss in a subject; wherein the compound is administered in a dose ranging from 0.5-350 mg.

[0441] Embodiment III-21. Use of a compound of formula (II):or a pharmaceutically acceptable salt thereof, for inducing or sustaining weight loss in a subject undergoing treatment with an incretin mimetic.

[0442] Embodiment III-22. The use of Embodiment III-21, wherein the amount of the incretin mimetic is reduced after the initiation of administration of the compound of formula (II).

[0443] Embodiment III-23. The use of Embodiment III-21 or III-22, wherein the incretin mimetic is discontinued after the initiation of administration of the compound of formula (II).

[0444] Embodiment III-24. Use of a compound of formula (II):pharmaceutically acceptable salt thereof, in combination with an incretin mimetic; for inducing or sustaining weight loss in a subject, wherein the subject is not administered the compound of formula (II), or a pharmaceutically acceptable salt thereof, or the incretin mimetic prior the administration of the combination of the compound of formula (II), or pharmaceutically acceptable salts thereof, and the incretin mimetic.

[0445] Embodiment III-25. Use of a compound of formula (III):or a pharmaceutically acceptable salt thereof, for treating or preventing a condition in a subject, wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0446] Embodiment III-26. Use of a compound of formula (III):or a pharmaceutically acceptable salt thereof, for treating or preventing a condition in a subject, wherein the compound is administered in a dose ranging from 0.5-350 mg; wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0447] Embodiment III-27. Use of a compound of formula (III):or a pharmaceutically acceptable salt thereof, for treating or preventing a condition in a subject undergoing treatment with an incretin mimetic, wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0448] Embodiment III-28. The use of Embodiment III-27, wherein the amount of the incretin mimetic is reduced after the initiation of administration of the compound of formula (III).

[0449] Embodiment III-29. The use of Embodiments HI-27 or III-28, wherein the incretin mimetic is discontinued after the initiation of administration of the compound of formula (III).

[0450] Embodiment III-30. Use of a compound of formula (III):or a pharmaceutically acceptable salt thereof, in combination with an incretin mimetic; for treating or preventing a condition in a subject, wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0451] Embodiment III-31. Use of a compound of formula (III):or a pharmaceutically acceptable salt thereof, for inducing or sustaining weight loss in a subject, wherein the administration of the compound is effective to result in an increase of energy expenditure in the subject without thermogenesis.

[0452] Embodiment III-32. Use of a compound of formula (III):or a pharmaceutically acceptable salt thereof, for inducing or sustaining weight loss in a subject; wherein the compound is administered in a dose ranging from 0.5-350 mg.

[0453] Embodiment III-33. Use of a compound of formula (III):or a pharmaceutically acceptable salt thereof, for inducing or sustaining weight loss in a subject undergoing treatment with an incretin mimetic.

[0454] Embodiment III-34. The use of Embodiment III-33, wherein the amount of the incretin mimetic is reduced after the initiation of administration of the compound of formula (III).

[0455] Embodiment III-35. The use of Embodiment III-33 or III-34, wherein the incretin mimetic is discontinued after the initiation of administration of the compound of formula (III).

[0456] Embodiment III-36. Use of a compound of formula (III):pharmaceutically acceptable salt thereof, in combination with an incretin mimetic; for inducing or sustaining weight loss in a subject, wherein the subject is not administered the compound of formula (III), or a pharmaceutically acceptable salt thereof, or the incretin mimetic prior the administration of the combination of the compound of formula (III), or pharmaceutically acceptable salts thereof, and the incretin mimetic.

[0457] Embodiment IV-1. Use of a compound of formula (I):or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a condition in a subject, wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0458] Embodiment IV-2. Use of a compound of formula (I):or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a condition in a subject, wherein the compound is administered in a dose ranging from 30-380 mg; wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0459] Embodiment IV-3. Use of a compound of formula (I):or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a condition in a subject undergoing treatment with an incretin mimetic, wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0460] Embodiment IV-4. The use of Embodiment IV-4, wherein the amount of the incretin mimetic is reduced after the initiation of administration of the compound of formula (I).

[0461] Embodiment IV-5. The use of Embodiments IV-3 or IV-4, wherein the incretin mimetic is discontinued after the initiation of administration of the compound of formula (I).

[0462] Embodiment IV-6. Use of a compound of formula (I):or a pharmaceutically acceptable salt thereof, in combination with an incretin mimetic; in the manufacture of a medicament for treating or preventing a condition in a subject, wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0463] Embodiment IV-7. Use of a compound of formula (I):or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inducing or sustaining weight loss in a subject, wherein the administration of the compound is effective to result in an increase of energy expenditure in the subject without thermogenesis.

[0464] Embodiment IV-8. Use of a compound of formula (I):or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inducing or sustaining weight loss in a subject; wherein the compound is administered in a dose ranging from 30-380 mg.

[0465] Embodiment IV-9. Use of a compound of formula (I):or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inducing or sustaining weight loss in a subject undergoing treatment with an incretin mimetic.

[0466] Embodiment IV- 10. The use of Embodiment IV-9, wherein the amount of the incretin mimetic is reduced after the initiation of administration of the compound of formula (I).

[0467] Embodiment IV- 11. The use of Embodiment IV-9 or IV- 10, wherein the incretin mimetic is discontinued after the initiation of administration of the compound of formula (I).

[0468] Embodiment IV-12. Use of a compound of formula (I):pharmaceutically acceptable salt thereof, in combination with an incretin mimetic; in the manufacture of a medicament for inducing or sustaining weight loss in a subject, wherein the subject is not administered the compound of formula (I), or a pharmaceutically acceptable salt thereof, or the incretin mimetic prior the administration of the combination of the compound of formula (I), or pharmaceutically acceptable salts thereof, and the incretin mimetic.

[0469] Embodiment IV-13. Use of a compound of formula (II):or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a condition in a subject, wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0470] Embodiment IV-14. Use of a compound of formula (II):or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a condition in a subject, wherein the compound is administered in a dose ranging from 0.5-350 mg; wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0471] Embodiment IV-15. Use of a compound of formula (II):or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a condition in a subject undergoing treatment with an incretin mimetic,wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0472] Embodiment IV- 16. The use of Embodiment IV- 15, wherein the amount of the incretin mimetic is reduced after the initiation of administration of the compound of formula (II).

[0473] Embodiment IV-17. The use of Embodiments IV-15 or IV-16, wherein the incretin mimetic is discontinued after the initiation of administration of the compound of formula (II).

[0474] Embodiment IV-18. Use of a compound of formula (II):or a pharmaceutically acceptable salt thereof, in combination with an incretin mimetic; in the manufacture of a medicament for treating or preventing a condition in a subject, wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0475] Embodiment IV- 19. Use of a compound of formula (II):or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inducing or sustaining weight loss in a subject, wherein the administration of the compound is effective to result in an increase of energy expenditure in the subject without thermogenesis.

[0476] Embodiment IV-20. Use of a compound of formula (II):or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inducing or sustaining weight loss in a subject; wherein the compound is administered in a dose ranging from 0.5-350 mg.

[0477] Embodiment IV-21. Use of a compound of formula (II):or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inducing or sustaining weight loss in a subject undergoing treatment with an incretin mimetic.

[0478] Embodiment IV-22. The use of Embodiment IV-21, wherein the amount of the incretin mimetic is reduced after the initiation of administration of the compound of formula (II).

[0479] Embodiment IV-23. The use of Embodiment IV-21 or IV-22, wherein the incretin mimetic is discontinued after the initiation of administration of the compound of formula (II).

[0480] Embodiment IV-24. Use of a compound of formula (II):pharmaceutically acceptable salt thereof, in combination with an incretin mimetic; in the manufacture of a medicament for inducing or sustaining weight loss in a subject, wherein the subject is not administered the compound of formula (II), or a pharmaceutically acceptable salt thereof, or the incretin mimetic prior the administration of the combination of the compound of formula (II), or pharmaceutically acceptable salts thereof, and the incretin mimetic.

[0481] Embodiment IV-25. Use of a compound of formula (III):or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a condition in a subject, wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0482] Embodiment IV-26. Use of a compound of formula (III):or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a condition in a subject, wherein the compound is administered in a dose ranging from 0.5-350 mg;wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0483] Embodiment IV-27. Use of a compound of formula (III):or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a condition in a subject undergoing treatment with an incretin mimetic, wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0484] Embodiment IV-28. The use of Embodiment IV-27, wherein the amount of the incretin mimetic is reduced after the initiation of administration of the compound of formula (III).

[0485] Embodiment IV-29. The use of Embodiments IV-27 or IV-28, wherein the incretin mimetic is discontinued after the initiation of administration of the compound of formula (III).

[0486] Embodiment IV-30. Use of a compound of formula (III):or a pharmaceutically acceptable salt thereof, in combination with an incretin mimetic; in the manufacture of a medicament for treating or preventing a condition in a subject,wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

[0487] Embodiment IV-31. Use of a compound of formula (III):or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inducing or sustaining weight loss in a subject, wherein the administration of the compound is effective to result in an increase of energy expenditure in the subject without thermogenesis.

[0488] Embodiment IV-32. Use of a compound of formula (III):or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inducing or sustaining weight loss in a subject; wherein the compound is administered in a dose ranging from 0.5-350 mg.

[0489] Embodiment IV-33. Use of a compound of formula (III):or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inducing or sustaining weight loss in a subject undergoing treatment with an incretin mimetic.

[0490] Embodiment IV-34. The use of Embodiment IV-33, wherein the amount of the incretin mimetic is reduced after the initiation of administration of the compound of formula (III).

[0491] Embodiment IV-35. The use of Embodiment IV-33 or IV-34, wherein the incretin mimetic is discontinued after the initiation of administration of the compound of formula (III).

[0492] Embodiment IV-36. Use of a compound of formula (III):pharmaceutically acceptable salt thereof, in combination with an incretin mimetic; in the manufacture of a medicament for inducing or sustaining weight loss in a subject, wherein the subject is not administered the compound of formula (III), or a pharmaceutically acceptable salt thereof, or the incretin mimetic prior the administration of the combination of the compound of formula (III), or pharmaceutically acceptable salts thereof, and the incretin mimetic.EXAMPLES

[0493] The following examples are provided to illustrate the present disclosure and should not be construed as limiting thereof.

[0494] In the examples, “Compound 1” is a compound is formula (I)or a pharmaceutically acceptable salt thereof.

[0495] In the examples, “Compound 2” is a compound is formula (II)or a pharmaceutically acceptable salt thereof.

[0496] In the examples, “Compound 3” is a compound is formula (III)or a pharmaceutically acceptable salt thereof.Example 1: Compound 1 Increases Energy Expenditure and Causes Weight Loss in Obese Mice

[0497] Male C57 BL / 6 mice housed at thermoneutrality (28°C) were fed a high-fat diet (HFD) for >28 weeks and dosed with Vehicle (0.5% methylcelluose) or Compound 1 (6mg / kg, low; 20 mg / kg, mid; 60mg / kg, high) PO BID for 8 days. Energy expenditure (EE), measured by indirect calorimetry on Days 6-7, for the 2 hour period post Vehicle or Compound 1 dose in the light and dark cycles were calculated. Baseline was considered as the 2 hour period with lowest energy expenditure in the 24 hour period.

[0498] FIGS. 1 A and IB show increased (-20%) energy expenditure in the dark phase in DIO mice acclimated to thermoneutrality that were treated with Compound 1. FIG. 1C shows dose-dependent reduction in body weight in the DIO mice relative to Vehicle. Data are mean ± SD. *p<0.05, **p<0.01 vs. Vehicle;#p<0.05 vs. baseline.

[0499] The results show that Compound 1 causes increase in energy expenditure and associated weight loss in DIO mice.Example 2: Acute Effects of Compound 1 on Energy Expenditure, Lipid Utilization and Weight Loss in DIO mice

[0500] Male C57 BL / 6 mice housed at thermoneutrality (28°C) were fed a high-fat diet (HFD) for >23 weeks and dosed with Compound 1 either formulated in the HFD (60 and 120 mg / kg / day) or via oral gavage (60 mg / kg twice daily) over 10 days. A separate group of animals were used as controls / vehicles (HFD or vehicle (0.5% methylcellulose, twice daily via oral gavage)), respectively. The primary endpoints were body weight and measurement of energy expenditure and RER by indirect calorimetry.

[0501] Treatment with Compound 1 dose dependently decreased body weight in DIO mice. FIGS. 2A and 2B show relative body weight of DIO mice treated with Compound 1 formulated in HFD or dosed twice daily by oral gavage, respectively.

[0502] FIG. 3 shows that Compound 1, formulated in HFD, caused a dosedependent negative energy balance, which is calculated by subtracting energy expenditure from energy intake. This indicates caloric deficit which would be expected to cause weight loss.

[0503] FIG. 4 shows that Compound 1 acutely increases energy expenditure in DIO mice housed at thermoneutrality. Significant increase in energy expenditure (26%) was noted after a single dose of Compound 1 by oral gavage.

[0504] FIG. 5 shows that Compound 1 dosed via oral gavage also causes a negative energy balance was observed with Compound 1 (-2.67 kcal / day) vs. vehicle (3.35 kcal / day), correlating with weight loss.

[0505] FIG. 6 shows the association between energy balance and change in body weight in DIO mice dosed with vehicle or Compound 1 (either formulated in HFD or dosed via oral gavage). Compound 1 caused dose dependent reduction in body weight which was significantly and inversely correlated with energy balance, i.e., greater negative energy balance was associated with greater weight loss.

[0506] FIG. 7 shows reduced respiratory exchange ratio (RER), indicating increased lipid utilization. Compound 1 decreased RER in a dose dependent manner after a single day on diet compared to vehicle treated animals. This is indicative of increased systemic lipid utilization. Lower RER in the treatment groups was sustained in the treatment groups on day 2. Animals fed the 60 and 120 mg / kg diet haddecreased RER during the dark and light phases on day 1 and 2 compared to baseline. RER of animals treated with vehicle did not change over the course of the study compared to baseline. FIG. 7 shows RER for mice in various dose groups in light phase and dark phase.

[0507] Treatment of Compound 1 via oral gavage reduced RER after a single dose compared to baseline. Oral treatment of Compound 1 reduced RER after a single dose during both the light and dark phases compared to baseline. Lower RER in the treated animals was sustained on day 2. RER was significantly reduced during the light phase on day 1 compared to vehicle treated animals. RER of animals treated with vehicle did not change over the course of the study compared to baseline. FIG. 8 shows RER for mice in various dose groups in light phase and dark phase.Example 3 - 39-Week Repeat-Dose Oral Toxicity and Toxicokinetic Study with a Four- Week Recovery Period in Beagle Dogs

[0508] Beagle dogs (4 / sex / group) were administered vehicle or Compound 1 at doses of 0.5, 1.5, 5, or 10 mg / kg BID (1, 3, 10, or 20 mg / kg / day at a dose volume of 2 mL / kg / day) by oral gavage for 39 weeks. Satellite groups of animals (2 / sex / group) were included for recovery sacrifice 4 weeks after dosing cessation in the vehicle and 5 and 10 mg / kg BID dose groups. The toxicokinetic evaluation was performed on all dogs in the terminal and recovery groups on Days 1 and 273. All animals were observed for clinical signs of toxicity and changes to body weight, food consumption, body temperature, ophthalmology, electrocardiograms, hematology, coagulation, clinical chemistry, urine, organ weights, macroscopic findings at necropsy, and microscopic evaluation of designated tissues.

[0509] All animals survived until their scheduled necropsy and no adverse clinical signs were noted. There were no Compound 1 -related changes in food consumption, body temperature, ophthalmic findings, urinalysis, or electrocardiography or coagulation parameters. Compound 1 -related trends for lower body weight were observed in males (-2.91 to -11.79%) and females (-2.29 to -9.46%) relative to vehicle-treated controls on Day 273, and this showed partial-to-complete recovery in the 10 and 20 mg / kg / day groups during the recovery period. These findings likely represent a pharmacological effect of Compound 1.Example 4: Safety and Tolerability of Compound 1 in Phase 1 Studies Methods

[0510] Compound 1 was studied in a Phase 1 randomized, sponsor-unblinded, placebo-controlled, single- (SAD) and multiple-ascending dose (MAD) study that evaluated the safety, tolerability, PK, and pharmacodynamics (PD) of Compound 1 administered for up to 10 days to healthy adult subjects. For each SAD cohort, six subjects were randomized to receive single doses of Compound 1 and two subjects to receive placebo in the fasted state, and for each MAD cohort, eight subjects were randomized to receive single doses of Compound 1 and two subjects to receive placebo in the fasted state, as summarized in the table below:

[0511] Safety and tolerability assessments, including adverse event (AE) monitoring, laboratory tests, physical examinations, and electrocardiographic (ECG) evaluations were performed throughout the study.Results

[0512] Single and multiple daily doses of Compound 1 for 10 days were safe and well tolerated in healthy subjects, with no evidence of hyperthermia, and no serious adverse events reported in any subject. All subjects completed the study, except for two subjects who discontinued treatment due to a viral illness, and one subject who withdrew due to a family emergency. Neither of these discontinuations were related to study drug.

[0513] Summaries of treatment-emergent (TE) AEs in the SAD (Parts A and C) and MAD cohorts (Parts B and C) are provided in Table 1 and Table 2, respectively.Parts A and C (SAD Cohorts)

[0514] In the SAD cohorts, all TEAEs were Grade 1 in severity, except for one subject in the 270mg cohort who had a Grade 2 AE of catheter site pain, which was deemed unrelated to treatment with Compound 1. The majority of AEs were deemed not related to study drug (Table 1). In total, 5 subjects treated with Compound 1 experienced any treatment-related AE, all deemed Grade 1 in severity. No Grade > 3 or serious AEs (SAEs) were reported.Parts B and C (MAD Cohorts)

[0515] In the MAD cohorts, the majority of TEAEs were Grade 1 in severity (Table 2). In total, 5 subjects treated with Compound 1 experienced any Grade 2 TEAE, all of which were deemed unrelated to study drug, except for a case of reflux in the 240mg group. The majority of AEs were deemed not related to study drug. Overall, no Grade > 3 or SAEs were reported.

[0516] No clinically significant changes in vital signs — including body temperature — or laboratory or ECG parameters were reported in any of the subjects who completed the study.Table 1. Summary of Treatment-Emergent Adverse Events, Parts A and C (SAD)f Pain at cannula site (Gr 2, unrelated).J Headache (Gr 1).§ Nausea (N = 2), reflux (N = 1), all Gr 1. Diarrhea (N = 2), both Gr 1.Table 2. Summary of Treatment-Emergent Adverse Events, Parts B and C (MAD)* Two subjects (N = 1 in each of 15 mg and placebo groups) who resided next to each other in Phase 1 unit discontinued treatment due to viral illness (PCR-confirmed influenza B in one subject).** Anal fissure (unrelated). f Second degree burns secondary to hot water bottle (unrelated).J Reflux (related).§ Viral illness (N = 1), constipation (N = 1), cholecystitis (N = 1). a Constipation (N = 4), blurred vision (N = 2), dry mouth (N = 1), reflux (N = 1), dry throat (N = 1).¥ Abdominal pain (N = 1), diarrhea (N = 1), nausea (N = 1).£ Epigastric discomfort (N = 1), nausea (N = 1), decreased appetite (N = 1), headache (N = 1).II Constipation (N = 2), reflux (N = 1), dry mouth (N = 1), lethargy (N = 1).7, Nausea (N = 4), abdominal discomfort / pain (N = 4), dyspepsia (N = 1), reflux (N = 1), constipation (N = 1), headache (N = 1), dizziness (N = 1). a Conjunctivitis (N = 1), urinary tract infection (N = 1).P Nausea (N = 2).Example 5: Human Pharmacokinetics of Compound 1Methods

[0517] Intensive PK sampling was performed in the SAD (Parts A and C) and MAD (Parts B and C) cohorts of the Phase 1 study, and plasma concentrations of Compound 1 determined using a validated liquid chromatography -tandem mass spectrometry assay. PK parameters were estimated via noncompartmental methods using Phoenix® WinNonlin® 6.2.1 and 8.3.4 (Certara, LP, Princeton, NJ).ResultsSingle Ascending Doses (SAD): Parts A and C

[0518] Plasma PK parameters from SAD Cohorts which evaluated single doses of a formulation of Compound 1 at 3, 6, 15, 30, 60 and 120 mg administered orally in the fasted state in a total of 48 subjects. Results are presented in Table 3.

[0519] Compound 1 was rapidly absorbed, with median Tmax ranging between 3 and 12 hours postdose (3 to 4 hours at doses > 15 mg and 5 to 12 hours at doses of 3 mgand 6 mg, respectively). The median half life (ti / 2) of Compound 1 ranged from approximately 19 to 47 hours with median values generally decreasing as dose increased.Table 3. Compound 1: Part A (SAD) Preliminary PK ParametersPK parameters are presented as mean (%CV), with the exception of Tmaxand ti / 2, which are presented as median (min, max)Multiple Ascending Doses (MAD): Parts B and C

[0520] Plasma PK parameters on Day 1 and Day 10 from MAD cohorts which evaluated Compound 1 doses of 3, 6, 15, 30, 60, 120, administered QD for 10 days in the fasted state in a total of 48 subjects are presented in Table 4 A.

[0521] As observed in the SAD cohorts, Compound 1 was rapidly absorbed, and exhibited a median steady-state Tmax and ti / 2 ranging between 3 and 5 hours and 20 to 34 hours postdose, respectively, shown in Table 4B.

[0522] Steady-state AUCtau, Cmax, and Ctau increased with increasing dose across the dose range evaluated, with AUCtau and Ctau increasing in a modestly less than doseproportional manner up to 120 mg, and Cmax increasing in a modestly greater than dose-proportional manner. Accumulation ratios of AUCtau, Cmax, and Ctau appeared to generally decrease with increasing dose.Table 4A. Compound 1: Parts B and C (MAD) Preliminary PK ParametersTable 4B. Compound 1: Tmaxand Tw

[0523] FIGS. 9A and 9B show plasma concentration time profiles during the SAD and MAD components of the Phase 1 study of Compound 1 in healthy volunteers. Compound 1 was rapidly absorbed, with Tmax occurring 3 to 12 hours postdose. Mean Compound 1 ti / 2 ranged from 17 to 46 hours. Low plasma Cmax supportive of liver targeting pharmacology based on active hepatic uptake.

[0524] The present disclosure provides for a pharmaceutical composition that is safe and well tolerated after single and multiple doses. With a prolonged half-life, the pharmaceutical composition supports once daily, oral dosing. Also, the pharmaceutical composition results in plasma and liver concentrations at steady state such that there is a low plasma Cmax due to liver targeting, which results in avoiding exposures associated with toxicity due to systemic uncoupling (e.g., hyperthermia). Also, the pharmaceutical composition results in plasma and liver concentrations such that the compound reaches hepatic concentrations associated with efficacy in preclinical models (e.g., weight loss, improvements in hepatic and plasma triglycerides).Example 6: Energy Expenditure Measurements in a Phase 1 Study with Compound 1

[0525] The impact of Compound 1 on resting energy expenditure (REE) in a Phase 1 study was measured using a portable indirect calorimetry. Increased REE is Compound 1 exposure dependent and associated with reductions in LDL-C.

[0526] 48 healthy subjects participating in a Phase 1 study received multiple doses of Compound 1 or placebo, administered orally once daily, over 10 days. Energy expenditure in the subjects was assessed pre-dose, after an overnight fast, on days 1 and 10 of the study, using a US FDA cleared, mobile indirect calorimeter whichmeasured the rate of oxygen consumption and carbon dioxide generation in breath over a 10-minute sampling interval, based upon which rates of resting energy expenditure (REE) and respiratory quotient (RQ) were derived.

[0527] Subjects treated with Compound 1 tended to show a dose-dependent increase in energy expenditure as illustrated in FIG. 10. Subjects who received a dose of 120 mg / day of Compound 1 had a REE rate that was 30% higher on Day 10 compared with Day 1, whereas subjects who received a placebo had a rate of REE that was 19% lower on Day 10 compared with Day 1. The increases in REE with Compound 1 were also found to be inversely correlated with baseline REE (p<0.0005), and exposure dependent, as illustrated in FIG 11.

[0528] Subjects who received Compound 1 in the study also had a reduced respiratory quotient (RQ), which is indicative of enhanced fat oxidation. FIG. 12 shows the change in RQ from day 1 to day 10 in relation to dose of Compound 1 administered.

[0529] The administration of Compound 1 tended to result in improvements in metabolic parameters in the subjects (as shown in Table 5). These improvements tended to be associated with the increase in energy expenditure caused by the administration of Compound 1.Table 5*p<0.05

[0530] FIG. 13 shows the inverse relationship between increase in REE and decrease in LDL-C in subjects in the study.

[0531] Increased REE is associated with reduced respiratory quotient (RQ), which is indicative of enhanced fat oxidation. FIG. 14A shows respiratory quotient withrelation to dose of Compound 1 on day 1 and day 10. FIG. 14B shows relative change in respiratory quotient from day 1 to day 10 with relation to dose of Compound 1.Example 7: Compound 2 Increases Energy Expenditure and Lipid Utilization in Obese Mice

[0532] Male C57BL / 6 mice housed at thermoneutrality were fed a high-fat diet (DIO) for 24 weeks, dosed with vehicle (Veh) or Compound 2 (3, 10, or 30 mg / kg) on Days 1 and 4, and necropsied on Day 7. Energy expenditure (EE) was measured by indirect calorimetry for one day prior to dosing (baseline) and up to 2 days post Compound 2 administration.

[0533] Further to the above, energy expenditure (EE) was determined by indirect calorimetry. Mice were single housed in cages connected to special designed air-tight lids of the EE system (PhenoMaster, TSE Systems, Germany). A continuous airflow in the cage optimized for indirect calorimetry measurement of O2 consumption and CO2 production was used. O2 consumption and CO2 production were measured every 20 minutes for a total of 36 hours including two dark phases and one light phase. Water and food were provided in the cage ad libitum and the dosing regimen continued during this period. Calibration procedures were performed when needed before each study period. O2 consumption was reported both as measured values and body weight adjusted O2 and heat production. The objective of body weight adjustment is to obtain a mass-independent measure of differences between treatment groups. Body weight adjusted values are, similar to the approach reported in Muller et al. (Muller et al., Nature Metabolism, VOL 3, Sep 2021, 1134-1136), obtained using a regression approach in which a linear regression is fitted to datapoints from each treatment group individually and used to adjust values. O2 consumed (VO2; ml / h) and CO2 produced (VCO2; ml / h) are calculated as volumes of inspired and expired O2 and CO2. Respiratory Exchange Ratio (RER; VCO2 / VO2) as a ratio and heat production (heat; (RER*1.232+3.815)*V02) / 1000 as energy per hour (Kcal / h).Results

[0534] In DIO mice, a single dose of Compound 2 caused dose-dependent and continuous increase in EE over 2 days post dose, supporting its extended pharmacology. EE increased dose-dependently up to 8% on Day 1 and up to 23% on Day 2 with Compound 2 vs. Veh (p<0.01). Compound 2 dose dependently increasedenergy expenditure in DIO mice after a single dose. Greatest increase (-20%) occurred at approximately the Tmax on Day 2. A decrease in RER, which is indicative of increased lipid utilization, was also observed in the dark phase on Day 2. FIG. 16 shows energy expenditure for mice in various dose groups.

[0535] Respiratory exchange ratio was lower with Compound 2 treatment indicating a shift towards increased peripheral lipid metabolism. A significant reduction in RER was observed on Day 2 post dose. FIG. 17A shows RER in dark phase for mice in various dose groups. FIG. 17B shows RER in light phase for mice in various dose groups.

[0536] Compound 2-induced changes in EE were associated with significant and dose-dependent reductions in body weight (3-5% vs. Veh, p<0.001) and fasting blood glucose (13-18% vs Veh, p<0.01) in all groups at Day 7, without altering food intake. Compound 2 reduced body weight and glycemia in DIO mice after one week. Compound 2 caused dose dependent weight loss in DIO mice after 1 week. Fasted blood glucose was lowered in all dose groups, independent of weight loss, suggesting direct benefits of mitochondrial uncoupling. Compound 2 was well tolerated. FIG. 15A shows relative body weight up to Day 7 for mice in various dose groups. FIG. 15B shows fasted blood glucose at Day 7 for mice in various dose groups.

[0537] Compound 2 caused a rapid, sustained, and dose-dependent increase in EE after a single dose, resulting in weight loss and improved glycemia in DIO mice within 7 days.Example 8: Combinations of Compound 1 and / or the ACC2 inhibitor TLC-3595 provide additive glycemic benefits to GLP-1 receptor agonist semaglutide (SEMA) in db / db mice

[0538] Compound 1 and TLC-3595, a selective ACC2 inhibitor, have complementary mechanisms to GLP-1 receptor agonists. Here, we characterized effects of Compound 1, TLC-3595, and semaglutide (SEMA) as monotherapy (mono) and in combinations (combos) in db / db mice.

[0539] Male db / db mice (fasting glucose, FG>180mg / dL) were treated for 4 wk with vehicle (Veh), Compound 1, TLC-3595, or SEMA mono or dual / triple combos.At 3 wk, an oral glucose tolerance test (oGTT) was performed and incremental AUC (iAUC) of glucose was calculated normalizing for glycemia prior to glucose bolus.Results:

[0540] Fasting glucose (FG) was lower in all groups vs Veh with the greatest reductions in Compound 1 + TLC-3595, Compound 1 + SEMA, and Compound 1 + TLC-3595 + SEMA combos (-42 to -56%). While HbAlc was lower with all monos vs Veh (-0.6 to -1.0%), combos had the greatest effect (-1.4 to -1.7%). Food intake was lower in all SEMA groups, but only SEMA + TLC-3595 caused weight loss (-11%). oGTT iAUC was reduced vs Veh with only Compound 1 mono (-26%) and SEMA in combo with Compound 1 (-40%), TLC-3595 (-31%), and Compound l+TLC-3595 (-41%). (FIG. 18)

[0541] In db / db mice, Compound 1 improved glucose tolerance, FG, and HbAlc similarly to SEMA. The addition of Compound 1 and / or TLC-3595 to SEMA improved glycemic parameters.Example 9: Compound 2 provide additive benefits to semaglutide (SEMA) in DIO mice

[0542] The objective of this study was to evaluate weight loss efficacy of Compound 2 as monotherapy (10 mg / kg, low; 30 mg / kg, high) dosed twice weekly via subcutaneous injection or in combination of Compound 2 (30 mg / kg, twice weekly) with GLP-1 receptor agonist (SEMA, 10 nmol / kg dosed once daily via subcutaneous injection) for 4 weeks in DIO mice. At the end of 4 week, potential of Compound 2 as maintenance therapy post discontinuation of SEMA was evaluated in a subset of animals for 2 additional weeks.

[0543] FIGS. 19A and 19B show that Compound 2 reduced body weight as monotherapy and in combination with semaglutide. Compound 2 monotherapy decreased body weight by about 5-11% vs baseline by day 28. Semaglutide monotherapy alone reduced body weight by about 20%. A combination of semaglutide with Compound 2 further reduced body weight (about 26% vs baseline) demonstrating complementarity of mode of action.

[0544] Decreases in body weight with Compound 2 monotherapy are predominantly driven by fat mass loss. Compound 2 monotherapy significantly anddose dependently decreased fat mass without further reducing lean body mass vs Vehicle or baseline. SEMA monotherapy significantly reduced both fat mass (-36%) and lean body mass (-13%) vs baseline. A combination of semaglutide with Compound 2 further reduced fat mass (47% vs baseline) without altering lean body mass. These data demonstrate that Compound 2 is lean body mass neutral with predominant effects on reducing fat mass. FIGS. 20A-20D shows weight loss composition for subjects in various dose groups.

[0545] Compound 2 monotherapy dose-dependently improved insulin sensitivity, assessed by determination of HOMA-IR score. HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) is an indirect method for quantifying insulin resistance and pancreatic [3-cell function. HOMA-IR in Compound 2 and SEMA combination group was reduced by -70% and in fact normalized to chow levels after 4 weeks of dosing. FIG. 21 A shows HOMA-IR scores for subjects in various dose groups with Compound 2 monotherapy. FIG. 2 IB shows HOMA-IR scores for subjects in various dose groups with Compound 2 and semaglutide combo therapy.

[0546] Body weight and fat mass in DIO mice in maintenance phase is shown in FIGS. 22A and 22B. Rebound in body weight was observed in maintenance phase after semaglutide treatment was stopped. Compound 2 combo groups maintained a lower body weight (-18% vs vehicle) compared to semaglutide monotherapy (-9% vs vehicle). FIG. 22A shows body weight change from baseline for subjects in various dose groups in the main phase and maintenance phase.

[0547] Compound 2 maintains lower fat mass in the combo group compared to semaglutide monotherapy during maintenance phase. Subjects in the combo group receiving continued Compound 2 dose had less fat mass regain (16%) than semaglutide monotherapy (48%) after discontinuation of SEMA treatment. FIG. 22B shows fat mass loss in subjects with Compound 2 monotherapy and SEMA combo therapy after discontinuation of SEMA.

[0548] Compound 2 monotherapy reduced fasted plasma insulin comparable to SEMA monotherapy. Insulin levels in semaglutide-treated groups were normalized to chow levels after 4 weeks of dosing. Stopping semaglutide treatment increased insulinin the semaglutide monotherapy, but not Compound 2-high dose combo group. FIG.23 A shows insulin levels in subjects in various dose groups over a period of 42 days.

[0549] Compound 2 monotherapy caused sustained reduction in HOMA-IR. HOMA-IR in semaglutide-treated groups were normalized to chow levels after 4 weeks of dosing. Stopping semaglutide treatment increased insulin in the semaglutide monotherapy, but not Compound 2-high dose combo group. FIG. 23B shows HOMA- IR in subjects in various dose groups over a period of 42 days.

[0550] Compound 2 monotherapy improved liver biochemistry, assessed by plasma ALT levels, comparable to SEMA monotherapy after 4 weeks of dosing. Combination of Compound 2 with SEMA tended to have greater benefits than either monotherapy. Discontinuation SEMA treatment caused a slight increase in ALT is in the SEMA monotherapy group, and this was prevented in the mice receiving continued Compound 2 treatment. FIG. 24 shows ALT levels for subjects in various dose groups over a period of 42 days.Example 10: Combination of Compound 1 With Low Dose Semaglutide Normalizes Body Weight, Fat Mass and Glucose Tolerance in DIO Mice

[0551] Weight loss efficacy and insulin sensitivity of Compound 1 in combination with semaglutide (SEMA) were evaluated in DIO mice. Briefly, male mice fed a HFD for 15 weeks and treated with vehicle, Compound 1 (120 mg / kg / day dosed in HFD), or SEMAhigh (10 nmol / kg / day, s.c., dose titrated over one week) for a total of six weeks. After three weeks of treatment, the vehicle and Compound 1 groups were each split into two cohorts where half of the mice continued to receive vehicle or Compound 1, and the other half started receiving SEMAiow (3 nmol / kg / day s.c., dose titrated over one week) on top of vehicle or Compound 1 treatment for the remainder of the study.

[0552] At the end of three weeks of treatment, Compound 1 or SEMAhigh monotherapies caused -14% and -24% weight loss, respectively compared to vehicle (FIG. 25 A). At the end of the study, Compound 1, but not SEMAhigh, caused additional weight loss, to a total of -18% vs vehicle. Initiation of SEMAiow in vehicle- treated mice at Week 3 caused -14% weight loss vs. vehicle at the end of the study. However, initiation of SEMAiow on top of continued Compound 1 treatment causedadditional -16% weight loss between Weeks 3-6, leading to a total of -33% weight loss versus vehicle and normalization of body weight to lean control levels. Weight loss in the Compound 1 + SEMAiow combination was not associated with any adverse clinical signs and was significantly greater than either monotherapy and SEMAhigh (FIG. 25B). Compound 1 monotherapy did not impact food intake, and SEMAhigh and SEMAiow monotherapies and Compound 1 + SEMAiow combination had similar reductions in food intake.

[0553] Treatment with Compound 1 or SEMAhigh monotherapy reduced fat mass by -51% or -69%, respectively vs vehicle at the end of the study. Initiating SEMAiow monotherapy starting on Day 21 caused -26% fat mass loss versus vehicle. Compound 1 + SEMAiow combination caused an additional -34% fat mass loss vs Compound 1 monothereapy leading to a total of -78% versus vehicle (p < 0.05 versus all) (FIG. 25C).

[0554] At the end of the study, Compound 1, SEMAiow and SEMAhigh monotherapies reduced fasted blood glucose (FBG) by -20%, -22% and -31% compared to vehicle, respectively. Compound 1 + SEMAiow combination had the greatest benefit on FBG (-39% vs vehicle; p < 0.05 versus all monotherapies). Moreover, Compound 1 and SEMAhigh, but not SEMAiow, monotherapies normalized HOMA-IR to lean controls. Compound 1 + SEMAiow combination further improved HOMO-IR (-84% versus vehicle) (FIGS. 25D-25E).

[0555] To summarize FIGS. 25A-25E, DIO mice were treated with vehicle, Compound 1 (120 mg / kg in HFD), or SEMAhigh (10 nmol / kg, QD, subcutaneously) monotherapy for 6 weeks. After 3 weeks of treatment, SEMAiow (3 nmol / kg, QD, subcutaneously) was initiated in half the vehicle or Compound 1 cohorts through the end of the study. FIGS. 25A-25B show relative body weight results. FIG. 25C shows fat mass results. FIG. 25D shows fasted blood glucose results. FIG. 25E shows HOMA-IR results. Data are shown as mean ± SEM. n = 6-25 per group. *p < 0.05 versus vehicle, two-way repeated measures ANOVA (A-B) Kruskal-Wallis (C-E); #p < 0.05 versus SEMAhigh, two-way repeated measures ANOVA; ip < 0.05 versus Compound 1 + SEMAiow combination, Mann-Whitney.Ill

[0556] Glucose tolerance was assessed by glucose AUC measured during an OGTT. All monotherapies significantly improved glucose AUC (Compound 1, -10%;SEMAiow, -16%; SEMAhigh, -20%) versus vehicle. Compound 1 + SEMAiow combination had an additive effect on glucose AUC (-28% versus vehicle; p <0.05 versus all monotherapies). Plasma insulin levels, measured 15 min post glucose bolus during the OGTT, was minimally reduced with Compound 1 and SEMAiow monotherapies but was normalized to lean control levels in the Compound 1 + SEMAiow combination and SEMAhigh combination groups, shown in the table below.Combination of Compound 1 with SEMAiowis Non-Inferior to SEMAhigh and Normalizes Glucose Tolerance and Hyperinsulinemia in DIO MiceData are shown as mean ± SEM. n = 6-10. *p < 0.05 versus vehicle; #p < 0.05 versus SEMAhigh, Kruskal- Wallis test; J p < 0.05 vs Compound 1 + SEMAiow, Mann- Whitney test.Example 11: Compound 1 Treatment Post SEMA Discontinuation Prevents Weight and Fat Mass Re-gain in DIO Mice

[0557] The effects of Compound 1 as maintenance therapy after SEMA discontinuation was evaluated in DIO mice. Briefly, male mice fed a HFD for 15 weeks were administered SEMA (10 nmol / kg, QD, SC) for 3 weeks at which point the mice were randomized to three cohorts for an additional 3 weeks: continued SEMA therapy (SEMA— > SEMA), SEMA discontinuation (SEMA— >Vehicle), SEMA replacement with Compound 1 (120 mg / kg / day in HFD; SEMA^ Compound 1).

[0558] SEMA treatment for 3 weeks caused -24% reduction in body weight relative to vehicle. Continued SEMA treatment (SEMA— > SEMA) maintained weight loss at - 24% versus vehicle through the end of the study. SEMA discontinuation(SEMA— > Vehicle) caused -68% re-gain in weight lost to a final body weight that was-13% lower than vehicle. Replacing SEMA with Compound 1 (SEMA— > Compound 1) maintained weight loss through the end of the study (-22% versus vehicle) and was not inferior to continued SEMA treatment (FIG. 26A).

[0559] Similar trends were observed for fat mass loss. Continued SEMA treatment caused a -69% reduction in fat mass at the end of the study. SEMAhigh discontinuation caused a -56% re-gain to a final fat mass loss of -37% versus vehicle. Replacing SEMA with Compound 1 caused a slight (13%) re-gain in fat mass such that final fat mass loss in this group (-60% versus vehicle) was not inferior to continued SEMA treatment (FIG. 26B).

[0560] Continued SEMA treatment reduced FBG below lean controls (-31% versus vehicle) at the end of the study. SEMA discontinuation (SEMA— > Vehicle) caused a full rebound in FBG to vehicle levels, while FBG was normalized to lean controls in the SEMA^ Compound 1 group (FIG. 26C). Moreover, while SEMA discontinuation worsened HOMA-IR to vehicle levels, replacing SEMA with Compound 1 or continued SEMA therapy normalized HOMA-IR to lean controls (FIG. 26D).Continued SEMA therapy improved glucose tolerance relative to vehicle and lean controls (-20% glucose AUC versus vehicle). SEMA discontinuation worsened glucose tolerance during OGTT (+6% glucose AUC versus vehicle). However, replacing SEMA with Compound 1 maintained improvements in glucose tolerance which was normalized to lean controls. Replacing SEMA with Compound 1 (SEMA^ Compound 1) also blunted insulin levels, measured 15 min post glucose bolus during the OGTT, relative to SEMA^Vehicle group, shown in the table below.Treatment with Compound 1 After SEMA Discontinuation Normalized Glucose Tolerance to Lean ControlsData are shown as mean ± SEM. n = 8-10. *p < 0.05 versus vehicle; #p < 0.05 versus SEMAhigh, Kruskal- Wallis test.

[0561] To summarize FIGS. 26A-26D, DIO mice were treated with vehicle or SEMA (10 nmol / kg, QD, subcutaneously) monotherapy for 3 weeks. After 3 weeks of treatment, SEMA-treated animals were randomized to 3 cohorts for an additional 3 weeks: continued SEMA treatment (SEMA— > SEMA), SEMA discontinuation (SEMA— ehicle) or SEMA replacement with Compound 1 (120 mg / kg in HFD; SEMA^ Compound 1). FIG. 26A shows relative body weight results. FIG. 26B shows fat mass results. FIG. 26C shows fasted blood glucose results. FIG. 26D shows HOMA-IR results. Data are shown as mean ± SEM. n = 8-25 per group. *p < 0.05 versus vehicle, two-way repeated measures ANOVA (A) Kruskal-Wallis (B-D); #p < 0.05 versus SEMAhigh, two-way repeated measures ANOVA (A) Kruskal -Wallis (B- D); fp < 0.05 versus Week 3, Mann-Whitney.Example 12: Sequential Combination of Compound 2 with SEMA Improves Weight Loss and Preserves Lean Body Mass in DIO mice

[0562] Male DIO mice housed at thermoneutrality were dosed with either vehicle or Compound 2 monotherapy for 3 weeks. The vehicle group was further randomized to receive either vehicle or low dose SEMA (SEMAi0W; 3 nmol / kg) for an additional 3 weeks, while the Compound 2 monotherapy group were further randomized to receive either Compound 2 monotherapy, or a combination of Compound 2 and SEMAiow for an additional 3 weeks. A separate group received high dose semaglutide (SEMAhigh; lOnmol / kg) monotherapy for 6 weeks. Body weight, fat mass and lean mass werequantified by Echo-MRI. Plasma ALT levels, plasma insulin levels, liver, and muscle triglyceride levels were measured with respective analysis methods.Over 6 weeks, Compound 2 monotherapy significantly reduced body weight (-20%) and fat mass (-56%) with no lean mass loss, while SEMAhigh monotherapy reduced body weight (-25%), fat mass (-63%), and lean mass (-9.5%; p<0.05 vs vehicle). Compound 2 + SEMAiow combination enhanced body weight (-30%) and fat mass (- 76%) loss vs Compound 2 or SEMAhigh monotherapy (all p<0.05). Lean mass loss was similar between the combination, SEMAiow and SEMAhigh, suggesting that the additional weight loss in the combination arm was driven by fat mass loss. Unlike SEMA, Compound 2 did not impact food intake. Both Compound 2 monotherapy and Compound 2 + SEMAiow combination reduced plasma ALT by 85% and liver triglycerides by -50% (p<0.05 vs vehicle) as seen with SEMAhigh monotherapy. Compound 2 and SEMAhigh monotherapy reduced muscle triglycerides by 50% (p<0.05 vs vehicle). Compound 2 + SEMAiow combination further reduced muscle triglycerides, normalizing them to lean control levels (p<0.05 vs vehicle or SEMAhigh). Compound 2 and SEMAhigh monotherapy reduced plasma insulin 15 min- post glucose bolus by 88% and 65%, respectively (p<0.05 vs vehicle). Compound 2 + SEMAiow combination provided additional reduction in fasting plasma insulin (p<0.05 vs Compound 2 or SEMAhigh monotherapy), normalizing to lean control levels.

[0563] FIGS. 27A-27H show results in this experiment for the groups as discussed above where —> indicates a transition to a therapy with a different composition: (1) vehicle; (2) vehicle —> SEMAiow; (3) Compound 2; (4) Compound 2 —> Compound 2 + SEMAiow; (5) SEMAhigh. FIG. 27A shows relative body weight results for the groups. FIG. 27B shows fat mass results for the groups. FIG. 27C shows lean mass results for the groups. FIG. 27D shows ALT (alanine aminotransferase) results for the groups. FIG. 27E shows liver triglycerides results for the groups. FIG. 27F shows muscle triglycerides results for the groups. FIG. 27G shows plasma insulin results for the groups. FIG. 27H shows plasma insulin-15 min. post glucose results for the groups.

[0564] These data highlight the potential of Compound 2 as monotherapy and in combination with incretin mimetics, in the treatment of obesity and associated metabolic disorders.Example 13: Studies to explore the safety and efficacy of Compound 2 as monotherapy, and in combination with SEMA, in non-human primates (NHPs)

[0565] Compound 2 was evaluated in non-human primates (NHP) across multiple exploratory studies. In an initial study in cynomolgus monkeys, Compound 2 administered subcutaneously at a dose of 1.5mg / kg / week over two weeks resulted in mean weight loss of 8.2% (FIG. 28). In subsequent studies, cynos administered a once-daily oral dose of 0.3 mg / kg lost an average of 3% of their body weight (FIG. 29), and animals administered a once-daily oral dose of 1.3mg / kg lost an average of 10% of their body weight over 14 days. There was no evidence of hyperthermia in the animals in any of these studies.

[0566] Based on these results, a study is being conducted to explore the efficacy of Compound 2 as monotherapy and in combination with SEMA in obese NHPs. Spontaneously obese female cynomolgus monkeys were randomized based on their body weight and BMI (Body Mass Index) to receive vehicle, two doses of Compound 2, a combination of Compound 2 and Semaglutide, or Semaglutide monotherapy for 8 weeks as shown below.

[0567] In this study, body weight is monitored twice a week (Q2W) and food intake monitored daily. Body composition is analyzed by DEXA at base line, week 6 andweek 8) to evaluate the efficacy on fat mass. Plasma samples will be collected and analyzed for Compound 2 concentrations. Plasma samples will also be analyzed by clinical chemistry parameters (ALT, AST, plasma glucose and plasma insulin) to determine the other metabolic benefits of Compound 2 as monotherapy and in combination with SEMA.Example 14: Combination of Compound 2 and an Acetyl-CoA Carboxylase 2 (ACC2) Inhibitor Causes Weight Loss and Preserves Lean Body Mass in Obese Mice

[0568] Compound 2 and TLC-3595, an ACC2-selective inhibitor, enhance fatty acid oxidation via complementary mechanisms and are in development for obesity- associated disorders. Here, we compared the efficacy of a combination of Compound 2 and TLC-3595 to semaglutide (SEMA) in diet-induced obese (DIO) mice.

[0569] Methods: Male DIO mice, fed a high-fat diet for 16 weeks, were housed at thermoneutrality and administered TLC-3595, Compound 2, semaglutide, or the combination of TLC-3595 and Compound 2 for 6 weeks. Body weight and food intake were measured over the course of the study. Body composition was measured using Echo-MRI at baseline and week 6.

[0570] Results: TLC-3595 and Compound 2 monotherapies lowered body weight (- 5% and -13%, respectively), which was primarily driven by fat mass loss (-12% and - 27%, respectively) vs vehicle. The combination of TLC-3595 and Compound 2 further reduced body weight by -16%, similar to semaglutide (-17%). Reductions in fat mass were similar with the combination of TLC-3595 and Compound 2 (-36%) and semaglutide (-33%). While semaglutide reduced food intake, no changes in food intake were seen with the combination. Unlike semaglutide, which reduced lean body mass, no decrease in lean body mass was observed with the combination of TLC-3595 and Compound 2 (p<0.05 vs SEMA). FIG. 30A shows relative body weight results for the test groups, including groups receiving TLC-3595 or Compound 2. FIG. 30B shows body composition results for the test groups, including groups receiving TLC- 3595 or Compound 2.

[0571] In DIO mice, a combination of Compound 2 and an ACC2 inhibitor caused comparable weight loss to an incretin but preserved lean body mass.Example 15: Phase lb - Clinical Trial Study Protocol- Safety, Tolerability, PK, and Efficacy of Compound 1

[0572] Phase lb (Part F) of the study is designed to evaluate the safety, tolerability, PK, and efficacy of Compound 1 in 60 subjects with obesity. Specifically, Cohort 20 will be a multicenter, blinded, placebo-controlled study in which 60 subjects with obesity (BMI > 30 kg / m2) are randomized in a 2.5:2.5: 1 ratio to receive Compound 1, 30 mg (N = 25); Compound 1, 90 mg (N = 25); or placebo (N = 10), all orally once daily, for 12 weeks. Randomization will be stratified by the presence or absence of diabetes at Screening.

[0573] Efficacy endpoints include changes between Baseline / Day 1 and Week 12 in body weight, waist circumference, plasma lipids and glycemic parameters, liver biochemistry and noninvasive tests of fibrosis, liver fat and body composition by MRI, and energy expenditure by the DLW method.

[0574] A schematic diagram of the study is provided in FIG. 31. Study procedures for safety assessments include assessment of clinical laboratory tests, ECGs, and physical examinations including vital signs at various time points throughout the study, and by documentation of adverse events and concomitant medications throughout the study.Study Treatments

[0575] Treatment Group A: Compound 1, 30 mg (2 x 15 mg Compound 1 tablets, 2 x 45 mg Compound 1 PTM tablets), administered orally, once daily for 84 days (n = 25 subjects)

[0576] Treatment Group B: Compound 1, 90 mg (2 x 45 mg Compound 1 tablets, 2 x 15 mg Compound 1 PTM tablets), administered orally, once daily for 84 days (n = 25 subjects)

[0577] Treatment Group C: Compound 1 Placebo (2 x 45 mg PTM tablets, 2 x 15 mg PTM tablets), administered orally, once daily for 84 days (n = 10 subjects)Assessments

[0578] Doubly Labeled Water (DLW) assessment is used for all subjects at three timepoints (Baseline, Week 4 and Week 12). The Calorify® kit is used to evaluate REE and body composition.

[0579] MRI (optional) is used to evaluate body composition (lean body mass, total fat mass, SAT, VAT), liver fat % by MRI-PDFF, and muscle (volume, contractile muscle volume and cross sectional area, intramuscular fat).

[0580] Resting energy expenditure (REE) is measured with the Breezing device, a noninvasive, wearable, indirect calorimeter that has received 501 (k) clearance by the US FDA. This portable mask-like device evaluates energy expenditure by detecting the rate of oxygen consumption and carbon dioxide generation in breath over a 10- minute sampling interval (Xian, X., A. Quach, D. Bridgeman, F. Tsow, E. Forzani and N. Tao (2015). "Personalized Indirect Calorimeter for Energy Expenditure (EE) Measurement." Global Journal of Obesity, Diabetes and Metabolic Syndrome 2: 004- 008. Deng, Y., F. Chen, E. Forzani and V. Juturu (2017). "Capsaicinoids Enhance Metabolic Rate in Normal Healthy Individuals using a Novel Metabolic Tracker Breezing Device-An Open Label Placebo Controlled Acute Study." Obesity: Open Access).Results

[0581] Following the protocol above, a clinical trial study was performed, as discussed below.Subject Disposition

[0582] A total of 98 adult subjects with obesity were treated as follows: 27 subjects received Compound 1 at 30 mg QD (Cohort 20), 27 subjects received 90 mg QD (Cohort 20), 25 subjects received 135 mg QD (Cohort 21), and 19 subjects received placebo (Cohorts 20-21). Across Cohorts 20-21, ages ranged between 23 and 68 years, 70% of subjects were female, and BMI ranged from 30 to 57 kg / m2. In Cohort 20, all 63 subjects (100%) who received Compound 1 (30 or 90 mg) or placebo completed study drug treatment and the study. In Cohort 21, of the 35 subjects who received Compound 1 at 135 mg or placebo, 34 (97%) completed study drug treatment and the study. One subject (3%) treated with Compound 1 at 135 mgwithdrew consent at the Week 8 visit, citing personal reasons including scheduling challenges related to a change in work commitments.Safety Results

[0583] Treatment with Compound 1 at 30, 90, or 135 mg was generally well tolerated. Table 6 presents an overall summary of TEAEs in Cohorts 20-21. In these cohorts, no Grade 4 AEs, deaths, or pregnancies were reported in any treatment group.

[0584] In Cohort 20, 54 of 63 subjects (86%) had a TEAE, including 85% (46 of 54) of subjects receiving Compound 1 at 30 or 90 mg QD as compared to 89% (8 of 9) subjects receiving placebo. The majority of AEs were Grade 1 in severity and considered not related to study drug by the investigator. A total of 18 subjects experienced any treatment-related TEAE, including in 6 (22%), 8 (30%), and 4 (44%) subjects in the Compound 1 at 30 mg, 90 mg, and placebo groups, respectively. Treatment-related AEs reported in more than 1 subject treated with either dose of Compound 1 included headache, decreased appetite, nausea, abdominal pain, flatulence, diarrhea, and dry mouth, all in two subjects (4%) each and the majority Grade 1 in severity. In total, 44% of subjects (24 of 54) treated with either dose of Compound 1 reported any Grade 2 AE, compared to 44% of subjects (4 of 9) treated with placebo. Grade 2 AEs reported in more than 1 subject treated with either dose of Compound 1 included headache in 5 subjects (9%), influenza-like illness in 3 subjects (6%), and diarrhea, COVID-19 infection, and viral infection, all in two Compound 1- treated subjects (4%) each.

[0585] In Cohort 20, one subject treated with Compound 1 at 90 mg with a medical history notable for cholelithiasis experienced a Grade 3 SAE of bile duct stone requiring elective cholecystectomy, deemed related to study drug in the opinion of the investigator. One subject treated with placebo interrupted study drug due to noncardiac chest pain.

[0586] In Cohort 21, 26 of 35 subjects (74%) had a TEAE, including 72% (18 of 25) of subjects receiving Compound 1 at 135 mg QD as compared to 80% (8 of 10) of subjects receiving placebo. The majority of AEs were Grade 1 in severity and considered to not be related to study drug by the investigator. A total of 10 subjectsexperienced any AE considered related to study drug, including in 8 (32%) and 2 (20%) subjects treated with Compound 1 at 135 mg or placebo, respectively. Treatment-related AEs reported in more than 1 subject treated with Compound 1 at 135 mg included abdominal pain, nausea, and decreased appetite, all in two subjects (8%) each and Grade 1 in severity. In total, 28% of subjects (7 of 25) treated with Compound 1 at 135 mg reported any Grade 2 AE, compared to 40% of subjects (4 of 10) treated with placebo. Among subjects treated with Compound 1 at 135 mg, Grade 2 influenza-like illness was reported in two subjects (8%), with both cases deemed unrelated to study drug in the opinion of the investigator.Table 6. Summary of Treatment-Emergent Adverse Events, Part F (Cohorts 20-21)

[0587] For Cohorts 20-21, Table 7 presents a summary of TEAEs reported in > 5% of subjects treated with any dose of Compound 1. Adverse events reported in > 10% of subjects treated with Compound 1 included upper respiratory tract infection (URTI) (18%) and headache (17%), which were reported in 37% and 11% of placebo subjects, respectively. Abdominal pain was reported in one subject (5%) in the combined placebo group, no subjects treated with Compound 1 at 30 mg (0%), and in three subjects in each of the Compound 1 at 90 mg (11%) and 135 mg (12%) groups (11%). The frequency of other AEs were similar between the combined Compound 1- treated population and the pooled placebo group. Additionally, among subjects treated with Compound 1, no dose-dependent or notable changes in safety laboratory parameters, 12-lead ECGs, or vital signs, including body temperature, were observed.Table 7. Treatment-Emergent Adverse Events Reported for at Least 5% ofCompound 1-Treated Subjects by Preferred Term (Cohorts 20-21)Example 16: Phase lb - Clinical Trial Study Protocol-Compound 1 and Tirzepatide

[0588] The safety, tolerability, PK, and efficacy of Compound 1 is being evaluated in a multicenter, blinded, placebo-controlled study. In Cohort 1, approximately 50 subjects with obesity (BMI > 30 kg / m2) were randomized to receive Compound 1 and tirzepatide (N = 30), or placebo and tirzepatide (N = 20), for 24 weeks. In Cohort 2, an additional approximately 50 subjects with obesity may be randomized to receive a different dose of Compound 1 in combination with tirzepatide (N = 30), or placebo with tirzepatide (N = 20), for 24 weeks.

[0589] In both cohorts, efficacy endpoints include changes between Baseline / Day 1 and Week 24 in body weight, hip and waist circumference, plasma lipids, glycemic parameters, liver biochemistry and noninvasive tests of liver fibrosis, liver fat and body composition by MRI, and energy expenditure by the DLW method.

[0590] A schematic diagram of the study is provided in FIG. 32. Study procedures for safety assessments include assessment of clinical laboratory tests, ECGs, andphysical examinations including vital signs at various time points throughout the study, and by documentation of adverse events and concomitant medications throughout the study.Study Treatments

[0591] Cohort 1, Treatment Group A: Compound 1, 180 mg (administered orally, once daily) plus tirzepatide administered as a once weekly subcutaneous injection at 2.5 mg for the first four weeks, and at 5 mg from week 5 onwards for an additional 20 weeks (n = 30 subjects).

[0592] Cohort 1, Treatment Group B: Placebo (administered orally, once daily) plus tirzepatide administered as a weekly subcutaneous injection at 2.5 mg for the first four weeks, and at 5 mg from week 5 onwards for an additional 20 weeks (n = 20 subjects).

[0593] Cohort 2, Treatment Group C: Compound 1, 270 mg (administered orally, once daily) plus tirzepatide administered as a once weekly subcutaneous injection at 2.5 mg for the first four weeks, and at 5 mg from week 5 onwards for an additional 20 weeks (n = 30 subjects).

[0594] Cohort 2, Treatment Group D: Placebo (administered orally, once daily) plus tirzepatide administered as a weekly subcutaneous injection at 2.5 mg for the first four weeks, and at 5 mg from week 5 onwards for an additional 20 weeks (n = 20 subjects).Assessments

[0595] MRI is used to evaluate body composition (lean body mass, total adiposity, SAT, VAT), liver fat % by MRI-PDFF, liver volume, spleen volume, and various muscle assessments, including SAT, muscle volume, contractile muscle volume, cross sectional area, and intramuscular fat.Example 17: A Single Subcutaneous Dose Pharmacokinetics Study of Compound 3 in Cynomolgus Monkeys

[0596] Male cynomolgus monkeys (3 per group) were administered a single subcutaneous dose of Compound 3 at 7.5 mg / kg (at a dose volume of 3 mL / kg). Oneuntreated cage mate animal was included as a control. The plasma concentrations of Compound 3 and the body weights were measured over 28 days post administration.

[0597] All three animals treated with Compound 3 demonstrated weight loss with a mean of 6.6% weight loss on Day 14 whereas a slight increase in body weight was observed in the untreated animal (FIG. 33). During the study, there were no signs of clinical safety or changes in body temperatures.

[0598] Following a single subcutaneous administration of Compound 3, the mean maximum concentration (Cmax) was achieved at 32 hours post dose. The plasma concentration declined up to Day 10 with a half-life of 54 h. After Day 10, the plasma concentration gradually increased to Day 28 (FIG. 34). These unique PK profiles suggest flip-flop kinetics caused by a depot formation in the subcutaneous space with a slow dissolution followed by absorption into systemic circulation.

[0599] In conclusion, after a single subcutaneous administration of Compound 3 in cynomolgus monkeys, Compound 3 was detectable up to 28 days post administration. The mean body weight reduced up to 14 days and gradually recovered.Example 18: Non-GLP Single Dose Pharmacokinetic Study of Compound 3 Administered Subcutaneously in C57bl / 6 Mice

[0600] Male C57B1 / 6 mice (12 animals total) were administered a single subcutaneous dose of Compound 3 at 7.5 mg / kg (at a dose volume of 3 mL / kg). The plasma, liver, adipose, and muscle concentrations of Compound 3 were measured over 14 days post administration.

[0601] Following a single subcutaneous administration, Compound 3 was detectable in plasma up to 72 hours post administration. The mean maximum concentration (Cmax) was achieved at 4 hours post dose and gradually cleared with a terminal half-life of 25.7 hours (FIG. 35).

[0602] Compound 3 demonstrated high liver and adipose tissue loading with approximately 100- and 10-fold higher concentrations than those in plasma, respectively (FIG. 36). There was no evidence for preferential loading on Compound 3 in skeletal muscle tissue.Example 19: Compound 3: Non-GLP Single Oral Dose Pharmacokinetic Study in C57bl / 6 Mice

[0603] Male C57B1 / 6 mice (24 animals total) were administered a single oral dose of Compound 3 at 10, 50, and 100 mg / kg (at a dose volume of 10, 10, and 20 mL / kg, respectively). The plasma, liver, and adipose concentrations of Compound 3 were measured over 72 hours post administration.

[0604] Following a single subcutaneous administration, Compound 3 was detectable in plasma up to 48 hours post administration at all three doses. Compound 3 was rapidly absorbed with a Tmax of 0.5 - 1.0 h post dose and cleared with a terminal half-life of 4.7 - 8.3 hours (FIG. 37). The exposures increased less than dose proportionally between 10 and 100 mg / kg suggesting a saturation of oral absorption at 10 mg / kg in mice.

[0605] Based on the liver and adipose concentrations at 24 h post dose, preferential loading into liver and adipose was observed with approximately 89-, 54-, and 16-fold liver-to-plasma ratio and approximately 8-, 11-, and 1.6-fold at 10, 50, and 100 mg / kg dose, respectively (FIG. 38A-38C).Equivalents

[0606] While the present disclosure has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and other variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present disclosure.

Claims

Claims:

1. A method of treating or preventing a condition in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

2. A method of treating or preventing a condition in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (I):or a pharmaceutically acceptable salt thereof, in a dose ranging from 30-380 mg; wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

3. The method of claim 1 or 2, wherein the administration of the compound is effective to result in an increase of energy expenditure in the subject without causing hyperthermia.

4. The method of any one of claims 1-3, wherein the compound is administered orally to the subject.

5. The method of any one of claims 1-4, wherein the compound is administered once daily to the subject.

6. The method of any one of claims 1-5, wherein the compound is administered at about 90-360 mg per day.

7. The method of any one of claims 1-6, wherein the compound is administered at about 135 mg per day.

8. The method of any one of claims 1-6, wherein the compound is administered at about 180 mg per day.

9. The method of any one of claims 1-6, wherein the compound is administered at about 270 mg per day.

10. The method of any one of claims 1-9, wherein the administration results in a reduction of fat mass.

11. The method of claim 10, wherein the administration results in a reduction of fat mass in the subject by at least about 5%.

12. The method of any one of claims 10-11, wherein the administration results in reduction of fat mass while substantially maintaining lean body mass.

13. The method of any one of claims 1-12, wherein the administration results in inducing weight loss or sustaining weight loss.

14. The method of any one of claims 1-13, wherein the weight loss is at least about 5% over a period of 52 weeks.

15. The method of any one of claims 1-13, wherein the weight loss is at least about 3% over 36 weeks.

16. The method of any one of claims 1-13, wherein the weight loss is at least about 2% over 24 weeks.

17. The method of any one of claims 1-13, wherein the weight loss is at least about 1% over 12 weeks.

18. The method of any one of claims 1-17, wherein at least 80-90% of the weight loss is from fat mass.

19. The method of any one of claims 1-18, wherein the administration results in improving glycemic control.

20. The method of any one of claims 1-19, wherein the administration lowers fasted blood glucose of the subject.

21. The method of any one of claims 1-20, wherein the administration lowers HbAlc level in the subject.

22. A method of treating or preventing a condition in a subject undergoing treatment with an incretin mimetic, comprising administering to the subject in need thereof an effective amount of a compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

23. The method of claim 22, wherein the amount of the incretin mimetic is reduced after the initiation of administration of the compound of formula (I).

24. The method of claim 22 or 23, wherein the incretin mimetic is discontinued after the initiation of administration of the compound of formula (I).

25. The method of claim 24, wherein the incretin mimetic is discontinued about 4 weeks after the initiation of administration of the compound of formula (I).

26. The method of claim 24, wherein the incretin mimetic is discontinued about 8 weeks after the initiation of administration of the compound of formula (I).

27. The method of claim 24, wherein the incretin mimetic is discontinued about 12 weeks after the initiation of administration of the compound of formula (I).

28. The method of claim 24, wherein the incretin mimetic is discontinued about24 weeks after the initiation of administration of the compound of formula (I).

29. A method of treating or preventing a condition in a subject, comprising administering to the subject in need thereof a compound of formula (I):pharmaceutically acceptable salt thereof, in combination with an incretin mimetic; wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

30. The method of any one of claims 22-29, wherein the incretin mimetic is semaglutide or tirzepatide.

31. The method of claim 30, wherein semaglutide is administered orally at about 1.5-15 mg per day or subcutaneously at about 0.25-2.4 mg per week.

32. The method of claim 30, wherein tirzepatide is administered subcutaneously at about 2.5-15 mg per week.

33. The method of any one of claims 22-32, wherein the compound of formula (I) is administered at about 180-380 mg per day.

34. The method of any one of claims 22-32, wherein the compound of formula (I) is administered at about 30-180 mg per day.

35. A method of inducing or sustaining weight loss in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein the administration of the compound is effective to result in an increase of energy expenditure in the subject without thermogenesis.

36. A method of inducing or sustaining weight loss in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (I):or a pharmaceutically acceptable salt thereof, in a dose ranging from 30-380 mg.

37. The method of any one of claims 35-36, wherein the compound is administered orally to the subject.

38. The method of any one of claims 35-37, wherein the compound is administered once daily to the subject.

39. The method of any one of claims 35-38, wherein the compound is administered at about 90-360 mg per day.

40. The method of any one of claims 35-39, wherein the compound is administered at about 135 mg per day.

41. The method of any one of claims 35-39, wherein the compound is administered at about 180 mg per day.

42. The method of any one of claims 35-39, wherein the compound is administered at about 270 mg per day.

43. A method of inducing or sustaining weight loss in a subj ect undergoing treatment with an incretin mimetic, comprising administering to the subject in need thereof an effective amount of a compound of formula (I):or a pharmaceutically acceptable salt thereof.

44. The method of claim 43, wherein the amount of the incretin mimetic is reduced after the initiation of administration of the compound of formula (I).

45. The method of claim 43 or 44, wherein the incretin mimetic is discontinued after the initiation of administration of the compound of formula (I).

46. The method of claim 45, wherein the incretin mimetic is discontinued about 4 weeks after the initiation of administration of the compound of formula (I).

47. The method of claim 45, wherein the incretin mimetic is discontinued about 8 weeks after the initiation of administration of the compound of formula (I).

48. The method of claim 45, wherein the incretin mimetic is discontinued about 12 weeks after the initiation of administration of the compound of formula (I).

49. The method of claim 45, wherein the incretin mimetic is discontinued about24 weeks after the initiation of administration of the compound of formula (I).

50. A method of inducing or sustaining weight loss in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (I):pharmaceutically acceptable salt thereof, in combination with an incretin mimetic; wherein the subject is not administered the compound of formula (I), or a pharmaceutically acceptable salt thereof, or the incretin mimetic prior the administration of the combination of the compound of formula (I), or pharmaceutically acceptable salts thereof, and the incretin mimetic.

51. The method of any one of claims 43-50, wherein the incretin mimetic is semaglutide or tirzepatide.

52. The method of claim 51, wherein semaglutide is administered orally at about 1.5-15 mg per day or subcutaneously at about 0.25-2.4 mg per week.

53. The method of claim 51, wherein tirzepatide is administered subcutaneously at about 2.5-15 mg per week.

54. The method of any one of claims 43-53, wherein the compound of formula (I) is administered at about 135-270 mg per day.

55. The method of any one of claims 43-53, wherein the compound of formula (I) is administered at about 30-135 mg per day.

56. A method of treating or preventing a condition in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (II):or a pharmaceutically acceptable salt thereof, wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

57. A method of treating or preventing a condition in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (II):or a pharmaceutically acceptable salt thereof, in a dose ranging from 0.5-350 mg;wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

58. The method of claim 56 or 57, wherein the administration of the compound is effective to result in an increase of energy expenditure in the subject without causing hyperthermia.

59. The method of any one of claims 56-58, wherein the compound is administered orally to the subject.

60. The method of any one of claims 56-59, wherein the compound is administered once daily to the subject.

61. The method of claim 60, wherein the compound is administered at about 0.5 to 350 mg per day.

62. The method of claim 60, wherein the compound is administered at about 0.5 to 50 mg per day.

63. The method of any one of claims 56-58, wherein the compound is administered parenterally to the subject.

64. The method of any one of claims 56-58, wherein the compound is administered subcutaneously to the subject.

65. The method of claim 63 or 64, wherein the compound is administered at about 2.5 to 350 mg per week.

66. The method of any one of claims 56-65, wherein the administration results in a reduction of fat mass.

67. The method of claim 66, wherein the administration results in a reduction of fat mass in the subject by at least about 5%.

68. The method of any one of claims 66-67, wherein the administration results in reduction of fat mass while substantially maintaining lean body mass.

69. The method of any one of claims 56-68, wherein the administration results in inducing weight loss or sustaining weight loss.

70. The method of any one of claims 56-69, wherein the weight loss is at least about 5% over a period of 52 weeks.

71. The method of any one of claims 56-69, wherein the weight loss is at least about 3% over 36 weeks.

72. The method of any one of claims 56-69, wherein the weight loss is at least about 2% over 24 weeks.

73. The method of any one of claims 56-69, wherein the weight loss is at least about 1% over 12 weeks.

74. The method of any one of claims 56-73, wherein at least 80-90% of the weight loss is from fat mass.

75. The method of any one of claims 56-74, wherein the administration results in improving glycemic control.

76. The method of any one of claims 56-75, wherein the administration lowers fasted blood glucose of the subject.

77. The method of any one of claims 56-76, wherein the administration lowers HbAlc level in the subject.

78. A method of treating or preventing a condition in a subject undergoing treatment with an incretin mimetic, comprising administering to the subject in need thereof an effective amount of a compound of formula (II):or a pharmaceutically acceptable salt thereof, wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

79. The method of claim 78, wherein the amount of the incretin mimetic is reduced after the initiation of administration of the compound of formula (II).

80. The method of claim 78 or 79, wherein the incretin mimetic is discontinued after the initiation of administration of the compound of formula (II).

81. The method of claim 80, wherein the incretin mimetic is discontinued about 4 weeks after the initiation of administration of the compound of formula (II).

82. The method of claim 80, wherein the incretin mimetic is discontinued about 8 weeks after the initiation of administration of the compound of formula (II).

83. The method of claim 80, wherein the incretin mimetic is discontinued about 12 weeks after the initiation of administration of the compound of formula (II).

84. The method of claim 80, wherein the incretin mimetic is discontinued about 24 weeks after the initiation of administration of the compound of formula (II).

85. A method of treating or preventing a condition in a subject, comprising administering to the subject in need thereof a compound of formula (II):pharmaceutically acceptable salt thereof, in combination with an incretin mimetic; wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

86. The method of any one of claims 78-85, wherein the incretin mimetic is semaglutide or tirzepatide.

87. The method of claim 86, wherein semaglutide is administered orally at about 1.5-15 mg per day or subcutaneously at about 0.25-2.4 mg per week.

88. The method of claim 86, wherein tirzepatide is administered subcutaneously at about 2.5-15 mg per week.

89. The method of any one of claims 78-88, wherein the compound of formula (II) is administered at about 0.5-350 mg per day.

90. The method of any one of claims 78-88, wherein the compound of formula (II) is administered at about 2.5-350 mg per week.

91. A method of inducing or sustaining weight loss in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (II):or a pharmaceutically acceptable salt thereof,wherein the administration of the compound is effective to result in an increase of energy expenditure in the subject without thermogenesis.

92. A method of inducing or sustaining weight loss in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (II):or a pharmaceutically acceptable salt thereof, in a dose ranging from 0.5 to350 mg.

93. The method of any one of claims 91-92, wherein the compound is administered orally to the subject.

94. The method of any one of claims 91-93, wherein the compound is administered once daily to the subject.

95. The method of any one of claims 91-92, wherein the compound is administered parenterally to the subject.

96. The method of any one of claims 91-92, wherein the compound is administered subcutaneously to the subject.

97. The method of any one of claims 95-96, wherein the compound is administered at about 2.5 to 350 mg per week.

98. A method of inducing or sustaining weight loss in a subject undergoing treatment with an incretin mimetic, comprising administering to the subject in need thereof an effective amount of a compound of formula (II):or a pharmaceutically acceptable salt thereof.

99. The method of claim 98, wherein the amount of the incretin mimetic is reduced after the initiation of administration of the compound of formula (II).

100. The method of claim 98 or 99, wherein the incretin mimetic is discontinued about 4-24 weeks after the initiation of administration of the compound of formula (II).

101. The method of claim 100, wherein the incretin mimetic is discontinued about 4 weeks after the initiation of administration of the compound of formula (II).

102. The method of claim 100, wherein the incretin mimetic is discontinued about 8 weeks after the initiation of administration of the compound of formula (II).

103. The method of claim 100, wherein the incretin mimetic is discontinued about 12 weeks after the initiation of administration of the compound of formula (II).

104. The method of claim 100, wherein the incretin mimetic is discontinued about 24 weeks after the initiation of administration of the compound of formula (II).

105. A method of inducing or sustaining weight loss in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (II):pharmaceutically acceptable salt thereof, in combination with an incretin mimetic; wherein the subject is not administered the compound of formula (II), or a pharmaceutically acceptable salt thereof, or the incretin mimetic prior the administration of the combination of the compound of formula (II), or pharmaceutically acceptable salts thereof, and the incretin mimetic.

106. The method of any one of claims 98-105, wherein the incretin mimetic is semaglutide or tirzepatide.

107. The method of claim 106, wherein semaglutide is administered orally at about 1.5-15 mg per day or subcutaneously at about 0.25-2.4 mg per week.

108. The method of claim 106, wherein tirzepatide is administered subcutaneously at about 2.5-15 mg per week.

109. The method of any one of claims 98-108, wherein the compound of formula (II) is administered at about 0.5 to 350 mg per day.

110. The method of any one of claims 98-108, wherein the compound of formula (II) is administered at about 2.5 to 350 mg per week.

111. A method of treating or preventing a condition in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (III):or a pharmaceutically acceptable salt thereof, wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

112. A method of treating or preventing a condition in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (III):or a pharmaceutically acceptable salt thereof, in a dose ranging from 0.5-350 mg; wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

113. The method of claim 111 or 112, wherein the administration of the compound is effective to result in an increase of energy expenditure in the subject without causing hyperthermia.

114. The method of any one of claims 111-113, wherein the compound is administered orally to the subject.

115. The method of any one of claims 111-114, wherein the compound is administered once daily to the subject.

116. The method of claim 115, wherein the compound is administered at about 0.5 to 350 mg per day.

117. The method of any one of claims 111-113, wherein the compound is administered parenterally to the subject.

118. The method of any one of claims 111-113, wherein the compound is administered subcutaneously to the subject.

119. The method of claim 117 or 118, wherein the compound is administered at about 2.5 to 350 mg per week.

120. The method of any one of claims 111-119, wherein the administration results in a reduction of fat mass.

121. The method of claim 120, wherein the administration results in a reduction of fat mass in the subject by at least about 5%.

122. The method of any one of claims 120-121, wherein the administration results in reduction of fat mass while substantially maintaining lean body mass.

123. The method of any one of claims 111-122, wherein the administration results in inducing weight loss or sustaining weight loss.

124. The method of any one of claims 111-123, wherein the weight loss is at least about 5% over a period of 52 weeks.

125. The method of any one of claims 111-123, wherein the weight loss is at least about 3% over 36 weeks.

126. The method of any one of claims 111-123, wherein the weight loss is at least about 2% over 24 weeks.

127. The method of any one of claims 111-123, wherein the weight loss is at least about 1% over 12 weeks.

128. The method of any one of claims 111-127, wherein at least 80-90% of the weight loss is from fat mass.

129. The method of any one of claims 111-128, wherein the administration results in improving glycemic control.

130. The method of any one of claims 111-129, wherein the administration lowers fasted blood glucose of the subject.

131. The method of any one of claims 111-130, wherein the administration lowers HbAlc level in the subject.

132. A method of treating or preventing a condition in a subject undergoing treatment with an incretin mimetic, comprising administering to the subject in need thereof an effective amount of a compound of formula (III):or a pharmaceutically acceptable salt thereof, wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

133. The method of claim 132, wherein the amount of the incretin mimetic is reduced after the initiation of administration of the compound of formula (III).

134. The method of claim 132 or 133, wherein the incretin mimetic is discontinued after the initiation of administration of the compound of formula (III).

135. The method of claim 134, wherein the incretin mimetic is discontinued about 4 weeks after the initiation of administration of the compound of formula (III).

136. The method of claim 134, wherein the incretin mimetic is discontinued about 8 weeks after the initiation of administration of the compound of formula (III).

137. The method of claim 134, wherein the incretin mimetic is discontinued about12 weeks after the initiation of administration of the compound of formula (III).

138. The method of claim 134, wherein the incretin mimetic is discontinued about 24 weeks after the initiation of administration of the compound of formula (III).

139. A method of treating or preventing a condition in a subject, comprising administering to the subject in need thereof a compound of formula (III):pharmaceutically acceptable salt thereof, in combination with an incretin mimetic; wherein the treatment or prevention of the condition is reducing fat mass, maintaining lean body mass, inducing weight loss, sustaining weight loss, or improving glycemic control.

140. The method of any one of claims 132-139, wherein the incretin mimetic is semaglutide or tirzepatide.

141. The method of claim 140, wherein semaglutide is administered orally at about 1.5-15 mg per day or subcutaneously at about 0.25-2.4 mg per week.

142. The method of claim 140, wherein tirzepatide is administered subcutaneously at about 2.5-15 mg per week.

143. The method of any one of claims 132-142, wherein the compound of formula (III) is administered at about 0.5-350 mg per day.

144. The method of any one of claims 132-142, wherein the compound of formula (III) is administered at about 2.5-350 mg per week.

145. A method of inducing or sustaining weight loss in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (III):or a pharmaceutically acceptable salt thereof, wherein the administration of the compound is effective to result in an increase of energy expenditure in the subject without thermogenesis.

146. A method of inducing or sustaining weight loss in a subject, comprising administering to the subject in need thereof an effective amount of a compound of formula (III):or a pharmaceutically acceptable salt thereof, in a dose ranging from 0.5 to350 mg.

147. The method of any one of claims 145-146, wherein the compound is administered orally to the subject.

148. The method of any one of claims 145-147, wherein the compound is administered once daily to the subject.

149. The method of any one of claims 145-146, wherein the compound is administered parenterally to the subject.

150. The method of any one of claims 145-146, wherein the compound is administered subcutaneously to the subject.

151. The method of any one of claims 149-150, wherein the compound is administered at about 2.5 to 350 mg per week.

152. A method of inducing or sustaining weight loss in a subject undergoing treatment with an incretin mimetic, comprising administering to the subject in need thereof an effective amount of a compound of formula (III):or a pharmaceutically acceptable salt thereof.

153. The method of claim 152, wherein the amount of the incretin mimetic is reduced after the initiation of administration of the compound of formula (III).

154. The method of claim 152 or 153, wherein the incretin mimetic is discontinued after the initiation of administration of the compound of formula (III).

155. The method of claim 154, wherein the incretin mimetic is discontinued about 4 weeks after the initiation of administration of the compound of formula (III).

156. The method of claim 154, wherein the incretin mimetic is discontinued about 8 weeks after the initiation of administration of the compound of formula (III).

157. The method of claim 154, wherein the incretin mimetic is discontinued about 12 weeks after the initiation of administration of the compound of formula (III).

158. The method of claim 154, wherein the incretin mimetic is discontinued about 24 weeks after the initiation of administration of the compound of formula (III).

159. A method of inducing or sustaining weight loss in a subject, comprising administering to the subject in need thereofan effective amount of a compound of formula (III):pharmaceutically acceptable salt thereof, in combination with an incretin mimetic; wherein the subject is not administered the compound of formula (III), or a pharmaceutically acceptable salt thereof, or the incretin mimetic prior the administration of the combination of the compound of formula (III), or pharmaceutically acceptable salts thereof, and the incretin mimetic.

160. The method of any one of claims 152-159, wherein the incretin mimetic is semaglutide or tirzepatide.

161. The method of claim 160, wherein semaglutide is administered orally at about 1.5-15 mg per day or subcutaneously at about 0.25-2.4 mg per week.

162. The method of claim 160, wherein tirzepatide is administered subcutaneously at about 2.5-15 mg per week.

163. The method of any one of claims 152-162, wherein the compound of formula (III) is administered at about 0.5 to 350 mg per day.

164. The method of any one of claims 152-162, wherein the compound of formula (III) is administered at about 2.5 to 350 mg per week.

165. A composition comprising a compound of formula (I):or a pharmaceutically acceptable salt thereof; and a compound selected from the group consisting of an ACC2 inhibitor and an incretin mimetic.

166. A composition comprising a compound of formula (II)or a pharmaceutically acceptable salt thereof; and a compound selected from the group consisting of an ACC2 inhibitor, and an incretin mimetic.

167. A composition comprising a compound of formula (III)or a pharmaceutically acceptable salt thereof; and a compound selected from the group consisting of an ACC2 inhibitor, and an incretin mimetic.

168. The composition of any one of claims 165-167, wherein the ACC2 inhibitor is TLC-3595.

169. The composition of any one of claims 165-167, wherein the incretin mimetic is a GLP-1 receptor agonist.

170. The composition of claim 169, wherein the GLP-1 receptor agonist is semaglutide.

171. The composition of claim 169, wherein the GLP-1 receptor agonist is tirzepatide.

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