Compounds for the treatment of hypothalamic obesity

Abstract

Provided herein are methods for treating non-genetic obesity and / or acquired obesity and related disorders (e.g., hypothalamic obesity) with an MC4R agonist.

Description

[0001] COMPOUNDS FOR THE TREATMENT OF HYPOTHALAMIC OBESITY

[0002] CLAIM OF PRIORITY

[0003] This application claims priority to U.S. Application No. 63 / 674,234, filed on July 22, 2024, and U.S. Application No. 63 / 840,590, filed on July 8, 2025. The entire contents of each of the foregoing applications are incorporated herein by reference in their entirety.

[0004] BACKGROUND

[0005] Hypothalamic obesity is a complex neuroendocrine disorder caused by hypothalamic damage characterized by rapid weight gain, obesity, hyperphagia, decreased resting energy expenditure, and / or reduced physical activity. Amongst suprasellar tumors, craniopharyngioma is the most common cause with about half of craniopharyngioma patients developing altered eating behavior and extreme obesity. Craniopharyngioma patients also typically suffer from panhypopituitarism and demonstrate significant hyperleptinemia due to anatomic leptin resistance, inadequate hyperinsulinemia, impaired incretin response, and reduced levels of a- MSH. There are currently no approved treatments for hypothalamic obesity and available interventions provide only modest and variable effects. As such, there is a need for new treatments for hypothalamic obesity.

[0006] SUMMARY

[0007] Provided herein are methods for treating non-genetic obesity and / or acquired obesity and related disorders (e.g., hypothalamic obesity) with an MC4R agonist. In a first aspect, the present application features a method of treating hypothalamic obesity in a subject, comprising administering to the subject a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof: wherein R1is C2-C5 alkyl; R2is halo; R3is hydrogen or halo; R4is C1-C3 alkyl; and n is 1 or 2. In an embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is provided as an oral dosage form (e.g., a capsule or a tablet). In an embodiment, the oral dosage form provides a dosage of a compound of Formula (I) of between about 10 mg and about 1000 mg (e.g., about 20 mg and 900 mg, about 30 mg and 800 mg, about 40 mg and 700 mg, about 50 mg and 600 mg, about 100 mg and 500 mg, about 200 mg and 400 mg, or about 300 mg). In an embodiment, the oral dosage form provides a dosage of a compound of Formula (I) of between about 20 mg and about 900 mg. In an embodiment, the oral dosage form provides a dosage of a compound of Formula (I) of between about 30 mg and about 800 mg. In an embodiment, the oral dosage form provides a dosage of a compound of Formula (I) of between about 40 mg and about 700 mg. In an embodiment, the oral dosage form provides a dosage of a compound of Formula (I) of between about 50 mg and about 600 mg. In an embodiment, the oral dosage form provides a dosage of a compound of Formula (I) of between about 100 mg and about 500 mg. In an embodiment, the oral dosage form provides a dosage of a compound of Formula (I) of between about 200 mg and about 400 mg. In an embodiment, the oral dosage form provides a dosage of a compound of Formula (I) of about 300 mg. In some embodiments, the compound is administered daily, e.g., once per day, twice per day, three times per day, four times per day, five times per day, six times per day, or seven times per day. In some embodiments, the compound is administered weekly, e.g., once per week, twice per week, three times per week, four times per week, five times per week, six times per week, or seven times per week. In some embodiments, the compound is administered once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, or once every eight weeks. In some embodiments, the compound is administered daily, weekly, monthly, or yearly. In some embodiments, the compound is administered once daily. In some embodiments of the foregoing aspect, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered for at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, or more. In some embodiments, the compound is administered for at least one month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In some embodiments, the compound is administered for at least 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, or more.

[0008] In some embodiments of the foregoing aspect, the subject’s response to the compound of Formula (I) or a pharmaceutically acceptable salt thereof is assessed by measuring a parameter selected from body weight, body mass index (BMI), waist circumference, waist-to-hip circumference ratio, body composition, hunger, and fatigue. In some embodiments, the subject’s response to the compound of Formula (I) or a pharmaceutically acceptable salt thereof is assessed by measuring the percent change in the subject’s body weight relative to baseline at intervals. In some embodiments, the intervals comprise 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks. In some embodiments, the intervals comprise 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months. In some embodiments, the intervals comprise 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years.

[0009] In some embodiments of the foregoing aspect, the subject is identified as having or diagnosed with hypothalamic obesity. In some embodiments, the subject displays or experiences a symptom or risk factor of hypothalamic obesity. In some embodiments, the symptoms or risk factor of comprises weight gain, increased hunger, decreased energy, high level of damage to the hypothalamus, endocrine dysfunction, or receiving high amounts of radiation to the hypothalamic area. In some embodiments, the symptom or risk factor comprises weight gain. In some embodiments, the symptom or risk factor comprises increased hunger. In some embodiments, the symptom or risk factor comprises decreased energy. In some embodiments, the symptom or risk factor comprises high level of damage to the hypothalamus. In some embodiments, the symptom or risk factor comprises endocrine dysfunction. In some embodiments, the symptom or risk factor comprises receiving high amounts of radiation to the hypothalamic area. In some embodiments of the foregoing aspect, the treatment with a compound of Formula (I) or a pharmaceutically acceptable salt thereof comprises a reduction in a symptom by about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more. In some embodiments, the treatment with a compound of Formula (I) or a pharmaceutically acceptable salt thereof comprises a reduction in body weight by about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more. In some embodiments, the treatment with a compound of Formula (I) or a pharmaceutically acceptable salt thereof comprises a reduction in hunger by about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more. In some embodiments, the treatment with a compound of Formula (I) or a pharmaceutically acceptable salt thereof comprises a reduction in decreased energy by about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more. In some embodiments, the treatment with a compound of Formula (I) or a pharmaceutically acceptable salt thereof comprises a reduction in endocrine dysfunction by about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more.

[0010] In some embodiments of the foregoing aspect, following treatment of the subject by a compound of Formula (I) or a pharmaceutically acceptable salt thereof, the subject experiences a reduction in a parameter selected from: body weight, body mass index (BMI), waist circumference, waist-to-hip circumference ratio, body composition, hunger, and fatigue. In some embodiments, the parameter is body weight. In some embodiments, the parameter is BMI. In some embodiments, the parameter is waist circumference. In some embodiments, the parameter is waist-to-hip circumference ratio. In some embodiments, the parameter is body composition. In some embodiments, the parameter is hunger. In some embodiments, the parameter is fatigue.

[0011] In some embodiments of the foregoing aspect, the treatment with a compound of Formula (I) or a pharmaceutically acceptable salt thereof comprises a reduction in a parameter by about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more, relative to baseline. In some embodiments, the treatment with a compound of Formula (I) or a pharmaceutically acceptable salt thereof comprises a reduction in body weight by about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more, relative to baseline. In some embodiments, the reduction in body weight comprises between about 2% to about 30%. In some embodiments, the reduction in body weight comprises between about 5% to about 20%. In some embodiments, the treatment with a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof comprises a reduction in BMI by about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more, relative to baseline. In some embodiments, the reduction in BMI comprises between about 1% to about 20%. In some embodiments, the reduction in BMI comprises between about 5% to about 15%. In some embodiments, the treatment with a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof comprises a reduction in waist circumference by about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more, relative to baseline. In some embodiments, the reduction in waist circumference comprises between about 1% to about 20%. In some embodiments, the reduction in waist circumference comprises between about 5% to about 15%.

[0012] In some embodiments of the foregoing aspect, the treatment with a compound of Formula (I) or a pharmaceutically acceptable salt thereof comprises a reduction in waist-to-hip circumference ratio by about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more, relative to baseline. In some embodiments, the reduction in waist-to-hip circumference ratio comprises between about 1% to about 50%. In some embodiments, the reduction in waist-to-hip circumference ratio comprises between about 10% to about 40%. In some embodiments, the treatment with a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof comprises a reduction in body composition (e.g., a reduction in a DEXA score) by about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more, relative to baseline. In some embodiments, the reduction in body composition (e.g., a reduction in the DEXA score) comprises between about 1% to about 50%. In some embodiments, the reduction in body composition (e.g., a reduction in the DEXA score) comprises between about 1% to about 30%. In some embodiments, the treatment with a compound of Formula (I) or a pharmaceutically acceptable salt thereof comprises a reduction in hunger (e.g., a reduction in total daily caloric intake) by about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more, relative to baseline. In some embodiments, the reduction in hunger(e.g., a reduction in total daily caloric intake) comprises between about 10% to about 70%. In some embodiments, the reduction in hunger (e.g., a reduction in total daily caloric intake) comprises between about 40% to about 60%. In some embodiments, the treatment with a compound of Formula (I) or a pharmaceutically acceptable salt thereof comprises a reduction in fatigue by about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more, relative to baseline. In some embodiments, the reduction in fatigue comprises between about 1% to about 50%. In some embodiments, the reduction in fatigue comprises at least about 20%.

[0013] In some embodiments of the foregoing aspect, the oral dosage form comprises chewable tablets, quick melting tablets, foam tablets, solid form gelatin capsules, soft gelatin capsules, reducing particles, particulates, suspensions, elixirs, caplets, syrups, liquid, liquid gels, oils, or gels. In some embodiments, the subject is a mammal, e.g., a human. In some embodiments, the subject is a human. In some embodiments, the subject is at least 18 years of age. In some embodiments, the subject is less than 18 years of age. In some embodiments, the subject has been diagnosed with hypothalamic obesity. In some embodiments, the subject has not been diagnosed with hypothalamic obesity. In some embodiments, the subject does not have a genetic obesity. In some embodiments, the subject has diabetes, e.g., Type 2 diabetes (T2D).

[0014] In some embodiments of the foregoing aspect, the subject is not being treated for obesity and / or weight gain prior to administration of a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the subject is being treated with an additional pharmaceutical agent, wherein the additional pharmaceutical agent may comprise growth hormone, contraceptives, hydrocortisone, desmopressin, sex hormone replacement therapy, antihypertensives, GLP-1 receptor agonists (such agonists may be used only for the treatment of diabetes mellitus and not for weight loss), statins and other lipid lowering therapies, thyroxine or other thyroid supplements, administration of live or inactivated vaccines (e.g., SARS-CoV-2 vaccines), other medications commonly used in subjects with obesity (e.g., anticonstipation medications, anti-allergic medications, estrogens, alendronic acid, hydrocortisone, carnitine, Coenzyme Q10, vitamins, or calcium supplements). In some embodiments, the subject is being treated with an additional pharmaceutical agent, wherein the additional pharmaceutical agent may not comprise anorectic agents or drugs with anorexia as a non-rare side effect; strong inhibitors and strong inducers of CYP3A4 including grapefruit juice; inhibitors or substrates of P-glycoprotein; GLP-l's (e.g., GLP-1 agonists) except for the treatment of diabetes; nirmatrelvir / ritonavir. BRIEF DESCRIPTION OF THE FIGURES

[0015] FIG. 1 is an illustration depicting the agonism and antagonism of the MC4R receptor by POMC and AgRP neuron hormones.

[0016] FIGS. 2A and 2B are graphs depicting the effect of repeated doses of a compound of Formula (I), e.g., Compound 100, on body weight in a mouse diet-induced obesity (DIO) model. Eighteen week old male C57BL / 6 mice were fed a 60% kcal fat diet for 13 weeks prior to being administered once daily with Compound 100 at doses of 0, 3, 10, and 30 mg / kg for 7 weeks. Sibutramine, an appetite suppressant, was administered as a control once daily at 10 mg / kg. Data represents the mean ± S.E.M. (n=10 per group). Significant difference from DIO control group by one-way ANOVA followed by the Dunnett's test: * p<0.05, ** p<0.01, *** p<0.001. All of the Compound 100 groups showed a significant reduction in food intake compared to the vehicle control (p<0.01 and p<0.001) and in the cumulative food intake at Week 1 and Week 2 of Compound 100 administration.

[0017] FIGS. 3A-3C are graphs depicting the effect of repeated doses of Compound 100 on food intake in a mouse diet-induced obesity (DIO) model. As in FIG. 2, eighteen week old male C57BL / 6 mice were fed a 60% kcal fat diet for 13 weeks prior to being administered once daily with Compound 100 at doses of 0, 3, 10, and 30 mg / kg for 7 weeks, and Sibutramine was administered as a control. Data represents the mean ± S.E.M. Significant difference from DIO control group by one-way ANOVA followed by the Dunnett's test: * p<0.05, ** p<0.01, *** p<0.001. All of the Compound 100 groups showed a significant reduction in food intake compared to the vehicle control (p<0.01 and p<0.001) and in the cumulative food intake at Week 1 and Week 2 of Compound 100 administration. Food intake returned to vehicle control levels by Week 3.

[0018] FIG. 4 is a graph depicting the effect of repeated doses of Compound 100 on the total body fat mass in a mouse diet-induced obesity (DIO) model. As in FIGS. 2-4, eighteen week old male C57BL / 6 mice were fed a 60% kcal fat diet for 13 weeks prior to being administered once daily with Compound 100 at doses of 0, 3, 10, and 30 mg / kg for 7 weeks, and Sibutramine was administered as a control. Data represents the mean ± S.E.M. (n=10 per group). Significant difference from DIO control group by one-way ANOVA followed by the Dunnett's test: * p<0.05, ** p<0.01, *** p<0.001. The groups dosed with Compound 100 showed a dose- dependent body fat-reducing effect, reaching significance in the Compound 100 (10 and 30 mg / kg) groups (p<0.01 and p<0.001).

[0019] FIG. 5 is a graph depicting the effect of repeated doses of Compound 100 on the weight of fat from different parts of the body and liver tissue in a mouse diet-induced obesity (DIO) model. As in FIGS. 2-4, eighteen week old male C57BL / 6 mice were fed a 60% kcal fat diet for 13 weeks prior to being administered once daily with Compound 100 at doses of 0, 3, 10, and 30 mg / kg for 7 weeks, and Sibutramine was administered as a control. Data represents the mean + S.E.M. (n=10 per group). Significant difference from DIO control group by one-way ANOVA followed by the Dunnett's test: * p<0.05, ** p<0.01, *** p<0.001. The Compound 100 (10 and 30 mg / kg) groups showed a significant weight reduction in mesenteric fat (p<0.001), interscapular fat (p<0.001), perirenal fat (p<0.001) and retroperitoneal fat (p<0.05) compared to vehicle. The weight of subcutaneous fat was significantly lower in the Compound 100 (30 mg / kg) group (p<0.01) only. The liver weight was significantly lower in the Compound 100 10 and 30 mg / kg groups compared to the vehicle control (p<0.05 and p<0.01).

[0020] FIG. 6 is a graph depicting the effect of repeated doses of Compound 100 on liver triglyceride levels in a mouse diet-induced obesity (DIO) model. As in FIGS. 2-5, eighteen week old male C57BL / 6 mice were fed a 60% kcal fat diet for 13 weeks prior to being administered once daily with Compound 100 at doses of 0, 3, 10, and 30 mg / kg for 7 weeks, and Sibutramine was administered as a control. Data represents the mean ± S.E.M. (n=10 per group). Significant difference from DIO control group by one-way ANOVA followed by the Dunnett's test: * p<0.05, ** p<0.01, *** pcO.OOl. Compound 100 treatment caused a significant reduction in liver steatosis at 10 and 30 mg / kg dose (p<0.01 and pcO.OOl).

[0021] FIGS. 7A and 7B are graphs depicting the effect of repeated doses of Compound 100 on non-fasting blood glucose and HbAlc in a mouse diet-induced obesity (DIO) model. As in FIGS. 2-6, eighteen week old male C57BL / 6 mice were fed a 60% kcal fat diet for 13 weeks prior to being administered once daily with Compound 100 at doses of 0, 3, 10, and 30 mg / kg for 7 weeks, and Sibutramine was administered as a control. Data represents the mean ± S.E.M. ( n= 10 per group). Significant difference from DIO control group by one-way ANOVA followed by the Dunnett's test: * p<0.05, ** p<0.01, *** p<0.001. A significant reduction in non-fasting blood glucose (p<0.01 and pcO.OOl) and HbAlc (p<0.01 and p<0.05) was shown in the Compound 100 groups compared to the vehicle control. FIGS. 8A and 8B are graphs depicting the effect of repeated doses of Compound 100 on glucose tolerance in a mouse diet-induced obesity (DIO) model. As in FIGS. 2-8, eighteen week old male C57BL / 6 mice were fed a 60% kcal fat diet for 13 weeks prior to being administered once daily with Compound 100 at doses of 0, 3, 10, and 30 mg / kg for 7 weeks, and Sibutramine was administered as a control. Data represents the mean ± S.E.M. (n= 10 per group). Significant difference from DIO control group by one-way ANOVA followed by the Dunnett's test: * p<0.05, ** p<0.01, *** p<0.001. All of the groups provided with Compound 100 showed a significant reduction in blood glucose after challenge as shown by blood glucose levels and calculated AUCs (p<0.001).

[0022] FIGS. 9A and 9B are graphs depicting the effect of repeated doses of Compound 100 on body weight in a KK-Ay mouse model of genetic obesity. Fourteen week old female KK-Ay mice were fed a 45% kcal fat diet for 7 weeks, and Compound 100 was administered to the mice once a day at doses of 0, 3, 10, 15 and 30 mg / kg for 5 weeks; Sibutramine (10 mg / kg) was used as a control. Data represents the mean ± S.E.M. (n=9 per group). Significant difference from DIO control group by one-way ANOVA followed by the Dunnett's test: * p<0.05, ** p<0.01, *** p<0.001. The Compound 100 groups showed a dose-dependent weight loss on Day 26. A continuous weight loss effect was observed in the 15 and 30 mg / kg groups (FIG. 9A). At Day 26 of administration, a significant weight loss effect was confirmed in the Compound 100 15 and 30 mg / kg groups compared to the vehicle control, showing comparable or higher efficacy compared to sibutramine (p<0.01 and p<0.001) (change in body weight compared to the vehicle control: - 7.5% [sibutramine 10 mg / kg], -4.9% [Compound 1003 mg / kg], -7.8% [Compound 100 10 mg / kg], -16.3% [Compound 100, 15 mg / kg] and -17.4% [Compound 100 30 mg / kg]). The MED of Compound 100 for the weight loss effect was 15 mg / kg in this study (FIG. 9B).

[0023] FIGS. 10A-10C are graphs depicting the effect of repeated doses of Compound 100 on food intake in a KK-Ay mouse model of genetic obesity. Data represents the mean ± S.E.M. (n=9 per group). Significant difference from DIO control group by one-way ANOVA followed by the Dunnett's test: * p<0.05, ** p<0.01, *** pcO.OOl. Repeated administration of Compound 100 resulted in reduction in food intake on Weeks 1 (FIG. 10B) and 2 (FIG. 10C) of administration, in Compound 100 15 and 30 mg / kg groups (p<0.01 and p<0.001 ) . Food intake had returned to vehicle control levels by Week 3 (FIG. 10A). FIG. 11 is a graph depicting the effect of repeated doses of Compound 100 on the total fat volume in a KK-Ay mouse model of genetic obesity. Data represents the mean ± S.E.M. (n=9 per group). Significant difference from DIO control group by one-way ANOVA followed by the Dunnett's test: * p<0.05, ** p<0.01, *** p<0.001. A dose-dependent significant reduction of total fat, abdominal fat and subcutaneous fat volumes were shown in the Compound 100 15 and 30 mg / kg dose groups (p<0.01 and p<0.001).

[0024] FIGS. 12A and 12B are graphs depicting the effect of repeated doses of Compound 100 on body weight in a db / db mouse model of genetic obesity. Six week old male db / db mice were fed a high fat diet for 6 weeks and during that time Compound 100 was dosed orally at 0, 3, 10, and 30 mg / kg once a day. Untreated db / db mice and sibutramine treated mice (10 mg / kg, administered once a day) were used as the controls. Data represents the mean ± S.E.M.. Significant difference from db / db control group by one-way ANOVA followed by the Dunnett’s test: * p<0.05, ** p<0.01, *** p<0.001. (db / dm control [n=9], other groups [n=10]). The Compound 100 groups showed a dose-dependent weight loss after 28 days of dosing. (FIG. 12A). At Day 28 of administration, a significant weight loss effect was shown in the Compound 100 30 mg / kg group compared to the vehicle control, showing comparable or higher efficacy compared to sibutramine (pcO.OO 1 ) (change in body weight compared to the vehicle control:- 0.6% [sibutramine 10 mg / kg], -2.4% [Compound 1003 mg / kg], -7.5% [Compound 100, 10 mg / kg] and -10.7% [Compound 100, 30 mg / kg]). The weight gain after 28 days of administration was reduced in Compound 100-administered groups in a dose-dependent manner (FIG. 12B).

[0025] FIG. 13 is a graph depicting the effect of repeated doses of Compound 100 on whole body fat mass in a db / db mouse model of obesity. As in FIG. 25, six week old male db / db mice were fed a high fat diet for 6 weeks and during that time Compound 100 was dosed orally at 0, 3, 10, and 30 mg / kg once a day. Untreated db / db mice and sibutramine treated mice (10 mg / kg, administered once a day) were used as the controls. Data represents the mean ± S.E.M.. Significant difference from db / db control group by one-way ANOVA followed by the Dunnett’s test: * p<0.05, ** p<0.01, *** p<0.001. (db / dm control, Compound 100 10 mg / kg [n=9], Other groups [n= 10] ) . A dose-dependent reduction of body fat mass was confirmed in the Compound 100 groups, and the Compound 100 10 and 30 mg / kg groups showed a significant reduction in whole body fat mass (p<0.05 and p<0.001). There was no change in fat-free mass, calculated by subtracting the amount of body fat mass from body weight.

[0026] FIGS. 14A-14C are graphs depicting the effect of Compound 100 on body weight changes over the experimental period, cumulative food intake in week 1, and body composition changes in high fat diet (HFD) fed POMC homozygous deficient mice. Mean ± SEM. One way ANOVA, post Dunnett’s test. *p<0.05, **p<0.01, ***p<0.001 vs HFD Vehicle. The body weight of animals in the Compound 100 treated groups showed substantial weight loss in a dose dependent manner over the study period. Percentage change in body weight corrected to the vehicle control after 10 days of Compound 100 treatment were -16.3% and -31.9% for 10 mg / kg and 30 mg / kg, respectively (FIG. 14A). These body weight changes were associated with a marked reduction in food consumption (FIG. 14B). Compound 100 significantly reduced the weight of epididymal fat and subcutaneous fat in a dose dependent manner (FIG. 14C).

[0027] FIGS. 15A-15C are graphs depicting the effect of Compound 100 on body weight changes over the experimental period, cumulative food intake in week 1, and body composition changes in high fat diet (HFD) fed PCSK1 heterozygous deficient mice. Mean + SEM. One way ANOVA, post Dunnett’s test. *p<0.05, **p<0.01, ***p<0.001 vs HFD Vehicle. PCSK1 heterozygous deficiency mice administered Compound 100 showed a significant body weight loss and inhibitory effect on body weight gain throughout the study period (p<0.05). Percent body weight reductions corrected to vehicle at the last day of administration were -6.23% and - 13.42% for 10 mg / kg and 30 mg / kg, respectively (FIG. 15A). When weekly food intake was compared, a significant reduction was observed by the first week of administration, which was associated with weight loss (p<0.001 ) (FIG. 15B). Along with body weight loss, significant changes in body fat mass without changes in lean mass were observed in all Compound 100 dosed groups (10 and 30 mg / kg) (p<0.05 and p<0.001) (FIG. 15C).

[0028] FIGS. 16A and 16B are graphs depicting the effect of Compound 100 on body weight changes over the experimental period and cumulative food intake in week 1 in high fat diet (HFD) fed SH2B 1 heterozygous deficient mice. Mean ± SEM. One way ANOVA, post Dunnett’s test. *p<0.05, **p<0.01, ***p<0.001 vs HFD Vehicle. SH2B1 heterozygous deficiency mice administered with Compound 100 showed significant body weight loss throughout the study period. Percent body weight reduction corrected to vehicle at the last day of administration were -3.19% and -5.31% (p<0.001) for 10 mg / kg and 30 mg / kg, respectively (FIG. 16A). When weekly food intake was compared, a significant reduction was observed during the first week of administration (FIG. 16B).

[0029] FIGS. 17A and 17B are graphs depicting the body weight changes over the experimental period and cumulative food intake in week 1 of HFD-fed SRC1 Homozygous Deficiency Mice Treated with Compound 100. Data are represented as Mean ± SEM. One way ANOVA, post Dunnett’s test. *p<0.05, **p<0.01, ***p<0.001 vs HFD Vehicle. Compound 100 showed dosedependent body weight loss over the experimental period. Body weight changes expressed as percent reduction corrected to vehicle at the last day of administration were -3.80% and -8.73% for 10 mg / kg and 30 mg / kg, respectively (FIG. 17A), and Compound 100 led to decreased food intake during the first week of treatment (FIG. 17B).

[0030] FIGS. 18A and 18B are graphs depicting the effect of Compound 100 on energy expenditure in a DIO mouse model during the CLAMS study. (A) Energy expenditure monitored over 48 hours (kcal / kg / hr). (B) Energy expenditure after Analysis of Covariance (ANCOVA) (kcal / mouse / hr). Data are represented as mean + SEM. (n=10 per group). Data are analyzed by Dunnett’s analysis as post hoc for one-way ANOVA. Energy expenditure adjusted to body weights was analyzed by Bonferroni’s analysis as post hoc test for the analysis of covariance procedure using the IBM SPSS statistics 22 program. (*p<0.05 vs Vehicle control; ###p<0.001 vs Pair- fed Vehicle). Energy expenditure of the Compound 100 30 mg / kg group was significantly increased compared to the vehicle control group and pair-fed group of the profiles for 48 hours (p<0.05). However, energy expenditure of pair-fed group was similar to vehicle control group (FIG. 18A). The ANCOVA results indicated that energy expenditure of the Compound 100 group was higher than that of the pair-fed group (FIG. 18B).

[0031] FIGS. 19A-19C are graphs depicting the effect of Compound 100 on body weight and body composition during 19 days of oral administration in a DIO mouse model. (A) Changes of body weight (g) during the drug treatment for 19 days. (B) Body weight changes (%) after drug treatment for 19 days. (C) Body weight (g), whole body fat mass (g) and lean body mass (g) after CLAMS study. Data are represented as mean ± SEM. (n= 10 per group). Data are analyzed by Dunnett’s analysis as post hoc forone-way ANOVA. (vehicle control vs Compound 100 / pair-fed group, *, p<0.05. **, p<0.01. ***, p<0.001, Compound 100 group vs pair-fed group, #, p<0.05. ##, p<0.01. ###, p<0.001.). The body weights of the Compound 10030 mg / kg group started to significantly decrease after 2 days of drug treatment and then continuously decreased up to the end of the treatment period. In pair-fed group body weights decreased similarly to the Compound 100 group. However, body weights of the Compound 100 group were more decreased than those of the pair-fed group after 12 days of drug treatment (FIG. 19A). The body weight changes of Compound 100 and pair-fed groups were significantly decreased by - 10.9 % and -7.2 % respectively, compared to the vehicle control group after 19 days of drug administration (p<0.05). The body weight changes of pair-fed group did not reach statistical significance (FIG. 19B). Body composition after 19 days of drug treatment is presented in FIG. 19C. The whole body fat mass of the Compound 100 group was significantly reduced compared to the vehicle control group (p<0.01). In the pair- fed group, lean body mass was decreased but there was no significant change in whole body fat mass compared to the vehicle control group.

[0032] FIGS. 20A and 20B are graphs depicting the effect of food intake during 19 days of oral administration in a DIO mouse model. (A) Food intake (g / day) during the drug treatment for 19 days. (B) Average food intake (g / day) after drug treatment for 19 days. Data are represented as mean ± SEM. (n=10 per group). Data are analyzed by Dunnett’s analysis as post hoc for one-way ANOVA. (vehicle control vs Compound 1001 pair-fed group, *, p<0.05. **, p<0.01. ***, p<0.001, Compound 100 group vs pair-fed group, #, p<0.05. ##, p<0.01. ###, p<0.001.). Daily food intake of the Compound 100 30 mg / kg and pair-fed groups was significantly reduced during the 19 days of drug administration compared to the vehicle control group (p<0.001) (FIG. 20A). The initial food intake of the Compound 100 group abruptly decreased from Day 1, right after treatment administration, and then food intake gradually returned to vehicle control levels (FIG. 20B).

[0033] FIGS. 21A and 21B are graphs depicting the effect of Compound 100 on body weight in C57BL / 6J (WT DIO) and MC4R knock-out mice (MC4R KO). Data represents the mean ± S.E.M. (n=5 per group). Significant difference from vehicle control group by unpaired student’s t-test (two-tailed): * p<0.05, ** p<0.01, *** p<0.001. The Compound 100 group of WT DIO mice showed a significant weight loss compared to the vehicle control (p<0.05) (FIG. 21A), while no significant change in body weight was observed in the Compound 100 group of MC4R KO mice compared to the vehicle control (change in body weight compared to the vehicle control: -10.6% [WT DIO, Compound 10030 mg / kg], -0.6% [MC4R KO, Compound 100 30 mg / kg]) (FIG. 21B). FIGS. 22A and 22B are graphs depicting the effect of Compound 100 on food intake in C57BL / 6J (WT DIO) and MC4R knock-out mice (MC4R KO). Data represents the mean ± S.E.M. (n=5 per group). Significant difference from vehicle control group by unpaired student’s t-test (two-tailed): * p<0.05, ** p<0.01, *** p<0.001. The Compound 100 treated group of WT DIO mice had a significant reduction in food intake compared to the vehicle control (p<0.01), while no significant change was observed in the Compound 100 group of MC4R KO mice compared to the vehicle control.

[0034] FIGS. 23A and 23B are graphs depicting the effect of Compound 100 on (A) the weight of the epididymal fat tissue and (B) non-fasting blood glucose in C57B1 / 6J mice (WT DIO) and MC4R knock-out mice (MC4R KO). Data represents the mean ± S.E.M. (n=5 per group). Significant difference from vehicle control group by unpaired student’s t-test (two-tailed): * p<0.05, ** p<0.01, *** pcO.OOl. The Compound 100 group of WT DIO mice had a significant reduction in fat tissue weight (FIG. 23A) and non-fasting blood glucose (FIG. 23B) compared to the vehicle control (p<0.001 ), while no significant change was observed in the Compound 100 group of MC4R KO mice.

[0035] FIGS. 24A and 24B are graphs depicting the mean plasma concentration-time profile of Compound 100 following (FIG. 24A) intravenous and (FIG. 24B) oral administration in male beagle dogs. PK properties were evaluated after oral and intravenous single dose administration of Compound 100 to male Beagle dogs at doses of 1, 3, and 10 mg / kg.

[0036] FIG. 25 is a graph depicting the mean plasma concentration-time profde of Compound 100 following oral administration in male cynomolgus monkeys. PK properties were evaluated after oral and intravenous single dose administration of Compound 100.

[0037] FIG. 26 is a graph depicting the representative tissue to plasma concentration ratio in male SD rats. Black bar: T / P ratio at 6 hours post-dose. White bar: T / P ratio at 3 hours post-dose. Tissue to plasma radioactivity concentration ratios (T / P ratio), as well as its range for each organ and tissue was not significantly different between genders. The visceral T / P ratio was highest in liver, followed by kidney and heart, and the order was similar to the results of a previous study (PKCompound 100-02) using unlabeled compound. The T / P ratio in female brain ranged from 0.44 to 2.4 depending on the sampling timepoint.

[0038] FIG. 27 is a graph depicting the mean plasma and brain concentration-time profile of Compound 100 following oral administration in male C57BL6 mice. DETAILED DESCRIPTION

[0039] The present disclosure is based at least in part on the discovery that obesity, specifically a non-genetic obesity and / or an acquired obesity including hypothalamic obesity, may be treated in a subject by administering a therapeutic agent, e.g., a small molecule, targeting the melanocortin 4 receptor (MC4R) pathway, e.g., an MC4R agonist, such as an MC4R agonist compound. In an embodiment, the subject has hypothalamic obesity. In an embodiment, the subject has been identified as having or diagnosed with hypothalamic obesity or is displaying one or more symptoms or risk factors for hypothalamic obesity. In an embodiment, administering an MC4R agonist compound to a subject leads to a reduction in the subject in one or more of the following parameters selected from: body weight, BMI, waist circumference, waist-to-hip circumference ratio, body composition (e.g., by dual energy X-ray absorptiometry (DEXA)) and hunger. Exemplary MC4R agonist compounds e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof as well as related formulations and methods of use, are described in further detail herein.

[0040] Definitions

[0041] As used herein, “about” and "approximately" generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given value or range of values.

[0042] “Acquire” or “acquiring” as the terms are used herein, refer to obtaining possession of a physical entity, or a value, e.g., a numerical value, or knowledge of (e.g., knowledge of the sequence or mutational state of) a genotype or a nucleic acid or polypeptide, by “directly acquiring” or “indirectly acquiring” the physical entity, value, or knowledge. “Directly acquiring” means performing a physical process (e.g., performing a synthetic or analytical method) to obtain the physical entity, value, or knowledge. “Indirectly acquiring” refers to receiving the physical entity, value, or knowledge from another party or source (e.g., a third- party laboratory that directly acquired the physical entity, value, or knowledge). Directly acquiring a physical entity includes performing a process that includes a physical change in a physical substance, e.g., a starting material. Exemplary changes include making a physical entity from two or more starting materials, shearing or fragmenting a substance, separating or purifying a substance, combining two or more separate entities into a mixture, performing a chemical reaction that includes breaking or forming a covalent or non-covalent bond. Directly acquiring a value or knowledge includes performing a process that includes a physical change in a sample or another substance. Examples include performing an analytical process which includes a physical change in a substance, e.g., a sample, analyte, or reagent (sometimes referred to herein as “physical analysis”), performing an analytical method, e.g., a method which includes one or more of the following: separating or purifying a substance, e.g., an analyte, or a fragment or other derivative thereof, from another substance; combining an analyte, or fragment or other derivative thereof, with another substance, e.g., a buffer, solvent, or reactant; or changing the structure of an analyte, or a fragment or other derivative thereof, e.g., by breaking or forming a covalent or non-covalent bond, between a first and a second atom of the analyte; or by changing the structure of a reagent, or a fragment or other derivative thereof, e.g., by breaking or forming a covalent or non-covalent bond, between a first and a second atom of the reagent.

[0043] As used herein, the term “agonist” refers to any chemical compound, either naturally occurring or synthetic, that, upon interacting with (e.g., binding to) its target, e.g., MC4R, raises the signaling activity of MC4R above its basal level. An agonist can be a superagonist (i.e., a compound that is capable of producing a greater maximal response than the endogenous agonist for the target receptor, and thus has an efficacy of more than 100%), a full agonist (i.e., a compound that elicits a maximal response following receptor occupation and activation), or a partial agonist (i.e. a compounds that can activate receptors but are unable to elicit the maximal response of the receptor system). In some embodiments, the agonist is a small molecule, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof.

[0044] As used herein, “treating” includes achieving one or more of the following results: reducing the body weight (as measured, for example, by a body mass index (BMI) and / or body weight), e.g., compared to a control (e.g., body weight before treatment or a predetermined body weight); reducing the waist circumference, e.g., compared to a control (e.g., waist circumference before treatment or a predetermined waist circumference); reducing the waist-to-hip circumference ratio, e.g., compared to a control (e.g., waist-to-hip circumference ratio before treatment or a predetermined waist-to-hip circumference ratio); improving body composition, e.g., compared to a control (e.g., dual energy X-ray absorptiometry (DEXA) scan T score before treatment or a predetermined DEXA scan T score); reducing the hunger level, e.g., compared to a control (e.g., hunger level before treatment or a predetermined hunger level); increasing the resting energy expenditure (REE), e.g., compared to a control (e.g., REE before treatment or a predetermined REE); decreasing the food intake, e.g., compared to a control level (e.g., before treatment or a predetermined food intake); ameliorating or improving a clinical symptom or indicators associated with a disorder described herein, such as obesity, Prader Willi Syndrome, Smith-Magenis syndrome, e.g., type-II diabetes, a pre-diabetic condition, blood level of hemoglobin A1C (HblAc) above 6%, hyperinsulinemia, hyperlipidemia, insulin insensitivity, or glucose intolerance; delaying, inhibiting or preventing the progression of obesity and / or obesity related indications; or partially or totally delaying, inhibiting or preventing the onset or development of obesity or an obesity related indication. Delaying, inhibiting or preventing the progression of the obesity includes for example, delaying, inhibiting or preventing the progression of a subject having normal weight to obesity. In embodiments, a control is a value of a parameter measured before treatment by an MC4R agonist described herein or a predetermined value. The term “treating” further includes partially or totally reducing the risk for coronary artery disease, stroke, and type 2 diabetes associated with the metabolic syndrome as well as ameliorating or improving a clinical symptom or signs of metabolic syndrome associated with metabolic syndrome, such as any one or more of the five indicators listed above. For example, the term “treating” includes delaying, inhibiting or preventing the progression of parameters associated with the metabolic syndrome, including insulin resistance, glucose clearance and parameters of cardiovascular disease including heart rate and blood pressure.

[0045] As used herein, the term “subject” refers to a mammal, e.g., a human.

[0046] As used herein “dosage” refers to a quantity or amount of a therapeutic agent. In some embodiments, a dosage is the amount administered to the subject in a single administration, e.g., in a single injection, a single infusion, or single administration of one or more unit dosages. In embodiments, a dosage is the amount administered to the subject in multiple administrations, e.g., multiple injections, multiple infusions, or multiple administrations of one or more unit dosages. In other embodiments, a dosage can refer to the total amount administered to the subject in a certain time period, e.g., per day. In such examples, the dosage is typically referred to as “daily dosage” or dosage in terms of quantity per day. The term "pharmaceutically acceptable salt" as used herein is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds used in the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds used in the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galacturonic acids and the like (see, e.g., Berge SM et al., Pharmaceutical salts. Journal of Pharmaceutical Sciences. 1977 Jan;66(l):l-19. DOI: 10.1002 / jps .2600660104. PMID: 833720.). Certain specific compounds used in the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. These salts may be prepared by methods known to those skilled in the art. Other pharmaceutically acceptable carriers known to those of skill in the art are suitable for use in the present disclosure.

[0047] Hypothalamic Obesity

[0048] Obesity is a disease or disorder characterized, for example, by abnormal or excessive fat accumulation that presents a risk to health. Obesity may also be accompanied with an increased risk of various secondary diseases including cardiovascular disease, type 2 diabetes mellitus, certain types of cancer, hyperlipidaemia, non-alcoholic fatty liver disease, and asthma. Obesity can have a significant impact on mortality and quality of life. The central melanocortin pathway, driven by the peripheral adipocyte hormone leptin, is the critical signaling system regulating body weight and energy homeostasis. Disruption of this hypothalamic circuit by inherited gene mutations, as well as hypothalamic injury, can lead to severe obesity in humans. Genes that have been identified to contribute to rare forms of early - onset, severe obesity include pro-opiomelanocortin (POMC prohormone convertase 1 (PCSKI). leptin receptor (LEPR), steroid receptor coactivator- 1 (SRC I) and Src-homology-2B-adaptor protein- 1 (SH2BI) genes. Bardet-Biedl syndrome (BBS) is a rare pleiotropic autosomal recessive disorder caused by mutations in more than 20 different genes and the obesity phenotype in BBS is caused by impaired transport of the LEPR to the ciliary membrane of POMC neurons in the arcuate nucleus of the hypothalamus. Hypothalamic obesity is a rare, acquired form of extreme obesity that occurs following damage to the hypothalamic region of the brain, which results in dysregulation of satiety and energy expenditure and can lead to hyperphagia and rapid weight gain.

[0049] Hypothalamic obesity (HO) is a form of obesity caused by physical or inherited damage to the hypothalamus, resulting in symptoms such as uncontrollable hunger (hyperphagia), rapid and / or excessive weight gain, and a low metabolic rate. The hypothalamus is responsible for regulating energy balance and body weight by integrating metabolic information that governs the drive for food intake and energy expenditure, primarily via signaling through the MC4 receptor (MC4R), which has been identified as the critical melanocortin receptor involved in the regulation of body weight, hunger, and energy homeostasis (Holland J, et al. A brain- melanocortin-vagus axis mediates adipose tissue expansion independently of energy intake. Cell Rep. 2019;27:2399-2410. doi: 10.1016 / j.celrep.2019.04.089). Recently, MRI findings in subjects with HO displayed anatomical disruption of the hypothalamus which contains MC4 receptors and POMC neurons residing in the arcuate nuclei and in the paraventricular nucleus, respectively (FIG. 1). 5 MCR subtypes have been identified, among which MC1R is expressed predominantly in skin cells and is involved in skin pigmentation of melanin, while MC2R is expressed mainly in the adrenal gland and involved in production of glucocorticoid hormones, having adrenocorticotropic hormone (ACTH) derived from POMC as the only corresponding ligand. MC3R and MC4R, expressed mainly in the CNS, are involved in regulation of appetite, energy metabolism and storage efficiency of body fat, and MC5R, expressed in various tissues, is known to regulate exocrine functions (Wikberg JE, et al. New aspects on the melanocortins and their receptors. Pharmacol Res. 2000;42:393-420.). MC4R is the major target in development of anti-obesity drugs as activation of MC4R shows an efficient weight loss effect by inducing appetite suppression and increase in energy metabolism (Watanobe Het al., The melanocortin 4 receptor mediates leptin stimulation of luteinizing hormone and prolactin surges in steroid- primed ovariectomized rats. Biochem Biophys Res Commun 257:860-864; Skuladottir GVet al., Long term orexigenic effect of a novel melanocortin 4 receptor selective antagonist. Br J Pharmacol 126:27-34; Wikberg JE et al., New aspects on the melanocortins and their receptors. Pharmacol Res. 2000;42:393-420.; MacNeil DJ et al., The role of melanocortins in body weight regulation: opportunities for the treatment of obesity. Eur J Pharmacol. 2002 Apr 12;440(2-3): 141-57. doi: 10.1016 / s0014-2999(02)01425-5. Corrected and republished in: Eur J Pharmacol. 2002 Aug 16;450(l):93- 109. doi: 10.1016 / s0014-2999(02)01989-l. PMID: 12007532.; Farooqi IS et al., Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med. 2003 Mar 20;348(12): 1085-95. doi: 10.1056 / NEJMoa022050. PMID: 12646665.).

[0050] Damage to the arcuate nucleus, paraventricular nucleus, dorsomedial nucleus, and dorsal hypothalamic area most commonly results in impairments in regulation of both peripheral energy expenditure and satiety (Abuzzahab MJ et al., Hypothalamic Obesity: Prologue and Promise. Horm Res Paediatr. 2019;91(2): 128-136. doi: 10.1159 / 000496564. Epub 2019 Mar 18. PMID: 30884480.). This impairment in the MC4R pathway may lead to a high degree of sudden, severe, and sustained weight gain which is unresponsive to general lifestyle changes or current antiobesity pharmacotherapies (Sterkenburg As et al., Survival, hypothalamic obesity, and neuropsychological / psychosocial status after childhood-onset craniopharyngioma: newly reported long-term outcomes. Neuro Oncol. 2015 Jul; 17(7): 1029-38. doi: 10.1093 / neuonc / nov044. Epub 2015 Apr 2. PMID: 25838139; PMCID: PMC5654354.). Approximately 50% of subjects with HO also manifest with a marked increase in hunger. A key difference from other disease entities which may originate due to impairment to the MC4 pathway is that in the case of HO, the impairment is due to structural damage, whereas in the other diseases it is due to a genetic impairment; several genetic variants have been associated with reduced signaling through the MC4 pathway and consequent hyperphagia and obesity.

[0051] In addition to tumors (e.g., craniopharyngiomas, gliomas, pituitary adenomas, hamartomas), and / or the surgery or radiation therapy used to treat the tumor (Hochberg I et al., Expanding the definition of hypothalamic obesity. Obes Rev. 2010 Oct; 11 (10):709-21. doi: 10.1111 / j .1467-789X.2010.00727.x. PMID: 20233310.), other much rarer causes of injury include inflammatory conditions involving the hypothalamus or trauma. Craniopharyngiomas represent the most common tumor associated with the development of HO and accounts for 5% to 15% of pediatric intracranial tumors. A bimodal age distribution has been observed for new cases of craniopharyngioma with a first peak seen in children aged 4 to 14 years and a second peak in adults ages >40 years (Miller KD et al., Brain and other central nervous system tumor statistics, 2021. CA Cancer J Clin. 2021 Sep;71(5):381-406. doi: 10.3322 / caac.21693. Epub 2021 Aug 24. PMID: 34427324.; Ostrom QT et al., Epidemiology of Brain and Other CNS Tumors. Curr Neurol Neurosci Rep. 2021 Nov 24;21(12):68. doi: 10.1007 / sl 1910-021-01152-9. PMID: 34817716; PMCID: PMC8613072.).

[0052] Other causes for this condition include swelling in the brain, head trauma, brain surgery, or the presence of certain genetic mutations. Genetic mutations in the LEP, LEPR, POMC, MC4R, and CART genes may also lead to this disease (see, e.g., Kim et al. Ann Pediatr Endocrinol Metab (2013) 18(4): 161-167). Hypothalamic obesity has also been linked to diminished a-MSH levels (see, e.g., Roth et al. Metabol Clin Exper (2010) 59:186-194). Hypothalamic obesity is a distinct disease that differs from general obesity (e.g., a genetic obesity or other non-genetic obesity or a syndromic disease). For example, HO is most often the result of an acquired injury as opposed to a genetically driven impairment in the MC4R pathway which results in a decrease in the hormone a-MSH. In addition, a subject that has or is identified as having HO may exhibit a dramatic shift in clinical phenotype compared to a subject having general obesity (e.g., a genetic obesity or other non-genetic obesity or a syndromic disease), such as rapid weight gain, increased hunger, and decreased energy dating from the time of the injury. Further, a subject that has or is identified as having HO often does not present with a secondary or additional disease manifestations that frequently characterizes some genetic obesities.

[0053] MC4R Agonist Compounds

[0054] Provided herein are MC4R agonists, e.g., MC4R agonist compounds, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, for use in treating a non- genetic obesity and / or an acquired obesity, e.g., hypothalamic obesity. In some embodiments, the MC4R agonist compound activates or upregulates expression of the melanocortin 4 receptor (MC4R). In some embodiments, the MC4R agonist compounds described herein modulate leptin levels. In some embodiments, MC4R agonists described herein bind to MC4R.

[0055] In an aspect, the MC4R agonist compound is a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof: wherein R1is C2-C5 alkyl; R2is halo; R3is hydrogen or halo; R4is C1-C3 alkyl; and n is an integer of 1 or 2.

[0056] In one embodiment, the MC4R agonist compound of Formula (I) is a compound of

[0057] Formula (La) or a pharmaceutically acceptable salt or isomer thereof: wherein R1is C2-C5 alkyl, R2and R3is each independently halo; R4is C1-C3 alkyl; and n is an integer of 1 or 2.

[0058] In one embodiment, the MC4R agonist compound of Formula (I) is a compound of

[0059] Formula (I-b) or a pharmaceutically acceptable salt thereof, wherein R1is C2-C5 alkyl, R2is halo; R3is hydrogen or halo;

[0060] R4is methyl; and n is an integer of 1 or 2.

[0061] In one embodiment, the MC4R agonist compound of Formula (I) is a compound of

[0062] Formula (I-c) or a pharmaceutically acceptable salt thereof, wherein R1is C3-C4 alkyl, R2is Cl; R3is hydrogen or halo; R4 is methyl; and n is an integer of 1 or 2.

[0063] In some embodiments of any one of Formulas (I), (I-a), (I-b), or (I-c), R3is hydrogen and R2is halo. In some embodiments, R3is hydrogen and R2is fluorine. In some embodiments, R3is hydrogen and R2is chlorine. In some embodiments, R3is hydrogen and R2is bromine. In some embodiments, R3is hydrogen and R2is iodine.

[0064] In some embodiments, each of R2and R3is halo. In some embodiments, R2is fluorine and R3is fluorine, chlorine, bromine, or iodine. In some embodiments, R2is fluorine and R3is fluorine. In some embodiments, R2is fluorine and R3is chlorine. In some embodiments, R2is fluorine and R3is bromine. In some embodiments, R2is fluorine and R3is iodine. In some embodiments, R2is chlorine and R3is fluorine. In some embodiments, R2is chlorine and R3is chlorine. In some embodiments, R2is chlorine and R3is bromine. In some embodiments, R2is chlorine and R3is iodine. In some embodiments, R2is bromine and R3is fluorine. In some embodiments, R2is bromine and R3is chlorine. In some embodiments, R2is bromine and R3is bromine. In some embodiments, R2is bromine and R3is iodine. In some embodiments, R2is iodine and R3is fluorine. In some embodiments, R2is iodine and R3is chlorine. In some embodiments, R2is iodine and R3is bromine. In some embodiments, R2is iodine and R3is iodine.

[0065] In some embodiments, R2is halo, R3is hydrogen, R4is methyl, and n is 1. In some embodiments, R2is fluorine, chlorine, bromine or iodine, R3is hydrogen, R4is methyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is hydrogen, R4is methyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is hydrogen, R4is methyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is hydrogen, R4is methyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is hydrogen, R4is methyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is hydrogen, R4is ethyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is hydrogen, R4is ethyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is hydrogen, R4is ethyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is hydrogen, R4is ethyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is hydrogen, R4is propyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is hydrogen, R4is propyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is hydrogen, R4is propyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is hydrogen, R4is propyl, and n is 1 or 2.

[0066] In some embodiments, R2is fluorine, R3is hydrogen, R4is isopropyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is hydrogen, R4is isopropyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is hydrogen, R4is isopropyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is hydrogen, R4is isopropyl, and n is 1 or 2.

[0067] In some embodiments, each of R2and R3is independently halo, R4is methyl, and n is 1 or 2. In some embodiments, each of R2and R3is independently fluorine, chlorine, bromine, or iodine, R4is methyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is fluorine, R4is methyl, and n is 1. In some embodiments, R2is fluorine, R3is chlorine, R4is methyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is bromine, R4is methyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is iodine, R4is methyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is fluorine, R4is methyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is chlorine, R4is methyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is bromine, R4is methyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is iodine, R4is methyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is fluorine, R4is methyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is chlorine, R4is methyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is bromine, R4is methyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is iodine, R4is methyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is fluorine, R4is methyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is chlorine, R4is methyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is bromine, R4is methyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is iodine, R4is methyl, and n is 1 or 2.

[0068] In some embodiments, each of R2and R3is independently halo, R4is ethyl, and n is 1. In some embodiments, each of R2and R3is independently fluorine, chlorine, bromine, or iodine, R4is ethyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is fluorine, R4is ethyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is chlorine, R4is ethyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is bromine, R4is ethyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is iodine, R4is ethyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is fluorine, R4is ethyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is chlorine, R4is ethyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is bromine, R4is ethyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is iodine, R4is ethyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is fluorine, R4is ethyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is chlorine, R4is ethyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is bromine, R4is ethyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is iodine, R4is ethyl, and n is lor 2. In some embodiments, R2is iodine, R3is fluorine, R4is ethyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is chlorine, R4is ethyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is bromine, R4is ethyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is iodine, R4is ethyl, and n is 1 or 2.

[0069] In some embodiments, each of R2and R3is independently halo, R4is propyl, and n is 1. In some embodiments, each of R2and R3is independently fluorine, chlorine, bromine, or iodine, R4is propyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is fluorine, R4is propyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is chlorine, R4is propyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is bromine, R4is propyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is iodine, R4is propyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is fluorine, R4is propyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is chlorine, R4is propyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is bromine, R4is propyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is iodine, R4is propyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is fluorine, R4is propyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is chlorine, R4is propyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is bromine, R4is propyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is iodine, R4is propyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is fluorine, R4is propyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is chlorine, R4is propyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is bromine, R4is propyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is iodine, R4is propyl, and n is 1 or 2.

[0070] In some embodiments, each of R2and R3is independently halo, R4is isopropyl, and n is

[0071] 1. In some embodiments, each of R2and R3is independently fluorine, chlorine, bromine, or iodine, R4is isopropyl, and n is 1. In some embodiments, R2is fluorine, R3is fluorine, R4is isopropyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is chlorine, R4is isopropyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is bromine, R4is isopropyl, and n is 1 or

[0072] 2. In some embodiments, R2is fluorine, R3is iodine, R4is isopropyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is fluorine, R4is isopropyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is chlorine, R4is isopropyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is bromine, R4is isopropyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is iodine, R4is isopropyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is fluorine, R4is isopropyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is chlorine, R4is isopropyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is bromine, R4is isopropyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is iodine, R4is isopropyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is fluorine, R4is isopropyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is chlorine, R4is isopropyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is bromine, R4is isopropyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is iodine, R4is isopropyl, and n is 1 or 2.

[0073] In some embodiments, R1is C2 alkyl. In some embodiments, R1is C3 alkyl. In some embodiments, R1is C4 alkyl. In some embodiments, R1is C5 alkyl. In some embodiments, R1is ethyl, propyl, isopropyl, butyl, isobutyl, 2-butyl, pentyl, 1,1 -dimethylpropyl, 3-methylbutyl, 2,2- dimethylpropyl, 1 -methylbutyl, 1,2-dimethylpropyl, 1 -ethylpropyl, or 2-methylbutyl.

[0074] In some embodiments, R4is methyl, R1is C2 alkyl, and n is 1. In some embodiments, R4is methyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R4is methyl, R1is C4 alkyl, and n is lor 2. In some embodiments, R4is methyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R4is ethyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R4is ethyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R4is ethyl, R1is C4 alkyl, and n is 1. In some embodiments, R4is ethyl, R1is C5 alkyl, and n is 1 or 2.

[0075] In some embodiments, R4is propyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R4is propyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R4is propyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R4is propyl, R1is C5 alkyl, and n is 1 or 2.

[0076] In some embodiments, R4is isopropyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R4is isopropyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R4is isopropyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R4is isopropyl, R1is C5 alkyl, and n is 1 or 2.

[0077] In some embodiments, R3is hydrogen, R2is halo, R4is methyl, R1is C2 alkyl, and n is 1. In some embodiments, R3is hydrogen, R2is fluorine, chlorine, bromine, or iodine, R4is methyl, Ri is C2 alkyl, and n is 1 or 2, provided that n is 2, when R2is chloride and R3is hydrogen. In some embodiments, R3is hydrogen, R2is fluorine, R4is methyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is chlorine, R4is methyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is bromine, R4is methyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is iodine, R4is methyl, R1is C2 alkyl, and n is 1 or 2.

[0078] In some embodiments, R3is hydrogen, R2is halo, R4is ethyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is fluorine, chlorine, bromine, or iodine, R4is ethyl, Ri is C2 alkyl, and n is 1 or 2, In some embodiments, R3is hydrogen, R2is fluorine, R4is ethyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is chlorine, R4is ethyl, R1is C2 alkyl, and n is 2. In some embodiments, R3is hydrogen, R2is bromine, R4is ethyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is iodine, R4is ethyl, R1is C2 alkyl, and n is 1 or 2.

[0079] In some embodiments, R3is hydrogen, R2is halo, R4is propyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is fluorine, chlorine, bromine, or iodine, R4is propyl, Ri is C2 alkyl, and n is 1 or 2, In some embodiments, R3is hydrogen, R2is fluorine, R4is propyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is chlorine, R4is propyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is bromine, R4is propyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is iodine, R4is propyl, R1is C2 alkyl, and n is 1 or 2.

[0080] In some embodiments, R3is hydrogen, R2is halo, R4is isopropyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is fluorine, chlorine, bromine, or iodine, R4is isopropyl, Ri is C2 alkyl, and n is 1 or 2, In some embodiments, R3is hydrogen, R2is fluorine, R4is isopropyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is chlorine, R4is isopropyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is bromine, R4is isopropyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is iodine, R4is isopropyl, R1is C2 alkyl, and n is 1 or 2.

[0081] In some embodiments, R3is hydrogen, R2is halo, R4is methyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is fluorine, chlorine, bromine, or iodine, R4is methyl, Ri is C3 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is fluorine, R4is methyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is chlorine, R4is methyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is bromine, R4is methyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is iodine, R4is methyl, R1is C3 alkyl, and n is 1 or 2.

[0082] In some embodiments, R3is hydrogen, R2is halo, R4is ethyl, R1is C3 alkyl, and n is 1. In some embodiments, R3is hydrogen, R2is fluorine, chlorine, bromine, or iodine, R4is ethyl, Ri is C3 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is fluorine, R4is ethyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is chlorine, R4is ethyl, R1is C3 alkyl, and n is 2. In some embodiments, R3is hydrogen, R2is bromine, R4is ethyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is iodine, R4is ethyl, R1is C3 alkyl, and n is 1 or 2.

[0083] In some embodiments, R3is hydrogen, R2is halo, R4is propyl, R1is C3 alkyl, and n is 1. In some embodiments, R3is hydrogen, R2is fluorine, chlorine, bromine, or iodine, R4is propyl, Ri is C3 alkyl, and n is 1 or 2, provided that n is 2, when R2is chloride and R3is hydrogen. In some embodiments, R3is hydrogen, R2is fluorine, R4is propyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is chlorine, R4is propyl, R1is C3 alkyl, and n is 2. In some embodiments, R3is hydrogen, R2is bromine, R4is propyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is iodine, R4is propyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is halo, R4is isopropyl, R1is C3 alkyl, and n is 1. In some embodiments, R3is hydrogen, R2is fluorine, chlorine, bromine, or iodine, R4is isopropyl, Ri is C3 alkyl, and n is 1 or 2, provided that n is 2, when R2is chloride and R3is hydrogen. In some embodiments, R3is hydrogen, R2is fluorine, R4is isopropyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is chlorine, R4is isopropyl, R1is C3 alkyl, and n is 2. In some embodiments, R3is hydrogen, R2is bromine, R4is isopropyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is iodine, R4is isopropyl, R1is C3 alkyl, and n is 1 or 2.

[0084] In some embodiments, R3is hydrogen, R2is halo, R4is methyl, R1is C4 alkyl, and n is 1. In some embodiments, R3is hydrogen, R2is fluorine, chlorine, bromine, or iodine, R4is methyl, Ri is C4 alkyl, and n is 1 or 2, provided that n is 2, when R2is chloride and R3is hydrogen. In some embodiments, R3is hydrogen, R2is fluorine, R4is methyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is chlorine, R4is methyl, R1is C4 alkyl, and n is 2. In some embodiments, R3is hydrogen, R2is bromine, R4is methyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is iodine, R4is methyl, R1is C4 alkyl, and n is 1 or 2.

[0085] In some embodiments, R3is hydrogen, R2is halo, R4is ethyl, R1is C4 alkyl, and n is 1. In some embodiments, R3is hydrogen, R2is fluorine, chlorine, bromine, or iodine, R4is ethyl, Ri is C4 alkyl, and n is 1 or 2, provided that n is 2, when R2is chloride and R3is hydrogen. In some embodiments, R3is hydrogen, R2is fluorine, R4is ethyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is chlorine, R4is ethyl, R1is C4 alkyl, and n is 2. In some embodiments, R3is hydrogen, R2is bromine, R4is ethyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is iodine, R4is ethyl, R1is C4 alkyl, and n is 1 or 2.

[0086] In some embodiments, R3is hydrogen, R2is halo, R4is propyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is fluorine, chlorine, bromine, or iodine, R4is propyl, Ri is C4 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is fluorine, R4is propyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is chlorine, R4is propyl, R1is C4 alkyl, and n is 2. In some embodiments, R3is hydrogen, R2is bromine, R4is propyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is iodine, R4is propyl, R1is C4 alkyl, and n is 1 or 2.

[0087] In some embodiments, R3is hydrogen, R2is halo, R4is isopropyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is fluorine, chlorine, bromine, or iodine, R4is isopropyl, Ri is C4 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is fluorine, R4is isopropyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is chlorine, R4is isopropyl, R1is C4 alkyl, and n is 2. In some embodiments, R3is hydrogen, R2is bromine, R4is isopropyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is iodine, R4is isopropyl, R1is C4 alkyl, and n is 1 or 2.

[0088] In some embodiments, R3is hydrogen, R2is halo, R4is methyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is fluorine, chlorine, bromine, or iodine, R4is methyl, Ri is C5 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is fluorine, R4is methyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is chlorine, R4is methyl, R1is C5 alkyl, and n is 2. In some embodiments, R3is hydrogen, R2is bromine, R4is methyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is iodine, R4is methyl, R1is C5 alkyl, and n is 1 or 2.

[0089] In some embodiments, R3is hydrogen, R2is halo, R4is ethyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is fluorine, chlorine, bromine, or iodine, R4is ethyl, Ri is C5 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is fluorine, R4is ethyl,

[0090] R1is C5 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is chlorine, R4is ethyl,

[0091] R1is C5 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is bromine, R4is ethyl,

[0092] R1is C5 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is iodine, R4is ethyl, R1is C5 alkyl, and n is 1 or 2.

[0093] In some embodiments, R3is hydrogen, R2is halo, R4is propyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is fluorine, chlorine, bromine, or iodine, R4is propyl, Ri is C5 alkyl, and n is 1 or 2 In some embodiments, R3is hydrogen, R2is fluorine, R4is propyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is chlorine, R4is propyl, R1is C5 alkyl, and n is 2. In some embodiments, R3is hydrogen, R2is bromine, R4is propyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is iodine, R4is propyl, R1is C5 alkyl, and n is 1 or 2.

[0094] In some embodiments, R3is hydrogen, R2is halo, R4is isopropyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is fluorine, chlorine, bromine, or iodine, R4is isopropyl, Ri is C5 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is fluorine, R4is isopropyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is chlorine, R4is isopropyl, R1is C5 alkyl, and n is 2. In some embodiments, R3is hydrogen, R2is bromine, R4is isopropyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R3is hydrogen, R2is iodine, R4is isopropyl, R1is C5 alkyl, and n is 1 or 2.

[0095] In some embodiments, each of R2and R3is independently halo, R4is methyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, each of R2and R3is independently fluorine, chlorine, bromine, or iodine, R4is methyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is fluorine, R4is methyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is chlorine, R4is methyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is bromine, R4is methyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is iodine, R4is methyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is fluorine, R4is methyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is chlorine, R4is methyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is bromine, R4is methyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is iodine, R4is methyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is fluorine, R4is methyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is chlorine, R4is methyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is bromine, R4is methyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is iodine, R4is methyl, R1is C2 alkyl, and n is 1 or 2.1n some embodiments, R2is iodine, R3is fluorine, R4is methyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is chlorine, R4is methyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is bromine, R4is methyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is iodine, R4is methyl, R1is C2 alkyl, and n is 1 or 2.

[0096] In some embodiments, each of R2and R3is independently halo, R4is ethyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, each of R2and R3is independently fluorine, chlorine, bromine, or iodine, R4is ethyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is fluorine, R4is ethyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is chlorine, R4is ethyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is bromine, R4is ethyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is iodine, R4is ethyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is fluorine, R4is ethyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is chlorine, R4is ethyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is bromine, R4is ethyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is iodine, R4is ethyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is fluorine, R4is ethyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is chlorine, R4is ethyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is bromine, R4is ethyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is iodine, R4is ethyl, R1is C2 alkyl, and n is 1 or 2.1n some embodiments, R2is iodine, R3is fluorine, R4is ethyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is chlorine, R4is ethyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is bromine, R4is ethyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is iodine, R4is ethyl, R1is C2 alkyl, and n is 1 or 2.

[0097] In some embodiments, each of R2and R3is independently halo, R4is propyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, each of R2and R3is independently fluorine, chlorine, bromine, or iodine, R4is propyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is fluorine, R4is propyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is chlorine, R4is propyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is bromine, R4is propyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is iodine, R4is propyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is fluorine, R4is propyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is chlorine, R4is propyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is bromine, R4is propyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is iodine, R4is propyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is fluorine, R4is propyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is chlorine, R4is propyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is bromine, R4is propyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is iodine, R4is propyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is fluorine, R4is propyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is chlorine, R4is propyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is bromine, R4is propyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is iodine, R4is propyl, R1is C2 alkyl, and n is 1 or 2.

[0098] In some embodiments, each of R2and R3is independently halo, R4is isopropyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, each of R2and R3is independently fluorine, chlorine, bromine, or iodine, R4is isopropyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is fluorine, R4is isopropyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is chlorine, R4is isopropyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is bromine, R4is isopropyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is iodine, R4is isopropyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is fluorine, R4is isopropyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is chlorine, R4is isopropyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is bromine, R4is isopropyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is iodine, R4is isopropyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is fluorine, R4is isopropyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is chlorine, R4is isopropyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is bromine, R4is isopropyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is iodine, R4is isopropyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is fluorine, R4is isopropyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is chlorine, R4is isopropyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is bromine, R4is isopropyl, R1is C2 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is iodine, R4is isopropyl, R1is C2 alkyl, and n is 1 or 2.

[0099] In some embodiments, each of R2and R3is independently halo, R4is methyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, each of R2and R3is independently fluorine, chlorine, bromine, or iodine, R4is methyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is fluorine, R4is methyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is chlorine, R4is methyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is bromine, R4is methyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is iodine, R4is methyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is fluorine, R4is methyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is chlorine, R4is methyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is bromine, R4is methyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is iodine, R4is methyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is fluorine, R4is methyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is chlorine, R4is methyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is bromine, R4is methyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is iodine, R4is methyl, R1is C3 alkyl, and n is 1 or 2.1n some embodiments, R2is iodine, R3is fluorine, R4is methyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is chlorine, R4is methyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is bromine, R4is methyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is iodine, R4is methyl, R1is C3 alkyl, and n is 1 or 2.

[0100] In some embodiments, each of R2and R3is independently halo, R4is ethyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, each of R2and R3is independently fluorine, chlorine, bromine, or iodine, R4is ethyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is fluorine, R4is ethyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is chlorine, R4is ethyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is bromine, R4is ethyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is iodine, R4is ethyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is fluorine, R4is ethyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is chlorine, R4is ethyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is bromine, R4is ethyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is iodine, R4is ethyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is fluorine, R4is ethyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is chlorine, R4is ethyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is bromine, R4is ethyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is iodine, R4is ethyl, R1is C3 alkyl, and n is 1 or 2.1n some embodiments, R2is iodine, R3is fluorine, R4is ethyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is chlorine, R4is ethyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is bromine, R4is ethyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is iodine, R4is ethyl, R1is C3 alkyl, and n is 1 or 2.

[0101] In some embodiments, each of R2and R3is independently halo, R4is propyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, each of R2and R3is independently fluorine, chlorine, bromine, or iodine, R4is propyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is fluorine, R4is propyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is chlorine, R4is propyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is bromine, R4is propyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is iodine, R4is propyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2 is chlorine, R3is fluorine, R4is propyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is chlorine, R4is propyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is bromine, R4is propyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is iodine, R4is propyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is fluorine, R4is propyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is chlorine, R4is propyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is bromine, R4is propyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is iodine, R4is propyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is fluorine, R4is propyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is chlorine, R4is propyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is bromine, R4is propyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is iodine, R4is propyl, R1is C3 alkyl, and n is 1 or 2.

[0102] In some embodiments, each of R2and R3is independently halo, R4is isopropyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, each of R2and R3is independently fluorine, chlorine, bromine, or iodine, R4is isopropyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is fluorine, R4is isopropyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is chlorine, R4is isopropyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is bromine, R4is isopropyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is iodine, R4is isopropyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is fluorine, R4is isopropyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is chlorine, R4is isopropyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is bromine, R4is isopropyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is iodine, R4is isopropyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is fluorine, R4is isopropyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is chlorine, R4is isopropyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is bromine, R4is isopropyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is iodine, R4is isopropyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is fluorine, R4is isopropyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is chlorine, R4is isopropyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is bromine, R4is isopropyl, R1is C3 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is iodine, R4is isopropyl, R1is C3 alkyl, and n is 1 or 2.

[0103] In some embodiments, each of R2and R3is independently halo, R4is methyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, each of R2and R3is independently fluorine, chlorine, bromine, or iodine, R4is methyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is fluorine, R4is methyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is chlorine, R4is methyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is bromine, R4is methyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is iodine, R4is methyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is fluorine, R4is methyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is chlorine, R4is methyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is bromine, R4is methyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is iodine, R4is methyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is fluorine, R4is methyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is chlorine, R4is methyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is bromine, R4is methyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is iodine, R4is methyl, R1is C4 alkyl, and n is 1 or 2.1n some embodiments, R2is iodine, R3is fluorine, R4is methyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is chlorine, R4is methyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is bromine, R4is methyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is iodine, R4is methyl, R1is C4 alkyl, and n is 1 or 2.

[0104] In some embodiments, each of R2and R3is independently halo, R4is ethyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, each of R2and R3is independently fluorine, chlorine, bromine, or iodine, R4is ethyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is fluorine, R4is ethyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is chlorine, R4is ethyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is bromine, R4is ethyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is iodine, R4is ethyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is fluorine, R4is ethyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is chlorine, R4is ethyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is bromine, R4is ethyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is iodine, R4is ethyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is fluorine, R4is ethyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is chlorine, R4is ethyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is bromine, R4is ethyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is iodine, R4is ethyl, R1is C4 alkyl, and n is 1 or 2.1n some embodiments, R2is iodine, R3is fluorine, R4is ethyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is chlorine, R4is ethyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is bromine, R4is ethyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is iodine, R4is ethyl, R1is C4 alkyl, and n is 1 or 2.

[0105] In some embodiments, each of R2and R3is independently halo, R4is propyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, each of R2and R3is independently fluorine, chlorine, bromine, or iodine, R4is propyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is fluorine, R4is propyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is chlorine, R4is propyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is bromine, R4is propyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is iodine, R4is propyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is fluorine, R4is propyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is chlorine, R4is propyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is bromine, R4is propyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is iodine, R4is propyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is fluorine, R4is propyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is chlorine, R4is propyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is bromine, R4is propyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is iodine, R4is propyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is fluorine, R4is propyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is chlorine, R4is propyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is bromine, R4is propyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is iodine, R4is propyl, R1is C4 alkyl, and n is 1 or 2.

[0106] In some embodiments, each of R2and R3is independently halo, R4is isopropyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, each of R2and R3is independently fluorine, chlorine, bromine, or iodine, R4is isopropyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is fluorine, R4is isopropyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is chlorine, R4is isopropyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is bromine, R4is isopropyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is iodine, R4is isopropyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is fluorine, R4is isopropyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is chlorine, R4is isopropyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is bromine, R4is isopropyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is iodine, R4is isopropyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is fluorine, R4is isopropyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is chlorine, R4is isopropyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is bromine, R4is isopropyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is iodine, R4is isopropyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is fluorine, R4is isopropyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is chlorine, R4is isopropyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is bromine, R4is isopropyl, R1is C4 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is iodine, R4is isopropyl, R1is C4 alkyl, and n is 1 or 2.

[0107] In some embodiments, each of R2and R3is independently halo, R4is methyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, each of R2and R3is independently fluorine, chlorine, bromine, or iodine, R4is methyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is fluorine, R4is methyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is chlorine, R4is methyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is bromine, R4is methyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is iodine, R4is methyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is fluorine, R4is methyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is chlorine, R4is methyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is bromine, R4is methyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is iodine, R4is methyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is fluorine, R4is methyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is chlorine, R4is methyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is bromine, R4is methyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is iodine, R4is methyl, R1is C5 alkyl, and n is 1 or 2.1n some embodiments, R2is iodine, R3is fluorine, R4is methyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is chlorine, R4is methyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is bromine, R4is methyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is iodine, R4is methyl, R1is C5 alkyl, and n is 1 or 2.

[0108] In some embodiments, each of R2and R3is independently halo, R4is ethyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, each of R2and R3is independently fluorine, chlorine, bromine, or iodine, R4is ethyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is fluorine, R4is ethyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is chlorine, R4is ethyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is bromine, R4is ethyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is iodine, R4is ethyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is fluorine, R4is ethyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is chlorine, R4is ethyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is bromine, R4is ethyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is iodine, R4is ethyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is fluorine, R4is ethyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is chlorine, R4is ethyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is bromine, R4is ethyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is iodine, R4is ethyl, R1is C5 alkyl, and n is 1 or 2.1n some embodiments, R2is iodine, R3is fluorine, R4is ethyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is chlorine, R4is ethyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is bromine, R4is ethyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is iodine, R4is ethyl, R1is C5 alkyl, and n is 1 or 2.

[0109] In some embodiments, each of R2and R3is independently halo, R4is propyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, each of R2and R3is independently fluorine, chlorine, bromine, or iodine, R4is propyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is fluorine, R4is propyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is chlorine, R4is propyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is bromine, R4is propyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is iodine, R4is propyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2 is chlorine, R3is fluorine, R4is propyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is chlorine, R4is propyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is bromine, R4is propyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is iodine, R4is propyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is fluorine, R4is propyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is chlorine, R4is propyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is bromine, R4is propyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is iodine, R4is propyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is fluorine, R4is propyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is chlorine, R4is propyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is bromine, R4is propyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is iodine, R4is propyl, R1is C5 alkyl, and n is 1 or 2.

[0110] In some embodiments, each of R2and R3is independently halo, R4is isopropyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, each of R2and R3is independently fluorine, chlorine, bromine, or iodine, R4is isopropyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is fluorine, R4is isopropyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is chlorine, R4is isopropyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is bromine, R4is isopropyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is fluorine, R3is iodine, R4is isopropyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is fluorine, R4is isopropyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is chlorine, R4is isopropyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is bromine, R4is isopropyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is chlorine, R3is iodine, R4is isopropyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is fluorine, R4is isopropyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is chlorine, R4is isopropyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is bromine, R4is isopropyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is bromine, R3is iodine, R4is isopropyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is fluorine, R4is isopropyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is chlorine, R4is isopropyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is bromine, R4is isopropyl, R1is C5 alkyl, and n is 1 or 2. In some embodiments, R2is iodine, R3is iodine, R4is isopropyl, R1is C5 alkyl, and n is 1 or 2.

[0111] In an aspect, the MC4R agonist compound is a compound of Formula (I) appearing in the Table below:

[0112] Table 1: Exemplary MC4R Agonist Compounds

[0113] In an embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is a compound provided in Table 1. In an embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is Compound 100. In an embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is Compound 101. In an embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is Compound 102. In an embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is Compound 103. In an embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is Compound 104. In an embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is Compound 105. In an embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is Compound 106. In an embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is Compound 107. In an embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is Compound 108. In an embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is Compound 109. In an embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is Compound 110. In an embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is Compound 111. In an embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is Compound 112. In an embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is Compound 113. In an embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is Compound 114. In an embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is Compound 115. In an embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is Compound 116. In an embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is Compound 117. In an embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is Compound 118.

[0114] Oral Dosage Forms

[0115] Pharmaceutically acceptable compositions of this disclosure may be orally administered in any orally acceptable dosage form including, but not limited to, beverages, capsules, tablets, aqueous suspensions, solutions, emulsions, microemulsions, solutions, suspensions, syrups, elixirs, or candies. Liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. In some embodiments, a provided oral formulation is formulated for immediate release or sustained / delayed release. In some embodiments, the composition is suitable for buccal or sublingual administration, including tablets, lozenges and pastilles. A provided compound can also be in micro-encapsulated form.

[0116] In some embodiments, compounds provided herein are administered, for example, as sublingual tablets, gums, mouth washes, toothpaste, candy, gels, films, etc. the compounds can be formulated readily by combining the active compound(s) with pharmaceutically acceptable carriers well known in the art in amounts effective to form oral unit doses. Such carriers enable the compounds of the disclosure to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a subject to be treated. Pharmaceutical preparations for oral use can be obtained by combining the composition with a suitable solid phase excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, for example, calcium carbonate, calcium phosphate, polymers such as polyethylene oxide), fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross -linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene oxide), and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. Pharmaceutical preparations, which can be used orally, include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.

[0117] Compounds provided herein are typically formulated in dosage unit form, e.g., single unit dosage form, for ease of administration and uniformity of dosage. It will be understood, however, that the total daily, weekly, monthly, and / or yearly usage of the compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0118] The unit-dosage form of the compound may be formulated to dissolve in an aqueous solution (e.g., water, milk, juice, and the like) and is orally administered as a beverage, syrup, solution, or suspension. For example, the unit-form dosage of the compound may comprise a cube, packet, lozenge, pill, tablet, capsule, candy, powder, elixir, or concentrated syrup formulated for dissolving into an aqueous solution prior to oral administration. In other embodiments, the unit-dosage form of the compound may comprise a cube, packet, lozenge, pill, tablet, capsule, candy, powder, elixir, or concentrated syrup formulated to dissolve in vivo, e.g., in the mouth, stomach, intestine, or colon of the subject upon oral administration.

[0119] The dosage forms described herein can be manufactured using processes that are known to those of skill in the art. For example, for the manufacture of tablets, an effective amount of a prebiotic can be dispersed uniformly in one or more excipients or additives, for example, using high shear granulation, low shear granulation, fluid bed granulation, or by blending for direct compression. Excipients and additives include diluents, binders, disintegrants, dispersants, lubricants, glidants, stabilizers, surfactants, antiadherents, sorbents, sweeteners, and colorants, or a combination thereof. Diluents, also termed fillers, can be used to increase the bulk of a tablet so that a practical size is provided for compression. Non-limiting examples of diluents include lactose, cellulose, microcrystalline cellulose, mannitol, dry starch, hydrolyzed starches, powdered sugar, talc, sodium chloride, silicon dioxide, titanium oxide, dicalcium phosphate dihydrate, calcium sulfate, calcium carbonate, alumina and kaolin. Binders can impart cohesive qualities to a tablet formulation and can be used to help a tablet remain intact after compression. Non-limiting examples of suitable binders include starch (including corn starch and pregelatinized starch), gelatin, sugars (e.g., glucose, dextrose, sucrose, lactose and sorbitol), celluloses, polyethylene glycol, alginic acid, dextrin, casein, methyl cellulose, waxes, natural and synthetic gums, e.g., acacia, tragacanth, sodium alginate, gum arabic, xantan gum, and synthetic polymers such as polymethacrylates, polyvinyl alcohols, hydroxypropylcellulose, and polyvinylpyrrolidone. Lubricants can also facilitate tablet manufacture; non-limiting examples thereof include magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, and polyethylene glycol. Disintegrants can facilitate tablet disintegration after administration, and non-limiting examples thereof include starches, alginic acid, crosslinked polymers such as, e.g., crosslinked polyvinylpyrrolidone, croscarmellose sodium, potassium or sodium starch glycolate, clays, celluloses (e.g., carboxymethylcelluloses (e.g., carboxymethylcellulose (CMC), CMC-Na, CMC-Ca)), starches, gums and the like. Non-limiting examples of suitable glidants include silicon dioxide, talc, and the like. Stabilizers can inhibit or retard drug decomposition reactions, including oxidative reactions. Surfactants can also include and can be anionic, cationic, amphoteric or nonionic. Exemplary sweeteners may include stevia extract, aspartame, sucrose, alitame, saccharin, and the like. If desired, the tablets can also comprise nontoxic auxiliary substances such as pH buffering agents, preservatives, e.g., antioxidants, wetting or emulsifying agents, solubilizing agents, coating agents, flavoring agents (e.g., mint, cherry, anise, peach, apricot, licorice, raspberry, vanilla), and the like. Additional excipients and additives may include aluminum acetate, benzyl alcohol, butyl paraben, butylated hydroxy toluene, calcium disodium EDTA, calcium hydrogen phosphate dihydrate, dibasic calcium phosphate, tribasic calcium phosphate, candelilla wax, camuba wax, castor oil hydrogenated, cetylpyridine chloride, citric acid, colloidal silicone dioxide, copolyvidone, com starch, cysteine HC1, dimethicone, disodium hydrogen phosphate, erythrosine sodium, ethyl cellulose, gelatin, glycerin, glyceryl monooleate, glyceryl monostearate, glycine, HPMC pthalate, hydroxypropylcellulose, hydroxyl propyl methyl cellulose, hypromellose, iron oxide red or ferric oxide, iron oxide yellow, iron oxide or ferric oxide, magnesium carbonate, magnesium oxide, magnesium stearate, methionine, methacrylic acid copolymer, methyl paraben, silicified microcrystalline cellulose, mineral oil, phosphoric acid, plain calcium phosphate, anhydrous calcium phosphate, polaxamer 407, polaxamer 188, plain polaxamer, polyethylene oxide, polyoxy 140 stearate, polysorbate 80, potassium bicarbonate, potassium sorbate, potato starch, povidone, propylene glycol, propylene paraben, propyl paraben, retinyl palmitate, saccharin sodium, selenium, silica, silica gel, fumed silica, sodium benzoate, sodium carbonate, sodium citrate dihydrate, sodium crossmellose, sodium lauryl sulfate, sodium metabisulfite, sodium propionate, sodium starch, sodium starch glycolate, sodium stearyl fumarate, sorbic acid, sorbitol, sorbitan monooleate, pregelatinized starch, succinic acid, triacetin, triethyl citrate, vegetable stearin, vitamin A, vitamin E, vitamin C, or a combination thereof. The amounts of these excipients and additives can be properly selected based on their relation to other components and properties of the preparation and production method.

[0120] The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound(s), mode of administration, and the like. The desired dosage can be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage can be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).

[0121] In an embodiment, the oral dosage form provides a dosage of a compound of Formula (I) of between about 10 mg and about 1000 mg (e.g., about 20 mg and 900 mg, about 30 mg and 800 mg, about 40 mg and 700 mg, about 50 mg and 600 mg, about 100 mg and 500 mg, about 200 mg and 400 mg, or about 300 mg). In an embodiment, the oral dosage form provides a dosage of a compound of Formula (I) of between about 20 mg and about 900 mg. In an embodiment, the oral dosage form provides a dosage of a compound of Formula (I) of between about 30 mg and about 800 mg. In an embodiment, the oral dosage form provides a dosage of a compound of Formula (I) of between about 40 mg and about 700 mg. In an embodiment, the oral dosage form provides a dosage of a compound of Formula (I) of between about 50 mg and about 600 mg. In an embodiment, the oral dosage form provides a dosage of a compound of Formula (I) of between about 100 mg and about 500 mg. In an embodiment, the oral dosage form provides a dosage of a compound of Formula (I) of between about 200 mg and about 4000 mg. In an embodiment, the oral dosage form provides a dosage of a compound of Formula (I) of about 300 mg.

[0122] In some embodiments, an amount of a compound for administration one or more times a day subject may comprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.

[0123] In some embodiments, the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is administered in the form of a tablet, e.g., a film coated tablet, comprising about 10 mg. In some embodiments, the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is administered in the form of a tablet, e.g., a film coated tablet, comprising about 20 mg. In some embodiments, the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is administered in the form of a tablet, e.g., a film coated tablet, comprising about 30 mg. In some embodiments, the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is administered in the form of a tablet, e.g., a film coated tablet, comprising about 40 mg. In some embodiments, the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is administered in the form of a tablet, e.g., a film coated tablet, comprising about 50 mg. In some embodiments, the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is administered in the form of a tablet, e.g., a film coated tablet, comprising about 60 mg. In some embodiments, the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is administered in the form of a tablet, e.g., a film coated tablet, comprising about 70 mg. In some embodiments, the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is administered in the form of a tablet, e.g., a film coated tablet, comprising about 80 mg. In some embodiments, the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is administered in the form of a tablet, e.g., a film coated tablet, comprising about 90 mg. In some embodiments, the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is administered in the form of a tablet, e.g., a film coated tablet, comprising about 100 mg.

[0124] In some embodiments, an amount of a compound for administration one or more times a day to a subject may comprise between about 200-600 mg (e.g., between about 250-550 mg, 300-500mg, 350-450 mg, or 400 mg). For example, in some embodiments, an amount of a compound for administration one or more times a day to a subject may comprise between about 2550-550 mg. In some embodiments, an amount of a compound for administration one or more times a day to a subject may comprise between about 300-500 mg. In some embodiments, an amount of a compound for administration one or more times a day to a subject may comprise between about 350-450 mg. In some embodiments, an amount of a compound for administration one or more times a day to a subject may comprise about 400 mg.

[0125] In some embodiments, an amount of a compound for administration one or more times a day to a subject may comprise 100 mg. In some embodiments, an amount of a compound for administration one or more times a day to a subject may comprise 150 mg. In some embodiments, an amount of a compound for administration one or more times a day to a subject may comprise 200 mg. In some embodiments, an amount of a compound for administration one or more times a day to a subject may comprise 300 mg. In some embodiments, an amount of a compound for administration one or more times a day to a subject may comprise 400 mg. In some embodiments, an amount of a compound for administration one or more times a day to a subject may comprise 600 mg. In some embodiments, an amount of a compound for administration one or more times a day to a subject may comprise 800 mg. In some embodiments, an amount of a compound for administration one or more times a day to a subject may comprise 1000 mg.

[0126] In some embodiments, the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is administered in the form of a tablet, e.g., a film coated tablet, comprising between about 100-800 mg (e.g., between about 200-700 mg, 300- 600 mg, 400-500 mg, or about 450 mg). For example, in some embodiments, the MC4R agonist e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is administered in the form of a tablet, e.g., a film coated tablet, comprising between about 200-700 mg. In some embodiments, the MC4R agonist e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is administered in the form of a tablet, e.g., a film coated tablet, comprising between about 300-600 mg. In some embodiments, the MC4R agonist e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is administered in the form of a tablet, e.g., a film coated tablet, comprising between about 400- 500 mg. In some embodiments, the MC4R agonist e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is administered in the form of a tablet, e.g., a film coated tablet, comprising about 450 mg.

[0127] In some embodiments, the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is administered in the form of a tablet, e.g., a film coated tablet, comprising about 100 mg. In some embodiments, the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is administered in the form of a tablet, e.g., a film coated tablet, comprising about 150 mg. In some embodiments, the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is administered in the form of a tablet, e.g., a film coated tablet, comprising about 200 mg. In some embodiments, the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is administered in the form of a tablet, e.g., a film coated tablet, comprising about 250 mg. In some embodiments, the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is administered in the form of a tablet, e.g., a film coated tablet, comprising about 400 mg. In some embodiments, the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is administered in the form of a tablet, e.g., a film coated tablet, comprising about 500 mg. In some embodiments, the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is administered in the form of a tablet, e.g., a film coated tablet, comprising about 600 mg. In some embodiments, the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is administered in the form of a tablet, e.g., a film coated tablet, comprising about 800 mg.

[0128] In some embodiments, the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is at dosage levels sufficient to deliver from about 0.001 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to about 50 mg / kg, preferably from about 0.1 mg / kg to about 40 mg / kg, preferably from about 0.5 mg / kg to about 30 mg / kg, from about 0.01 mg / kg to about 10 mg / kg, from about 0.1 mg / kg to about 10 mg / kg, and more preferably from about 1 mg / kg to about 25 mg / kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

[0129] In some embodiments, the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is provided at 1 mg / kg. In some embodiments, the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is provided at 3 mg / kg. In some embodiments, the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is provided at 5 mg / kg. In some embodiments, the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is provided at 10 mg / kg. In some embodiments, the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is provided at 15 mg / kg. In some embodiments, the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is provided at 20 mg / kg. In some embodiments, the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is provided at 25 mg / kg. In some embodiments, the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is provided at 30 mg / kg. In some embodiments, the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is provided at 40 mg / kg. In some embodiments, the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is provided at 50 mg / kg.

[0130] It will be appreciated that dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

[0131] It will be also appreciated that a compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents. The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their bioavailability, reduce and / or modify their metabolism, inhibit their excretion, and / or modify their distribution within the body. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and / or it may achieve different effects.

[0132] The compound or composition can be administered concurrently with, prior to, or subsequent to, one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Each additional pharmaceutical agent may be administered at a dose and / or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and / or with the compound or composition described herein in a single dose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the inventive compound with the additional pharmaceutical agents and / or the desired therapeutic and / or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agents utilized in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

[0133] Exemplary additional pharmaceutical agents include, but are not limited to, anti-proliferative agents, anti-cancer agents, anti-diabetic agents, anti-inflammatory agents, immunosuppressant agents, and a pain-relieving agent. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.

[0134] In some embodiments, the one or more pharmaceutical agent is selected from growth hormone, contraceptives, hydrocortisone, desmopressin, sex hormone replacement therapy, antihypertensives, GLP-1 receptor agonists (such agonists may be used only for the treatment of diabetes mellitus and not for weight loss), statins and other lipid lowering therapies, thyroxine or other thyroid supplements, administration of live or inactivated vaccines (e.g., SARS-CoV-2 vaccines), other medications commonly used in subjects with obesity (e.g., anti-constipation medications, anti-allergic medications, estrogens, alendronic acid, hydrocortisone, carnitine, Coenzyme Q10, vitamins, calcium supplements, etc.). In some embodiments, the one or more pharmaceutical agent may comprise any medications, except for those with narrow therapeutic index (e.g., warfarin, etc.), that may be permitted after consultation with a physician, if the subject is receiving a stable dose. In some embodiments, the subject may receive concomitant therapeutic lifestyle management for weight loss.

[0135] The one or more pharmaceutical agents may not comprise: medications that could impact the efficacy assessments during the administration of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, such as anorectic agents or drugs with anorexia as a non-rare side effect; strong inhibitors and strong inducers of CYP3A4 including grapefruit juice; inhibitors or substrates of P-glycoprotein; GLP-l's (e.g., GLP-1 agonists) except for the treatment of diabetes; nirmatrelvir / ritonavir. In some embodiments, a subject having COVID- 19 may stop receiving administration of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof so that they may be treated with nirmatrelvir / ritonavir. Such subjects may resume receiving administration of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof72 hours post-completion of treatment with nirmatrelvir / ritonavir.

[0136] Steps of Methods:

[0137] MC4R agonist compounds described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof may be administered to a subject having hypothalamic obesity or displaying one or more symptoms of hypothalamic obesity according to the methods described herein. In some embodiments, after a subject is selected for treatment, the subject will undergo an initial screening period to assess body weight, BMI, waist circumference, waist-to-hip circumference ratio, body composition (e.g., by dual energy X-ray absorptiometry), and self-reported appetite. The subject will be assessed by a physician or other healthcare professional. In some embodiments, the subject is at least 6 years of age. In some embodiments, the subject is older than 6 years of age.

[0138] In some embodiments, the subject will be administered an MC4R agonist compound described herein, a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof via oral administration. In some embodiments, the administration will be performed daily for the duration of the treatment. In some embodiments, the administration will be performed twice per week for the duration of the treatment. In some embodiments, the administration will be performed once per week for the duration of the treatment. In some embodiments, the subject is administered an initial dose (e.g., loading dose) of the compound. In some embodiments, the initial dose (e.g., loading dose) is increased in a step- wise manner until the subject receives the maintenance dosage. In some embodiments, the initial dose (e.g., loading dose) is increased to the maintenance dosage as determined by a physician or other healthcare provider.

[0139] In some embodiments, subject parameters including, but not limited to, body weight, BMI, waist circumference, waist-to-hip circumference ratio, body composition (e.g., by dual energy X-ray absorptiometry), and self-reported appetite is measured at intervals. For example, in some embodiments, the subject’s body weight is measured. In some embodiments, the subject’s BMI is measured. In some embodiments, the subject’s waist circumference may be measured. In some embodiments, the subject’s hip circumference is measured. In some embodiments, the subject’s waist-to-hip circumference ratio is assessed, e.g., by measuring the subject’s waist circumference and hip circumference and then calculating the waist-to-hip circumference ratio. In some embodiments, the subject’s body composition is assessed, e.g., by a DEXA scan. In some embodiments, the subject’s self-reported appetite is assessed. In some embodiments, the intervals is daily, weekly, biweekly, monthly, bimonthly, or yearly. In some embodiments, the intervals may decrease in frequency after the subject begins receiving the maintenance dosage. In some embodiments, the percent change in body weight relative to baseline is measured.

[0140] In some embodiments, a level or value for the body weight of a subject is acquired. In some embodiments, the level or value for the body weight of the subject decreases following administration of the MC4R agonist compound described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the level or value for the body weight of the subject decreases by about 2% or more (e.g., by about 3%, 4%, 5%, 10%, 15%, 20%, or more), e.g., relative to baseline. For example, in some embodiments, the level or value for the body weight of the subject decreases by about 3% or more. In some embodiments, the level or value for the body weight of the subject decreases by about 4% or more. In some embodiments, the level or value for the body weight of the subject decreases by about 5% or more. In some embodiments, the level or value for the body weight of the subject decreases by about 10% or more. In some embodiments, the level or value for the body weight of the subject decreases by about 15% or more. In some embodiments, the level or value for the body weight of the subject decreases by about 20% or more.

[0141] In some embodiments, a level or value for the waist circumference of a subject is acquired. In some embodiments, the level or value for the waist circumference of the subject decreases following administration of the MC4R agonist compound described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the level or value for the waist circumference of the subject decreases by about 1% or more (e.g., by about 2%, 3%, 4%, 5%, 10%, 15%, 20%, or more), e.g., relative to baseline. For example, in some embodiments, the level or value for the waist circumference of the subject decreases by about 2% or more. In some embodiments, the level or value for the waist circumference of the subject decreases by about 3% or more. In some embodiments, the level or value for the waist circumference of the subject decreases by about 4% or more. In some embodiments, the level or value for the waist circumference of the subject decreases by about 5% or more. In some embodiments, the level or value for the waist circumference of the subject decreases by about 10% or more. In some embodiments, the level or value for the waist circumference of the subject decreases by about 15% or more. In some embodiments, the level or value for the waist circumference of the subject decreases by about 20% or more.

[0142] In some embodiments, a level or value for the waist-to-hip circumference ratio of a subject is acquired. In some embodiments, the level or value for the waist-to-hip circumference ratio of the subject decreases following administration of the MC4R agonist compound described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the level or value for the waist-to-hip circumference ratio of the subject decreases by about 1% or more (e.g., by about 2%, 3%, 4%, 5%, 10%, 15%, 20%, or more), e.g., relative to baseline. For example, in some embodiments, the level or value for the waist-to-hip circumference ratio of the subject decreases by about 2% or more. In some embodiments, the level or value for the waist-to-hip circumference ratio of the subject decreases by about 3% or more. In some embodiments, the level or value for the waist-to-hip circumference ratio of the subject decreases by about 4% or more. In some embodiments, the level or value for the waist- to-hip circumference ratio of the subject decreases by about 5% or more. In some embodiments, the level or value for the waist-to-hip circumference ratio of the subject decreases by about 10% or more. In some embodiments, the level or value for the waist-to-hip circumference ratio of the subject decreases by about 15% or more. In some embodiments, the level or value for the waist- to-hip circumference ratio of the subject decreases by about 20% or more.

[0143] In some embodiments, a level or value for the body composition (e.g., DEXA scan T value) of a subject is acquired. In some embodiments, the level or value for the body composition (e.g., DEXA scan T value) of the subject improves following administration of the MC4R agonist compound described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof In some embodiments, the level or value for the body composition (e.g., DEXA scan T value) of the subject improves by about 1% or more (e.g., by about 2%, 3%, 4%, 5%, 10%, 15%, 20%, or more), e.g., relative to baseline. For example, in some embodiments, the level or value for the body composition (e.g., DEXA scan T value) of the subject improves by about 2% or more. In some embodiments, the level or value for the body composition (e.g., DEXA scan T value) of the subject improves by about 3% or more. In some embodiments, the level or value for the body composition (e.g., DEXA scan T value) of the subject improves by about 4% or more. In some embodiments, the level or value for the body composition (e.g., DEXA scan T value) of the subject improves by about 5% or more. In some embodiments, the level or value for the body composition (e.g., DEXA scan T value) of the subject improves by about 10% or more. In some embodiments, the level or value for the body composition (e.g., DEXA scan T value) of the subject improves by about 15% or more. In some embodiments, the level or value for the body composition (e.g., DEXA scan T value) of the subject improves by about 20% or more.

[0144] In some embodiments, a level or value for the self-reported appetite of a subject is acquired. In some embodiments, the level or value for the self-reported appetite of the subject decreases following administration of the MC4R agonist compound described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the level or value for the self-reported appetite of the subject decreases by about 1% or more (e.g., by about 2%, 3%, 4%, 5%, 10%, 15%, 20%, or more), e.g., relative to baseline, as measured by daily caloric consumption. For example, in some embodiments, the level or value for the self-reported appetite of the subject decreases by about 2% or more. In some embodiments, the level or value for the self-reported appetite of the subject decreases by about 3% or more. In some embodiments, the level or value for the self-reported appetite of the subject decreases by about 4% or more. In some embodiments, the level or value for the self- reported appetite of the subject decreases by about 5% or more. In some embodiments, the level or value for the self-reported appetite of the subject decreases by about 10% or more. In some embodiments, the level or value for the self-reported appetite of the subject decreases by about 15% or more. In some embodiments, the level or value for the self-reported appetite of the subject decreases by about 20% or more.

[0145] Patient Selection

[0146] The present disclosure provides methods for treating hypothalamic obesity in a subject, featuring administering an MC4R agonist compound described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In an embodiment, the subject is a mammal, e.g., a human. In some embodiments, the subject is a female. In some embodiments, the subject is a male. In some embodiments, the subject is aged 18 years or older. In some embodiments, the subject is less than 18 years of age. In some embodiments, the subject is aged 6 years or older. In some embodiments, the subject is aged 12 years or older. In some embodiments, the subject has been diagnosed with hypothalamic obesity or is displaying one or more symptoms or risk factors of hypothalamic obesity.

[0147] Symptoms and / or risk factors of hypothalamic obesity may include, but are not limited to, rapid weight gain, increased hunger, decreased energy, high level of damage to the hypothalamus, endocrine dysfunction, and receiving high amounts of radiation to the hypothalamic area. In some embodiments, the subject has experienced rapid weight gain. In some embodiments, the subject has increased hunger. In some embodiments, the subject has decreased energy. In some embodiments, the subject has fatigue. In some embodiments, the subject has a high level of damage to the hypothalamus. In some embodiments, the subject has endocrine dysfunction. In some embodiments, the subject has received high amounts of radiation to the hypothalamic area.

[0148] In some embodiments, the subject is treatment-naive. In some embodiments, the subject has previously received a treatment for obesity, e.g., hypothalamic obesity, weight gain, and / or weight loss. In some embodiments, the subject is treatment-naive for an obesity drug.

[0149] In some embodiments, subjects are at least 12 years old (e.g., at least 13 years, 14 years, 15 years, 18 years, 20 years, 25 years, 50 years, or older). For example, in some embodiments, subjects are at least 13 years old. In some embodiments, subjects are at least 14 years old. In some embodiments, subjects are at least 15 years old. In some embodiments, subjects are at least 18 years old. In some embodiments, subjects are at least 20 years old. In some embodiments, subjects are at least 25 years old. In some embodiments, subjects are at least 50 years old. In some embodiments, subjects are older than 50 years old.

[0150] In some embodiments, subjects are obese. Obesity may be defined as BMI >30 kg / m2 for subjects >18 years of age or BMI >95th percentile for age and gender for subjects <18 years of age. In some embodiments, subjects have hypothalamic obesity, e.g., subjects have been diagnosed with a craniopharyngioma or other brain lesion affecting the hypothalamic region and have undergone surgery, chemotherapy, or radiation therapy involving the hypothalamus at least 6 months prior to administration of the MC4R agonist compound described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, subjects having hypothalamic obesity may comprise subjects having a documented injury to the hypothalamus at least 6 months prior to administration of the MC4R agonist compound described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, for which surgery / radiation is not indicated. In some embodiments, subjects may have a documented increase in BMI (change from pre-surgery baseline in BMI Z score >0.2 for subjects <18 years of age or BMI >5% for subjects >18 years of age) either during the first 6 months following surgery or within 1 year before surgery AND still present prior to administration of the MC4R agonist compound described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof.

[0151] In some embodiments, subjects are receiving hormone replacement therapy (e.g., hydrocortisone for adrenal insufficiency, sex hormone for hypogonadism, thyroid hormone for hypothyroidism and growth hormone for growth hormone deficiency). In such cases, the dose should have been stable for at least 2 months prior to administration of the MC4R agonist compound described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the body weight of the subject has been stable (less than 5% weight gain or 2% loss for subjects >18 years of age; BMI reduction >2% for subjects <18 years of age) for at least 3 months prior to administration of the MC4R agonist compound described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, female subjects (e.g., of childbearing age) may not be pregnant, breastfeeding, and may not be intending to become pregnant during administration of the MC4R agonist compound and for at least 90 days after the last dose of the MC4R agonist compound. In some embodiments, dietary and / or exercise regimens, with or without the use of medications, supplements or herbal treatments associated with weight loss (e.g., orlistat, lorcaserin, phentermine, topiramate, naltrexone, bupropion) or the treatment of diabetes mellitus are allowed if: the regimen and / or dose has been stable for at least 3 months prior to administration with the MC4R agonist compound; the subject has not experienced weight loss >2% (for subjects >18 years) or >2% BMI (for subjects aged 12 to <18 years) during the previous 3 months; and the subject intends to keep the regimen and / or dose stable throughout the course of the trial.

[0152] In some embodiments, the subject may not have experienced weight loss >2% in the previous 3 months for subjects aged >18 years or >2% reduction in BMI for subjects aged 12 to <18 years. In some embodiments, the subject does not have a diagnosis of, or symptoms of, Prader-Willi syndrome (PWS) or rapid-onset obesity with hypoventilation, hypothalamic, autonomic dysregulation, and / or neuroendocrine tumor syndrome. In some embodiments, the subject has never been treated with an MC4R agonists (e.g., setmelanotide, RM-718, or Compound 100). In some embodiments, the subject has not had weight loss surgery within the previous 6 months prior to administration of the MC4R agonist compound described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, or any prior weight loss surgery resulting in >10% weight loss durably maintained from the baseline preoperative weight with no evidence of weight regain.

[0153] In some embodiments, the subject has no history of major surgical procedure within 30 days prior to administration of the MC4R agonist compound described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the subject has no diagnosis of schizophrenia, bipolar disorder, personality disorder or other mood disorders. In some embodiments, the subject has no documented history of suicidal ideation. In some embodiments, the subject does not have a Patient Health Questionnaire-9 (PHQ-9) / PHQ- Adolescents (PHQ-A) score >15 at Screening. In some embodiments, the subject does not have any suicidal ideation of type 4 or 5 on the Columbia- Suicide Severity Rating Scale (C-SSRS), any history of a suicide attempt, or any suicidal behavior in the last month prior to Screening.

[0154] In some embodiments, the subject has no current, clinically significant pulmonary, cardiac, or oncologic disease considered severe enough to interfere with the treatment, as determined by a physician. In some embodiments, the subject does not have a HbAlc >10.9% prior to administration of the MC4R agonist compound described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the subject does not have a fasting glucose level >270 mg / dL prior to administration of the MC4R agonist compound described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the subject does not have history of significant liver disease or abnormal liver tests (i.e. >2 x upper limit of normal [ULN] for alanine transaminase [ALT], aspartate transaminase [AST]; >1.5 x ULN for alkaline phosphatase and serum bilirubin; cirrhosis Child Pugh class B or C with any etiology of liver disease) prior to administration of the MC4R agonist compound described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof.

[0155] In some embodiments, the subject does not have a history or presence of impaired renal function. In some embodiments, the subject does not have an estimated glomerular filtration rate (eGFR) (e.g., as calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD- EPI) equation) of <30 mL / min / 1.73 m2 (for subjects aged >18 years old) prior to administration of the MC4R agonist compound described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the subject does not have an eGFR calculated by updated Schwartz formula <30 mL / min / 1.73 m2 (for subjects aged <18 years) prior to administration of the MC4R agonist compound described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof.

[0156] In some embodiments, the subject does not have a personal history of melanoma or ocular cutaneous albinism. In some embodiments, the subject does not have a history of melanoma in immediate family members. In some embodiments, the subject does not have clinically dysplastic nevi or lesions suspicious for melanoma at comprehensive skin assessment prior to administration of the MC4R agonist compound described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, unless such nevi or lesions are confirmed to be benign (e.g., by biopsy) prior to administration of the MC4R agonist compound described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof.

[0157] In some embodiments, the subject is not using or being treated with strong CYP3A4 inhibitors or strong CYP3A4 inducers within 14 days prior to administration of the MC4R agonist compound described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the subject does not have the need for ongoing treatment with concomitant oral or intravenous therapy with strong CYP3A4 inhibitors or strong CYP3A4 inducers (e.g., as determined by a physician).

[0158] In some embodiments, the subject is not using inhibitors or substrates of P-glycoprotein within 14 days prior to administration of the MC4R agonist compound described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the subject does not have the need for on-going treatment with concomitant inhibitors or substrates of P-glycoprotein (e.g., as determined by a physician).

[0159] In some embodiments, the subject does not consume grapefruit (grapefruit containing food and beverages), star fruit (carambola), pomegranate, Seville orange and other food components that may interact with CYP3A4 within 14 days prior to, and during, administration of the MC4R agonist compound described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the subject is not undergoing treatment with any IMPs within 3 months or 5 half-lives, whichever time period is longer, prior to administration of the MC4R agonist compound described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof.

[0160] In some embodiments, the subject does not experience hypersensitivity to Compound 100 or any excipient of the MC4R agonist compound described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, for example, as determined by a physician.

[0161] In some embodiments, the subject may refrain from consuming caffeine and smoking for 1 hour prior to, and during, administration of the MC4R agonist compound described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the subject may restrict alcohol consumption for 24 hours prior to administration of the MC4R agonist compound described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the subject may not donate blood or plasma for at least 3 months after the last administration of the MC4R agonist compound described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the subject may refrain from any activities that will intentionally cause their skin to tan (e.g., visits to ultraviolet tanning salons, the use of spray tanners or self-tanning lotions, and / or exposure to sunlight for a long period).

[0162] Treatment Duration

[0163] A subject may be treated, e.g., by oral administration, with an MC4R agonist compound, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, at a specific frequency, for example, daily, weekly, biweekly, monthly, bimonthly, and / or yearly. In some embodiments, a subject is administered the compound once. In some embodiments, a subject is administered the compound more than once. In some embodiments, a subject is administered the compound at regular intervals, e.g., daily, weekly, biweekly, or monthly. In some embodiments, a subject is administered the compound daily. In some embodiments, a subject is administered the compound weekly. In some embodiments, a subject is administered the compound biweekly. In some embodiments, the subject is administered the compound monthly. In some embodiments, a subject is administered the compound bimonthly. In some embodiments, a subject is administered the compound yearly.

[0164] In some embodiments, a subject is administered the compound daily for a minimum of 1 week. In some embodiments, a subject is administered the compound daily for two weeks. In some embodiments, a subject is administered the compound daily for three weeks. In some embodiments, a subject is administered the compound daily for four weeks. In some embodiments, a subject is administered the compound daily for more than four weeks.

[0165] In some embodiments, a subject is administered the compound weekly for a minimum of 1 week. In some embodiments, a subject is administered the compound weekly for two weeks. In some embodiments, a subject is administered the compound weekly for three weeks. In some embodiments, a subject is administered the compound weekly for four weeks. In some embodiments, a subject is administered the compound weekly for more than four weeks.

[0166] In some embodiments, a subject is administered the compound at intervals as determined by a physician or other healthcare provider.

[0167] In some embodiments, the treatment period, e.g., the period between the first and final administration of the compound, comprises at least 8 weeks (e.g., at least 9 weeks, 10 weeks, 12 weeks, 15 weeks, 16 weeks, 20 weeks, 24 weeks, 26 weeks, 52 weeks, or more). For example, in some embodiments, the treatment period comprises at least 9 weeks. In some embodiments, the treatment period comprises at least 10 weeks. In some embodiments, the treatment period comprises at least 12 weeks. In some embodiments, the treatment period comprises at least 15 weeks. In some embodiments, the treatment period comprises at least 16 weeks. In some embodiments, the treatment period comprises at least 20 weeks. In some embodiments, the treatment period comprises at least 24 weeks. In some embodiments, the treatment period comprises at least 26 weeks. In some embodiments, the treatment comprises at least 52 weeks. In some embodiments, the treatment comprises more than 52 weeks.

[0168] Endpoints

[0169] A subject’s response to an MC4R agonist as described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, may be measured at intervals by a physician or other healthcare provider. In some embodiments, the subject’s response is measured by the change (e.g., from baseline) in one or more of the following parameters selected from: body weight, BMI, waist circumference, waist-to-hip circumference ratio, body composition (e.g., by dual energy X-ray absorptiometry (DEXA)), and hunger (e.g., self-reported hunger).

[0170] In some embodiments, the subject’s change in body weight from baseline is measured. In some embodiments, the change in body weight from baseline is measured at least one week (e.g., at least 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 26 weeks, 52 weeks, or more) after the subject receives the first dose of the MC4R agonist compound. For example, in some embodiments, the change in body weight from baseline is measured at least 2 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the percent change in body weight from baseline is measured at least 4 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the percent change in body weight from baseline is measured at least 8 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the percent change in body weight from baseline is measured at least 12 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the percent change in body weight from baseline is measured at least 16 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the percent change in body weight from baseline is measured at least 20 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the percent change in body weight from baseline is measured at least 26 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the percent change in body weight from baseline is measured at least 52 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the percent change in body weight from baseline is measured more than 52 weeks after the subject receives the first dose of the MC4R agonist compound.

[0171] In some embodiments, the subject’s percent change in body mass index (BMI) from baseline is measured. In some embodiments, the percent change in BMI from baseline is measured at least one week (e.g. at least 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 26 weeks, 52 weeks, or more) after the subject receives the first dose of the MC4R agonist compound. For example, in some embodiments, the percent change in BMI from baseline is measured at least 2 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the percent change in BMI from baseline is measured at least 4 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the percent change in BMI from baseline is measured at least 8 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the percent change in BMI from baseline is measured at least 12 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the percent change in BMI from baseline is measured at least 16 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the percent change in BMI from baseline is measured at least 20 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the percent change in BMI from baseline is measured at least 26 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the percent change in BMI from baseline is measured at least 52 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the percent change in BMI from baseline is measured more than 52 weeks after the subject receives the first dose of the MC4R agonist compound.

[0172] In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -1%, -2%, -3%, -4%, -5%, -6%, -7%, -8%, -9%, -10% or more after about 1 week or more of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -1% after about 1 week of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -2% after about 1 week of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -3% after about 1 week of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -4% after about 1 week of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -5% after about 1 week of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -6% after about 1 week of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -7% after about 1 week of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -8% after about 1 week of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -9% after about 1 week of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -10% after about 1 week of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 200 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 400 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 600 mg.

[0173] In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -1.1% after about 1 week of administration of a 200 mg daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -1.4% after about 1 week of administration of a 400 mg daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -1.7% after about 1 week of administration of a 600 mg daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof.

[0174] In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -1%, -2%, -3%, -4%, -5%, -6%, -7%, -8%, -9%, -10% or more after about 2 weeks or more of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -1% after about 2 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -2% after about 2 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -3% after about 2 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -4% after about 2 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -5% after about 2 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -6% after about 2 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -7% after about 2 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -8% after about 2 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -9% after about 2 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -10% after about 2 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 200 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 400 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 600 mg.

[0175] In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -0.8% after about 2 weeks of administration of a 200 mg daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -2.6% after about 2 weeks of administration of a 400 mg daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -1.7% after about 2 weeks of administration of a 600 mg daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof.

[0176] In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -1%, -2%, -3%, -4%, -5%, -6%, -7%, -8%, -9%, -10% or more after about 4 weeks or more of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -1% after about 4 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -2% after about 4 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -3% after about 4 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -4% after about 4 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -5% after about 4 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -6% after about 4 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -7% after about 4 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -8% after about 4 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -9% after about 4 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -10% after about 4 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 200 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 400 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 600 mg.

[0177] In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -1%, -2%, -3%, -4%, -5%, -6%, -7%, -8%, -9%, -10% or more after about 6 weeks or more of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -1% after about 6 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -2% after about 6 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -3% after about 6 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -4% after about 6 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -5% after about 6 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -6% after about 6 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -7% after about 6 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -8% after about 6 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -9% after about 6 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -10% after about 6 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 200 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 400 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 600 mg.

[0178] In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -1.1% after about 6 weeks of administration of a 200 mg daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -5.7% after about 6 weeks of administration of a 400 mg daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -5.8% after about 6 weeks of administration of a 600 mg daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof.

[0179] In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -1%, -2%, -3%, -4%, -5%, -6%, -7%, -8%, -9%, -10% or more after about 8 weeks or more of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -1% after about 8 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -2% after about 8 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from s reference standard, e.g., baseline, is about -3% after about 8 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -4% after about 8 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -5% after about 8 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -6% after about 8 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -7% after about 8 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -8% after about 8 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -9% after about 8 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -10% after about 8 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 200 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 400 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 600 mg.

[0180] In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -1%, -2%, -3%, -4%, -5%, -6%, -7%, -8%, -9%, -10% or more after about 10 weeks or more of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -1% after about 10 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -2% after about 10 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -3% after about 10 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -4% after about 10 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -5% after about 10 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -6% after about 10 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -7% after about 10 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -8% after about 10 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -9% after about 10 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -10% after about 10 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 200 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 400 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 600 mg.

[0181] In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -6.5% after about 10 weeks of administration of a 200 mg daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -8.4% after about 10 weeks of administration of a 400 mg daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -8.8% after about 10 weeks of administration of a 600 mg daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof.

[0182] In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -1%, -2%, -3%, -4%, -5%, -6%, -7%, -8%, -9%, -10% or more after about 12 weeks or more of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -1% after about 12 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -2% after about 12 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -3% after about 12 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -4% after about 12 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -5% after about 12 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -6% after about 12 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -7% after about 12 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -8% after about 12 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -9% after about 12 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -10% after about 12 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 200 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 400 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 600 mg.

[0183] In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -1%, -2%, -3%, -4%, -5%, -6%, -7%, -8%, -9%, -10% or more after about 14 weeks or more of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -1% after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -2% after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -3% after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -4% after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -5% after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -6% after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -7% after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -8% after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -9% after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -10% after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 200 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 400 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 600 mg.

[0184] In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -2.62% after about 14 weeks of administration of a 200 mg daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -8.39% after about 14 weeks of administration of a 400 mg daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -9.98% after about 14 weeks of administration of a 600 mg daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof.

[0185] In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -1%, -2%, -3%, -4%, -5%, -6%, -7%, -8%, -9%, -10% or more after about 16 weeks or more of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -1% after about 16 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -2% after about 16 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -3% after about 16 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -4% after about 16 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -5% after about 16 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -6% after about 16 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -7% after about 16 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -8% after about 16 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -9% after about 16 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -10% after about 16 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 200 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 400 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 600 mg.

[0186] In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -1%, -2%, -3%, -4%, -5%, -6%, -7%, -8%, -9%, -10% or more after about 20 weeks or more of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -1% after about 20 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -2% after about 20 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -3% after about 20 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -4% after about 20 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -5% after about 20 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -6% after about 20 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -7% after about 20 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -8% after about 20 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -9% after about 20 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -10% after about 20 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 200 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 400 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 600 mg.

[0187] In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -1%, -2%, -3%, -4%, -5%, -6%, -7%, -8%, -9%, -10% or more after about 26 weeks or more of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -1% after about 26 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -2% after about 26 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -3% after about 26 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -4% after about 26 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -5% after about 26 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -6% after about 26 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -7% after about 26 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -8% after about 26 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -9% after about 26 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -10% after about 26 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 200 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 400 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 600 mg.

[0188] In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -1%, -2%, -3%, -4%, -5%, -6%, -7%, -8%, -9%, -10% or more after about 52 weeks or more of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -1% after about 52 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -2% after about 52 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -3% after about 52 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -4% after about 52 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -5% after about 52 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -6% after about 52 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -7% after about 52 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -8% after about 52 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -9% after about 52 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., baseline, is about -10% after about 52 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 200 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 400 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 600 mg.

[0189] In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -1%, -2%, -3%, -4%, -5%, -6%, -7%, -8%, -9%, -10% or more after about 1 week or more of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -1% after about 1 week of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -2% after about 1 week of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -3% after about 1 week of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -4% after about 1 week of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -5% after about 1 week of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -6% after about 1 week of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -7% after about 1 week of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -8% after about 1 week of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -9% after about 1 week of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -10% after about 1 week of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 200 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 400 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 600 mg.

[0190] In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -1%, -2%, -3%, -4%, -5%, -6%, -7%, -8%, -9%, -10% or more after about 2 weeks or more of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -1% after about 2 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -2% after about 2 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -3% after about 2 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -4% after about 2 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -5% after about 2 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -6% after about 2 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -7% after about 2 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -8% after about 2 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -9% after about 2 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -10% after about 2 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 200 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 400 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 600 mg.

[0191] In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -1%, -2%, -3%, -4%, -5%, -6%, -7%, -8%, -9%, -10% or more after about 4 weeks or more of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -1% after about 4 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -2% after about 4 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -3% after about 4 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -4% after about 4 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -5% after about 4 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo is about -6% after about 4 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -7% after about 4 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -8% after about 4 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -9% after about 4 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -10% after about 4 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 200 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 400 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 600 mg. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -1%, -2%, -3%, -4%, -5%, -6%, -7%, -8%, -9%, -10% or more after about 6 weeks or more of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -1% after about 6 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -2% after about 6 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -3% after about 6 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -4% after about 6 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -5% after about 6 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo is about -6% after about 6 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -7% after about 6 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -8% after about 6 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -9% after about 6 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -10% after about 6 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 200 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 400 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 600 mg.

[0192] In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -1%, -2%, -3%, -4%, -5%, -6%, -7%, -8%, -9%, -10% or more after about 8 weeks or more of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -1% after about 8 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -2% after about 8 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -3% after about 8 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -4% after about 8 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -5% after about 8 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -6% after about 8 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -7% after about 8 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -8% after about 8 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -9% after about 8 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -10% after about 8 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 200 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 400 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 600 mg. n some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -1%, -2%, -3%, -4%, -5%, -6%, -7%, -8%, -9%, -10% or more after about 10 weeks or more of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -1% after about 10 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -2% after about 10 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -3% after about 10 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -4% after about 10 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -5% after about 10 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo is about -6% after about 10 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -7% after about 10 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -8% after about 10 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -9% after about 10 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -10% after about 10 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 200 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 400 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 600 mg.

[0193] In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -1%, -2%, -3%, -4%, -5%, -6%, -7%, -8%, -9%, -10% or more after about 12 weeks or more of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -1% after about 12 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -2% after about 12 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -3% after about 12 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -4% after about 12 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -5% after about 12 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -6% after about 12 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -7% after about 12 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -8% after about 12 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -9% after about 12 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -10% after about 12 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 200 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 400 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 600 mg.

[0194] In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -1%, -2%, -3%, -4%, -5%, -6%, -7%, -8%, -9%, -10% or more after about 14 weeks or more of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -1% after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -2% after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -3% after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -4% after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -5% after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -6% after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -7% after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -8% after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -9% after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -10% after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 200 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 400 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 600 mg.

[0195] In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is between -1.0% and -6.0% after about 14 weeks of administration of a 200 mg daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -5.24% after about 14 weeks of administration of a 200 mg daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -2.7% after about 14 weeks of administration of a 200 mg daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof.

[0196] In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is between -4.0% and -13.0% after about 14 weeks of administration of a 400 mg daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -11% after about 14 weeks of administration of a 400 mg daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -7.7% after about 14 weeks of administration of a 400 mg daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof.

[0197] In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is between -7.0% and -16.0% after about 14 weeks of administration of a 600 mg daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -12.9% after about 14 weeks of administration of a 600 mg daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -9.3% after about 14 weeks of administration of a 600 mg daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof.

[0198] In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -1%, -2%, -3%, -4%, -5%, -6%, -7%, -8%, -9%, -10% or more after about 16 weeks or more of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -1% after about 16 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -2% after about 16 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -3% after about 16 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -4% after about 16 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -5% after about 16 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -6% after about 16 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -7% after about 16 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -8% after about 16 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard,, e.g., placebo, is about -9% after about 16 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -10% after about 16 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 200 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 400 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 600 mg.

[0199] In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -1%, -2%, -3%, -4%, -5%, -6%, -7%, -8%, -9%, -10% or more after about 20 weeks or more of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -1% after about 20 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -2% after about 20 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -3% after about 20 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -4% after about 20 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -5% after about 20 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -6% after about 20 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -7% after about 20 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -8% after about 20 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -9% after about 20 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -10% after about 20 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 200 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 400 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 600 mg.

[0200] In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -1%, -2%, -3%, -4%, -5%, -6%, -7%, -8%, -9%, -10% or more after about 26 weeks or more of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -1% after about 26 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -2% after about 26 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo is about -3% after about 26 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -4% after about 26 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -5% after about 26 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -6% after about 26 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -7% after about 26 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -8% after about 26 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -9% after about 26 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -10% after about 26 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 200 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 400 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 600 mg.

[0201] In some embodiments, the percent change in BMI from placebo is about -1%, -2%, -3%, -4%, -5%, -6%, -7%, -8%, -9%, -10% or more after about 52 weeks or more of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -1% after about 52 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -2% after about 52 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -3% after about 52 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -4% after about 52 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -5% after about 52 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -6% after about 52 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -7% after about 52 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -8% after about 52 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -9% after about 52 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the percent change in BMI from a reference standard, e.g., placebo, is about -10% after about 52 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof 100, is 200 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 400 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 600 mg.

[0202] In some embodiments, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more of subjects achieve a reduction in BMI greater than 5% relative to a reference standard, e.g., baseline, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 10% of subjects achieve a reduction in BMI greater than 5% relative to a reference standard, e.g., baseline, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 20% of subjects achieve a reduction in BMI greater than 5% relative to a reference standard, e.g., baseline, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 30% of subjects achieve a reduction in BMI greater than 5% relative to a reference standard, e.g., baseline, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 40% of subjects achieve a reduction in BMI greater than 5% relative to a reference standard, e.g., baseline, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 50% of subjects achieve a reduction in BMI greater than 5% relative to a reference standard, e.g., baseline, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 60% of subjects achieve a reduction in BMI greater than 5% relative to a reference standard, e.g., baseline, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 70% of subjects achieve a reduction in BMI greater than 5% relative to a reference standard, e.g., baseline, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 80% of subjects achieve a reduction in BMI greater than 5% relative to a reference standard, e.g., baseline, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 90% of subjects achieve a reduction in BMI greater than 5% relative to a reference standard, e.g., baseline, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 200 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 400 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 600 mg.

[0203] In some embodiments, 16.7% of subjects achieve a reduction in BMI greater than 5% relative to a reference standard, e.g., baseline, after about 14 weeks of administration of 200 mg of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 71.4% of subjects achieve a reduction in BMI greater than 5% relative to a reference standard, e.g., baseline, after about 14 weeks of administration of 400 mg of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 75% of subjects achieve a reduction in BMI greater than 5% relative to a reference standard, e.g., baseline, after about 14 weeks of administration of 600 mg of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof.

[0204] In some embodiments, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more of subjects achieve a reduction in BMI greater than 10% relative to a reference standard, e.g., baseline, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 10% of subjects achieve a reduction in BMI greater than 10% relative to a reference standard, e.g., baseline, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 20% of subjects achieve a reduction in BMI greater than 10% relative to a reference standard, e.g., baseline, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 30% of subjects achieve a reduction in BMI greater than 10% relative to a reference standard, e.g., baseline, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 40% of subjects achieve a reduction in BMI greater than 10% relative to a reference standard, e.g., baseline, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 50% of subjects achieve a reduction in BMI greater than 10% relative to a reference standard, e.g., baseline, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 60% of subjects achieve a reduction in BMI greater than 10% relative to a reference standard, e.g., baseline, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 70% of subjects achieve a reduction in BMI greater than 10% relative to a reference standard, e.g., baseline, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 80% of subjects achieve a reduction in BMI greater than 10% relative to a reference standard, e.g., baseline, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 90% of subjects achieve a reduction in BMI greater than 10% relative to a reference standard, e.g., baseline, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 200 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 400 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 600 mg.

[0205] In some embodiments, 0% of subjects achieve a reduction in BMI greater than 10% relative to a reference standard, e.g., baseline, after about 14 weeks of administration of 200 mg of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 14.3% of subjects achieve a reduction in BMI greater than 10% relative to a reference standard, e.g., baseline, after about 14 weeks of administration of 400 mg of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 37.5% of subjects achieve a reduction in BMI greater than 10% relative to a reference standard, e.g., baseline, after about 14 weeks of administration of 600 mg of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof.

[0206] In some embodiments, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more of subjects achieve a reduction in BMI greater than 5% relative to a reference standard, e.g., placebo, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 10% of subjects achieve a reduction in BMI greater than 5% relative to a reference standard, e.g., placebo, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 20% of subjects achieve a reduction in BMI greater than 5% relative to a reference standard, e.g., placebo, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 30% of subjects achieve a reduction in BMI greater than 5% relative to a reference standard, e.g., placebo, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 40% of subjects achieve a reduction in BMI greater than 5% relative to a reference standard, e.g., placebo, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 50% of subjects achieve a reduction in BMI greater than 5% relative to a reference standard, e.g., placebo, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 60% of subjects achieve a reduction in BMI greater than 5% relative to a reference standard, e.g., placebo, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 70% of subjects achieve a reduction in BMI greater than 5% relative to a reference standard, e.g., placebo, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 80% of subjects achieve a reduction in BMI greater than 5% relative to a reference standard, e.g., placebo, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 90% of subjects achieve a reduction in BMI greater than 5% relative to a reference standard, e.g., placebo, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 200 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 400 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 600 mg.

[0207] In some embodiments, 16.7% of subjects achieve a reduction in BMI greater than 5% relative to a reference standard, e.g., placebo, after about 14 weeks of administration of 200 mg of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 71.4% of subjects achieve a reduction in BMI greater than 5% relative to a reference standard, e.g., placebo, after about 14 weeks of administration of 400 mg of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 75% of subjects achieve a reduction in BMI greater than 5% relative to a reference standard, e.g., placebo, after about 14 weeks of administration of 600 mg of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof.

[0208] In some embodiments, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more of subjects achieve a reduction in BMI greater than 10% relative to a reference standard, e.g., placebo, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 10% of subjects achieve a reduction in BMI greater than 10% relative to a reference standard, e.g., placebo, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 20% of subjects achieve a reduction in BMI greater than 10% relative to a reference standard, e.g., placebo, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 30% of subjects achieve a reduction in BMI greater than 10% relative to a reference standard, e.g., placebo, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 40% of subjects achieve a reduction in BMI greater than 10% relative to a reference standard, e.g., placebo, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 10% of subjects achieve a reduction in BMI greater than 50% relative to a reference standard, e.g., placebo, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 60% of subjects achieve a reduction in BMI greater than 10% relative to a reference standard, e.g., placebo, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 70% of subjects achieve a reduction in BMI greater than 10% relative to a reference standard, e.g., placebo, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 80% of subjects achieve a reduction in BMI greater than 10% relative to a reference standard, e.g., placebo, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 90% of subjects achieve a reduction in BMI greater than 10% relative to a reference standard, e.g., placebo, after about 14 weeks of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 200 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 400 mg. In some embodiments, the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is 600 mg.

[0209] In some embodiments, 0% of subjects achieve a reduction in BMI greater than 10% relative to a reference standard, e.g., baseline, after about 14 weeks of administration of 200 mg of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 14.3% of subjects achieve a reduction in BMI greater than 10% relative to a reference standard, e.g., baseline, after about 14 weeks of administration of 400 mg of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, 37.5% of subjects achieve a reduction in BMI greater than 10% relative to a reference standard, e.g., baseline, after about 14 weeks of administration of 600 mg of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof.

[0210] In some embodiments, the subject’s change in waist circumference from baseline is measured. In some embodiments, the change in waist circumference from baseline is measured at least one week (e.g. at least 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 26 weeks, 52 weeks, or more) after the subject receives the first dose of the MC4R agonist compound. For example, in some embodiments, the change in waist circumference from baseline is measured at least 2 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in waist circumference from baseline is measured at least 4 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in waist circumference from baseline is measured at least 8 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in waist circumference from baseline is measured at least 12 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in waist circumference from baseline is measured at least 16 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in waist circumference from baseline is measured at least 20 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in waist circumference from baseline is measured at least 26 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in waist circumference from baseline is measured at least 52 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in waist circumference from baseline is measured more than 52 weeks after the subject receives the first dose of the MC4R agonist compound.

[0211] In some embodiments, the subject’s change in waist-to-hip circumference ratio from baseline is measured. In some embodiments, the change in waist-to-hip circumference ratio from baseline is measured at least one week (e.g. at least 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 26 weeks, 52 weeks, or more) after the subject receives the first dose of the MC4R agonist compound. For example, in some embodiments, the change in waist- to-hip circumference ratio from baseline is measured at least 2 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in waist-to-hip circumference ratio from baseline is measured at least 4 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in waist-to-hip circumference ratio from baseline is measured at least 8 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in waist-to-hip circumference ratio from baseline is measured at least 12 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in waist-to-hip circumference ratio from baseline is measured at least 16 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in waist-to-hip circumference ratio from baseline is measured at least 20 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in waist-to-hip circumference ratio from baseline is measured at least 26 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in waist-to-hip circumference ratio from baseline is measured at least 52 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in waist-to-hip circumference ratio from baseline is measured more than 52 weeks after the subject receives the first dose of the MC4R agonist compound.

[0212] In some embodiments, the subject’s change in body composition (e.g., by dual energy X- ray absorptiometry (DEXA)) from baseline is measured. In some embodiments, the change in body composition from baseline is measured at least one week (e.g. at least 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 26 weeks, 52 weeks, or more) after the subject receives the first dose of the MC4R agonist compound. For example, in some embodiments, the change in body composition from baseline is measured at least 2 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in body composition from baseline is measured at least 4 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in body composition from baseline is measured at least 8 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in body composition from baseline is measured at least 12 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in body composition from baseline is measured at least 16 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in body composition from baseline is measured at least 20 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in body composition from baseline is measured at least 26 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in body composition from baseline is measured at least 52 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in body composition from baseline is measured more than 52 weeks after the subject receives the first dose of the MC4R agonist compound.

[0213] In some embodiments, the subject’s change in hunger (e.g., self-reported hunger) from baseline is measured. In some embodiments, the change in hunger from baseline is measured at least one week (e.g. at least 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 26 weeks, 52 weeks, or more) after the subject receives the first dose of the MC4R agonist compound. For example, in some embodiments, the change in hunger from baseline is measured at least 2 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in hunger from baseline is measured at least 4 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in hunger from baseline is measured at least 8 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in hunger from baseline is measured at least 12 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in hunger from baseline is measured at least 16 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in hunger from baseline is measured at least 20 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in hunger from baseline is measured at least 26 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in hunger from baseline is measured at least 52 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in hunger from baseline is measured more than 52 weeks after the subject receives the first dose of the MC4R agonist compound.

[0214] In some embodiments, the percent change in hunger from a reference standard, e.g., baseline, is about -0.5%, -1%, -2%, -3%, -4%, -5%, -6%, -7%, -8%, -9%, -10% or more, e.g., after about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 weeks or more of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the mean reduction in hunger (e.g., hunger score), e.g., from a reference standard, e.g., baseline, is about -0.5%, -1%, - 2%, -3%, -4%, -5%, -6%, -7%, -8%, -9%, -10% or more, e.g., after about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 weeks or more of administration of the daily dose of the MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. In some embodiments, the mean reduction in hunger (e.g., hunger score), e.g., from a reference standard, e.g., baseline, is between about -0.5% and -5%, e.g., between about -1.0% and about -4%.

[0215] In some embodiments, the subject’s change in fatigue (e.g., self-reported fatigue) from baseline is measured. In some embodiments, the change in fatigue from baseline is measured at least one week (e.g. at least 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 26 weeks, 52 weeks, or more) after the subject receives the first dose of the MC4R agonist compound. For example, in some embodiments, the change in fatigue from baseline is measured at least 2 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in fatigue from baseline is measured at least 4 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in fatigue from baseline is measured at least 8 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in fatigue from baseline is measured at least 12 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in fatigue from baseline is measured at least 16 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in fatigue from baseline is measured at least 20 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in fatigue from baseline is measured at least 26 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in fatigue from baseline is measured at least 52 weeks after the subject receives the first dose of the MC4R agonist compound. In some embodiments, the change in fatigue from baseline is measured more than 52 weeks after the subject receives the first dose of the MC4R agonist compound.

[0216] In some embodiments, other endpoints are assessed, evaluated, and / or monitored at intervals (e.g., weekly intervals or at intervals determined by, e.g., a physician). Such endpoints include one or more endpoints selected from: mean percentage change in BMI, mean change in BMI, mean change in the (gender- and age-specific) BMI Z-score (e.g., for subjects <18 years of age), mean change in percentage of the (gender- and age-specific) 95th percentile of BMI (e.g., for subjects <18 years of age), mean change and / or mean percentage change in body weight, mean change and / or mean percentage change in waist circumference, mean change and / or mean percentage change from baseline in waist-to-hip circumference ratio, mean change and mean percentage change in body composition (fat mass, lean mass) assessed by dual energy x-ray absorptiometry (DEXA), mean change in the weekly average of the daily most hunger score in subjects >12 years old from, mean change in the weekly average of the Symptoms of Hyperphagia total score, frequency and / or severity of adverse events (AE), change from baseline in vital sign measurements (e.g., blood pressure, temperature, respiratory rate, and heart rate), change from baseline in laboratory results (e.g., as ordered by or prescribed by a physician), change from baseline in Endocrine function assessment, change from baseline in electrocardiogram (ECG) parameters, change from baseline in Patient Health Questionnaire (PHQ 9 / PHQ-A) total score, change in the subject’s performance on the Columbia Suicide Severity Rating Scale (C-SSRS), change in pubertal development for subjects who have yet to reach Tanner Staging V, change in maximum observed concentration in plasma (Cmax), change in time to Cmax (Tmax), change in the area under the concentration-time curve from 0 to last quantifiable concentration (AUCO-t), and change in trough plasma concentration (Ctrough). In some embodiments, one or more endpoints may comprise assessing one or more of the following changes from baseline in the following metabolism parameters: HbAlc, Insulin, C-peptide, Leptin, and High-sensitivity C-reactive protein (Hs-CRP). In some embodiments, one or more endpoints may comprise assessing one or more of the following changes from baseline in the following lipid parameters: total cholesterol, Low-density lipoprotein cholesterol (LDL-C), High-density lipoprotein cholesterol (HDL-C), and Triglycerides (TGs). In some embodiments, one or more endpoints may comprise assessing one or more of the following changes from baseline in the following parameters: change in Impact of Weight on Quality of Life Questionnaire -Lite-Clinical Trials (IWQOL-Lite-CT) (age >18 years) and IWQOL-Kids / Parent Proxy (age <18 years), and mean change in total score for the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale (FACIT-Fatigue in subjects >18 and peds FACIT-F in subjects 12 to <18 years of age).

[0217] In some embodiments, improvements or palliation of other symptoms are monitored to assess a subject’s response to a compound described herein, e.g., an MC4R agonist, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof. For example, in some embodiments, a subject’s self-reported level of fatigue are monitored and / or measured at intervals. In some embodiments, a subject’s self-reported mood and / or self-reported appetite are monitored, for example, on a daily or weekly basis following administration of the compound.

[0218] In some embodiments, following administration of an MC4R agonist as described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, to a subject, the subject’s triglyceride levels may decrease. In some embodiments, following administration of an MC4R agonist as described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, to a subject, the subject’s fat globule size may decrease.

[0219] In some embodiments, an MC4R agonist described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, has a half life of between about 1 minute and about 24 hours (e.g., between about 5 minutes and about 23 hours, between about 10 minutes and about 22 hours, between about 30 minutes and about 20 hours, between about 1 hour and about 18 hours, between about 2 hours and about 12 hours, between about 4 hours and 8 hours, or about 6 hours). For example, in some embodiments, an MC4R agonist described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, has a half life of between about 5 minutes and about 23 hours. In some embodiments, an MC4R agonist described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, has a half life of between about 10 minutes and about 22 hours. In some embodiments, an MC4R agonist described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, has a half life of between about 30 minutes and about 20 hours. In some embodiments, an MC4R agonist described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, has a half life of between about 1 hour and about 18 hours. In some embodiments, an MC4R agonist described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, has a half life of between about 2 minutes and about 12 hours. In some embodiments, an MC4R agonist described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, has a half life of between about 4 minutes and about 8 hours. In some embodiments, an MC4R agonist described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, has a half life of about 6 hours.

[0220] In some embodiments, an MC4R agonist described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is detectable in the blood for between about 1 minute and about 24 hours (e.g., between about 5 minutes and about 23 hours, between about 10 minutes and about 22 hours, between about 30 minutes and about 20 hours, between about 1 hour and about 18 hours, between about 2 hours and about 12 hours, between about 4 hours and 8 hours, or about 6 hours). For example, in some embodiments, an MC4R agonist described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is detectable in the blood for between about 5 minutes and about 23 hours. In some embodiments, an MC4R agonist described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is detectable in the blood for between about 10 minutes and about 22 hours. In some embodiments, an MC4R agonist described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is detectable in the blood for between about 30 minutes and about 20 hours. In some embodiments, an MC4R agonist described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is detectable in the blood for between about 1 hour and about 18 hours. In some embodiments, an MC4R agonist described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is detectable in the blood for between about 2 minutes and about 12 hours. In some embodiments, an MC4R agonist described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is detectable in the blood for between about 4 minutes and about 8 hours. In some embodiments, an MC4R agonist described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is detectable in the blood for about 6 hours. In some embodiments, an MC4R agonist described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is detectable in the blood for longer than about 24 hours. In some embodiments, an MC4R agonist described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is detectable in the blood for about 48 hours.

[0221] In some embodiments, an MC4R agonist described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, has a pharmacokinetic profile in which the compound is substantially absent or cleared from the subject in 48 hours or less, e.g., 36 hours or less, 24 hours or less, 18 hours or less, 16 hours or less, 12 hours or less, or 8 hours or less, 4 hours or less, or 2 hours or less. For example, in some embodiments, an MC4R agonist described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is cleared in at least 5 hours. In some embodiments, an MC4R agonist described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is cleared in at least 8 hours. In some embodiments, an MC4R agonist described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is cleared in at least 12 hours. In some embodiments, an MC4R agonist described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is cleared in at least 16 hours. In some embodiments, an MC4R agonist described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is cleared in at least 18 hours. In some embodiments, an MC4R agonist described herein, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, is cleared in at least 24 hours.

[0222] Kits

[0223] Kits with unit doses of one or more of the MC4R agonists, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof, described herein, in oral doses, are provided. Such kits may include a container containing the unit dose, an informational package insert describing the use and attendant benefits of the pharmaceutical composition in treating hypothalamic obesity.

[0224] ENUMERATED EMBODIMENTS

[0225] 1. A method of treating hypothalamic obesity in a subject, wherein the method comprises administering to the subject a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof as an oral dosage form comprising a dosage of the compound of Formula (I)

[0226] Ill between about 10 mg and about 1000 mg, wherein the compound of Formula (I) has the following structural formula: , (I) wherein R1is C2-C5 alkyl; R2is halo; R3is hydrogen or halo; R4is C1-C3 alkyl; and n is an integer of 1 or 2, thereby treating hypothalamic obesity in the subject.

[0227] 2. The method of any one of the preceding embodiments, wherein the compound is administered daily, e.g., once per day, twice per day, thrice per day, four times per day, five times per day, six times per day, or seven times per day.

[0228] 3. The method of any one of the preceding embodiments, wherein the compound is administered weekly, e.g., once per week, twice per week, thrice per week, four times per week, five times per week, six times per week, or seven times per week.

[0229] 4. The method of any one of the preceding embodiments, wherein the compound is administered once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, or once every eight weeks.

[0230] 5. The method of any one of the preceding embodiments, wherein the compound is administered daily, weekly, monthly, or yearly.

[0231] 6. The method of any one of the preceding embodiments, wherein the compound is administered once daily.

[0232] 7. The method of any one of the preceding embodiments, wherein the compound is administered for at least 1 week, at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 14 weeks, at least 16 weeks, at least 20 weeks, at least 26 weeks, at least 52 weeks, or more.

[0233] 8. The method of any one of the preceding embodiments, wherein the compound is administered for at least 1 week.

[0234] 9. The method of any one of the preceding embodiments, wherein the compound is administered for at least 2 weeks.

[0235] 10. The method of any one of the preceding embodiments, wherein the compound is administered for at least 4 weeks.

[0236] 11. The method of any one of the preceding embodiments, wherein the compound is administered for at least 6 weeks.

[0237] 12. The method of any one of the preceding embodiments, wherein the compound is administered for at least 8 weeks.

[0238] 13. The method of any one of the preceding embodiments, wherein the compound is administered for at least 10 weeks.

[0239] 14. The method of any one of the preceding embodiments, wherein the compound is administered for at least 12 weeks.

[0240] 15. The method of any one of the preceding embodiments, wherein the compound is administered for at least 14 weeks.

[0241] 16. The method of any one of the preceding embodiments, wherein the compound is administered for at least 16 weeks. 17. The method of any one of the preceding embodiments, wherein the compound is administered for at least 20 weeks.

[0242] 18. The method of any one of the preceding embodiments, wherein the compound is administered for at least 26 weeks.

[0243] 19. The method of any one of the preceding embodiments, wherein the compound is administered for at least 52 weeks.

[0244] 20. The method of any one of the preceding embodiments, wherein the compound is administered for at least one month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.

[0245] 21. The method of any one of the preceding embodiments, wherein the compound is administered for at least 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, or more.

[0246] 22. The method of any one of the preceding embodiments, wherein the subject’s response to the compound is assessed by measuring parameters comprising body weight, body mass index (BMI), waist circumference, waist-to-hip circumference ratio, body composition, hunger, and fatigue.

[0247] 23. The method of any one of the preceding embodiments, wherein the subject’s response to the compound is assessed by measuring the percent change in the subject’s body weight relative to baseline, e.g., at intervals.

[0248] 24. The method of any one of the preceding embodiments, wherein the intervals comprise 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 20 weeks, 26 weeks, or 52 weeks. 25. The method of any one of the preceding embodiments, wherein the intervals comprise 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or

[0249] 12 months.

[0250] 26. The method of any one of the preceding embodiments, wherein the intervals comprise 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years.

[0251] 27. The method of any one of the preceding embodiments, wherein the subject has been diagnosed with hypothalamic obesity.

[0252] 28. The method of any one of the preceding embodiments, wherein the subject displays or experiences a symptom or risk factor of hypothalamic obesity.

[0253] 29. The method of any one of the preceding embodiments, wherein the symptom or risk factor comprises weight gain, increased hunger, decreased energy, high level of damage to the hypothalamus, endocrine dysfunction, or receiving high amounts of radiation to the hypothalamic area.

[0254] 30. The method of any one of the preceding embodiments, wherein the symptom or risk factor comprises weight gain.

[0255] 31. The method of any one of the preceding embodiments, wherein the symptom or risk factor comprises increased hunger.

[0256] 32. The method of any one of the preceding embodiments, wherein the symptom or risk factor comprises decreased energy.

[0257] 33. The method of any one of the preceding embodiments, wherein the symptom or risk factor comprises a high level of damage to the hypothalamus. 34. The method of any one of the preceding embodiments, wherein the symptom or risk factor comprises endocrine dysfunction.

[0258] 35. The method of any one of the preceding embodiments, wherein the symptom or risk factor comprises receiving high amounts of radiation to the hypothalamic area.

[0259] 36. The method of any one of the preceding embodiments, wherein the treatment with the compound comprises a reduction in a symptom by about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more.

[0260] 37. The method of any one of the preceding embo...

Claims

1. CLAIMS1. A method of treating hypothalamic obesity in a subject, wherein the method comprises administering to the subject a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof as an oral dosage form comprising a dosage of the compound of Formula (I) between about 10 mg and about 1000 mg, wherein the compound of Formula (I) has the following structural formula:, (I) wherein R1is C2-C5 alkyl; R2is halo; R3is hydrogen or halo; R4is C1-C3 alkyl; and n is an integer of 1 or 2, thereby treating hypothalamic obesity in the subject.

2. The method of claim 1, wherein the compound is administered daily, e.g., once per day, twice per day, thrice per day, four times per day, five times per day, six times per day, or seven times per day.

3. The method of claim 1, wherein the compound is administered weekly, e.g., once per week, twice per week, thrice per week, four times per week, five times per week, six times per week, or seven times per week.

4. The method of claim 1, wherein the compound is administered once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, or once every eight weeks.

5. The method of claim 1, wherein the compound is administered daily, weekly, monthly, or yearly.

6. The method of claim 1, wherein the compound is administered once daily.

7. The method of claim 1, wherein the compound is administered for at least 1 week, at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 14 weeks, at least 16 weeks, at least 20 weeks, at least 26 weeks, at least 52 weeks, or more.

8. The method of claim 1, wherein the compound is administered for at least 1 week.

9. The method of claim 1, wherein the subject’s response to the compound is assessed by measuring parameters comprising body weight, body mass index (BMI), waist circumference, waist-to-hip circumference ratio, body composition, hunger, and fatigue.

10. The method of claim 1, wherein the subject’s response to the compound is assessed by measuring the percent change in the subject’s body weight relative to baseline, e.g., at intervals.

11. The method of claim 1, wherein the subject has been diagnosed with hypothalamic obesity.

12. The method of claim 1, wherein the subject displays or experiences a symptom or risk factor of hypothalamic obesity.

13. The method of claim 1, wherein the symptom or risk factor comprises weight gain, increased hunger, decreased energy, high level of damage to the hypothalamus, endocrine dysfunction, or receiving high amounts of radiation to the hypothalamic area.

14. The method of claim 1, wherein the treatment with the compound comprises a reduction in a symptom by about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more.

15. The method of claim 1, wherein the treatment with the compound comprises a reduction in body weight by about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more.

16. The method of claim 1, wherein the treatment with the compound comprises a reduction in hunger by about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more.

17. The method of claim 1, wherein the treatment with the compound comprises a reduction in decreased energy by about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more.

18. The method of claim 1, wherein the treatment with the compound comprises a reduction in endocrine dysfunction by about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more.

19. The method of claim 1, wherein, following treatment of the subject by the compound, the subject experiences a reduction in a parameter selected from: body weight, BMI, waist circumference, waist-to-hip circumference ratio, body composition, hunger, and fatigue.

20. The method of claim 1, wherein the treatment with the compound comprises a reduction in a parameter by about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more, relative to a reference standard.

21. The method of claim 1, wherein the reduction in body weight comprises between about 2% to about 30%.

22. The method of claim 1, wherein the reduction in body weight comprises between about5% to about 20%.

23. The method of claim 1, wherein the treatment with the compound comprises a reduction in BMI by about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more, relative to a reference standard.

24. The method of claim 23, wherein the reduction in BMI comprises between about 1% to about 20%.

25. The method of claim 23, wherein the reduction in BMI comprises between about 5% to about 15%.

26. The method of claim 23, wherein the reduction in BMI from a reference standard, e.g., baseline, is greater than about -1% after about 1 week of administration of a 200 mg daily dose of the compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof.

27. The method of claim 23, wherein the reduction in BMI from a reference standard, e.g., baseline, is greater than about -1% after administration of a 400 mg daily dose of the compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof.

28. The method of claim 23, wherein the reduction in BMI from a reference standard, e.g., baseline, is greater than about -1% after administration of a 600 mg daily dose of the compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof.

29. The method of claim 1, wherein the treatment with the compound comprises a reduction in body composition (e.g., a reduction in a DEXA score) by about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more, relative to a reference standard.

30. The method of claim 29, wherein the reduction in body composition (e.g., a reduction in the DEXA score) comprises between about 1% to about 50%.

31. The method of claim 29, wherein the reduction in body composition (e.g., a reduction in the DEXA score) comprises between about 1% to about 30%.

32. The method of claim 1, wherein the treatment with the compound of Formula (I) comprises a reduction in fatigue by about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95%, 99%, or more, relative to a reference standard.

33. The method of claim 32, wherein the reduction in fatigue comprises between about 1% to about 50%.

34. The method of claim 32, wherein the reduction in fatigue comprises at least about 20%.

35. The method of claim 1, wherein R1is ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl.

36. The method of claim 1, wherein R1is ethyl.

37. The method of claim 1, wherein R1is isopropyl.

38. The method of claim 1, wherein R1is tert-butyl.

39. The method of claim 1, wherein R3is hydrogen and R2is selected from F, Cl, or I.

40. The method of claim 1, wherein R3is hydrogen and R2is Cl.

41. The method of claim 1, wherein R2and R3each is, independently, F or Cl.

42. The method of claim 1, wherein R4is methyl and n is 1 or 2.

43. The method of claim 1, wherein R4is methyl and n is 1.

44. The method of claim 1, wherein R4is methyl and n is 2.

45. The method of claim 1, wherein the compound is selected from any one or more of a compound provided in Table 1 (e.g. Compounds 100 - 118) or a pharmaceutically acceptable salt or isomer thereof.

46. The method of claim 1, wherein the dosage of the compound is between about 100 mg to about 1000 mg.

47. The method of claim 1, wherein the dosage of the compound is between about 200 mg to about 800 mg.

48. The method of any one of the preceding claims, wherein the dosage of the compound is about 100 mg, 200 mg, 400 mg, 600 mg, 800 mg, or 1000 mg.

49. The method of claim 1, wherein the dosage of the compound is about 200 mg, 400 mg, or 600 mg.

50. The method of claim 1, wherein the dosage of the compound is about 200 mg.

51. The method of claim 1 , wherein the dosage of the compound is about 400 mg.

52. The method of claim 1, wherein the dosage of the compound is about 600 mg.

53. The method of claim 1, wherein the oral dosage form comprises chewable tablets, quick melting tablets, foam tablets, solid form gelatin capsules, soft gelatin capsules, reducing particles, particulates, suspensions, elixirs, caplets, syrups, liquid, liquid gels, oils, or gels.

54. The method of claim 1, wherein the subject is a mammal, e.g., a human.

55. The method of claim 1, wherein the method further comprises administration of an additional pharmaceutical agent.

56. The method of claim 55, wherein the additional pharmaceutical agent comprises growth hormone, contraceptives, hydrocortisone, desmopressin, sex hormone replacement therapy, antihypertensives, GLP-1 receptor agonists (such agonists may be used only for the treatment of diabetes mellitus and not for weight loss), statins and other lipid lowering therapies, thyroxine or other thyroid supplements, administration of live or inactivated vaccines (e.g., SARS-CoV-2 vaccines), other medications commonly used in subjects with obesity (e.g., anti-constipation medications, anti-allergic medications, estrogens, alendronic acid, hydrocortisone, carnitine, Coenzyme Q10, vitamins, or calcium supplements).

57. The method of claim 55, the additional pharmaceutical agent does not comprise anorectic agents or drugs with anorexia as a non-rare side effect; strong inhibitors and strong inducers of CYP3A4 including grapefruit juice; inhibitors or substrates of P-gly coprotein; GLP-l's (e.g., GLP-1 agonists) except for the treatment of diabetes; nirmatrelvir / ritonavir.68.

58. The method of claim 1, wherein the compound is formulated for oral administration.

59. A composition for use in treating hypothalamic obesity in a subject, comprising a compound of Formula (I) or a pharmaceutically acceptable salt or isomer thereof as an oral dosage form comprising a dosage of the compound of Formula (I) between about 10 mg and about 1000 mg, wherein the compound of Formula (I) has the following structural formula:, (I) wherein R1is C2-C5 alkyl; R2is halo; R3is hydrogen or halo; R4is C1-C3 alkyl; and n is an integer of 1 or 2.

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