Combinations of g-protein coupled hormone receptor modulators and melanocortin 4 receptor agonists and related methods of use

Abstract

The present disclosure relates to methods of treating a disease or disorder comprising administering a combination of GLP1R agonists and MC4R agonists.

Description

[0001] COMBINATIONS OF G-PROTEIN COUPLED HORMONE RECEPTOR MODULATORS AND MELANOCORTIN 4 RECEPTOR AGONISTS AND RELATED METHODS OF USE

[0002] CLAIM OF PRIORITY

[0003] This application claims priority to U. S. Application No. 63 / 714,130, filed October 30, 2024; the entire contents of the foregoing application is incorporated herein by reference.

[0004] BACKGROUND

[0005] Melanocortin 4 receptor disorders include obesity, which is a condition defined by excessive and / or abnormal accumulation of fat or adipose tissue. It is associated with many life-threatening diseases, such as cardiovascular disease, respiratory dysfunction, musculoskeletal disorders, obstructive sleep apnea, stroke, renal disease, hyperlipidemia, hypertension, infertility, type 2 diabetes, and certain cancers (e.g., breast, colorectal, endometrial, gallbladder, and pancreatic cancer). Many current therapies for the treatment of obesity comprise administering compounds that reduce insulin resistance and / or body weight or involve bariatric surgeries, e.g., gastric bypass or sleeve gastrectomy; however, these therapies often entail serious complications and side effects and are not suitable for many patients. As such, there is a need for improved therapies.

[0006] SUMMARY

[0007] The present disclosure features combinations of a melanocortin 4 receptor (MC4R) agonist and a G-protein coupled hormone receptor (GCHR) modulator, e.g., such as a glucagon-like peptide-1 receptor (GLP1R) agonist, as well as pharmaceutical compositions thereof and related methods of use. These combinations may be useful in providing improved treatments for disease or disorders such as obesity, by, for example, improving weight loss and enhancing glycemic control and lipid metabolism beyond outcomes currently reported when either therapy is administered alone. In an embodiment, the GCHR modulator and MC4R agonist are provided to a subject concurrently, e.g., wherein the subject is receiving both the GCHR modulator and MC4R agonist in the same treatment window. In another embodiment, the GCHR modulator and MC4R agonist are provided to a subject in an alternating fashion, e.g., wherein the subject receives either the GCHR modulator or the MC4R agonist for a period of time, followed by the other of the GCHR modulator or the MC4R agonist for a period of time. In an embodiment, the combination of the GCHR modulator and the MC4R agonist function in a synergistic manner, resulting in tolerance of a lower dose of one or both of the GCHR modulator and the MC4R agonist to achieve efficacy, e.g., in the treatment of obesity in the subject. In another embodiment, the combination of the GCHR modulator and the MC4R agonist function in a synergistic manner, resulting in tolerance of a lower dose of one or both of the GCHR modulator and the MC4R agonist to achieve efficacy, e.g., in the treatment of obesity in the subject.

[0008] In an aspect, featured herein is a method of treating obesity in a subject comprising administering to the subject: (i) a G-protein coupled hormone receptor (GCHR) modulator; and (ii) a melanocortin receptor 4 (MC4R) agonist. In an embodiment, the GCHR modulator comprises a glucagon-like peptide-1 receptor (GLP1R) agonist, a dual GLP1R, or a triple GLP1R. In an embodiment, the GCHR modulator is a GLP1R agonist. In an embodiment, the GLP1R agonist comprises semaglutide, orforglipron, albiglutide, dulaglutide, extendin-4, tirzepatide, liraglutide, exenatide, or lixisenatide. In an embodiment, the GCHR modulator comprises a dual GLP1R and gastric inhibitory peptide agonist. In an embodiment, the dual GLP1R and gastric inhibitory peptide agonist comprises survodutide, pemvidutide, or cotadutide. In an embodiment, the GCHR modulator comprises a triple GLP1R, gastric inhibitory peptide, and glucose-dependent insulinotropic polypeptide agonist. In an embodiment, the triple GLP1R, gastric inhibitory peptide, and glucose-dependent insulinotropic polypeptide agonist comprises retatrutide. In an embodiment, the MC4R agonist is a small molecule compound. In an embodiment, the GCHR modulator is a peptide. In an embodiment, each of the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof is independently formulated as a pharmaceutical composition. In an embodiment, each of the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof is formulated together as a single pharmaceutical composition. In an embodiment, each of the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof is administered concomitantly to the human subject. In an embodiment, In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered within 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, or more of each other. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered within 30 minutes of each other. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered within 1 hour of each other. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered within 2 hours of each other. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered within 6 hours of each other. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered within 12 hours of each other. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered within 24 hours of each other. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof is administered sequentially to the human subject. In an embodiment, administered sequentially comprises administration of the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof within 24 hours. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof is administered first to the human subject, followed by the MC4R agonist or a pharmaceutically acceptable salt thereof. In an embodiment, the MC4R agonist or a pharmaceutically acceptable salt thereof is administered first to the human subject, followed by the GCHR modulator or a pharmaceutically acceptable salt thereof. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof is administered for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, or more prior to administration of the MC4R agonist or a pharmaceutically acceptable salt thereof. In an embodiment, the MC4R agonist or a pharmaceutically acceptable salt thereof is administered for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, or more prior to administration of the GCHR modulator or a pharmaceutically acceptable salt thereof.

[0009] In an embodiment of the foregoing aspect, the GCHR modulator or a pharmaceutically acceptable salt thereof is administered at a dosage of between 0.1 to 500 mg. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof is administered at a dosage of 0.1 mg. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof is administered at a dosage of 1 mg. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof is administered at a dosage of 10 mg. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof is administered at a dosage of 50 mg. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof is administered at a dosage of 100 mg. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof is administered at a dosage of 200 mg. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof is administered at a dosage of 250 mg. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof is administered at a dosage of 500 mg. In an embodiment, the MC4R agonist or a pharmaceutically acceptable salt thereof is administered at a dosage of between 0.1 to 10 mg. In an embodiment, the MC4R agonist or a pharmaceutically acceptable salt thereof is administered at a dosage of 0.1 mg. In an embodiment, the MC4R agonist or a pharmaceutically acceptable salt thereof is administered at a dosage of 0.5 mg. In an embodiment, the MC4R agonist or a pharmaceutically acceptable salt thereof is administered at a dosage of 1 mg. In an embodiment, the MC4R agonist or a pharmaceutically acceptable salt thereof is administered at a dosage of 2.5 mg. In an embodiment, the MC4R agonist or a pharmaceutically acceptable salt thereof is administered at a dosage of 5 mg. In an embodiment, the MC4R agonist or a pharmaceutically acceptable salt thereof is administered at a dosage of 10 mg. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered orally. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered subcutaneously. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof is administered orally and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered subcutaneously. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof is administered subcutaneously and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered orally. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof is administered orally. In an embodiment, the GCHR modulator or a pharmaceutically acceptable salt thereof is administered subcutaneously. In an embodiment, the MC4R agonist or a pharmaceutically acceptable salt thereof is administered orally. In an embodiment, the MC4R agonist or a pharmaceutically acceptable salt thereof is administered subcutaneously. In an embodiment, the obesity is a genetic obesity or a non-genetic obesity. In an embodiment, the subject has been diagnosed with obesity. In an embodiment, the subject has a body mass index (BMI) greater than 30. In an embodiment, the subject has a waist circumference of greater than 40 cm. In an embodiment, the subject has a waist-to-hip circumference ratio of greater than 2. In an embodiment, the subject has a mutation in an MC4R pathway agonizable gene. In an embodiment, the MC4R pathway agonizable gene comprises ARL6, RAH, SRC1, BBS 19, BBS21, CEP290, IFT74, LZTFL1, MKS1, TRIM32, WDPCP, RPS6KA3, HTR2C, KSR2, PROK2, RAB23, MRAP2, AFF4, ADCY3, TUB, OTP, GPR101, or TBX3. In an embodiment, the subject has a mutation in POMC, LEPR, PC SKI, SRC1, or SH2B1. In an embodiment, the efficacy of the combination of the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof is at least Xi-fold greater than the efficacy of the hypericin alone at the molar amount used in the combination, wherein Xi is 1, 1.25, 1.5, 1.75, 2, 2.5, or greater. In an embodiment, the GCHR modulator and the MC4R agonist are administered in an alternating manner or in phases, wherein during each phase, only one of the GCHR modulator and the MC4R agonist are administered. In an embodiment, the phases comprise periods of time. In an embodiment, the phases comprise administration of different doses of the GCHR modulator and the MC4R agonist.

[0010] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In addition, the materials, methods, and examples are illustrative only and not intended to be limited.

[0011] DETAILED DESCRIPTION

[0012] The present patent application discloses methods of treating diseases or disorders, such as obesity, comprising administering to a subject in need thereof a melanocortin-4 receptor (MC4R) agonist and a G-protein coupled hormone receptor (GCHR) agonist, e.g., a glucagon-like peptide- 1 receptor (GLP1R) agonist. In an embodiment, administering a combination of an MC4R agonist and a GCHR modulator, e g., a GLP1R agonist, acts synergistically in a subject in treating the disease or disorder, such as obesity, thereby leading to weight loss, decrease in hunger and food intake, and / or increase in energy expenditure in the subject.

[0013] BRIEF DESCRIPTION OF THE DRAWINGS FIGs. 1A-1F are graphs depicting the effect of co-administration of a GCHR modulator, e.g., a GCHR small molecule agonist, e.g., danuglipron (“D”), and a MC4R agonist, e.g., LB54640 (“A”), on changes in body weight, weight gain, and fat mass during 28 days of administration in a mouse model of diet induced obesity (DIO). FIG. 1A depicts changes in body weight in grams. FIG. 1B depicts weight gain in grams. FIG. 1C depicts the percentage change in body weight from baseline, while FIG. 1D depicts the whole body fat mass in grams. FIG. 1E illustrates epididymal fat weight in milligrams, and FIG. IF shows inguinal fat weight in milligrams. The initial body weights of mice were 29.4 ± 0.5 g for the normal group and 43.9 ± 0.7 g for the DIO groups. After 28 days of drug administration, the normal and Con(-) groups gained body weight to 29.9 ± 0.6 g and 46.7 ± 2.0 g, respectively. The body weights of the A10 and A30 groups tended to reduce to 43.2 ± 1.9 g and 41.4 ± 2.1 g in a dose-dependent manner. However, they did not show a significant reduction compared to Con(-) group. The body weight of the D30 group significantly decreased to 37.3 ± 1.4 g compared to Con(-) group. The body weights of the A10+D30 and A3O+D3O groups tended to reduce to 36.7 ± 1.4 g and 34.9 ± 1.3 g, respectively, compared to A10, A30, and D30 groups (FIG. 1A). However, they did not reach a significant weight reduction. After 28 days of administration, the weight gains from the initial body weights for the normal and Con(-) groups increased to 0.5 ± 0.2 g and 2.7 ± 0.5 g, respectively. The weight gains of the A10 and A30 groups significantly reduced to -0.7 ± 0.4 g and -2.6 ± 0.5 g in a dose-dependent manner compared to Con(-) group. The weight gain of the D30 group significantly reduced to -5.9 ± 1.0 g compared to Con(-) group. The weight gains of the A10+D30 and A30+D30 groups significantly reduced to -7.4± 1.2 g and -9.0 ± 0.7 g compared to A10 and A30 groups, but there was no difference from that of the D30 group (FIG. IB). The changes in body weight from baseline for each group were similar to the changes in weight gain (FIG. 1C). The changes in whole-body fat mass were similar to the whole-body weight changes. The wholebody fat masses of the A10 and A30 groups tended to reduce by 15.4% and 24.2%, respectively, in a dose-dependent manner compared to Con(-) group. The whole-body fat mass of the D30 group significantly reduced to 41.2%, compared to Con(-) group. The whole-body fat masses of the A10+D30 and A30+D30 groups tended to decrease to 40.8% and 50.7% compared to A10, A30, and D30 groups (FIG. ID). However, they did not reach a significant fat mass reduction. The weight changes in epididymal and inguinal fat were similar to the changes in body weight and fat mass, respectively (FIGs. 1E-1F).

[0014] FIGs. 2A-2D are graphs depicting the effect of co-administration of a GCHR modulator, e.g., a GCHR small molecule agonist, e.g., danuglipron (“D”), and a MC4R agonist, e.g., LB54640 (“A”), on food intake during 28 days of administration in a mouse model of diet induced obesity (DIO). FIG. 2A depicts food intake in kcal / day; FIG.2B depicts average food intake in kcal / day; FIG. 2C depicts cumulative food intake in kcal; and FIG. 2D depicts cumulative food intake in kcal. The food intakes of all treatment groups dramatically decreased immediately after administration compared to the Con(-) group and then gradually recovered. The mean values of daily food intake of the A10 and A30 were similar to that of the Con(-) group, but the D30 group showed a significant reduction in daily food intake compared to the Con(-) group. The mean values of daily food intake of the A10+D30 and A30+D30 groups significantly decreased compared to the Con(-) group but were not significantly different from those of the A 10, A30, and D30 groups. The cumulative food intakes of all groups were similar to their mean values of daily food intake.

[0015] FIGs. 3A-3D are graphs depicting the effect of co-administration of a GCHR modulator, e.g., a GCHR small molecule agonist, e.g., danuglipron (“D”), and a MC4R agonist, e.g., LB54640 (“A”), on changes in HbAlc (FIG. 3A), non-fasting glucose (FIG. 3B), fasting glucose (FIG. 3C) and fasting insulin (FIG.3D) after 28 days of administration in a mouse model of diet induced obesity (DIO). HbAlc levels of all treatment groups were similar to that of the Con(-) group (FIG.3A). The initial levels of non-fasting blood glucose were 192.0 ± 3.8 mg / dL for the normal group and 238.7 ± 2.8 mg / dL for the DIO groups. Following administration of Compound A and / or D, the non-fasting blood glucose levels of the normal and Con(-) groups were 202.4 ± 5.4 mg / dL and 235.6 ± 13.1 mg / dL, respectively. The non-fasting blood glucose levels of the A10 and A30 groups tended to reduce to 212.5 ± 10.6 mg / dL and 214.6 ± 10.6 mg / dL but were not significant compared to Con(-) group. The non-fasting blood glucose level of the D30 group significantly decreased to 170.3 ± 4.2 mg / dL compared to Con(-) group. The non-fasting blood glucose levels of the A10+D30 and A30+D30 groups significantly decreased to 160.1 ± 6.2 mg / dL and 169.6 ± 4.7 mg / dL, respectively, compared to A10, A30, and Con(-) groups, but there was no difference from that of the D30 group (FIG.3B). Following administration of Compound A and / or D, the fasting glucose levels of the normal and Con(-) groups were 126.7 ± 4.1 mg / dL and 165.1 ± 8.0 mg / dL, respectively. The fasting blood glucose levels of the A10 and A30 groups were 166.1 ± 9.0 mg / dL and 155.3 ± 9.8 mg / dL, respectively, similar to that of the Con(-) group. The fasting blood glucose level of the D30 group significantly decreased to 117.2 ± 7.3 mg / dL compared to Con(-) group. The fasting blood glucose levels of the A10+D30 and A30+D30 groups significantly decreased to 122.7 ± 7.9 mg / dL and 119.8 ± 5.3 mg / dL, respectively, compared to the A 10, A30, and Con(-) groups, but there was no difference from that of the D30 group (FIG. 3C). Additionally, following administration, the fasting insulin levels of all treatment groups were identical (FIG.3D).

[0016] FIGs. 4A-4D are graphs depicting the effect of co-administration of a GCHR modulator, e.g., a GCHR small molecule agonist, e.g., danuglipron (“D”), and a MC4R agonist, e.g., LB54640 (“A”), on performance on an oral glucose tolerance test (OGTT) after 5 weeks of administration in a mouse model of diet induced obesity (DIO). In week 5, the OGTT was conducted after overnight fasting. The fasting blood glucose levels were measured, followed by drug administration. The blood glucose levels measured 1 hour after drug administration were similar to the fasting blood glucose levels among groups. After glucose loading, the Al 0 and A30 groups showed a similar glucose profile to the Con(-) group. The D30 group showed a statistically significant improvement in glucose tolerance compared to Con(-) group. The A10+D30 and A30+D30 groups also showed a statistically significant improvement in glucose tolerance compared to A 10, A30, and Con(-) groups, but they did not differ from the D30 group. The areas under the curve (AUC) of glucose for all groups were similar to their glucose profiles (FIGs. 4A-4B). The AUC value of the A30+D30 group significantly reduced compared to Con(-) group but was not different from those of the A10, A30, and D30 groups. The insulin levels of all treatment groups were similar to those of the Con(-) group (FIGs. 4C-4D).

[0017] FIGs. 5A-5G are graphs depicting the effect of co-administration of a GCHR modulator, e.g., a GCHR small molecule agonist, e.g., danuglipron (“D”), and a MC4R agonist, e.g., LB54640 (“A”), on changes in liver weight, liver triglyceride and liver biochemical parameters after 28 days of administration in a mouse model of diet induced obesity (DIO). After the last drug administration at week 6, the weights of liver collected after 16-hour fasting for all treatment groups were similar to that of the Con(-) group (FIG.

[0018] 5A). The contents of liver triglyceride in all treatment groups were similar to that of the Con(-) group (FIG. 5B). The levels of AST (FIG. 5C), ALT (FIG. 5D), ALP (FIG. 5E), and LDH (FIG. 5G) of all treatment groups were similar to those of the Con(-) group. The total bilirubin levels of the D30, A10+D30, and A30+D30 groups tended to increase compared to Con(-) group (FIG. 5F).

[0019] FIGs. 6A-6E are graphs depicting the effect of co-administration of a GCHR modulator, e.g., a GCHR small molecule agonist, e.g., danuglipron (“D”), and a MC4R agonist, e.g., LB54640 (“A”), on plasma lipid profdes after 6 weeks of administration in a mouse model of diet induced obesity (DIO). Following the administration of the final dose of Compound A and / or D, mice were fasted for 16 hours and blood was subsequently collected. The plasma triglyceride levels of the A10 and A30 groups were similar to that of the Con(-) group (FIG. 6A). The plasma triglyceride levels of the D30 group significantly reduced compared to Con(-) group. The plasma triglyceride levels of the A1O+D30 and A3O+D3O groups significantly decreased compared to the A10, A30, and Con(-) groups but were not different from that of the D30 group. The free fatty acid levels of all groups were similar (FIG. 6B). Cholesterol levels (total cholesterol (FIG. 6C), HDL-cholesterol (FIG. 6D), LDL-cholesterol (FIG. 6E)) of all treatment groups were similar. FIG. 7 depicts changes in body weight of control and HFD fed C57BL / 6J mice treated with test articles for experimental period. Data are expressed as mean ± SE.

[0020] FIG. 8 depicts changes in body weight gain (%, vs G2 HFD Vehicle control) of control and HFD fed C57BL / 6J mice treated with test articles for experimental period. Data are expressed as mean ± SE.

[0021] FIG. 9 depicts body weight of control and HFD fed C57BL / 6J mice treated with test articles on Day 28. Data are expressed as mean ± SE. Significant difference was conducted by One-way ANOVA followed by the Dunnett’s test: * p<0.05, ** p<0.01, *** p<0.001 from G2 HFD Vehicle control group, d p<0.05, dd p<0.01, ddd p<0.001 from G6 HFD Test article 3 72 nmol / kg group.

[0022] FIG. 10 depicts changes in daily food consumption of control and HFD fed C57BL / 6J mice treated with test articles for experimental period. Data are expressed as mean ± SE.

[0023] FIG. 11 depicts changes in food consumption for 1 week of control and HFD fed C57BL / 6J mice treated with test articles for experimental period. Data are expressed as mean ± SE.

[0024] FIGs. 12A-12D depicts changes in food consumption for 1 week of control and HFD fed C57BL / 6J mice treated with test articles for experimental period. Data are expressed as mean ± SE. Measurement of the cumulative food consumption for 1 week showed that food consumption decreased significantly in all test article administration groups 1 week after administration compared with that in the G2 group (FIG. 12A). In the G4 group, the cumulative food consumption for 1 week decreased significantly until 2 weeks after administration compared to the G2 group, and in the G7 and G8 groups, the cumulative food consumption for 1 week decreased significantly until 3 weeks after administration, compared with that in the G2 group (FIGs. 12A, 12B, 12C). The G7 group showed a significant decrease in the cumulative food consumption compared to the G3 group on Week 1 after administration, and the G8 group showed a significant decrease in the cumulative food consumption compared to the G4 group on Week 2 after administration. The G7 group and G8 group showed a significant decrease in the cumulative food consumption compared with the G6 group on Week 1-2 after administration (FIG. 12D). Significant difference was conducted by One-way ANOVA followed by the Dunnett’s test: * p<0.05, ** p<0.01, *** p<0.001 from G2 HFD Vehicle control group, a p<0.05, aa p<0.01, aaa p<0.001 from G3 HFD Test article 1 10 mg / kg group, b p<0.05, bb p<0.01, bbb p<0.001 from G4 HFD Test article 1 30 mg / kg group, d p<0.05, dd p<0.01, ddd p<0.001 from G6 HFD Test article 3 72 nmol / kg group.

[0025] FIG. 13 depicts changes in non-fasting blood glucose level of control and HFD fed C57BL / 6J mice treated with test articles for experimental period. No group showed a significant difference in non-fasting blood glucose levels compared to the G2 group. Data are expressed as mean ± SE.

[0026] FIG. 14 depicts changes in blood glycosylated hemoglobin (HbAlc) level of control and HFD fed C57BL / 6J mice treated with test articles for experimental period. No group showed a significant difference in HbAlc levels compared to the G2 group. Data are expressed as mean ± SE. Significant difference was conducted by One-way ANOVA followed by the Dunnett’s test: * p<0.05, ** p<0.01, *** p<0.001 from G2 HFD Vehicle control group.

[0027] FIG. 15 illustrates the effects on non-fasting blood insulin level in control and HFD fed C57BL / 6J mice treated with test articles for experimental period. The G4 group(23.66 ± 3.53 ng / mL), G5 group(29.03 ± 4.28 ng / mL), G6 group(26.19 ± 3.68 ng / mL), G7 group(22.37 ± 1.34 ng / mL), G8 group(16.86 ± 1.35 ng / mL), and G9 group(23.10 ± 3.00 ng / mL)showed a significant reduction in non-fasting blood insulin level compared to the G2 group(52.15 ± 11.03 ng / mL(. Data are expressed as mean ± SE. Significant difference was conducted by One-way ANOVA followed by the Dunnett’s test: * p<0.05, ** p<0.01, *** p<0.001 from G2 HFD Vehicle control group.

[0028] FIG. 16 illustrates the effects on fasting blood insulin level in control and HFD fed C57BL / 6J mice treated with test articles for experimental period. The G5 group(5.70 ± 0.62 ng / mL), G7 group(4.95 ± 1.36 ng / mL), and G8 group(4.87 ± 0.87 ng / mL)showed a significant reduction in the fasting blood insulin level compared to the G2 group(9.08 ± 0.66 ng / mL). Data are expressed as mean ± SE. Significant difference was conducted by One-way ANOVA followed by the Dunnett’s test: * p<0.05, ** p<0.01, *** p<0.001 from G2 HFD Vehicle control group.

[0029] FIG. 17 illustrates the effects on fat mass and lean mass in control and HFD fed C57BL / 6J mice treated with test articles for experimental period. Body fat mass was measured on Day 29 after administration of the test articles. The G4 group (19.16 ± 0.94 g), G5 group (19.34 ± 0.84 g), G7 group (17.57 ± 0.56 g), G8 group(16.24 ± 0.69 g), and G9 group (17.38 ± 0.68 g)showed a significant decrease in the fat mass compared to the G2 group (22.92± 0.68 g), and the G8 group (16.24 ±0.69 g) showed a significant decrease in the fat mass compared to the G6 group (20.13 ±1.35 g). Compared to the G2 group(28.47 ± 0.64 g), the G5 group(25.35 ± 0.71 g), G7 group (25.61 ± 0.68 g), G8 group (25.04 ± 0.66 g), and G9 group(25.70 ± 0.72 g)showed a significant decrease in the lean mass. Data are expressed as mean ± SE. Significant difference was conducted by One-way ANOVA followed by the Dunnett’s test: * p<0.05, ** p<0.01, *** p<0.001 from G2 HFD Vehicle control group, d p<0.05, dd p<0.01, ddd p<0.001 from G6 HFD Test article 3 72 nmol / kg group.

[0030] FIG. 18 illustrates the effects on blood glucose level during oral glucose tolerance test (OGTT) in control and HFD fed C57BL / 6J mice treated with test articles for experimental period. The mice were fasted overnight and then orally administered 2 g / kg glucose. The blood glucose was then measured. The blood glucose levels of all groups showed a rapid increase 15 minutes after glucose administration compared to the levels before administration and began to decrease 30 minutes later. Compared to the G3, G4, and G5 groups, the combined treatment groups G7, G8, and G9, respectively, showed a significant decrease in blood glucose levels measured before and up to 120 minutes after glucose administration. Data are expressed as mean ± SE.

[0031] FIG. 19 depicts the area under the blood glucose concentration-time curve for 120 min (AUC0-120 min) of control and HFD fed C57BL / 6J mice treated with test articles during OGTT. The area under the curve (AUC) of the glucose response curve showed a similar trend to that of the blood glucose level measurements in FIG. 12. Specifically, the AUC values of the G6 group(16891.50 ± 635.92 mg / dL min), G7 group(15689.25 ± 417.50 mg / dL min), G8 group( 15620.25 ± 1478.23 mg / dL min), and G9 group(14482.50 ± 316.09 mg / dL min)were significantly lower than that of the G2 group(28895.25 ± 950.61 mg / dL min). Data are expressed as mean ± SE. Significant difference was conducted by Oneway ANOVA followed by the Dunnett’s test: * p<0.05, ** p<0.01, *** p<0.001 from G2 HFD Vehicle control group, a p<0.05, aa p<0.01, aaa p<0.001 from G3 HFD Test article 1 10 mg / kg group, b p<0.05, bb p<0.01, bbb p<0.001 from G4 HFD Test article 1 30 mg / kg group, c p<0.05, cc p<0.01, ccc p<0.001 from G5 HFD Test article 23 mg / kg group. FIG. 20 illustrates the effects on hepatic TG level in control and HFD fed C57BL / 6J mice treated with test articles for experimental period. The hepatic TG level showed a significant reduction in all administration groups. Data are expressed as mean ± SE.

[0032] Significant difference was conducted by One-way ANOVA followed by the Dunnett’s test: * p<0.05, ** p<0.01, *** p<0.001 from G2 HFD Vehicle control group, a p<0.05, aa p<0.01, aaa p<0.001 from G3 HFD Test article 1 10 mg / kg group, b p<0.05, bb p<0.01, bbb p<0.001 from G4 HFD Test article 1 30 mg / kg group.

[0033] Definitions

[0034] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although any methods and materials similar or equivalent to those described herein can be used in the practice for testing of the present invention, the preferred materials and methods are described herein. In describing and claiming the present invention, the following terminology will be used.

[0035] The articles “a” and “an” are used herein to refer to one or to more than one (e.g., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0036] “About” as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20% or ±10%, more preferably ±5%, even more preferably ±1%, and still more preferably ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.

[0037] “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.

[0038] 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.

[0039] As used herein, the term “functional,” as applied to an allele, e.g., of a MC4R pathway agonizable gene, refers to an allele having, e.g., at least 5, 10, 20, 30, 40, 50, 70, or 80% of the activity of a reference allele, e.g., a wildtype allele.

[0040] As used herein, the term “nonfunctional,” as applied to an allele, e g., a MC4R pathway agonizable gene, refers to an allele which has less than 5, 10, 20, 30, 40, 50, 70, or 80% of the activity of a reference allele, e.g., a wildtype allele. In an embodiment, a nonfunctional allele is an allele of the gene that is other than a functional allele, as the term functional allele is defined herein. By way of example, in an embodiment, if a functional allele has at least 20% of the activity of a reference allele a nonfunctional allele is an allele with less than 20% of the activity.

[0041] As used herein, the term “MC4R pathway agonizable gene” refers to a gene associated with a phenotype which can be modulated, e.g., ameliorated or lessened, by modulating MC4R, e.g., agonizing MC4R, e.g., with an MC4R agonist, e.g., with a combination of an MC4R agonist and GCHR modulator. In an embodiment, the phenotype is hyperphagia, appetite, unwanted appetite, obesity, weight, body mass, or a metabolic syndrome (e.g., diabetes) and the phenotype is, e.g., modulated, e.g., reduced or ameliorated.

[0042] In an embodiment, the term “MC4R pathway agonizable gene” does not include the melanocortin-4 receptor (MC4R) gene. In an embodiment, the term “MC4R pathway agonizable gene” does not include POMC. In an embodiment, the MC4R pathway agonizable gene does not comprise any one of POMC, Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1, also called PC1 / 3), MAGE-like-2 (MAGEL2), leptin receptor (leptin-R), leptin, 5-hydroxytryptamine (serotonin) receptor 2C, G protein-coupled (5-HT2c receptor), nescient helix loop helix 2 (NhHL2, also called NSCL2), pro-hormone convertase, carboxypeptidase E (CPE), and single-minded 1 (Siml). In an embodiment, the MC4R pathway agonizable gene does not comprise any gene disclosed in W02013 / 102047 or WO 2017 / 059076, the full contents of each of which is incorporated herein by reference in its entirety.

[0043] In an embodiment, at least one of the MC4R alleles is functional, e.g., it has at least 5, 10, 20, 30, 40, 50, 70, or 80% of the activity of a reference allele, e.g., a wildtype allele, e.g., as measured by a functional assay. In an embodiment, one of the MC4R alleles is functional. In an embodiment, both MC4R alleles are functional. In an embodiment, the subject is heterozygous at the MC4R gene and both alleles are functional. In an embodiment, the subject is homozygous at the MC4R gene for a functional allele.

[0044] In an embodiment, both MC4R alleles are nonfunctional. (A nonfunctional allele is an allele which is not functional, as functional is defined herein.) In an embodiment, the subject is heterozygous at the MC4R gene and both alleles are nonfunctional. In an embodiment the subject is homozygous at the MC4R gene for a nonfunctional allele.

[0045] In an embodiment, at least one allele of an MC4R pathway agonizable gene other than MC4R is functional, e.g., it has at least 5, 10, 20, 30, 40, 50, 70, or 80% of the activity of a reference allele, e.g., a wildtype allele, e.g., as measured by a functional assay. In an embodiment one allele of an MC4R pathway agonizable gene other than MC4R is functional. In an embodiment both alleles of an MC4R pathway agonizable gene other than MC4R are functional. In an embodiment the subject is heterozygous at an MC4R pathway agonizable gene other than MC4R and both alleles are functional. In an embodiment the subject is homozygous at an MC4R pathway agonizable gene other than MC4R for a functional allele. In an embodiment, both MC4R alleles are nonfunctional. (A nonfunctional allele is an allele which is not functional, as functional is defined herein.) In an embodiment the subject is heterozygous at the MC4R gene and both alleles are nonfunctional. In an embodiment the subject is homozygous at the MC4R gene for a nonfunctional allele.

[0046] As used herein, the term “metabolic syndrome” refers to a group of symptoms that occur together and increase the risk for coronary artery disease, stroke, and type 2 diabetes. According to the American Heart Association and the National Heart, Lung, and Blood Institute, metabolic syndrome also referred to as Syndrome X) is present if a subject has three or more of the following signs: 1) Blood pressure equal to or higher than 130 / 85 mmHg;

[0047] 2) Fasting blood sugar (glucose) equal to or higher than 100 mg / dL; 3) Large waist circumference (length around the waist): - Men - 40 inches or more; - Women - 35 inches or more; 4) Low HDL cholesterol: - Men - under 40 mg / dL; - Women - under 50 mg / dL; 5) Triglycerides equal to or higher than 150 mg / dL. Metabolic syndrome can be diagnosed by testing subject’s blood pressure, blood glucose level, HDL cholesterol level, LDL cholesterol level, total cholesterol level, and triglyceride level.

[0048] 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, or e.g., a GCHR, which raises the signaling activity of GCHR 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).

[0049] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of one or more of a symptom, manifestation, or underlying cause of a disease, disorder, or condition (e.g., as described herein), e.g., by administering a therapy, e.g., administering a compound described herein (e.g., an MC4R agonist of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) (e.g., as described herein) or a G-protein coupled hormone receptor (GCHR) agonist, e.g., a GCHR modulator, e.g., a GLP1R agonist as described herein. In an embodiment, treating comprises reducing, reversing, alleviating, delaying the onset of, or inhibiting the progress of a symptom of a disease, disorder, or condition. In an embodiment, treating comprises reducing, reversing, alleviating, delaying the onset of, or inhibiting the progress of a manifestation of a disease, disorder, or condition. In an embodiment, treating comprises reducing, reversing, alleviating, reducing, or delaying the onset of, an underlying cause of a disease, disorder, or condition. In some embodiments, “treatment,” “treat,” and “treating” require that signs or symptoms of the disease, disorder, or condition have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease or condition, e.g., in preventive treatment. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence. Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence. In some embodiments, treatment comprises prevention and in other embodiments it does not. The term “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 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 (e.g., obesity), Prader Willi Syndrome, Smith-Magenis syndrome, type-II diabetes, a pre-diabetic condition, blood level of hemoglobin A1C (HblAc) above 6%, hyperinsulimenia, 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 a 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.

[0050] As used herein “inhibition” or “inhibits” can include a reduction in a certain parameter, such as a parameter described herein. For example, inhibition of a parameter, e.g., activity, can be at least 5%, 10%, 20%, 30%, 40%, or more is included by this term. Thus, inhibition need not be 100%.

[0051] As used herein, the term “subject” refers to a mammal, e.g., a human. Subject can also refer to an animal in need of veterinary treatment, e.g., companion animals (e g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like). In an embodiment, the subject is a pediatric subject (e.g., a subject under 21 or 18 years of age). In an embodiment, the subject is an adult subject (e.g., a subject over 18 or 21 years of age).

[0052] As used herein, the term “mutation” can refer to an altered nucleic acid sequence of a gene or fragment thereof compared to a wild-type sequence. For example, a mutation can include a point mutation, frame-shift mutation, missense mutation, inversion, deletion, insertion, truncation, chromosomal translocation. In embodiments, a mutation can result in the gene or fragment thereof coding for a non-functional protein, a protein with reduced activity (or a partially functional protein), or a protein with altered activity. For example, a “loss of function” mutation refers to a mutation that results in the gene or fragment thereof coding for a non-functional protein, which has substantially reduced activity compared to its wild-type counterpart (e.g., a non-functional protein has less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less activity than its wild-type counterpart). For example, “partial loss of function” mutation refers to a mutation that results in the gene or fragment thereof coding for a partially functional protein, which has reduced activity compared to its wild-type counterpart (e.g., a partially functional protein has less than 50% and greater than 10% of the activity of its wild-type counterpart).

[0053] As used herein “heterozygous” refers to the presence of two different alleles (having different nucleic acid sequences) for a given gene in a subject. In some embodiments, “heterozygous mutation” can refer to the presence of a mutation on one allele for a given gene and the lack of a mutation on the other allele of the same gene in a subject (e.g., one mutant allele and one wild type allele for a given gene). In other embodiments, a “heterozygous mutation” can be a “compound heterozygous” mutation, which refers to the presence of a mutation (e.g., loss of function mutation or partial loss of function mutation) on one allele for a given gene and a different (e.g., loss of function mutation or partial loss of function mutation) on the other allele for the same gene (e.g., two different alleles that are both mutated, e.g., non-functional or partially functional). In embodiments, where a compound heterozygous mutation includes two non-functional alleles, the genotype can be a null genotype or functionally deficient genotype.

[0054] As used herein “homozygous” refers to the presence of two identical alleles for a given gene. In some embodiments, a “homozygous mutation” refers to the presence of two mutant alleles for a given gene, where the two mutant alleles are identical.

[0055] As used herein, “unit dosage form” refers to a physically discrete unit suited as unitary doses for a subject to be treated. Each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

[0056] 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. As used herein “hunger” or “hunger level” refers to a subject’s appetite, desire to consume food, or perceived need for food. In embodiments, the hunger or hunger level of a subject can be quantified by using a scale to obtain a hunger score. In embodiments, the scale for hunger assigns a higher score for a subject that more frequently (e.g., often or always) feels unbearable hunger and a lower score for a subject that less frequently (e.g., sometimes or never) feels unbearable hunger. See, e.g., Sibilia. Psychological Topics 19 (2010), 2, 341-354. For example, a Likert scale for hunger can be used that assigns scores from 0 to 10 points (0=no hunger; 10=severe hunger). In other examples, a Likert scale for hunger can be used that assigns scores from 1 to 4 points, where a subject who never feels unbearable hunger is assigned a score of 1, where a subject who sometimes feels unbearable hunger is assigned a score of 2, where a subject who often feels unbearable hunger is assigned a score of 3, and where a subject who always feels unbearable hunger is assigned a score of 4.

[0057] “Combination,” as used herein refers to a selection of two or more elements or ingredients, e.g., a composition of a combination of agonists, e.g., an MC4R agonist as described herein and a G-protein coupled hormone receptor (GCHR) agonist, e g., a GLP1R agonist, as described herein for use as a medicament or as a pharmaceutical composition for treating a disease. For example, methods of treating a disease or a method of administering to a subject in need thereof may comprise a combination, e.g., an MC4R agonist as described herein and a GCHR modulator, e g., a GLP1R agonist, as described herein. For example, a “combination therapy” as used herein may refer to a therapy comprising a plurality of active agents, e.g., an MC4R agonist as described herein and a GLP1R agonist as described herein.

[0058] “Co-administration,” as used herein, refers to administration of unit dosages of the agonists and / or compounds disclosed herein, e.g., an MC4R agonist as described herein and a GCHR modulator, e g., a GLP1R agonist, as described herein, before or after administration of unit dosages of one or more additional therapeutic agents, for example, administration of the compound disclosed herein within seconds, minutes, or hours of the administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound of the present disclosure is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound of the present disclosure within seconds or minutes. In some embodiments, a unit dose of a compound of the present disclosure is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more additional therapeutic agents. In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of a compound of the present disclosure. Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents, such that therapeutically effective amounts of each agent are present in the body of the subject.

[0059] As used herein, the term "peptide" is any peptide comprising two or more amino acids. The term peptide includes short peptides (e.g., peptides comprising between 2 - 14 amino acids), medium-length peptides (15-50) or long-chain peptides (e.g., proteins). The terms peptide and protein may be used interchangeably herein. As used herein, "peptide" is interpreted to mean a polymer composed of amino acid residues, related naturally occurring structural variants, and synthetic non-naturally occurring analogs thereof linked

[0060] via peptide bonds, related naturally occurring structural variants, and synthetic non-naturally occurring analogs thereof. Synthetic peptides can be synthesized, for example, using an automated peptide synthesizer. Peptides may contain amino acids other than the 20 gene-encoded amino acids. "Peptide(s)" include those modified either by natural processes, such as processing and other post-translational modifications, but also by chemical modification techniques. Such modifications are well described in basic texts and in more detailed monographs, and are well known to those of skill in the art. It will be appreciated that in some embodiments, the same type of modification is present in the same or varying degree at several sites in a given peptide. Also, a given peptide, in some embodiments, contains more than one type of modifications. Modifications occur anywhere in a peptide, including the peptide backbone, the amino acid side chains, and the amino or carboxyl termini.

[0061] A “therapeutically effective amount” or “effective amount,” as used herein, refers to an amount that is effective to elicit the desired biological or medical response, including the amount of a compound that, when administered to a subject for treating a disease, is sufficient to affect such treatment for the disease. The effective amount will vary depending on the compound, the disease, and its severity and the age, weight, etc., of the subject to be treated. The effective amount can include a range of amounts. As is understood in the art, an effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved. Suitable doses of any coadministered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.

[0062] As used herein, the term "variant" is interpreted to mean a peptide that differs from a reference peptide but retains essential properties. Atypical variant of a peptide differs in amino acid sequence from another, e.g., reference, peptide. Generally, differences are limited so that the sequences of the reference peptide and the variant are closely similar overall and, in many regions, identical. A variant and reference peptide may differ in amino acid sequence by one or more substitutions, additions, deletions in any combination. A substituted or inserted amino acid residue may or may not be one encoded by the genetic code. Non-naturally occurring variants of peptides may be made by mutagenesis techniques, by direct synthesis, and by other suitable recombinant methods.

[0063] Selected Chemical Definitions

[0064] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, Marchs’ Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0065] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts. Also, all publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety.

[0066] The nomenclature used to define the peptides is that typically used in the art wherein the amino group at the N-terminus appears to the left and the carboxyl group at the C-terminus appears to the right. Where the amino acid has D and L isomeric forms, it is the L form of the amino acid that is represented unless otherwise explicitly indicated.

[0067] When a range of values is listed, it is intended to encompass each value and subrange within the range. For example, “C1-C6 alkyl” is intended to encompass, Ci, C2, C3, C4, C5, C6, Ci-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl.

[0068] The compounds useful for practicing the methods described herein may possess one or more chiral centers and so exist in a number of stereoisomeric forms. All stereoisomers and mixtures thereof are included in the scope of the present disclosure. Racemic compounds may either be separated using preparative HPLC and a column with a chiral stationary phase or resolved to yield individual enantiomers utilizing methods known to those skilled in the art. In addition, chiral intermediate compounds may be resolved and used to prepare chiral compounds of the disclosure.

[0069] The compounds useful for practicing the methods described herein may also comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including1H,2H (D or deuterium), and3H (T or tritium); C may be in any isotopic form, including12C,13C, and14C; O may be in any isotopic form, including16O and18O; N may be in any isotopic form, including14N and15N; F may be in any isotopic form, including18F,19F; and the like.

[0070] 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 et al, Journal of Pharmaceutical Science 66: 1-19 (1977)). 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.

[0071] In addition to salt forms, the present disclosure provides compounds in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0072] The compounds useful for practicing the methods described herein can also exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. The compounds useful for practicing the methods described herein may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0073] The term “solvate” refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. “Solvate” encompasses both solution phase and isolable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0074] The term “hydrate” refers to a compound which is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula Rx H2O, wherein R is the compound and wherein x is a number greater than 0. A given compound may form more than one type of hydrates, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R O.5 H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R-2 H2O) and hexahydrates (R-6 H2O)).

[0075] The term “tautomer” as used herein refers to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of n electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.

[0076] Symbol Meaning

[0077] Abu a-aminobutyric acid

[0078] Ac acyl group

[0079] Acc 1 -amino- l-cyclo(C3-C9)alkyl carboxylic acid

[0080] A3c 1 -amino- 1 cyclopropanecarboxylic acid

[0081] A5c 1 -amino- 1 -cyclopentanecarboxylic acid A6c 1 -amino- 1 -cyclohexanecarboxylic acid

[0082] Aha 7-aminoheptanoic acid

[0083] Ahx 6-aminohexanoic acid

[0084] Aib a-aminoisobutyric acid

[0085] Aic 2-aminoindan-2-carboxylic acid

[0086] Ala or A Alanine

[0087] P-Ala P-alanine

[0088] Ape denotes the structure:

[0089]

[0090] Apn 5-aminopentanoic acid (HN — (CH2)4 — C(O) Arg or R Arginine

[0091] hArg Homoarginine

[0092] Asn or N Asparagine

[0093] Asp or D aspartic acid

[0094] Ate 4-amino(methyl)-l,3-thiazole-5-caroobxylic acid Bal 3 -benzothienylalanine

[0095] Bip 4,4’-biphenylalanine, represented by the structure

[0096]

[0097] Bpa 4-benzoylphenylalanine

[0098] 4-Br-Phe 4-bromo-phenylalanine

[0099] Cha P -cyclohexylalanine

[0100] hCha homo-cyclohexylalanine Chg Cyclohexylglycine

[0101] sChp

[0102] Cya a-amino acid cysteic acid

[0103] Cys or C Cysteine

[0104] hCys Homocysteine

[0105] Dab 2,4-diaminobutyric acid

[0106] Dap 2,3-diaminopropionic acid

[0107] Dip, P-diphenylalanine

[0108] Doc 8-amino-3,6-dioxaoctanoic acid with the structure of:

[0109]

[0110] Dpr 2,3-Diaminopropionic acid

[0111] Gaba 4-aminobutyric acid

[0112] Gin or Q Glutamine

[0113] Glu or E glutamic acid

[0114] Gly or G Glycine

[0115] His or H Histidine

[0116] 3-Hyp trans-3-hydroxy-L -proline, i.e., (2S,3S)-3-hydroxy-pyrrolidine-2- carboxylic acid

[0117] 4-Hyp 4-hydroxyproline, i.e., (2S,4R)-4-hydorxypyrrolidine-2-carboxylic acid

[0118] He or 1 Isoleucine

[0119] Leu or L Leucine

[0120] hLeu Homoleucine

[0121] Lys or K Lysine

[0122] Met or M Methionine

[0123] P-hMet -homomethionine

[0124] 1-Nal P-(l-naphthyl)alanine

[0125] 2-Nal P-(2-naphthyl)alanine

[0126] Nip nipecotic acid Nle Norleucine

[0127] Oic Octahydroindole-2-carboxylic Acid

[0128] Om Ornithine

[0129] 2-Pal P -(2-py ri diy 1 )al ani ne

[0130] 3 -Pal P-(3-pyridiyl)al anine

[0131] 4-Pal P -(4-py ri diy 1 )al ani ne

[0132] Pen Penicillamine

[0133] Pflf (S)-pentafluorophenylalanine

[0134] Phe or F Phenylalanine

[0135] hPhe Homophenyl al anine

[0136] Pro or P Proline

[0137] hPro Homoproline

[0138] Sar Sarcosine (N-methylglycine)

[0139] Ser or S Serine

[0140] Tie tert-Leucine

[0141] Taz P-(4-thiazolyl)alanine

[0142] 2-Thi P-(2-thienyl)al anine

[0143] 3-Thi P-(3-thienyl)alanine

[0144] Thr or T Threonine

[0145] Trp or W Tryptopham

[0146] Tyr or Y Tyrosine

[0147] D-(Et) Tyr has a structure of

[0148]

[0149] Vai or V Valine

[0150] Certain other abbreviations used herein are defined as follows: Boc: tert-butyloxycarbonyl

[0151] OtBu oxy-tert-butyl

[0152] tBu: tert-butyl

[0153] Unless otherwise indicated, with the exception of the N-terminal amino acid, all abbreviations (e.g. Ala) of amino acids in this disclosure stand for the structure

[0154] of -NH-C(R)(R')-CO-, wherein R and R' each is, independently, hydrogen or the side chain of an amino acid (e.g., R=CHs and R — H for Ala), or R and R' may be joined to form a ring system.

[0155] For the N-terminal amino acid, the abbreviation stands for the structure of:

[0156]

[0157] The designation “NH2” in e.g., as in Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO: 13), indicates that the C-terminus of the peptide is amidated. Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys) (SEQ ID NO: 107), or alternatively Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH (SEQ ID NO: 107), indicates that the C-terminus is the free acid.

[0158] “-c(Cys-Cys)-” or “-cyclo(Cys-Cys)-” denotes the structure:

[0159]

[0160] “-c(Cys-Pen)-” or “-cyclo(Cys-Pen)-” denotes the structure:

[0161]

[0162] “-c(Asp-Lys)-” or “-cyclo(Asp-Lys)-” denotes the structure:

[0163]

[0164] The following abbreviations are used throughout the disclosure:

[0165] “Hydantoin-(C(O)-(Aa-Ab))” denotes the structure:

[0166]

[0167] , wherein amino acid “Aa” has the structure:

[0168]

[0169] and amino acid “Ab” the structure:

[0170] For example, “Hydantoin-(C(O)-Arg-Ab))” would have the following structure:

[0171]

[0172] For example, a compound represented as “c[Hydantoin(C(O)-(Cys-Ab))-A1-A2-A3- A4-Cys]-” would have the following the structure:

[0173]

[0174] whereas a compound represented as “c[Hydantoin(C(O)-(Ah-Cys))-A1-A2-A3-A4- Cys]-” would have the structure:

[0175]

[0176] For further guidance, “c[Hydantoin(C(O)-(Asp-Ab))-A1-A2-A3-A4-Lys]-” represents the following compound:

[0177]

[0178] whereas “c[Hydantoin(C(O)-(Dap-Ab))-A1-A2-A3-A4-Asp]-” has the following formula:

[0179]

[0180] “Acyl” refers to R"-C(O)-, where R" is H, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, aryl, alkylaryl, or substituted alklyaryl, and is indicated in the general formula of a particular embodiment as “Ac”. Exemplary substituted acyl groups include, without limitation, acetyl, trifluoroacetyl, hydroxyacetyl, methoxyacetyl, ethoxyacetyl, propionyl, ethoxypropionyl, isobutyryl, cyanoisobutyryl, hydroxyisobutyryl, carbamoylisobutyryl, 3,3-dimethylbutanoyl, pivaloyl, fluoropivaloyl, difluoropivaloyl, hydroxypivaloyl, mercaptopivaloyl, dihydroxypivaloyl, methoxypivaloyl, ethoxypivaloyl, aminopivaloyl, dimethylaminopivaloyl, hydroxyiminopivaloyl, acetylisobutyryl, -C(O)C(CH3)2CH(CH3)OH, -C(O)C(CH3)2C(CH3)2OH, acryloyl, methacryloyl, cyclopentanecarbonyl, cyclohexylenecarbonyl, carbamoyl, dimethylcarbamoyl, methanesulfonylcarbonyl, benzoyl, thiophenecarbonyl, furoyl, oxazolecarbonyl, thiazolecarbonyl, imidazolecarbonyl, pyrazolecarbonyl, tetrahydrofuroyl, dihydrofuroyl, tetrahydropyrancarbonyl, morpholinecarbonyl,

[0181] “Alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group containing one or more carbon atoms, where multiple carbon atoms if present are joined by single bonds. The alkyl hydrocarbon group may be straight-chain or contain one or more branches. In some embodiments, an alkyl group has 1 to 40 carbon atoms (“C1-C40 alkyl”). In some embodiments, an alkyl group has 1 to 24 carbon atoms (“C1-C24 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-C12 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“Ci-Cs alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“Ci-Ce alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-C6 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). Examples of Ci-Cealkyl groups include methyl (Ci), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (Cs), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (Cs), and n-hexyl (Ce). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (Cs) and the like. Each instance of an alkyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is unsubstituted C1-C10 alkyl (e.g., -CH3). In certain embodiments, the alkyl group is substituted Ci-Ce alkyl.

[0182] “Hydroxyalkyl” refers to an alkyl group wherein one or more hydrogen atoms of the hydrocarbon group are substituted with one or more hydroxy radicals, such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl and the like. “Substituted alkyl” refers to an alkyl wherein one or more hydrogen atoms of the hydrocarbon group are replaced with one or more substituents selected from the group consisting of halogen, (i.e., fluorine, chlorine, bromine, and iodine), -OH, -CN, -SH, amine (e.g., -NH2, -NHCH3), -NO2, guanidine, urea, amidine, and -(C1-C20) alkyl, wherein said -(C1-C20) alkyl optionally may be substituted with one or more substituents selected, independently for each occurrence, from the group consisting of halogens, — CF3, — OCH3, — OCF3, and -(CH2)O-2O-COOH. In different embodiments 1, 2, 3 or 4 substituents are present. The presence of -(CH2)o-2o-COOH results in the production of an alkyl acid. Nonlimiting examples of alkyl acids containing, or consisting of, -(CH2)o-2o-COOH include 2-norbomane acetic acid, tert-butyric acid, 3-cyclopentyl propionic acid, and the like.

[0183] As used herein, the term “halogen” or “halo” encompasses fluoro, chloro, bromo and iodo.

[0184] As used herein, the term “hydroxy” refers to -OH.

[0185] Guanidines are a group of organic compounds that share a common functional group with the general structure (R1R2N)(R3R4N)C=N-R5. The central bond within this group is an imine, and the group is related structurally to amidines and ureas.

[0186] “Heteroalkyl” refers to a non-cyclic stable straight or branched chain alkyl, or combination thereof, wherein one of more of the carbon atoms in the hydrocarbon group is replaced with one or more of the following groups: amino, amido, — O —, — S — or carbonyl. The heteroatom(s) O, N, P, S, and Si may be placed at any position of the heteroalkyl group, and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. In different embodiments 1 or 2 heteroatoms are present. Exemplary heteroalkyl groups include, but are not limited to: -CH2-CH2-0-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, and -O-CH2-CH3. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Where "heteroalkyl" is recited, followed by recitations of specific heteroalkyl groups, such as -CH2O, -NRCRD, or the like, it will be understood that the terms heteroalkyl and -CH2O or -NRCRDare not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term "heteroalkyl" should not be interpreted herein as excluding specific heteroalkyl groups, such as -CH2O, -NRCRD, or the like.

[0187] “Substituted heteroalkyl” refers to a heteroalkyl wherein one or more hydrogen atoms of the hydrocarbon group are replaced with one or more substituents selected from the group consisting of halogen, (i.e., fluorine, chlorine, bromine, and iodine), -OH, — CN, — SH, — NH2, — NHCH3, — NO2, and -(C1-C20) alkyl, wherein said -(C1-C20) alkyl optionally may be substituted with one or more substituents selected, independently for each occurrence, from the group consisting of halogens, — CF3, -OCH3, -OCF3, and -(CH2)o-20-COOH. In different embodiments 1, 2, 3 or 4 substituents are present.

[0188] “Alkenyl” refers to a hydrocarbon group made up of two or more carbons where one or more carbon-carbon double bonds are present (“C2-C24 alkenyl”). The alkenyl hydrocarbon group may be straight-chain or contain one or more branches or cyclic groups. In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-C10 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-C8 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-C6 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carboncarbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-C4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-Q alkenyl groups include the aforementioned C2 4 alkenyl groups as well as pentenyl (C5), pentadienyl (Cs), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), and the like.

[0189] “Substituted alkenyl” refers to an alkenyl wherein one or more hydrogens are replaced with one or more substituents selected from the group consisting of halogen (i.e., fluorine, chlorine, bromine, and iodine), — OH, — CN, — SH, — NH2, — NHCH3, — NO2, and -(C1-C20) alkyl, wherein said — C 1-20 alkyl optionally may be substituted with one or more substituents selected, independently for each occurrence, from the group consisting of halogens, — CF3, — OCH3, — OCF3, and — (CH2)o-2o — COOH. In different embodiments 1, 2, 3 or 4 substituents are present.

[0190] As used herein, the term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 24 carbon atoms, one or more carbon-carbon triple bonds (“C2-C24 alkynyl”). In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-C10 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-C8 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-C6 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-C4 alkynyl groups include ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Each instance of an alkynyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkynyl group is unsubstituted C2-10 alkynyl. In certain embodiments, the alkynyl group is substituted C2-6 alkynyl.

[0191] “Aryl” refers to an optionally substituted aromatic group with at least one ring having a conjugated pi-electron system (e.g., having 6, 10, or 1471 electrons shared in a cyclic array), containing up to three conjugated or fused ring systems, having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-C14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“Cioaryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“Cuaryl”; e.g., anthracyl). An aryl group may be described as, e.g., a Ce-Cio-membered aryl, wherein the term “membered” refers to the non-hydrogen ring atoms within the moiety. Aryl includes carbocyclic aryl, heterocyclic aryl and biaryl groups. Preferably, the aryl is a 5- or 6-membered ring. Preferred atoms for a heterocyclic aryl are one or more sulfur, oxygen, and / or nitrogen. Non-limiting examples of aryl include phenyl, 1 -naphthyl, 2-naphthyl, indole, quinoline, 2-imidazole, 9-anthracene, indenyl, tetrahydronaphthyl and the like. Aryl substituents are selected from the group consisting of -(C1-C20) alkyl, -(C1-C20) alkoxy, halogen (i.e., fluorine, chlorine, bromine, and iodine), — OH, — CN, — SH, — NH2, -NO2, -(C1-C20) alkyl substituted with halogens, — CF3, — OCF3, and — (CH2)o-2o — COOH. In different embodiments the aryl contains 0, 1, 2, 3, or 4 substituents.

[0192] As used herein, “heteroaryl” refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 n electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not bear a heteroatom (e.g., 5-indolyl). A heteroaryl group may be described as, e g., a 6-10-membered heteroaryl, wherein the term “membered” refers to the non-hydrogen ring atoms within the moiety. Each instance of a heteroaryl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0193] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Other exemplary heteroaryl groups include heme and heme derivatives.

[0194] “Alkylaryl” refers to an “alkyl” joined to an “aryl”.

[0195] The term “(Ci-i2)hydrocarbon moiety” encompasses alkyl, alkenyl and alkynyl and in the case of alkenyl and alkynyl there is C2-C12.

[0196] As used herein, “cycloalkyl” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C3-C10 cycloalkyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“Cs-Cs cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-C6 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-C6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-C10 cycloalkyl”). A cycloalkyl group may be described as, e.g., a C4-Cv-membered cycloalkyl, wherein the term “membered” refers to the non-hydrogen ring atoms within the moiety. Exemplary C3-C6 cycloalkyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (Cs), cyclopentenyl (Cs), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like. Exemplary C3-C8 cycloalkyl groups include, without limitation, the aforementioned C3-C6 cycloalkyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), cubanyl (Cs), bicyclo[l.l.l]pentanyl (Cs), bicyclo[2.2.2]octanyl (Cs), bicyclo[2.1.1]hexanyl (Ce), bicyclo[3.1.1]heptanyl (C7), and the like. Exemplary C3-C10 cycloalkyl groups include, without limitation, the aforementioned C3-C cycloalkyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-l / Z-indenyl (C9), decahydronaphthal enyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the cycloalkyl group is either monocyclic (“monocyclic cycloalkyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic cycloalkyl”) and can be saturated or can be partially unsaturated.

[0197] “Cycloalkyl” also includes ring systems wherein the cycloalkyl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is on the cycloalkyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the cycloalkyl ring system. Each instance of a cycloalkyl group may be independently optionally substituted, z.e., unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is unsubstituted C3-C10 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-C10 cycloalkyl.

[0198] “Heterocyclyl” as used herein refers to a radical of a 3- to 16-membered nonaromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-16 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more cycloalkyl groups wherein the point of attachment is either on the cycloalkyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. A heterocyclyl group may be described as, e.g., a 3-7-membered heterocyclyl, wherein the term “membered” refers to the non-hydrogen ring atoms, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, within the moiety. Each instance of heterocyclyl may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3-16 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3-16 membered heterocyclyl.

[0199] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl (e.g., 2,2,6,6-tetramethylpiperidinyl), tetrahydropyranyl, dihydropyridinyl, tetrahydrothiopyranyl, pyridinonyl (e.g., 1-methylpyridin2-onyl), and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, pyridazinonyl (2-methylpyridazin-3-onyl), pyrimidinonyl (e.g., l-methylpyrimidin-2-onyl, 3-methylpyrimidin-4-onyl), dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a Ce aryl ring (also referred to herein as a 5,6-bicyclic heterocyclyl ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 5-membered heterocyclyl groups fused to a heterocyclyl ring (also referred to herein as a 5,5-bicyclic heterocyclyl ring) include, without limitation, octahydropyrrol opyrrolyl (e.g., octahydropyrrolo[3,4-c]pyrrolyl), and the like. Exemplary 6-membered heterocyclyl groups fused to a heterocyclyl ring (also referred to as a 4,6-membered heterocyclyl ring) include, without limitation, diazaspirononanyl (e.g., 2,7-diazaspiro[3.5]nonanyl). Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclyl ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0200] Exemplary 6-membered heterocyclyl groups fused to a cycloalkyl ring (also referred to herein as a 6,7-bicyclic heterocyclyl ring) include, without limitation, azabicyclooctanyl (e.g., (l,5)-8-azabicyclo[3.2.1]octanyl). Exemplary 6-membered heterocyclyl groups fused to a cycloalkyl ring (also referred to herein as a 6,8-bicyclic heterocyclyl ring) include, without limitation, azabicyclononanyl (e.g., 9-azabicyclo[3.3.1]nonanyl).

[0201] As used herein, the terms “cyano” or “-CN” refer to a substituent having a carbon atom joined to a nitrogen atom by a triple bond, e. g, ON.

[0202] As used herein, the term “nitro” refers to a substituent having two oxygen atoms bound to a nitrogen atom, e.g., -NO2.

[0203] As used herein, “oxo” refers to a carbonyl, i.e., -C(O)-.

[0204] The symbol as used herein in relation to a compound of Formula (I) or (II) refers to an attachment point to another moiety or functional group within the compound.

[0205] Alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are optionally substituted. For the avoidance of doubt, unless otherwise indicated, the term “substituted”, whether preceded by the term “optionally” or not, means substituted by one or more defined groups, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. In the case where groups may be selected from a number of alternative groups, the selected groups may be the same or different. For the avoidance of doubt, the term “independently” means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.

[0206] Designation “(amino acid)n” means that an amino acid is repeated 11 times. For example, designation “(Pro)2” or “(Arg)a” mean that proline or arginine residues are repeated, respectively, two or three times.

[0207] Melanocortin-4 Receptor (MC4R)

[0208] Hmc4R is a protein encoded by a genomic sequence having GenBank

[0209] accession number CH471077.2. Mutations in the MC4R receptor are an associated cause of severe childhood obesity. The carrier prevalence for MC4R mutations in a juvenile-onset obese population has been noted to be around 2.5% with a highest prevalence of 6% among severely obese children. Humans with MC4R mutations show a more or less similar phenotype as has been described for mice with mutations in the MC4R gene. MC4R deficient patients show hyperphagia, hyperinsulinaemia, increased fat mass, accompanied by lean body mass, bone mineral density and linear growth rate increases, with no changes in cortisol levels, gonadotropin, thyroid and sex steroid levels. In contrast to MC4R deletion, hyperphagia and hyperinsulinaemia tends to subside with age in human subjects. Similar to the MC4R knockout mice, the phenotype in heterozygote carriers is intermediate in comparison to homozygote carriers. The exhibited hyperphagia observed upon a test meal is less severe than that observed in people with a leptin deficiency. The severity of MC4R dysfunction seen in assays in vitro can predict the amount of food ingested at a test meal by the subject harboring that particular mutation and correlates with the onset and severity of the obese phenotype. At least 90 different MC4R mutations have been associated with obesity and additional mutations in the MC4R are likely to be discovered, leading to a similar obesity phenotype.

[0210] Examples of the MC4R mutations that cause obesity in humans are described, e.g., in Farooqi et al, The Journal of Clinical Investigation, July 2000, vol. 106 (2), pp. 271-279 and Vaisse et al., The Journal of Clinical Investigation, July 2000, vol. 106(2), pp. 253-262, the relevant portions of which are incorporated herein by reference).

[0211] Additional mutations that potentially cause obesity in humans include, R18H, R18L, S36Y, P48S, V50M, F51L, E61K, I69T, D90N, S94R, G98R, I121T, A154D, Y157S, W174C, G181D, F202L, A219 V, I226T, G231S, G238D, N240S, C271R, S295P, P299L, E308K, 1317V, L325F, and 750DelGA, as described in Xiang etal., “Pharmacological characterization of 30 human melanocortin-4 receptor polymorphisms with the endogenous proopiomelanocortin-derived agonists, synthetic agonists, and the endogenous agouti-related protein antagonist.” Biochemistry, 2010 Jun 8; 49(22):4583-600, the relevant portions of which are incorporated herein by reference.

[0212] Further examples of mutations that potentially cause obesity in humans are those listed in Online Mendelian Inheritance in Man (OMIM), a database of human genes and genetic disorders, under the accession number 155541 (MC4R) (more precisely, accession nos. 155541.0001-155541.0023) at the URL http: / / omim.org / entry / 155541. Representative examples include 4-BP DEL, NT631; 4-BP INS, NT732; TYR35TER; ASP37VAL;

[0213] SER58CYS; ILE102SER; ASN274SER; 1-BP INS, 112A; 4-BP DEL, 211CTCT;

[0214] ILE125LYS; ALA175THR; ILE316SER; TYR287TER; ASN97ASP; 15-BP DEL (delta88-92 codons); and SER127LEU. The relevant portions of the OMIM database are incorporated herein by reference. Additional exemplary mutations in MC4R are described in Lee. Annals Acad. Med. 38.1(2009):34-44.

[0215] In example embodiments, the MC4R mutation results in retention of the MC4R signaling activity. Mutations in the genomic sequence encoding MC4R can be detected by the methods that are known to a person of ordinary skill in the art. For example, the genomic sequence can be cloned using nucleotide primers, such as e.g., the primers described in Farooqi etal., The Journal of Clinical Investigation, July 2000, vol. 106 (2), pp. 271-279 and Vaisse et al., The Journal of Clinical Investigation, July 2000, vol. 106(2), pp. 253-262, and the cloned sequence analyzed using commercially available sequencers and software.

[0216] Activity of MC4R can be measured by the methods known to a person of ordinary skill in the art. For example, cells can be transiently transfected with the cloned MC4R DNA, the transfected cells contacted by an agonist of MC4R (e.g. a-MSH), and the intracellular level of cAMP, the secondary messenger of MC4R, measured by an electrochemiluminescence assay described, e.g., in Roubert etal., Journal of Endocrinology (2010) 207, pp. 177-183. A reduction in MC4R signaling can be ascertained by comparing the intracellular level of cAMP produced in response to a given agonist by a wild type MC4R to that produced by a mutant MC4R.

[0217] The MC4R agonist may bind to the MC4R directly or indirectly. In an embodiment, the MC4R agonist binds to the MC4R in or near the ligand-binding pocket. In an embodiment, the MC4R agonist binds to the MC4R in or near the G-protein binding cavity. In an embodiment, the MC4R agonist binds to the MC4R binds in or near a transmembrane domain or extracellular loop, for example, TM2, TM3, TM5, TM7, EL2, and / or EL3. Additional interactions of the MC4R agonist and the MC4R may be exemplified in Nat Cell Research (2021) 31:1176-1189, which is incorporated herein by reference in its entirety.

[0218] Melanocortin-4 Receptor (MC4R) Pathway Genes

[0219] The melanocortin system, which includes melanocortins (MCs), agouti, agouti-related proteins, and their receptors, integrate hormonal, metabolic, and neural signals in order to control energy homeostasis and regulate appetite, energy expenditure, and body weight. The MCs, which include alpha-melanocyte-stimulating hormone (a-MSH), P-MSH, y-MSH, and ACTH, are a family of peptide hormones that are derived from a precursor protein called pro-opiomelanocortin (POMC). Activation of MC4 receptor (MC4R) in the P0MC-MC4R pathway increases energy expenditure and decreases food intake. See, e.g., Fan et al. Nature 1997;385:165-68. The P0MC-MC4R pathway includes a number of proteins, such as melanocortins (MCs), MC4 receptor (MC4R), POMC, Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1, also called PC 1 / 3), MAGE-like-2 (MAGEL2), leptin receptor (leptin-R), leptin, 5-hydroxytryptamine (serotonin) receptor 2C, G protein-coupled (5-HT2c receptor), nescient helix loop helix 2 (NhHL2, also called NSCL2), pro-hormone convertase, carboxypeptidase E (CPE), and single-minded 1 (Siml), that together contribute to the regulation of energy homeostasis, e g., by regulating appetite and energy expenditure. MC4R and other components of the P0MC-MC4R pathway have a significant role in weight regulation. A mutation of the MC4R gene was reported to result in early-onset and severe obesity. It is believed that other genetic defects in the P0MC-MC4R pathway likely also lead to early-onset and severe obesity. These genes are collectively termed “MC4R pathway agonizable genes” and examples are provided below. In an embodiment, the MC4R pathway agonizable gene does not comprise any one of POMC, Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1, also called PC 1 / 3), MAGE-like-2 (MAGEL2), leptin receptor (leptin-R), leptin, 5-hydroxytryptamine (serotonin) receptor 2C, G protein-coupled (5-HT2c receptor), nescient helix loop helix 2 (NhHL2, also called NSCL2), pro-hormone convertase, carboxypeptidase E (CPE), and single-minded 1 (Siml). In an embodiment, the MC4R pathway agonizable gene does not comprise MC4R. In an embodiment, the MC4R pathway agonizable gene does not comprise any gene disclosed in W02013 / 102047 or WO 2017 / 059076, the full contents of each of which is incorporated herein by reference in its entirety. In an embodiment, an MC4R agonist, e.g., an MC4R agonist of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), or a pharmaceutically acceptable salt, is used, e.g., to treat a disease, disorder, or condition caused by a mutation, deletion, or other aberration in an MC4R pathway agonizable gene. In an embodiment, a combination of an MC4R agonist, e.g., an MC4R agonist of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII), or a pharmaceutically acceptable salt, and a GCHR modulator, e.g., a GLP1R agonist as described herein, is used, e.g., to treat a disease, disorder, or condition caused by a mutation, deletion, or other aberration in an MC4R pathway agonizable gene.

[0220] In embodiments of any method described herein, the method comprises treating a subject having a mutation in a gene listed in Table 1 below. In embodiments, a method described herein comprises use of a MC4R agonist described herein to treat a subject having a mutation in an MC4R pathway agonizable gene, e.g., as listed in Table 1. Table 1 describes exemplary genes, alleles, transcripts, and proteins, though other genes, alleles, transcripts, and proteins may be included. Table 1: Exemplary MC4R pathway agonizable genes, alleles, and transcripts

[0221]

[0222] Melanocortin-4 Receptor (MC4R) Agonists

[0223] In some embodiments, the MC4R agonist is a compound described in U. S.

[0224] 2007 / 0105759, which is incorporated herein by reference in its entirety.

[0225] In some embodiments, the MC4R agonist is a compound described in U. S.

[0226] 2007 / 0293223, which is incorporated herein by reference in its entirety.

[0227] In one aspect, the MC4R agonist is a compound described in US20220289731 Al, EP4265255A1, EP4249485A1, EP4249484A1, EP4249483A1, EP4249482A1, EP4219475A1, EP4219474A1, EP4219473A1, EP4219472A1, or EP4219471A1, the teachings of which are incorporated herein by reference in their entirety.

[0228] In one aspect, the MC4 agonist is formulated as a pharmaceutical composition in combination with a glucagon-like peptide receptor agonist as described in WO2023191408A1, which is incorporated herein by reference in its entirety.

[0229] In an aspect, the MC4R agonist is a compound described in WO2023153762A1, which is herein incorporated by reference in its entirety.

[0230] In an aspect, the MC4R agonist is a compound described in WO2022235107A1, WO2022235106A1, WO2022235105A1, WO2022235104A1, WO2022235103A1, WO2022182194A1, or WO2022158868A1, the teachings of which are incorporated herein by reference in their entirety.

[0231] In some embodiments, the MC4R agonist is a compound described in U. S.

[0232] 2007 / 0293223, which is incorporated herein by reference in its entirety.

[0233] In one aspect, the MC4R agonist is a compound of Formula (I):

[0234]

[0235] wherein: R1represents hydrogen, amidino, C1-C4-alkylamidino, Ci-C4-alkanoylamidino, Ci-Cio-alkyl, Ca-Cv-cycloalkyl, Ce-Cio-aryl, heterocycle, heteroaryl, Ci-Ce-alkylcarbonyl, Ca-Cv-cycloalkylcarbonyl, C1-C4-alkoxycarbonyl, C6-Cio-aryl-Ci-C4-alkoxycarbonyl, -SO2, -Ci-C4-alkyl, -C(O)-N(R6)(R7) or -C(S)-N(R6)(R7), wherein R6and R7each independently represents hydrogen, Ci-Ce-alkyl or C3-C7-cycloalkyl, alkyl, cycloalkyl, heterocycle, aryl or heteroaryl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, amino, Ci-C4-alkyl, trifluoromethyl, hydroxy, Ci-C4-alkoxy and oxo; R2represents Ce-Cio-aryl or heteroaryl, each of which is unsubstituted or mono- or di -substituted with a substituent selected from the group consisting of halogen, hydroxy, Ci-C4-alkyl, C1-C4-alkoxy, cyano and amino; R3represents hydrogen, cyano, Ci-Ce-alkyl, Cs-Cv-cycloalkyl, C2-Ce-alkenyl, monocyclic heterocycle, monocyclic heteroaryl, -C(O)-R8or -C(S)-R8, wherein, R8represents hydroxy, Ci-C4-alkyl, Ci-C4-alkyloxy or N(R9)(R10), wherein R9and R10each independently represents hydrogen, Ci-C6-alkyl, C3-C?-cycloalkyl, Ci-C4-alkyloxy, phenyl or heteroaryl, or R9and R10may combine each other to form single ring or two rings, or further comprise oxygen atom or sulfur atom, wherein, alkyl, cycloalkyl, heterocycle, phenyl or heteroaryl is unsubstituted or substituted with a substituent selected from the group consisting of methyl, trifluoromethyl, hydroxy, hydroxyimino, amino, acetylamino, (C1-C4-alkyl)amino and (Ci-C4-alkyl)(Ci-C4-alkyl)amino; R4represents Cs-Cs-cycloalkyl, Ce-Cio-aryl, heteroaryl or heterocycle, wherein, Ce-Cio-aryl or heteroaryl is unsubstituted or mono-or poly-substituted with a substituent selected from the group consisting of halogen, hydroxy, Ci-C4-alkyl, trifluoromethyl, Ci-C4-alkoxy and amino, cycloalkyl or heterocycle is unsubstituted or mono- or poly-substituted with a substituent selected from the group consisting of halogen, hydroxy, Ci-C4-alkyl, trifluoromethyl, Ci-C4-alkoxy and oxo; R5represents hydrogen, Ci-Ce-alkyl, -C(O)-Rn, Ci-Ce-alkylsulfonyl, Ce-Cio-arylsulfonyl, -(CH2)p-Ce-Cio-aryl, -(CH2)P-heteroaryl or -(CH2)P-C3-Cs-cycloalkyl, wherein, p represents 1 or 2; R11represents Ci-Cio-alkyl, C2-C6-alkenyl, Cs-Cs-cycloalkyl, Cs-Cs-cycloalkenyl, amino, Ci-C4-alkylamino, (Ci-C4-alkyl)(Ci-C4-alkyl)amino, Ce-Cio-aryl, heteroaryl, or heterocycle, wherein, alkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, mercapto, C1-C4-alkoxy, Ci-C3-alkylcarboxy, amino, dimethylamino, Ci-C4-alkylcarbonylamino, cyano, carbamoyl, dimethylcarbamoyl, hydroxyimino and oxo, aryl or heteroaryl is unsubstituted or mono- or di-substituted with a substituent selected from the group consisting of halogen, hydroxy, Ci-C4-alkyl, trifluoromethyl, C1-C4 -alkoxy and amino, cycloalkyl, cycloalkenyl or heterocycle is unsubstituted or mono- or di-substituted with a substituent selected from the group consisting of halogen, hydroxy, amino, Ci-C4-alkyl, trifluoromethyl, Ci-C4-alkoxy and oxo.

[0236] In some embodiments, preferred compounds among the compounds of Formula (I) above are those wherein i) R1represents hydrogen, amidino, Ci-C4-alkylamidino, C1-C4-alkanoylamidino, Ci-Ce-alkyl, Cs-Cv-cycloalkyl, phenyl, monocyclic heterocycle, monocyclic heteroaryl, Ci-Ce-alkylcarbonyl, trifluoroacetyl, Ci-C4-alkoxycarbonyl, Ce-Cio-aryl-Ci-C4-alkoxycarbonyl, -SO2-Ci-C4-alkyl, carbamoyl, Ci-Ce-alkylcarbamoyl, (Ci-Ce-alkyl)(Ci-C6-alkyl)carbamoyl, thiocarbamoyl, Ci-Ce-alkylthiocarbamoyl or (Ci-C6-alkyl)(Ci-C6-alkyl)thiocarbamoyl, more preferably, R represents hydrogen, amidino, methylamidino, ethylamidino, acetylamidino, methyl, ethyl, trifluoroethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, oxazolynyl, imidazolynyl, thiazolynyl, piperidinyl, tetrahydropyranyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, pyridinyl, acetyl, trifluoroacetyl, propionyl, butyryl, isobutyryl, pivaloyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, methylsulfonyl, carbamoyl, methylcarbamoyl, ethyl carbamoyl, trifluoroethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, t-butylcarbamoyl, thiocarbamoyl, methylthio- carbamoyl, ethylthiocarbamoyl or methylethylcarbamoyl; ii) R2represents phenyl unsubstituted or mono- or di-substituted with a substituent selected from the group consisting of F, Cl and methyl, more preferably, R2represents phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl or 2,4-difluorophenyl; iii) R3represents hydrogen, cyano, Ci-C4-alkyl, C2-C4-alkenyl, -CFb C h^CFbOH, oxazolyl, thiazolyl, oxazolynyl, thiazolynyl, carboxy, C1-C4-alkylcarbonyl, Ci-C4-alkyloxycarbonyl, carbamoyl, thiocarbamoyl, Ci-C4-alkylcarbamoyl, (Ci-C4-alkyl)(Ci-C4-alkyl)carbamoyl, (Ci-C4-alkyl)(Ci-C4-alkyloxy)carbamoyl, C1-C4-alkylthiocarbamoyl or (Ci-C4-alkyl)(Ci-C4-alkyl)thiocarbamoyl, phenylcarbamoyl, heteroarylcarbamoyl, azetidinecarbonyl, pyrrolidinecarbonyl, piperidinecarbonyl or morpholinecarbonyl, wherein alkyl is unsubstituted or substituted with a substituent selected from the group consisting of hydroxy, hydroxyimino, amino, (Ci-C4-alkyl)amino and (C1-C4-alkyl)(Ci-C4-alkyl)amino, more preferably, R3represents hydrogen, cyano, methyl, ethyl, propyl, allyl, -CHNOH, hydroxymethyl, -CH(CH3)0H, aminomethyl, dimethylaminomethyl, oxazolyl, thiazolyl, oxazolynyl, thiazolynyl, carboxy, acetyl, propanoyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl, carbamoyl, thiocarbamoyl, ethylcarbamoyl, t-butyl carbamoyl, dimethylcarbamoyl, methyl ethyl carbamoyl, methylmethoxycarbamoyl, dimethylthiocarbamoyl, phenylcarbamoyl, heteroarylcarbamoyl, -C(O)NH(CH2)2NH, azetidinecarbonyl, pyrrolidinecarbonyl, piperidinecarbonyl or morpholinecarbonyl; iv) R4represents C4-C?-cycloalkyl or monocyclic heterocycle unsubstituted or mono- or poly-substituted with a substituent selected from the group consisting of halogen, hydroxy, Ci-C4-alkyl, trifluoromethyl, Ci-C4-alkoxy and oxo; or phenyl or monocyclic heteroaryl unsubstituted or mono- or di-substituted with a substituent selected from the group consisting of halogen, hydroxy, Ci-C4-alkyl, trifluoromethyl, C1-C2-alkoxy and amino, more preferably, R4represents cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 4-methylcyclohexyl, 4,4-dimethylcyclohexyl, 4,4-difluorocyclohexyl,

[0237] 4-trifluoromethylcyclohexyl, 3, 4-tetram ethylcyclopentyl, tetrahydropyranyl, pyridinyl, N-methylpyridinyl or phenyl, wherein, phenyl is unsubstituted or mono- or di-substituted with a substituent selected from the group consisting of F, Cl, methyl and methoxy; v) R5represents hydrogen, Ci-Cs-alkyl, trifluoromethyl, Ci-Ce-alkylcarbonyl, trifluoroacetyl, acryloyl, methacryloyl, Ca-Cs-cycloalkylcarbonyl, Cs-Cs-cycloalkenylcarbonyl, carbamoyl, Ci-C4-alkylcarbamoyl, (Ci-C4-alkyl)(Ci-C4-alkyl)carbamoyl, methanesulfonyl, ethanesulfonyl, propanesulfonyl, benzoyl, hydroxybenzoyl, aminobenzoyl, monocyclic heteroaryl carbonyl, heterocyclecarbonyl, benzyl, -CFfc-monocyclic heteroaryl, or -CH2-C3-Cs-cycloalkyl, more preferably, R5represents hydrogen, methyl, ethyl, propyl, isobutyl, hydroxyethyl, -CH2C(CH3)2CH2OH, -CH2C(CH3)2CH(CH3)OH, -CH2CH2NHC(O)CH3, aminoethyl, acetyl, trifluoroacetyl, hydroxyacetyl, methoxyacetyl, ethoxyacetyl, propionyl, ethoxypropionyl, isobutyryl, cyanoisobutyryl, hydroxyisobutyryl, carbamoylisobutyryl, 3,3-dimethylbutanoyl, pivaloyl, fluoropivaloyl, difluoropivaloyl, hydroxypivaloyl, mercaptopivaloyl, dihydroxypivaloyl, methoxypivaloyl, ethoxypivaloyl, aminopivaloyl, dimethylaminopivaloyl, hydroxyiminopivaloyl, acetylisobutyryl, -C(O)C(CH3)2CH(CH3)OH, -C(O)C(CH3)2C(CH3)2OH, acryloyl, methacryloyl, cyclopentanecarbonyl, cyclohexylenecarbonyl, carbamoyl, dimethylcarbamoyl, methanesulfonylcarbonyl, benzoyl, thiophenecarbonyl, furoyl, oxazolecarbonyl, thiazolecarbonyl, imidazolecarbonyl, pyrazolecarbonyl, tetrahydrofuroyl, dihydrofuroyl, tetrahydropyrancarbonyl, morpholinecarbonyl, methanesulfonyl, benzyl, furanmethyl, thiazolemethyl or

[0238] imidazolemethyl. In some embodiments, the MC4R agonist is a compound of Formula (I) selected from:

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272] In some embodiments, the MC4R agonist is a compound described in WO 2008 / 007930, which is incorporated herein by reference in its entirety.

[0273] In one aspect, the MC4R agonist is a compound of Formula (II):

[0274]

[0275] wherein: R1represents hydrogen, or represents C1-C10-alkyl, C3-C7-cycloalkyl, C6-C10-aryl, heterocycle or heteroaryl, each of which is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen, amino, C1-C4-alkyl, trifluoromethyl, hydroxy, C1-C4-alkoxy, cyano and oxo;

[0276] R2represents phenyl or six-membered heteroaryl, each of which is unsubstituted or mono- or di -substituted with substituents selected from the group consisting of halogen, hydroxy, C1-C4-alkyl, C1-C4-alkoxy, cyano and amino; R3 represents hydrogen, or represents C1-C8-alkyl or C3-C7-cycloalkyl each of which is unsubstituted or substituted with substituents selected from the group consisting of halogen, methyl, trifluoromethyl, hydroxy and amino;

[0277] R4represents C4-C7-cycloalkyl or monocyclic heterocycle, each of which is unsubstituted or mono- or poly-substituted with substituents selected from the group consisting of halogen, hydroxy, C1-C4-alkyl, trifluoromethyl, C1-C4-alkoxy and oxo; or represents phenyl or six-membered heteroaryl, each of which is unsubstituted or mono- or di-substituted with substituents selected from the group consisting of halogen, hydroxy, C1-C4-alkyl, trifluoromethyl, C1-C4-alkoxy and amino; and R5 represents C1-C6-alkyl, difluoromethyl, trifluoromethyl, C3-C8-cycloalkyl, amino, C1-C4-alkylamino, di(C1-C4-alkyl)amino, phenyl, monocyclic heteroaryl or monocyclic heterocycle where alkyl is unsubstituted or substituted with at least one substituent selected from the group consisting of fluoro, hydroxy, mercapto, C1-C4-alkoxy, acetoxy, amino, acetylamino, cyano, carbamoyl, dimethylcarbamoyl and oxo, and phenyl or heteroaryl is unsubstituted or mono- or di-substituted with substituents selected from the group consisting of halogen, hydroxy, methyl, trifluoromethyl, methoxy and amino.

[0278] In some embodiments, preferred compounds of Formula (II) include: i) R1represents hydrogen, methyl, ethyl, trifluoroethyl, propyl, isopropyl, butyl, isobutyl, / c 7-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or represents phenyl, oxazolinyl, imidazolinyl, thiazolinyl, tetrahydropyranyl, tetrahydrothiopyranyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, piperidinyl or pyridazinyl, each of which is unsubstituted or substituted with substituent(s) selected from the group consisting of halogen, methyl, cyano, oxo and hydroxy, and more preferably, R1represents isopropyl, tertbutyl or cyclopropyl; or represents phenyl, tetrahydropyranyl, thiazolyl, pyridinyl, pyrimidinyl or pyridazinyl, each of which is unsubstituted or substituted with substituent(s) selected from the group consisting of halogen, methyl, cyano and hydroxy; ii) R2represents phenyl which is unsubstituted or mono- or di-substituted with substituent(s) selected from the group consisting of fluorine, chlorine, bromine, methoxy and methyl, and more preferably, R2represents 4-chlorophenyl or 2,4-difluorophenyl; iii) R3represents hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, ter / -butyl, cyclopropyl, cyclobutyl or cyclopentyl, and more preferably, R3represents hydrogen, methyl, ethyl or isopropyl; iv) R4represents cyclopentyl, cyclohexyl, cycloheptyl, 4-methylcyclohexyl, 4,4-dimethylcyclohexyl, 4-fluorocyclohexyl, 4,4-difluorocyclohexyl or 4-trifluoromethylcyclohexyl; or represents phenyl which is unsubstituted or mono- or di-substituted with substituents selected from the group consisting of fluorine, chlorine, methyl and methoxy, and more preferably

[0279] R4represents cyclohexyl, 4-methylcyclohexyl, 4,4-dimethylcyclohexyl, 4,4-difluorocyclcohexyl or 2,4-difluorophenyl; and v) R5represents methyl, trifluoromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, propyl, isopropyl, isobutyl, / e / 7-butyl. -CH2CH2OH, -CH(CH3)CH2OH, -C(CH3)2CH2OH, -C(CH3)(CH2OH)2, -C(CH3)2CH2OMe, -C(CH3)2CH2OEt, phenyl, oxazolinyl, imidazolinyl, thiazolinyl, tetrahydropyranyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, furanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyridinyl or piperidinyl, and more preferably,

[0280] R5represents isopropyl, tert-butyl, -C(CH3)2CH2OH, furanyl or tetrahydrofuranyl.

[0281] In some embodiments, preferred compounds of Formula (II) include: R1represents isopropyl, tert-butyl or cyclopropyl; or represents phenyl, tetrahydropyranyl, thiazolyl, pyridinyl, pyrimidinyl or pyridazinyl, each of which is unsubstituted or substituted with substituent(s) selected from the group consisting of halogen, methyl, cyano and hydroxy; R2represents 4-chlorophenyl or 2,4-difluorophenyl; R3represents hydrogen, methyl, ethyl or isopropyl; R4represents cyclohexyl, 4-methylcyclohexyl, 4,4-dimethylcyclohexyl, 4,4-difluorocyclohexyl or 2,4-difluorophenyl; and R5represents isopropyl, tert-butyl, -C(CH3)2CH2OH, furanyl or tetrahydrofuranyl. In some embodiments, the MC4R agonist is a compound of Formula (I) selected from:

[0282]

[0283]

[0284]

[0285]

[0286] 'll

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302] In some embodiments, the MC4R agonist is a compound described in WO 2010 / 056022, which is incorporated herein by reference in its entirety.

[0303] In some embodiments, the MC4R agonist is a compound described in US 8,288,386, which is incorporated herein by reference in its entirety.

[0304] In some embodiments, the MC4R agonist is a compound described in US 8,039,622; US 8,183,243; or US 8,236,955; and each of which is incorporated herein by reference in its entirety.

[0305] In one aspect, the MC4R agonist is a compound of Formula (III):

[0306]

[0307] wherein R1is C1-C12 alkyl (e.g., C2-C5 alkyl). In some embodiments, the compound of Formula (III) includes a compound shown in the table below:

[0308]

[0309]

[0310] In some embodiments, the MC4R agonist is a compound described in WO 2021 / 091283, which is incorporated herein by reference in its entirety.

[0311] In another aspect, the MC4R agonist is a compound of Formula (IV):

[0312]

[0313] wherein: R1is C1-C12 alkyl (e.g., C2-C5 alkyl); R2is halo; R3is hydrogen or halo; R4is C2-C5 alkyl; and n is an integer of 1 or 2. In an embodiment, when R2is chlorine and R3is hydrogen, n is 2. In some embodiments, the MC4R agonist is selected from a compound shown in the table below:

[0314]

[0315]

[0316] or a pharmaceutically acceptable salt thereof.

[0317] In some embodiments, the MC4R agonist is a compound described in WO 2022 / 182194; WO 2022 / 092914; WO 2022 / 139443; WO 2022 / 139441; WO 2022 / 139444; WO 2022 / 092909; WO 2022 / 092910; WO 2022 / 092908; WO 2022 / 092913; WO 2022 / 139446; each of which is incorporated herein by reference in its entirety.

[0318] In another aspect, the MC4R agonist comprises an F^x^W3motif, e.g., as described in Cell Research (2021) 31:1176-1189. In an embodiment, the MC4R agonist has a structure of Formula (V):

[0319]

[0320] pharmaceutically acceptable salt thereof, wherein R1is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, acyl (e.g., acetyl), cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of alkyl, alkenyl, alkynyl, heteroalkyl, acyl (e g., acetyl), cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted; each of R6and R7is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, acyl (e.g., acetyl), cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of alkyl, alkenyl, alkynyl, heteroalkyl, acyl (e.g., acetyl), cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted; or wherein each of R6and R7is taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclyl ring; each of R2, R4, and R6is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted; each of R3a, R3b, R5aand R5bis independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of alkyl, alkenyl, alkynyl, heteroalkyl, acyl (e.g., acetyl), cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted; wherein each of R5aand R5bmay be taken together with the carbon atom to which they are attached to form an oxo group; wherein each of R2and R3amay be taken together with the carbon and nitrogen atoms to which they are attached to form an optionally substituted heterocyclyl group; wherein each of R4and R3amay be taken together with the carbon and nitrogen atoms to which they are attached to form an optionally substituted heterocyclyl group; wherein each of R4and R5amay be taken together with the carbon and nitrogen atoms to which they are attached to form an optionally substituted heterocyclyl group; wherein each of R6and R5amay be taken together with the carbon and nitrogen atoms to which they are attached to form an optionally substituted heterocyclyl group; and wherein m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10; and n is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0321] In an embodiment, the MC4R agonist has a structure of Formula (VI):

[0322]

[0323] salt thereof, wherein each of Rla, Rlb, R6aand R6bis independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, acyl (e.g., acetyl), cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of alkyl, alkenyl, alkynyl, heteroalkyl, acyl (e g., acetyl), cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted; or wherein each of Rlaand Rlbor R6aand R6bis taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclyl ring; R2is hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted; each of R3a, R3b, R4a, R4b, R5aand R5bis independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of alkyl, alkenyl, alkynyl, heteroalkyl, acyl (e.g., acetyl), cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted; wherein each of R5aand R5bmay be taken together with the carbon atom to which they are attached to form an oxo group; and wherein each of R2and R3amay be taken together with the carbon and nitrogen atoms to which they are attached to form an optionally substituted heterocyclyl group; and wherein x is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10; y is 1, 2, 3, 4, 5, 6, 7, or 8; and z is 0 or 1.

[0324] In an embodiment, Rlais acyl. In an embodiment, Rlbis optionally substituted cycloalkyl. In an embodiment, z is 0. In an embodiment, z is 1.

[0325] In another aspect, the MC4R agonist is a compound of Formula (VII):

[0326]

[0327] pharmaceutically acceptable salt, wherein: one of X and Y is N and the other is CH; R is F, Cl, CN, CF3 or methoxy, with the proviso that when Y is N, R is not F or Cl; R1is phenyl, 2-pyridyl, C3-C6 cycloalkyl or CH2(C3-C6 cycloalkyl), wherein the ring moiety is optionally substituted by one or more substituents independently selected from F, Cl, CN, methyl and methoxy; R2is H, F or Cl, with the proviso that when Y is N, R2is not F or Cl; Het is a 6-membered ring containing one or 2 N atoms, wherein the ring is either aromatic, or contains 2 double bonds in the ring and a =0 substituent, which ring is optionally substituted by one or more substituents independently selected from F, Cl, OH, CN, methyl, ethyl, NH2, NHCH3, N(CH3)2and methoxy; or alternatively, Het is a 6-membered ring containing one or 2 N atoms fused at the 3,4-positions, relative to the attachment to the pyrrolidine ring, to a 5-membered aromatic ring containing one or two further N atoms, which 5-membered ring is optionally substituted by OH; and the pharmaceutically acceptable salts, solvates (including hydrates), and prodrugs thereof.

[0328] In some embodiments, Het is one of:

[0329]

[0330] In some embodiments, preferred embodiments of Formula (Vll) include: Preferably, X is N and Y is CH; preferably R is chloro; preferably R1is phenyl optionally substituted by one or more substituents independently selected from F, Cl, CN, methyl and methoxy; more preferably R1is phenyl, 4-chlorophenyl or 4-fluorophenyl. Tn an alternative embodiment. R1is preferably C3-C6 cycloalkyl, more preferably cyclopropyl or cyclohexyl; preferably R2is H or F; more preferably R2is H. Preferably Het is pyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, 6-oxo-l,6-dihydropyridazin-3-yl, 6-oxo- l,6-dihydropyridin-3-yl, 2-oxo-l,2- dihydropyrimidin-4-yl, 6-oxo-l,6-dihydropyrimidin-4-yl, 2-oxo-l,2-dihydropyridin-4-yl, imidazo[l,2-b]pyridazin-6-yl, [l,2,4]triazolo[4,3-b]pyridazin-6-yl or 6-oxo-l,6- dihydropyridin-2-yl, optionally substituted by one or more substituents independently selected from F, Cl, OH, CN, methyl, ethyl and methoxy. More preferably Het is pyridin-2- yl, pyridin-3-yl, pyridazin-3-yl or 6-oxo-l,6-dihydropyridazin-3-yl, optionally substituted by one or more substituents independently selected from OH, CN, F, methyl and methoxy. Yet more preferably Het is pyridin-2-yl or pyridazin-3-yl, each of which is substituted at the para-position relative to the bond linking to the pyrrolidine moiety, by OH, CN or methoxy. Most preferably Het is pyridazin-3-yl substituted at the para-position relative to the bond linking to the pyrrolidine moiety, by OH, CN or methoxy.

[0331] In some embodiments, compounds of Formula (VII) include:

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340] and the pharmaceutically acceptable salts, solvates (including hydrates), and prodrugs thereof.

[0341] In some embodiments, more preferred compounds of Formula (VII) include:

[0342] Compound 410, Compound 411, Compound 413, Compound 414, Compound 415, Compound 416, Compound 417, Compound 432, Compound 433, Compound 434, Compound 435, Compound 436, Compound 437, Compound 438, Compound 440, Compound 441, Compound 442, Compound 443, Compound 444, Compound 445, Compound 446, Compound 447, Compound 448, and Compound 449, and the pharmaceutically acceptable salts, solvates (including hydrates), and prodrugs thereof.

[0343] In some embodiments, more preferred compounds of Formula (VII) include:

[0344] Compound 410, Compound 415, Compound 416, Compound 417, Compound 433, Compound 434, Compound 446, Compound 447, Compound 448, and Compound 449, and the pharmaceutically acceptable salts, solvates (including hydrates), and prodrugs thereof.

[0345] In some embodiments, the MC4R agonist is a compound described in US 8,138,188, which is incorporated herein by reference in its entirety.

[0346] In one aspect, the MC4R agonist is a compound of Formula (VIII):

[0347]

[0348] pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, geometric isomer or tautomer thereof, wherein: R1is selected from: -(Ci- C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-Cs)cycloalkyl, -(C5-C8)cycloalkenyl, -(Ci-C2)alkyl(C3-C8)cycloalkyl, aryl, -(Ci-C2)alkylaryl, heterocyclic, or -(Ci-C2)alkylheterocyclic groups, wherein each of the foregoing R1groups is optionally substituted by one or more groups selected from: -(Ci-C4)alkyl, -(CH2)m(C3-C5)cycloalkyl, halogen, -(CH2)mOR6, CN, -C(O)OR6, -(CH2)mNR7SO2R8, CF3, CH2CF3, OCF3 or OCH2CF3 wherein m = 0, 1 or 2; R2is H, OH or OCH3; R3is selected from: H, -(Ci-Ce)alkyl, -(C2-Ce)alkenyl, -(C2-Ce)alkynyl, -(C3-C8)cycloalkyl, -(C6-C8)cycloalkenyl, -(Ci-C2)alkyl(C3-C8)cycloalkyl, aryl, -(Ci-C2)alkylaryl, heterocyclic, or -(Ci-C2)alkylheterocyclic groups, wherein each of latter ten R3groups is optionally substituted by one or more groups selected from: OH, -(Ci-C4)alkyl, -(CH2)n(C3-C5)cycloalkyl, halogen, CN, -(CH2)nOR6or - (CH2)nNR7R8wherein n = 0, 1 or 2; R4is selected from: H, -(Ci-C4)alkyl, -(C2-C4)alkenyl, -(C2-C4)alkynyl, -(CH2)P(C3-Cs)cycloalkyl, -(CH2)P(C5)cyclo-alkenyl, halogen, -(CH2)POR6, -(CH2)PNR7R8, CN, -C(O)R6, -C(O)OR6, -C(O)NR7R8, -(CH2)PNR7SO2R8, CF3, CH2CF3, OCF3 or OCH2CF3 groups wherein p = 0, 1 or 2; R5is selected from: -(Ci-C4)alkyl, -(C2-C4)alkenyl, -(C2-C4)alkynyl, -(CH2)P(C3-C5)cycloalkyl, -(CH2)P(C5)cyclo-alkenyl, halogen, -(CH2)pOR6, - (CH2)PNR7R8, CN, - C(O)R6, -C(O)OR6, -C(O)NR7R8, -(CH2)PNR7SO2R8, CF3, CH2CF3, OCF3or OCH2CF3groups wherein p = 0, 1 or 2; or R4and R5can together form a fused 5- to 7-membered saturated or unsaturated ring; R6, R7and R8are each independently selected from H, CH3or CH2CH3; and wherein the heterocyclic groups of R1and R3are independently selected from 4- to 10-membered ring systems containing up to 4 heteroatoms independently selected from O, N or S.

[0349] Heterocyclic groups suitable for use herein are 4- to 10-membered mono or bicyclic heteroaryl rings containing one to three heteroatoms from the list N, S and O and combinations thereof and wherein said bicyclic heteroaryl rings are 9- or 10-membered ring systems which may be either two heteroaryl rings fused together or a heteroaryl ring fused to an aryl ring.

[0350] Suitable bicyclic heteroaryl groups for use herein include: benzimidazolyl, benzotriazolyl, benzothiazolyl, indazolyl, indolyl, imidazopyridinyl, imidazopyrimidinyl, pyrrolopyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, naphthyridinyl and pyridopyrimidinyl groups. Preferred for use herein are monocyclic 5- to 6-membered heteroaryl rings containing one or three heteroatoms from the list N and O and combinations thereof. Suitable 5-membered ring monocyclic heteroaryl groups for use herein include: triazinyl, oxadiazinyl, oxazolyl, thiazolyl, thiadiazolyl, furyl, thienyl and pyrrolyl and imidazolyl groups. Suitable 6-membered ring monocyclic heteroaryl groups for use herein include: pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl groups. Preferred R1heterocyclic rings are monocyclic 5- to 6-membered heteroaryl rings containing one or two heteroatoms from the list N and O and combinations thereof. More preferred R1heterocyclic rings are monocyclic 5- to 6-membered heteroaryl rings containing one or 2N heteroatoms. Highly preferred R1heterocyclic rings herein are monocyclic 6-membered heteroaryl rings containing one or two N heteroatoms such as pyridinyl and pyrimidinyl. An especially preferred R1heteroaryl group herein is the pyridinyl group. Preferred R3heterocyclic rings are monocyclic 5- to 6-membered heteroaryl rings containing one or two heteroatoms from the list N and O and combinations thereof such as tetrahydropyranyl, pyridinyl, pyridazinyl, pyrazinyl and pyrimidinyl groups. More preferred R3heterocyclic rings are monocyclic 5- to 6-membered heteroaryl rings containing one or two N heteroatoms. More preferred still as R3heterocyclic rings are monocyclic 6-membered heteroaryl rings containing one or two N heteroatoms such as pyridinyl, pyridazinyl, pyrazinyl and pyrimidinyl groups. Particularly preferred R36-membered ring monocyclic heteroaryl groups for use herein are pyridin-2-yl, pyri din-3 -yl, pyridazin-3-yl, pyrazinyl, pyrimidin-5-yl and pyrimidin-2-yl groups. Especially preferred R36-membered ring monocyclic heteroaryl groups for use herein include pyridin-2-yl, pyridin-3-yl and pyridazin-3-yl groups. Of these groups pyridazin-3-yl is most preferred.

[0351] Suitable fused ring systems formed by R4and R5together may be carbocyclic ring systems or heterocyclic ring systems containing up to two heteroatoms selected from O, N or S. Including the phenyl ring to which they are attached, preferred ring systems which R4and R5may form are: indane, 1,2,3,4-tetrahydronaphthalene, indolyl, indazolyl, naphthyl, quinolyl, benzothiazolyl, benzimidazolyl, benzo[l,3]dioxolane, 2,3-dihydrobenzo[l,4]di oxine, 2,3 -dihydrobenzofuran, 2,3 -dihydrobenzothiophene and 1,3-dihydroisobenzofuran.

[0352] In some embodiments, compounds of Formula (VIII) include compounds of one of Formulas (VIII-IA), (VIII-IB), (VIII-IC), (VIII-ID), (VIII-IE), (VIII-IF), (VIII-IG), or (VIII- IH):

[0353]

[0354]

[0355] wherein R1, R2, R3, R4and R5are as defined above. Also included are compounds having the formulas (V111-1B), and (V111-1D), wherein the stereochemistry of the groups at the 3 and 4 positions of the pyrrolidine ring are cis relative to each other.

[0356] In some embodiments, compounds of Formula (VIII), preferably formula (VIII-IA), more preferably formula (V111-1C),, more preferably still formula (V111-1E), and especially formula (VIII-IG),, wherein R1is selected from: -(Ci-C6)alkyl, -(C3-C8)cycloalkyl, -(Ci-C2)alkyl(C3-Cs)cycloalkyl, phenyl, -(Ci-C2)alkylaryl, heterocyclic, or -(Ci-C2)alkylheterocyclic groups and wherein R1is optionally substituted by one or more groups selected from -(Ci-C4)alkyl, -(CH2)mOR6, -(CH2)m(C3-C5)cycloalkyl, halogen, OCH3, OCH2CH3, CN, CF3, CH2CF3, OCF3 or OCH2CF3 wherein m = 1 or 2 and wherein when R1is a heterocyclic, or a -(Ci-C2)alkylheterocyclic group said heterocyclic groups are independently selected from mono-cyclic 5- to 6-membered ring systems containing up to 3 heteroatoms independently selected from O, N or S and combinations thereof.

[0357] In some embodiments, the present disclosure provides compounds having formula (VIII), preferably formula (VIII-IA), more preferably formula (VIII-IC), more preferably still formula (VIII-IE) and especially formula (VIII-IF), wherein R1is selected from: -(Ci-Ce)alkyl, -(C3-Cs)cycloalkyl, -(Ci-C2)alkyl(C3-Cs)cycloalkyl, phenyl, -(Ci-C2)alkylaryl, heterocyclic, or -(Ci-C2)alkylheterocyclic groups wherein each of the foregoing R1groups is optionally substituted by one or more groups selected from: -(Ci-C4)alkyl, halogen, -(CH2)mOR6, CN, CF3, OCF3, wherein m = 1 or 2; R2is OH; R3is selected from: H, -(Ci- Ce)alkyl, -(C3-Cs)cycloalkyl, -(Ci-C2)alkyl(C3-Cs)cycloalkyl, aryl, -(Ci-C2)alkylaryl, heterocyclic, or -(Ci-C2)alkylheterocyclic groups wherein each of latter seven R3groups is optionally substituted by one or more groups selected from: OH, -(Ci-C4)alkyl, -(CH2)n(C3-Cs)cycloalkyl, halogen, CN, -(CH2)nOR6or - (CH2)nNR7R8wherein n = 0, 1 or 2; R4is selected from: H, -(Ci-C4)alkyl, -(CH2)P(C3-C5)cycloalkyl, halogen, -(CH2)POR6, -(CH2)pNR7R8, CN, -C(O)R6, -C(O)OR6, -C(O)NR7R8, -(CH2)PNR7SO2R8, CF3, CH2CF3, OCF3 or OCH2CF3 groups wherein p = 0, 1 or 2; R5is selected from: -(Ci-C4)alkyl, -(CH2)P(C3-C5)cycloalkyl, halogen, -(CH2)POR6, - (CH2)PNR7R8, CN, -C(O)R6, -C(O)OR6, -C(O)NR7R8, -(CH2)PNR7SO2R8, CF3, CH2CF3, OCF3 or OCH2CF3 groups wherein p = 0,1 or 2; R6, R7and R8are each independently selected from H, CH3 or CH2CH3; wherein the heterocyclic group of R3is selected from mono-cyclic 5- to 6-membered ring systems containing up to 2 heteroatoms independently selected from O or N and combinations thereof; and wherein the heterocyclic group of R1is selected from mono-cyclic 5- to 6-membered ring systems containing 1 N heteroatom.

[0358] In some embodiments, compounds of Formula (VIII), preferably formula (VIII-IA), more preferably formula (VIII-IC), more preferably still formula (VIII-IE), and especially formula (VIII-IF), as defined hereinbefore wherein R3is H, -(Ci-Ce)alkyl, -(C3-Cs)cycloalkyl, -(Ci-C2)alkyl(C3-Cs)cycloalkyl, -(Ci-C2)alkylaryl or a heterocyclic group and wherein each of the latter five R3groups is optionally substituted by one or more groups selected from -OH, -(Ci-C4)alkyl, -(CH2)n(C3-C5)cycloalkyl, halogen, -CN or -(CH2)nOR6wherein n = 0 or 1 and wherein R6is H, CH3 or CH2CH3 and wherein when R3is a heterocyclic group said heterocyclic group is selected from mono-cyclic 5- to 6-membered ring systems containing up to 2 heteroatoms independently selected from O or N and combinations thereof. In some embodiments, compounds of Formula (VIII), preferably formula (VIII-IA), more preferably formula (VIII-IC), more preferably still formula (VIII-IE), and especially formula (VIII-IF), wherein R1is selected from -(Ci-Ce)alkyl, -(C3-Q)cycloalkyl, phenyl or heterocyclic groups and wherein each of the foregoing R1groups is optionally substituted by one or more groups selected from: -(Ci-C4)alkyl, halogen, -OR6or -CN; R2is OH; R3is selected from H, -(C2-Ce)alkyl, -(C3-Cs)cycloalkyl, -(Ci-C2)alkyl(C3-Cs)cycloalkyl or heterocyclic groups and wherein each of latter four R3groups is optionally substituted by one or more groups selected from: -OH, -(Ci-C4)alkyl, -(CH2)n(C3- C5)cycloalkyl, halogen, -CN, -OR6or -(CH2)nNR7R8wherein n = 0, 1 or 2; R4is selected from: H, F or Cl; R5is selected from: F or Cl; R6, R7and R8are each independently selected from H, CH3or CH2CH3; wherein the heterocyclic group of R3is selected from mono-cyclic 5- to 6-membered ring systems containing up to 2 heteroatoms independently selected from O or N and combinations thereof; and wherein the heterocyclic group of R1is selected from mono-cyclic 5- to 6-membered ring systems containing 1 N heteroatom.

[0359] In some embodiments, compounds of Formula (VIII), preferably formula (VIII-IA), more preferably formula (VIII-IC), more preferably still formula (VIII-IE), and especially formula (VIII-IF), as defined hereinbefore wherein the heterocyclic group of R1where present, is a monocyclic 6-membered ring systems containing up to 1 N heteroatom, the heterocyclic group of R3, where present, is a monocyclic 6-membered ring system containing up to 2 N heteroatoms.

[0360] Preferred R1groups for use herein are selected from -(Ci-C4)alkyl, -(C3-C6)cycloalkyl, phenyl, pyridyl or pyrimidinyl wherein R1is optionally substituted by one or more groups selected from CH3, CH2CH3, halogen, OCH3, OCH2CH3, CN, CF3or OCF3. More preferred R1groups for use herein are selected from n-propyl, i-propyl, n-butyl, methoxymethyl, cyclopropyl, cyclohexyl, phenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 3.4-difluorophenyl, pyridin-2-yl or pyridin-3-yl groups. Highly preferred R1groups for use herein are selected from pyridin-2-yl, phenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 2,6-difluorophenyl, 2,4-difluorophenyl or 3.4-difluorophenyl groups.

[0361] Preferred R3groups for use herein are selected from -H, -(C2-Ce)alkyl, -(C3-Cs)cycloalkyl, -(Ci-C2)alkyl(C3-Cg)cycloalkyl or heterocyclic and wherein each of the latter four R3groups is optionally substituted by one or more groups selected from -OH, -(Ci-C4)alkyl or -OR6and wherein R6is -H, CH3 or CH2CH3 and wherein when R3is a heterocyclic group said heterocyclic group is a monocyclic 6-membered ring system containing up to 2 N heteroatoms. More preferred R3groups for use herein are selected from: hydrogen, ethyl, i-propyl, n-propyl, n-butyl, t-butyl, i-butyl, 2-methoxyethyl, cyclopentyl, cyclobutyl, cyclopentylmethyl, pyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, pyrazinyl, pyrimidin-5-yl, pyrimidin-2-yl, pyrimidin-4-yl or tetrahydropyran-4-yl groups. Preferred R4groups for use herein are selected from H, F or Cl and preferred R5groups for use herein are selected from F or Cl. Preferred phenyl groups having R4and R3substituents for use herein are: a 2,4-substituted phenyl group wherein the R4and R5groups are each independently selected from F or Cl; or, a 4-mono-substituted phenyl group wherein R4is H and R5is F or Cl. More preferred phenyl groups for use herein to which R4and R5are attached are 4-chlorophenyl or 2,4-difluorophenyl groups. When R3is H, in a preferred group of compounds herein of formula (VIII-IC), more preferably (VIII-IE) and especially (VIII-IF), R1is a phenyl, 3 -fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl or pyridin-2-yl group; R2is OH; and R4is selected from: H or F and R5is selected from: F or Cl. Preferred compounds herein wherein R3is H are the compounds of examples 12, 16, 24 and 48 or pharmaceutically acceptable salts, solvates or hydrates thereof. When R3is a heterocyclic group as defined herein after, in a preferred group of compounds of formula (VIII-IC), more preferably (VIII-IE) and especially (VIII-IF), herein, R1is a phenyl or pyridin-2-yl group; R2is -OH; R3is a heterocyclic group selected from: pyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, pyrazinyl, pyrimidin-5-yl, pyrimidin-4-yl, pyrimidin-2-yl or tetrahyrdropyran-4-yl groups; and R4and R5are both F. Preferred compounds herein wherein R3is a heterocyclic group selected from: pyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, pyrazinyl, pyrimidin-5-yl, pyrimidin-4-yl, pyrimidin-2-yl or tetrahyrdropyran-4-yl groups are the compounds of examples numbers 31, 34, 35, 42 and 47 and pharmaceutically acceptable salts, solvates and hydrates thereof. When R3is Et, i-Pr or t-Bu, in a preferred group of compounds herein of formula (VIII-IC), more preferably (VIII-IE) and especially (VIII-IF), R1is phenyl, 4-fluorophenyl, 4-chlorophenyl, 3 -fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, pyridin-2-yl; R2is OH; and R4and R3are F.

[0362] Preferred compounds herein wherein R3is Et, i-Pr or t-Bu are the compounds of examples 1, 5, 6, 8, 9, 10, 13, 15, 22, 40, 50, 51, 52 and 53 and pharmaceutically acceptable salts, solvates and hydrates thereof.

[0363] In some embodiments, compounds of Formula (VIII) include:

[0364]

[0365]

[0366]

[0367]

[0368]

[0369] Preferred compounds of Formula (VIII) include: Compound 460, Compound 462, Compound 463, Compound 465, Compound 466, and Compound 478.

[0370] More preferred compounds of Formula (VIII) include: Compound 460 and / or pharmaceutically acceptable acid salts thereof.

[0371] In some embodiments, compound of Formula (VIII) can include the following groups: R1is selected from: (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-Cfi)alkynyl, (C3-Cs)cycloalkyl, (Cs-Cs)cycloalkenyl, (Ci-C2)alkyl(C3-Cs)cycloalkyl, aryl, (Ci-C2)alkylaryl, heterocyclic, or (Ci-C2)alkylheterocyclic groups, wherein each of the foregoing R1groups is optionally substituted by one or more groups selected from: (Ci-C4)alkyl, (CH2)m(C3-C5)cycloalkyl, halogen, (CH2)mOR6, (CH2)mNR7R8, CN, C(O)R6, C(O)OR6, CON(R7)2, (CH2)mNR7SO2R8, CF3, CH2CF3, OCF3, OCH2CF3, SMe or SEt wherein m = 0, 1 or 2; R2is H, Oh or OMe;

[0372] R3is selected from: H, (Ci-Ce)alkyl, (C2-Ce)alkenyl, (C2-Ce)alkynyl, (C3-C8)cycloalkyl, (C5-C8)cycloalkenyl, (Ci-C2)alkyl(C3-C8)cycloalkyl, aryl, (Ci-C2)alkylaryl, heterocyclic, or (Ci-C2)alkylheterocyclic groups, wherein each of latter ten R3groups is optionally substituted by one or more groups selected from: OH, (Ci-C4)alkyl, (CH2)n(C3-C5)cycloalkyl, halogen, CN, (CH2)nOR6, (CH2)nN(R7)2, SMe or SEt wherein n = 0, 1 or 2; R4and R5are each independently selected from: (Ci-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (CH2)P(C3-C5)cycloalkyl, (CH2)P(C5)cyclo-alkenyl, halogen, (CH2)POR6, (CH2)PNR7R8, CN, C(O)R6, C(O)OR6, CON(R7)2, (CH2)pNR7SO2R8, CF3, CH2CF3, OCF3, OCH2CF3, SMe or SEt wherein p = 0, 1 or 2, or R4and R5can together form a fused 5- to 7-membered saturated or unsaturated ring; R6, R7and R8are each independently selected from H, Me or Et; wherein the R1and R3heterocyclic groups, where present, are optionally fused 4- to 10-membered ring systems containing up to 4 heteroatoms selected from O, N or S.

[0373] In some embodiments, preferred substituents for Formula (VIII) include: R1is selected from: (Ci-Ce)alkyl, (C3-Cs)cycloalkyl, (Ci-C2)alkyl(C3-C8)cycloalkyl, aryl, (Ci-C2)alkylaryl, heterocyclic, or (Ci-C2)alkylheterocyclic groups and wherein R1is optionally substituted by one or more groups selected from (Ci-C4)alkyl, (CH2)m(C3-C5)cycloalkyl, halogen, OMe, OEt, CN, halogen, CF3, CH2CF3, OCF3, OCH2CF3, SMe or SEt wherein m = 0, 1 or 2 and wherein said heterocyclic group is selected from: pyridinyl, pyrimidinyl, triazinyl, oxadiazinyl, oxazolyl, thiazolyl, thiadiazolyl, imidazolyl, benzimidazoloyl, benzothiazolyl, indazolyl, quinolyl or isoquinolyl; R2is H or OH; R3is H, (Ci-Ce)alkyl, (C3-Cg)cycloalkyl, (Ci-C2)alkyl(C3-Cs)cycloalkyl, (Ci-C2)alkylaryl, groups and wherein each of the latter four R3groups is optionally substituted by one or more groups selected from OH, (Ci-C4)alkyl, (CH2)n(C3-Cs)cycloalkyl, halogen, CN, (CH2)nOR6, SMe or SEt wherein n = 0 or 1; R4and R5are independently selected from (Ci-C4)alkyl, cyclopropyl, halogen, OR6, CN, CF3, CH2CF3, OCF3, OCH2CF3, sMe, SEt or R4and R5together form a fused 5 to 6 membered saturated or unsaturated ring; and wherein R6is as defined hereinbefore. In an embodiment, R1is a (Ci-C4)alkyl, (C3-C6)cycloalkyl, (Ci-C2)alkyl(C -C5)cycloalkyl, phenyl, pyridyl or pyrimidinyl group wherein R1is optionally substituted by one or more groups selected from Me, Et, halogen, OMe, OEt, CN, CF3, OCF3 and SMe; R2is OH; R3is a (Ci - Ce)alkyl group optionally substituted with one of the following groups OH, OR6, CF3; R4and R5are each independently (Ci-C4)alkyl, halogen, OR6, CN, CF3, CH2CF3, OCF3, OCH2CF3; R6is H or Me. In an embodiment, R1is an n-butyl group, a cyclohexyl group, a phenyl group, or a 4-methyl phenyl group; R2is OH; R3is an ethyl group or a t-butyl group; and R4and R5are each independently F.

[0374] In some embodiments, the MC4R agonist is a compound described in EP 1716135B1, which is incorporated herein by reference in its entirety.

[0375] In some embodiments, the MC4R agonist is a compound described in US 7,649,002, which is incorporated herein by reference in its entirety.

[0376] In one aspect, the MC4R agonist is a compound of Formula (VIIII):

[0377]

[0378] pharmaceutically acceptable salt thereof, wherein R1is H, halogen, C1-C4 alkyl, C1-C4 haloalkyl, (C3-C6) cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, or Rla, wherein each of the (C3-C6) cycloalkyl and 4- to 7-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 independently selected C1-C4 alkyl, and wherein the phenyl is optionally substituted with 1, 2, 3, or 4 independently selected RB, wherein each RBis halogen, -OH, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, Ci- C4 haloalkoxy, (C3-C4) cycloalkyl, or RB1, or two adjacent RBtogether with the two ring-forming atoms of the phenyl to which they are attached form a fused 5- or 6-membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; Rlais 5-or 6-membered heteroaryl optionally substituted with 1, 2, 3, or 4 independently selected RA, wherein each RAis halogen, -OH, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, Ci-C4 haloalkoxy, (C3-C4) cycloalkyl, -N(CI-C4 alkyl)2, RA1, or ((C3-C4) cycloalkyl)- C1-C4 alkyl-, wherein each of the C1-C4 alkyl, (C3-C4) cycloalkyl, and ((C3-C4) cycloalkyl)- C1-C4 alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; or two adjacent RAtogether with the two ring-forming atoms of the 5- or 6-membered heteroaryl to which they are attached form a fused benzene ring or a fused 5- or 6-membered heteroaryl or a fused 5- or 6-membered heterocycloalkyl or a fused 5- or 6-membered cycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, Ci-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; RA1is 5- or 6-membered heteroaryl or 5- or 6-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-C4 alkyl, Ci-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; RB1is 5- or 6-membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; X1is C(RX)2, wherein each Rxis independently H or C1-C4 alkyl; each of R2and R3is independently H, halogen, C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl, (C1-C4 alkoxy)- C1-C4 alkyl-, (C3-C4) cycloalkyl, or ((C3-C4) cycloalkyl)- C1-C4 alkyl, wherein each of (C3-C4) cycloalkyl and ((C3-C4) cycloalkyl)- C1-C4 alkyl- is optionally substituted with 1, 2, 3, 4, or 5 oxy substituents each independently selected from halogen, -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; or R2and R3together with the carbon atom to which they are attached form (C3-C6) cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 and substituents each independently selected from halogen, -OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy; each of Y1, Y2, Y3, Y4, and Y5is independently CR4or N, provided that no more than 3 of Y1, Y2, Y3, Y4, and Y5are N; and each R4is independently H, halogen, -OH, -CN, C1-C4 alkyl, Ci-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -N(CI-2 alkyl)2, (C3-C4) cycloalkyl, or ((C3-C4) cycloalkyl)- C1-C4 alkyl-, wherein each of the C1-C4 alkyl, (C3-C4) cycloalkyl, and ((C3-C4) cycloalkyl)- C1-C4 alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, - CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy.

[0379] In some embodiments, compounds of Formula (IX) include Formulas (IXa), (IXb) and

[0380]

[0381] are as defined above.

[0382] In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (IXc) or a pharmaceutically acceptable salt thereof, and wherein the variables R1, R2, R3, Y1, Y2, Y3, Y4, and Y5are as defined in Formula (IX). In some embodiments, R1is H, halogen, (C1-C4) alkyl, (C1-C4) haloalkyl, (C3-C6) cycloalkyl, 4- to 7-membered heterocycloalkyl optionally substituted with 1 to 4 (C1-C4) alkyl, or Rla; Rlais 5- or 6-membered heteroaryl optionally substituted with 1, 2, 3, or 4 independently selected RA, wherein each RAis halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, (C3-C4) cycloalkyl, or ((C3-C4) cycloalkyl)- (C1-C4) alkyl-, wherein each of the (Ci-C4) alkyl, (C3-C4) cycloalkyl, and ((C3-C4) cycloalkyl)- (C1-C4) alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, and (C1-C4) haloalkoxy; or two adjacent RAtogether with the two-ring atoms of the 5- or 6- membered heteroaryl to which they are attached form a fused benzene ring or a fused 5- or 6- membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, (Ci-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, and (C1-C4) haloalkoxy. In an embodiment, R1is H, halogen, or a 4- to 7-membered heterocycloalkyl. In some embodiments, R1is H or halogen. In some embodiments, R1is H. In an embodiment, R1is halogen (e.g., Cl). In some embodiments, R1is 4- to 7-membered heterocycloalkyl (e.g., tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholino) optionally substituted with 1 to 4 (C1-C4) alkyl. In some embodiments, R1is Rla. In some embodiments, R1is Rla; and Rlais a 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 independently selected RA, wherein each RAis halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, (C3-C4) cycloalkyl, or ((C3-C4) cycloalkyl)-(Ci-C4) alkyl-, wherein each of the (C1-C4) alkyl, (C3-C4) cycloalkyl, and ((C3-C4) cycloalkyl)-(Ci-C4) alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, and (C1-C4) haloalkoxy; or two adjacent RAtogether with the two ring-atoms of the 5- membered heteroaryl to which they are attached form a fused 5- or 6-membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, and (C1-C4) haloalkoxy. In some embodiments, Rlais a 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 independently selected RA, wherein each RAis halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, (C3-C4) cycloalkyl, or ((C3-C4) cycloalkyl)-(Ci-C4) alkyl-, wherein each of the (C1-C4) alkyl, (C3-C4) cycloalkyl, and ((C3-C4) cycloalkyl)-(Ci-C4) alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, and (C1-C4) haloalkoxy. In some embodiments, Rlais a 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 independently selected RA, wherein each RAis halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, or (C3-C4) cycloalkyl. In some embodiments, each of the ring-forming atoms of the 5 -membered heteroaryl of Rlais a carbon or nitrogen atom. In some embodiments, Rlais pyrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2-thiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3 -thiazolyl, imidazolyl, pyrazolo[l,5-a]pyrimidinyl, or [l,2,4]triazolo[l,5-a]pyridinyl-, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, and (C3-C4) cycloalkyl. In some embodiments, Rlais 1H- pyrazol-4-yl, lH-l,2,4-triazol-3-yl, 2H-l,2,3-triazol-4-yl, 2H-tetrazol-5-yl, 1,2-thiazol-5-yl, 1,3,4- thiadiazol-2-yl, l,2,4-thiadiazol-5-yl, l,3,4-oxadiazol-2-yl, l,2,4-oxadiazol-3- yl, l,3-thiazol-2-yl, l,3-thiazol-4-yl, lH-imidazol-4-yl, pyrazolo[l,5-a]pyrimidin-3-yl, or [l,2,4]triazolo[l,5-a]pyridin-2-yl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, and (C3-C4) cycloalkyl. In some embodiments, R1is Rla; and Rlais a 5-membered heteroaryl substituted with 2, 3, or 4 independently selected RA, wherein each RAis halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (Ci-C4) haloalkoxy, (C3-C4) cycloalkyl, or ((C3-C4) cycloalkyl)-(Ci-C4) alkyl-, wherein each of the (C1-C4) alkyl, (C3-C4) cycloalkyl, and ((C3-C4) cycloalkyl)-(Ci-C4) alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, and (C1-C4) haloalkoxy; or two adjacent RAtogether with the two ring-atoms of the 5-membered heteroaryl to which they are attached form a fused 5- or 6-membered heteroaryl or a fused 5- or 6- membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, and (C1-C4) haloalkoxy. In some embodiments, two RAare adjacent and they, together with the two ring-atoms of the 5-membered heteroaryl to which they are attached, form a fused 5- or 6-membered heteroaryl which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, and (C1-C4) haloalkoxy; and wherein each of the rest RA, if present, is independently halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, (C3-C4) cycloalkyl, or ((C3-C4) cycloalkyl)-(Ci-C4) alkyl-, wherein each of the (C1-C4) alkyl, (C3-C4) cycloalkyl, and ((C3-C4) cycloalkyl)-(Ci-C4) alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, and (C1-C4) haloalkoxy. In some embodiments, two RAare adjacent and they, together with the two ring-atoms of the 5-membered heteroaryl to which they are attached form a fused 5-or 6-membered heterocycloalkyl which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, and (C1-C4) haloalkoxy; and wherein each of the rest RA, if present, is independently halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, (C3-C4) cycloalkyl, or ((C3-C4) cycloalkyl)- (C1-C4) alkyl-, wherein each of the (C1-C4) alkyl, (C3-C4) cycloalkyl, and ((C3-C4) cycloalkyl)- (C1-C4) alkyl- is optionally substituted with 1, 2, 3, 4, or 5

[0383] Ill substituents each independently selected from halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, and (C1-C4) haloalkoxy. In an embodiment, R1is Rla; and Rlais 6-membered heteroaryl optionally substituted with 1, 2, 3, or 4 independently selected RA, wherein each RAis halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, (C3-C4) cycloalkyl, or ((C3-C4) cycloalkyl)- (C1-C4) alkyl-, wherein each of the (Ci-C4) alkyl, (C3-C4) cycloalkyl, and ((C3-C4) cycloalkyl)- (C1-C4) alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, and (C1-C4) haloalkoxy; or two adjacent RAtogether with the two ring-atoms of the 6- membered heteroaryl to which they are attached form a fused benzene ring or a fused 5- or 6- membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, and (C1-C4) haloalkoxy. In some embodiments, Rlais 6-membered heteroaryl optionally substituted with 1, 2, 3, or 4 independently selected RA, wherein each RAis halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, (C3-C4) cycloalkyl, or ((C3-C4) cycloalkyl)- (C1-C4) alkyl-, wherein each of the (Ci-C4) alkyl, (C3-C4) cycloalkyl, and ((C3-C4) cycloalkyl)- (C1-C4) alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, and (C1-C4) haloalkoxy. In some embodiments, Rlais 6-membered heteroaryl optionally substituted with 1, 2, 3, or 4 independently selected RA, and wherein each RAis halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, or (C3-C4) cycloalkyl. In some embodiments, each of the ring-forming atoms of the 6-membered heteroaryl of Rlais a carbon or nitrogen atom. In some embodiments, 1, 2, or 3 of the ring-forming atoms of the 6-membered heteroaryl of Rlaare nitrogen atoms (and the rest of the ring-forming atoms are carbon atoms). In some embodiments, Rlais pyridinyl, pyridazinyl, pyrazinyl, or pyrimidinyl, each of which is optionally substituted with 1, 2, or 3 independently selected RA, wherein each RAis halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, or (C3-C4) cycloalkyl. In an embodiment, Rlais pyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazin-2-yl, pyrimidin-2-yl, pyrimidin-4-yl, or pyrimidin-5-yl, each of which is optionally substituted with 1, 2, or 3 independently selected RA, wherein each RAis halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, or (C3-C4) cycloalkyl. In some embodiments, Rlais pyrimidinyl optionally substituted with 1, 2, or 3 independently selected RA, wherein each RAis halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, or (C3-C4) cycloalkyl. In some embodiments, Rlais pyrimidin-2-yl optionally substituted with 1 or 2 independently selected RA, wherein each RAis halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, or (C3-C4) cycloalkyl. In some embodiments, Rlais pyrimidin-2-yl. In some embodiments, R1is phenyl, wherein the phenyl is substituted with 3 or 4 independently selected RB, wherein two adjacent RBtogether with the two ring-forming atoms of the phenyl to which they are attached form a fused 5- or 6-membered heteroaryl, each of which each is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, and (C1-C4) haloalkoxy; and wherein each of the rest RBis independently halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, or (C3-C4) cycloalkyl; In some embodiments, R1is 1,2- benzoxazolyl (e.g., 2-benzoxazol-6-yl) or 1,3 -benzothiazolyl (e.g., l,3-benzothiazol-5-yl), each optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, - OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy. In some embodiments, R1is phenyl, wherein the phenyl is substituted with RBIand optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, and (C3-C4) cycloalkyl. In some embodiments, RB1is 1,3,4-oxadiazolyl (e.g., l,3,4-oxadiazol-2-yl), 1,2,4-oxadiazolyl (e.g., l,2,4-oxadiazol-3-yl), or 1,3- oxazolyl (e.g., l,3-oxazol-5-y), each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, and (C3-C4) cycloalkyl. In some embodiments, X1is CH2. In some embodiments, X1is CH(CH3). In some embodiments, each of R2and R3is independently H, F, or (C1-C4) alkyl. In some embodiments, each of R2and R3is independently H, F, or (Ci-C2)alkyl. In some embodiments, each of R2and R3is independently H or (C1-C4) alkyl. In some embodiments, each of R2and R3is independently H or (Ci-C2)alkyl. In an embodiment, each of R2and R3is independently H or methyl. In some embodiments, R2is (Ci-C4) alkyl and R3is H. In some embodiments, R2is (Ci-C2)alkyl and R3is H. In some embodiments, R2is methyl and R3is H. In some embodiments, each of Y1, Y2, Y3, Y4, and Y5is independently CR4. In some embodiments, one of Y1, Y2, Y3, Y4, and Y5is N, and each of the rest is independently CR4. In some embodiments, Y3is N, and each of Y1, Y2, Y4, and Y is independently CR4. In some embodiments, two of Y1, Y2, Y3, Y4, and Y3are N, and each of the rest of Y1, Y2, Y3, Y4, and Y5is independently CR4. In some embodiments, Y1is N, Y3is N, and each of Y2, Y4, and Y5is independently CR4. In some embodiments, each R4is independently H, halogen, (Ci-C2)alkyl, (Ci-C2)haloalkyl, -N((CI-C4) alkyl)2, (Ci-C2)alkoxy, or (Ci-C2)haloalkoxy. In some embodiments, each R4is independently H, F, Cl, -CH3, Ci fluoroalkyl, -OCH3, or Ci fluoroalkoxy. In some embodiments, each R4is independently H, halogen, or (Ci-C2)alkoxy. In some embodiments, each R4is independently H, F, Cl, or -OCH3. In some embodiments, each R4is independently H, F, or -OCH3. In some embodiments, R1is Rla; Rlais pyrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2-thiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3 -thiazolyl, imidazolyl, pyrazolo[l,5-a]pyrimidinyl, or [l,2,4]triazolo[l,5-a]pyridinyl-, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, and (C3-C4) cycloalkyl; X1is CH2 or CH(CH3); R2is (C1-C2) alkyl and R3is H; one of Y1, Y2, Y3, Y4, and Y3is N, and each of the rest of Y1, Y2, Y3, Y4, and Y5is independently CR4; and each R4is independently H, F, Cl, -CH3,

[0384] Ci fluoroalkyl, -OCH3, or Ci fluoroalkoxy. In some embodiments, R1is R1a; Rlais 1,2,4-triazolyl, 1,2,3-triazolyl, or tetrazolyl (e.g., 2H-tetrazol-5-yl), each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, - OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, and (C3-C4) cycloalkyl; X1is CH2; R2is (Ci-C2)alkyl and R3is H; Y3is N, and each of Y1, Y2, Y4, and Y3is independently CR4; and each R4is independently H, F, Cl, -CH3, Ci fluoroalkyl, -OCH3, or Ci fluoroalkoxy. In some embodiments, R1is Rla; Rlais tetrazolyl (e.g., 2H-tetrazol-5-yl) optionally substituted with 1, 2, or 3 independently selected RA, wherein each RAis halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, or (C3-C4) cycloalkyl (e.g., Rlais 2H-tetrazol-5-yl substituted with (C1-C4) alkyl such as methyl); X1is CH2; R2is methyl and R3is H; Y3is N, and each of Y1, Y2, Y4, and Y5is independently CR4; and each R4is independently H, F, Cl, or -OCH3. In some embodiments, R1is Rla; Rlais pyrazolyl (e.g., lH-pyrazol-4-yl) optionally substituted with 1, 2, or 3 independently selected RA, wherein each RAis halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, or (C3-C4) cycloalkyl (e.g., Rlais lH-pyrazol-4-yl substituted with (C1-C4) alkyl such as methyl); X1is CH2; R2is methyl and R3is H; Y3is N, and each of Y1, Y2, Y4, and Y3is independently CR4; and each R4is independently H, F, Cl, or -OCH3 (e.g., each R4is independently H, F, or - OCH3). In some embodiments, R1is Rla; Rlais pyridinyl, pyridazinyl, pyrazinyl, or pyrimidinyl, each of which is optionally substituted with 1, 2, or 3 independently selected RA, wherein each RAis halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, or (C3-C4) cycloalkyl; X1is CH2 or CH(CH3); R2is (Ci-C2)alkyl and R3is H; one of Y1, Y2, Y3, Y4, and Y3is N, and each of the rest of Y1, Y2, Y3, Y4, and Y3is independently CR4; and each R4is independently H, F, Cl, -CHF2, or -OCH3. In some embodiments, R1is Rla; Rlais pyridinyl, pyridazinyl, pyrazinyl, or pyrimidinyl, each of which is optionally substituted with 1, 2, or 3 independently selected RA, wherein each RAis halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, or (C3-C4) cycloalkyl; X1is CH2; R2is (C1-C2) alkyl and R3is H; Y3is N, and each of Y1, Y2, Y4, and Y5is independently CR4; and each R4is independently H, F, or -OCH3. In some embodiments, R1is Rla; Rlais pyrimidinyl (e.g., pyrimidin-2-yl) optionally substituted with 1, 2, or 3 independently selected RA, wherein each RAis halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, or (C3-C4) cycloalkyl (e.g., Rlais unsubstituted pyrimidin-2-yl); X1is CH2; R2is methyl and R3is H; Y3is N, and each of Y1, Y2, Y4, and Y5is independently CR4; and each R4is independently H, F, Cl, or -OCH3 (e.g., each R4is independently H, F, or -OCH3). In some embodiments, R1is Rla; Rlais [l,2,4]triazolo[l,5-a]pyridin-2-yl optionally substituted with 1, 2, or 3 independently selected RA, wherein each RAis halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, or (C3-C4) cycloalkyl (e.g., Rlais unsubstituted [l,2,4]triazolo[l,5-a]pyridin-2-yl); X1is CH2; R2is methyl and R3is H; Y3is N, and each of Y1, Y2, Y4, and Y5is independently CR4; and each R4is independently H, F, Cl, or -OCH3 (e.g., each R4is independently H, F, or - OCH3). In some embodiments, R1is Rla; Rlais pyridinyl, pyridazinyl, pyrazinyl, or pyrimidinyl, each of which is optionally substituted with 1, 2, or 3 independently selected RA, wherein each RAis halogen, -OH, -CN, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, or (C3-C4) cycloalkyl; X1is CH2 or CH(CH3); R2is (Ci-C2)alkyl and R3is H; each of Y1, Y2, Y3, Y4, and Y3is independently CR4; and each R4is independently H, F, C1,-CH3, -CF3, -CHF2, or -OCH3. In some embodiments, R1is H; X1is CH2 or CH(CH3); each of R2and R3is independently H or (Ci-C2)alkyl (e.g., each of R2and R3is H); each of Y1, Y2, Y3, Y4, and Y3is independently CR4; and each R4is independently H, F, Cl, -CH3, -CF3, -CHF2, or -OCH3 (e.g., each R4is independently H or F, for example, one of R4is F and each of the remaining R4is H).

[0385] In some embodiments, compounds of Formula (IX) include:

[0386]

[0387]

[0388]

[0389]

[0390] or pharmaceutically acceptable salt thereof.

[0391] In some embodiments, compounds of Formula (IX) include:

[0392]

[0393]

[0394]

[0395]

[0396] or pharmaceutically acceptable salt thereof.

[0397] In some embodiments, the MC4R agonist is a compound described in WO 2021 / 250541, which is incorporated herein by reference in its entirety.

[0398] In one aspect, the MC4R agonist is a compound of Formula (X):

[0399]

[0400] r pharmaceutically acceptable salts, solvates (including hydrates), and prodrugs thereof, wherein n is 0 or 1; R1is -(Ci-C4)alkyl, or Het1; R2is phenyl or pyridyl, wherein said phenyl or pyridyl is optionally substituted by one to three substituents independently selected from halo, CN, -(Ci-C4)alkyl and -(Ci-C4)alkoxy wherein the -(Ci-C4)alkyl and -(Ci-C4)alkoxy groups are optionally substituted with 1 to 3 fluorine atoms; R3is phenyl or pyridyl, wherein said phenyl or pyridyl is optionally substituted by one to three substituents independently selected from halo, CN, -(Ci-C4)alkyl and -(Ci-C4)alkoxy wherein the -(Ci-C4)alkyl and -(Ci-C4)alkoxy groups are optionally substituted with 1 to 3 fluorine atoms; either L is -CO- and R4is -(Ci-C4)alkyl, -(Ci-C4)alkoxy, -(C3-C6)cycloalkyl, -(Ci-C2)alkyl(C3-C6)cycloalkyl, -(Ci-C2)alkyl(Ci-C4)alkoxy, -NH2, -NH(C-C4)alkyl, -N[(Ci-C4)alkyl]2 or Het2, wherein the -(Ci-C4)alkyl group is optionally substituted with 1 to 3 fluorine atoms and wherein the -(C3-C6)cycloalkyl group is optionally substituted with 1 to 3 fluorine atoms or -(Ci-C4)alkyl groups; or L is -SO2- and R4is -(Ci-C4)alkyl; -(C3-C6)cycloalkyl, -(Ci-C2)alkyl(C3-Ce)cycloalkyl, -(Ci-C2)alkyl(Ci-C4)alkoxy, -NH2, -NH(Ci-C4)alkyl, -N[(Ci-C4)alkyl]2, or Het2; Het1is (i) a 6-membered ring containing one or 2 N atoms, wherein the ring is either aromatic, or contains 2 double bonds in the ring and a =0 substituent, which ring is optionally substituted by one to three substituents independently selected from halo, CN, and -(Ci-C4)alkyl; (ii) a 6-membered aromatic ring containing one or 2 N atoms fused at the 3,4-positions, relative to the attachment to the pyrrolidine ring, to a 5- membered aromatic ring containing one to three further N atoms; or (iii) tetrahydropyranyl; Het2is (i) a 5-membered aromatic ring containing one or 2 N atoms and a further optional O atom, S atom or N atom, (ii) a 4- to 6-membered saturated ring containing one N atom; or (iii) a 6-membered saturated ring containing one O atom and a further optional N atom. The term "alkyl" refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon radical containing the specified number of carbon atoms.

[0401] In some embodiments, R1is -(Ci-C4)alkyl. In an embodiment, R1is t-butyl. In an embodiment, R1is Het1where Het1is (i) a 6-membered ring containing one or 2 N atoms, wherein the ring is either aromatic, or contains 2 double bonds in the ring and a =0 substituent, which ring is optionally substituted by a substituent selected from halo, CN, and -(Ci-C4)alkyl; or (ii) a 6-membered aromatic ring containing one or 2 N atoms fused at the 3,4-positions, relative to the attachment to the pyrrolidine ring, to a 5-membered aromatic ring containing one or two further N atoms. In an embodiment, R1is Het1where Het1is pyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, 6-oxo- l,6-dihydropyridazin-3-yl, 6-oxo-l,6-dihydropyridin-3-yl, 2-oxo-l,2-dihydropyrimidin-4-yl, 6-oxo- l,6-dihydropyrimidin-4-yl, 2-oxo-l,2-dihydropyridin-4-yl, [l,2,4]triazolo[4,3-b]pyridazin-6-yl or 6-oxo-l,6-dihydropyridin-2-yl, optionally substituted by one or two substituents independently selected from -(Ci-C4)alkyl, halo and CN. In an embodiment, R1is Het1where Het1is 6-oxo-l,6-dihydropyridazin-3-yl, l-methyl-6-oxo-l,6-dihydropyridazin-3-yl, or [l,2,4]thiazolo[4,3-b]pyridazin-6-yl.

[0402] In an embodiment, R2is phenyl or pyridyl, wherein said phenyl or pyridyl is optionally substituted by one or two substituents independently selected from halo, CN, -(Ci-C4)alkyl and -(Ci-C4)alkoxy. In an embodiment, R2is 2,4-difluorophenyl, 2-fluoro-4-methoxyphenyl, 4-cyanophenyl or 5-chloropyrid-2-yl. In an embodiment, R3is phenyl optionally substituted by one or two substituents independently selected from halo and (Ci-C4)alkoxy. In an embodiment, R3is 4-chlorophenyl. In an embodiment, L is -CO- and R4is -(Ci-C4)alkyl optionally substituted with 1 to 3 fluorine atoms, -(Ci-C4)alkoxy, -(C3-C6)cycloalkyl optionally substituted with 1 or 2 fluorine atoms or -(Ci-C4)alkyl groups, -(Ci-C2)alkyl(C3- Ce)cycloalkyl, -(Ci-C2)alkyl(Ci-C4)alkoxy, -NH(Ci-C4)alkyl, -N[(Ci-C4)alkyl]2 or Het2wherein Het2is a 5-membered aromatic ring containing 2 N atoms or a 6- membered saturated ring containing one O atom and a further optional N atom. In an embodiment, L is -CO- and R4is -(Ci-C4)alkyl or -(Ci-C4)alkoxy wherein the -(Ci-C4)alkyl group is optionally substituted with 1 to 3 fluorine atoms.

[0403] In some embodiments, compounds of Formula (X) include:

[0404]

[0405]

[0406]

[0407]

[0408] or pharmaceutically acceptable salts, solvates (including hydrates), and prodrugs thereof.

[0409] In some embodiments, the MC4R agonist is a compound described in WO 2010 / 015972, which is incorporated herein by reference in its entirety.

[0410] In one aspect, the MC4R agonist is a compound of Formula (XI):

[0411]

[0412] wherein n is 1 or 2; R6is selected from H, Ci-Ce alkyl, Cs-Cscycloalkyl, aryl, heterocyclyl, heteroaryl, C(O)Ci-Cealkyl, CChCi-Cealkyl, wherein each of said moieties is optionally substituted with one or more substituents independently selected from halo, CN, OH, =0, NH2, NHCH3, N(CH3)2, Ci-C4alkyl and Ci-C4alkoxy; R7is selected from pyridinyl and phenyl, wherein said pyridinyl or said phenyl is optionally substituted by 1-3 groups independently selected from halo, CN, CF3, OCF3, 0Ci-C4alkyl and Ci-C4alkyl;

[0413] R10is a substituted piperidine group of formula (

[0414]

[0415] wherein R1and R4are each independently selected from H, Ci-C4alkyl, OH, 0(Ci-C4alkyl), CH2OCH3 and NR8R9; R2is selected from H, OH, 0Ci-C4alkyl and NR8R9; R3is selected from aryl or heteroaryl, wherein said moieties are optionally substituted with one or more substituents independently selected from halo, CN, CF3, OCF3, O(Ci-C4alkyl), and Ci-C4alkyl; R5is selected from H and Ci-C4alkyl; R8is selected from H and Ci-C4alkyl, wherein said Ci-C4alkyl is optionally substituted with OH or OCH3; R9is selected from H, Ci-C4alkyl, SO2Ci-C4alkyl, C(O)Ci-C4alkyl; wherein aryl means a six or ten membered aromatic hydrocarbon ring which is optionally fused to another six or ten membered aromatic hydrocarbon ring; wherein heteroaryl means a 5 or 6 membered aromatic ring, containing from 1 to 4 heteroatoms, said heteroatoms each independently selected from O, S and N, wherein said aromatic ring may be optionally fused to an aryl or second, non-fused, aromatic heterocyclic ring; wherein heterocyclyl means a 4 to 7 membered saturated or partially saturated ring, containing from 1 to 2 heteroatoms each independently selected from O, S and N; wherein halo means Cl, F, Br or I; and pharmaceutically acceptable salts, hydrate, solvates, polymorphs and prodrugs thereof, with the provisos that: R1, R4and R5are not all simultaneously H; when R1is methyl and R4is H, then R5is not methyl; when R4is methyl and R5is H, then R1is not methyl; and when R5is methyl and R4is H, then R1is not methyl.

[0416] In some embodiments, preferred compounds of Formula (XI) include: preferably n is 1. Preferably R1is selected from H, methyl, OH, OCH3, OC2H5 and NR8R9. More preferably R1is selected from H, methyl, OH, OCH3 and OC2H5. More preferably still R1is selected from H, methyl, OH and OCH3. Most preferably R1is selected from H, methyl and OCH3. Preferably R2is selected from H, OH, and OCi-C4alkyl. More preferably R2is selected from H, OH, OCH3 and OC2H5. Most preferably R2is selected from OH, OCH3 and OC2H5. Preferably R3is selected from aryl or heteroaryl, wherein said moieties are optionally substituted with one or more substituents independently selected from halo, CN, CF3, OCF3, OCH3, OC2H5, methyl and ethyl. More preferably R3is selected from phenyl or heteroaryl, wherein said moieties are optionally substituted with one or more substituents independently selected from Cl, F, CN, CF3, OCF3, OCH3, and methyl. More preferably still R3is selected from phenyl or pyridinyl, wherein said moieties are optionally substituted with one or more substituents independently selected from F, Cl, CN, OCH3 and CF3. Most preferably R3is selected from phenyl and 2-pyridinyl, wherein said phenyl or 2-pyridinyl is optionally substituted with one or more substituents independently selected from F and Cl. Preferably R4is selected from H, methyl, OH, OCH3, OC2H5 and NR8R9. More preferably R4is selected from H, methyl, OH, OCH3 and OC2H5. More preferably still R4is selected from H, methyl, OCH3 and OC2H5. Most preferably R4is selected from H, methyl and OCH3. Preferably R5is selected from H, methyl and ethyl. More preferably R5is selected from H and methyl. Most preferably R3is H. Preferably R6is selected from Ci-Csalkyl, Cs-Cscycloalkyl, heterocyclyl, heteroaryl, C(O)Ci-Cealkyl, CChCi-Cealkyl, wherein each of said moieties are optionally substituted with one or more substituents independently selected from halo, CN, OH, =0, Ci-C4alkyl and Ci-C4alkoxy. More preferably R6is selected from Ci-Cealkyl, heterocyclyl, heteroaryl, C(O)Ci-Cealkyl, C02Ci-Cealkyl, wherein each of said moieties are optionally substituted with one or more substituents independently selected from halo, CN, OH, =0, Ci-C4alkyl and Ci-C4alkoxy. More preferably still R6is selected from Ci-C4alkyl, tetrahydropyranyl, tetrahydrofuranyl, pyrimidinyl, pyridinyl and pyridazinyl, wherein each of said moieties are optionally substituted with one or more substituents independently selected from halo, CN, OH, =0, methyl and OCH3. Most preferably R6is selected from t-butyl, 4-tetrahydropyranyl, 3-pyridazinyl, 4-pyrimidinyl, 2-pyridinyl and 3-pyridinyl, wherein the said heteroaryl group is optionally substituted by F, OH, =0, OCH3, and CN. Preferably R7is selected from pyridinyl and phenyl, wherein said pyridinyl or said phenyl is substituted by 1-3 groups independently selected from halo, CN, CF3, OCF3, OCH3 and methyl. More preferably R7is selected from pyridinyl and phenyl, wherein said pyridinyl or said phenyl is substituted by 1-2 groups independently selected from Cl, F, CN and OCH3. More preferably still R7is 5-chloropyridin-2-yl or phenyl substituted by 1-2 groups independently selected from Cl, F, OCH3 and CN. Most preferably R7is 5-chloropyridin-2-yl, 2,4-difluorophenyl or 4-methoxyphenyl. Preferably R8is selected from H, methyl, ethyl and propyl wherein said alkyl group is optionally substituted with OH or OCH3. More preferably R8is selected from H, methyl and ethyl. Most preferably R8is selected from H and methyl. Preferably R9is selected from H, Ci-C4alkyl and SO2Ci-C4alkyl. More preferably R9is selected from H and Ci-C4alkyl. Most preferably R9is selected from H and methyl.

[0417] In some embodiments, compounds of Formula (XI) include:

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424] and their pharmaceutically acceptable salts, hydrates, solvates, polymorphs and prodrugs.

[0425] In some embodiments, the MC4R agonist is a compound described in WO 2007 / 015162, which is incorporated herein by reference in its entirety.

[0426] In one aspect, the MC4R agonist is a compound of Formula (XXI):

[0427]

[0428] pharmaceutically acceptable salt, hydrate, solvate, isomer or prodrug thereof, wherein: R1is selected from: -(Ci-C6)alkyl, -(C2-Ce)alkenyl, -(C2-Ce)alkynyl, -(C3-Cs)cycloalkyl, -(C5-Cs)cycloalkenyl, -(Ci-C2)alkyl(C3-Cs)cycloalkyl, aryl, -(Ci-C2)alkylaryl, heterocyclic, or -(Ci-C2)alkylheterocyclic groups, wherein each of the foregoing R1groups is optionally substituted by one or more groups selected from: -(Ci-C4)alkyl, -(CH2)m(C3-C5)cycloalkyl, halogen, -(CH2)mOR6, -CN, -C(O)OR6, -(CH2)mNR7SO2R8, CF3, CH2CF3, OCF3 or OCH2CF3 wherein m = 0, 1 or 2; R2is H, OH or OCH3; R3is selected from: H, -(Ci-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-Cs)cycloalkyl, -(C5-Cs)cycloalkenyl, -(Ci-C2)alkyl(C3-C8)cycloalkyl, aryl, -(Ci-C2)alkylaryl, heterocyclic, or -(Ci-C2)alkylheterocyclic groups wherein each of the latter ten R3groups is optionally substituted by one or more groups selected from: -OH, -(Ci-C4)alkyl, -(CH2)n(C3-C5)cycloalkyl, halogen, -CN, -(CH2)nOR6or-(CH2)nNR7R8wherein n = 0, 1 or 2; R4is selected from: -H, -(Ci-C4)alkyl, -(C2-C4)alkenyl, -(C2-C4)alkynyl, -(CH2)p(C3-C5)cycloalkyl, -(CH2)P(C5)cyclo-alkenyl, halogen, -(CH2)POR6, (CH2)PNR7R8, -CN, -C(O)R6, -C(O)OR6, -C(O)NR7R8, -(CH2)pNR7SO2R8, CF3, CH2CF3, OCF3 or OCH2CF3 groups wherein p = 0, 1 or 2; R’ is selected from: -(Ci-C4)alkyl, -(C2-C4)alkenyl, -(C2-C4)alkynyl, -(CH2)P(C3-C5)cycloalkyl, -(CH2)P(C5)cyclo-alkenyl, halogen, -(CH2)POR6, -(CH2)PNR7R8, -CN, -C(O)R6, -C(O)OR6, -C(O)NR7R8, -(CH2)PNR7SO2R8, CF3, CH2CF3, OCF3 or OCH2CF groups wherein p = 0, 1 or 2; or R4and R5can together form a fused 5- to 7-membered saturated or unsaturated ring; R6, R7and R8are each independently selected from H, CH3 or CH2CH3; and wherein the heterocyclic groups of R1and R3are independently selected from 4- to 10- membered ring systems containing up to 4 heteroatoms independently selected from O, N or S.

[0429] In some embodiments, suitable bicyclic heteroaryl groups for use herein include: include: benzimidazolyl, benzotri azolyl, benzothiazolyl, indazolyl, indolyl, imidazopyridinyl, imidazopyrimidinyl, pyrrolopyridinyl, quinolinyl, isoquinolinyl, quinazolinyl, naphthyridinyl and pyridopyrimidinyl groups. Preferred for use herein are monocyclic 5- to 6-membered heteroaryl rings containing one or three heteroatoms from the list N and O and combinations thereof. Suitable 5-membered ring monocyclic heteroaryl groups for use herein include: triazinyl, oxadiazinyl, oxazolyl, thiazolyl, thiadiazolyl, furyl, thienyl and pyrrolyl and imidazolyl groups. Suitable 6-membered ring monocyclic heteroaryl groups for use herein include: pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl groups. Preferred R1heterocyclic rings are monocyclic 5- to 6-membered heteroaryl rings containing one or two heteroatoms from the list N and O and combinations thereof. More preferred R1heterocyclic rings are monocyclic 5- to 6-membered heteroaryl rings containing one or 2 N heteroatoms. Highly preferred R1heterocyclic rings herein are monocyclic 6-membered heteroaryl rings containing one or two N heteroatoms such as pyridinyl and pyrimidinyl. An especially preferred R1heteroaryl group herein is the pyridinyl group. Preferred R3heterocyclic rings are monocyclic 5- to 6-membered heteroaryl rings containing one or two heteroatoms from the list N and O and combinations thereof such as tetrahydropyranyl, pyridinyl, pyridazinyl, pyrazinyl and pyrimidinyl groups. More preferred R3heterocyclic rings are monocyclic 5- to 6-membered heteroaryl rings containing one or two N heteroatoms. More preferred still as R3heterocyclic rings are monocyclic 6-membered heteroaryl rings containing one or two N heteroatoms such as pyridinyl, pyridazinyl, pyrazinyl and pyrimidinyl groups. Particularly preferred R36-membered ring monocyclic heteroaryl groups for use herein are pyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, pyrazinyl, pyrimidin-5-yl and pyrimidin-2-yl groups. Especially preferred R36-membered ring monocyclic heteroaryl groups for use herein include pyri din-2 -yl, pyridin-3-yl and pyridazin-3-yl groups. Of these groups pyridazin-3-yl is most preferred. Suitable fused ring systems formed by R4and R5together may be carbocyclic ring systems or heterocyclic ring systems containing up to two heteroatoms selected from O, N or S. Including the phenyl ring to which they are attached, preferred ring systems which R4and R5may form are: indane, 1,2,3,4-tetrahydronaphthalene, indolyl, indazolyl, naphthyl, quinolyl, benzothiazolyl, benzimidazolyl, benzo[1,3]dioxolane, 2,3-dihydrobenzo[l,4]dioxine, 2,3-dihydrobenzofuran, 2,3 -dihydrobenzothiophene and 1,3-dihydroisobenzofuran.

[0430] In some embodiments, preferred groups of compounds of Formula (XXI) include those in which: (a) R1is selected from: -(Ci-Ce)alkyl, -(C3-Cs)cycloalkyl, -(Ci-C2)alkyl(C3-Cs)cycloalkyl, phenyl, -(Ci-C2)alkylaryl, heterocyclic, or -(Ci-C2)alkylheterocyclic groups wherein each of the foregoing R1groups is optionally substituted by one or more groups selected from: -(Ci-C4)alkyl, halogen, -(CH2)mOR6, CN, CF3 or OCF3, wherein m = 1 or 2;

[0431] R2is OH; R3is selected from: -H, -(Ci-C6)alkyl, -(C3-Cs)cycloalkyl, -(Ci-C2)alkyl(C3-Cs)cycloalkyl, aryl, -(Ci-C2)alkylaryl, heterocyclic, or -(Ci-C2)alkylheterocyclic groups wherein each of the latter seven R3groups is optionally substituted by one or more groups selected from: -OH, -(Ci-C4)alkyl, -(CH2)n(C3-C5)cycloalkyl, halogen, CN, -(CH2)nOR6or -(CH2)nNR7R8wherein n = 0, 1 or 2; R4is selected from: -H, -(Ci-C4)alkyl, -(CH2)P(C3-Cs)cycloalkyl, halogen, -(CH2)POR6, -(CH2)PNR7R8, -CN, -C(O)R6, -C(O)OR6, -C(O)NR7R8, -(CH2)PNR7SO2R8, CF3, CH2CF3, OCF3 or OCH2CF3 groups wherein p = 0, 1, or 2; R5is selected from: -(Ci-C4)alkyl, -(CH2)P(C3-C5)cycloalkyl, halogen, -(CH2)POR6, (CH2)PNR7R8, CN, C(O)R6, C(O)OR6, CONR7R8, (CH2)PNR7SO2R8, CF3, CH2CF3, OCF3 or OCH2CF3 groups wherein p = 0, 1 or 2; R6, R7and R8are each independently selected from H, CH3 or CH2CH3; wherein the heterocyclic group of R3is selected from mono-cyclic 5- to 6-membered ring systems containing up to 2 heteroatoms independently selected from O or N and combinations thereof, and wherein the heterocyclic group of R1is selected from mono-cyclic 5- to 6-membered ring systems containing up to 1 heteroatoms independently selected from O or N; (b) R1is selected from n-propyl, i-propyl, n-butyl, methoxymethyl, cyclopropyl, cyclohexyl, phenyl, 3 -fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, pyridin-2-yl or pyridin-3-yl groups; (c) R3is -H, -(C2-C6)alkyl, -(C3-Cs)cycloalkyl, -(Ci-C2)alkyl(C3-Cs)cycloalkyl or heterocyclic wherein each of the latter four R3groups is optionally substituted by one or more groups selected from -OH, -(Ci-C4)alkyl or -OR6wherein R6is -H, CH3 or CH2CH3 and wherein when R3is a heterocyclic group said heterocyclic group is a monocyclic 6-membered ring system containing up to 2 N heteroatoms; (d) R3is selected from: hydrogen, ethyl, i-propyl, n-propyl, n-butyl, t-butyl, i-butyl, 2-methoxyethyl, cyclopentyl, cyclobutyl, cyclopentylmethyl, pyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, pyrazinyl, pyrimidin-5-yl, pyrimidin-2-yl, pyrimidin-4-yl or tetrahydropyran-4-yl groups; (e) R4is selected from H, F or Cl and R5is selected from F or Cl; and (f) the compound is of formula (XXIc):

[0432]

[0433] wherein R1is a phenyl, 3 -fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl or pyridin-2-yl group; R2is OH; R3is t-butyl; R4is selected from: H or F and R5is selected from: F or Cl.

[0434] In one aspect, the MC4R agonist is a compound of Formula (XI):

[0435]

[0436] pharmaceutically acceptable salt, wherein n is 1 or 2; R6is selected from H, Ci-Cealkyl, Ca-Cscycloalkyl, aryl, heterocyclyl, heteroaryl, C(O)Ci-Ce alkyl and CO2C1-C6 alkyl, wherein said moieties may be optionally substituted with one or more substituents independently selected from halo, CN, C1-C4 alkyl and C1-C4 alkoxy; R7is selected from pyridinyl and phenyl, wherein said pyridinyl or said phenyl is substituted by 1-3 groups independently selected from halo, CN, CF3, OCF3, OC1-C4 alkyl and Ci-C4alkyl; R10is a

[0437]

[0438] substituted piperidine group of formula (A-i): (A-i); wherein R1and R4are each independently selected from H, Ci-C4alkyl, OH, O(Ci-C4alkyl), CH2OCH3 and NR8R9; R2is selected from H, OH, OCi-C4alkyl and NR8R9; R3is selected from aryl or heteroaryl, wherein said moieties are optionally substituted with one or more substituents independently selected from halo, CN, CF3, OCF3, O(Ci-C4alkyl), and Ci-C4alkyl; R5is selected from H and Ci-C4alkyl; R8is selected from H and Ci-C4alkyl, wherein said Ci-C4alkyl is optionally substituted with OH or OCH3; R9is selected from H, Ci-C4alkyl, SO2Ci-C4alkyl, C(O)Ci-C4alkyl; wherein aryl means a six or ten membered aromatic hydrocarbon ring which is optionally fused to another six or ten membered aromatic hydrocarbon ring; wherein heteroaryl means a 5 or 6 membered aromatic ring, containing from 1 to 4 heteroatoms, said heteroatoms each independently selected from O, S and N, wherein said aromatic ring may be optionally fused to an aryl or second, non-fused, aromatic heterocyclic ring; wherein heterocyclyl means a 4 to 7 membered saturated or partially saturated ring, containing from 1 to 2 heteroatoms each independently selected from O, S and N; wherein halo means Cl, F, Br or I; and pharmaceutically acceptable salts, hydrate, solvates, polymorphs and prodrugs thereof, with the provisos that: R1, R4and R5are not all simultaneously be H; when R1is methyl and R4is H, then R5is not methyl; when R4is methyl and R5is H, then R1is not methyl; and when R5is methyl and R4is H, then R1is not methyl.

[0439] In one aspect, the MC4R agonist is a compound of Formula (Xia):

[0440]

[0441] pharmaceutically acceptable salt thereof, wherein R1and R2are selected from the group consisting of: halogen, CF3, CH3, and OCH3; R3and R4are independently selected from (C1-C4) alkyl, -CF3, halogen, -O(Ci-C4) alkyl, -OCF3, -OCHF2, -S(O)P(Ci-C4) alkyl, and -CN, wherein alkyl is unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, (C1-C4) alkyl, trifluoromethyl, and (C1-C4) alkoxy, or wherein the R3and R4substituents taken together with the carbons to which they are attached form a 4-6 membered ring optionally containing a heteroatom selected from O, S, -NH, and -N(CI-C4) alkyl; R5is selected from the group consisting of: -C1-C3 alkyl, -(CH2)n-heteroaryl, -(CH2)nheterocycloalkyl, halogen, -OR6, -(CH2)nC(O)R6, -(CH2)nOC(O)R6, -(CH2)nC(O)OR6, -(CH2)nC N, -(CH2)nN(R6)2, -(CH2)nC(O)N(R6)2, -(CH2)nNR6C(O)R6, -(CH2)nNR6C(O)OR6, -(CH2)nNR6C(O)-heteroaryl, -(CH2)nNR6C(O)N(R6)2, -(CH2)nNR6-heteroaryl, -(CH2)nC(O)NR6N(R6)2, -(CHs)nC(O)NR6NR6C(O)R6, -(CH2)nNR6S(O)PR6, -(CH2)nS(O)PN(R6)2, -(CH2)nS(O)PR6, -O(CH2)nC(O)N(R6)2, -(CH2)nCF3, and -O(CH2)nCF3, wherein heteroaryl is unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, (C1-C4) alkyl, trifluoromethyl, and (C1-C4) alkoxy, and wherein any alkyl, heterocycloalkyl, and methylene (CH2) carbon atom in R3is unsubstituted or substituted with one to two substituents independently selected from halogen, hydroxy, oxo, (C1-C4) alkyl, trifluoromethyl, and (C1-C4) alkoxy, or two substituents on the same R5carbon atom are taken together with the carbon atom to form a 3- to 6- membered ring; each R6is independently selected from the group consisting of: hydrogen, (Ci-Cs) alkyl, phenyl, heteroaryl, -(CH2)nheterocycloalkyl, and (C3-C6) cycloalkyl, wherein alkyl, phenyl, heteroaryl, heterocycloalkyl, and cycloalkyl are unsubstituted or substituted with one to three substituents independently selected from halogen, (C1-C4) alkyl, hydroxy, and (C1-C4) alkoxy, or two R6substituents together with the atoms to which they are attached form a 4- to 8- membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, -NH, and -N(CI-C4) alkyl; r is 1 or 2; s is 0, 1, or 2; n is 0, 1, 2, 3, or 4; and p is 0, 1, or 2.

[0442] In one aspect, the MC4R agonist is a compound of Formula (Xlb):

[0443]

[0444] pharmaceutically acceptable salt thereof, wherein: R1is selected from the group consisting of: hydrogen, amidino, (C1-C4) alkyliminoyl, -(Ci-Cs) alkyl, -(CH2)H-(C3-C?) cycloalkyl, -(CH2)nheterocycloalkyl, -(CH2)n-phenyl, -(CH2)n-naphthyl, and -(CH2)n-heteroaryl, wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from R3, and alkyl, cycloalkyl, and heterocycloalkyl are unsubstituted or substituted with one to three substituents independently selected from R3and oxo; R2is selected from the group consisting of: phenyl, naphthyl, and heteroaryl, wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from R9; each R3is independently selected from the group consisting of: -(Ci-Cs) alkyl, -(CH2)n-phenyl, -(CH2)n-heteroaryl, -(CH2)nheterocycloalkyl, -(CH2)n(C3-C7) cycloalkyl, halogen, -OR8, -(CH2)nC =N, -(CH2)nN(R8)2, -(CH2)nC(O)N(R8)2, -(CH2)nC(O)NR8N(R8)2, -(CH2)nC(O)NR8NR8C(O)R8, -(CH2)nCF3, wherein phenyl and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, (C1-C4) alkyl, tri fluoromethyl, and (C1-C4) alkoxy, and wherein any alkyl, cycloalkyl, heterocycloalkyl, and methylene (CH2) carbon atom in R3is unsubstituted or substituted with one to two substituents independently selected from halogen, hydroxy, oxo, (Ci-C4) alkyl, trifluoromethyl, and (C1-C4) alkoxy, or two R3substituents on the same carbon atom are taken together with the carbon atom to form a cyclopropyl group; R4is selected from the group consisting of: hydrogen, -(Ci-Ce) alkyl, -O(Ci-Ce) alkyl, and -(CH2)^N(R8)C(O)R8; R5is selected from the group consisting of: -CF3, -(Ci-Ce) alkyl, -(Cz-Cs) alkenyl, -C2.8 alkynyl, -O(Ci-Cs) alkyl, -CH2)n(C3-C?) cycloalkyl, -(CH2)nheterocycloalkyl, -(CH2)n-phenyl, -(CH2)n-naphthyl, -(CH2)nheteroaryl, and -(CH2)n(C3-C?) bicycloalkyl, wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from R3, and alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, and bicycloalkyl are unsubstituted or substituted with one to three substituents independently selected from R3and oxo, and wherein any methylene (CH2) in R3is unsubstituted or substituted with one to two substituents independently selected from halogen, hydroxy, oxo, and (C1-C4) alkyl; R6is selected from the group consisting of: hydrogen, -(Ci-Ce) alkyl, and -O(Ci-Ce) alkyl; R7is selected from the group consisting of: -(CH2)nN(R8)2, -(CH2)nNR8C(O)R8, -(CH2)nOR8, -(CH2)nC=N, -(CH2)nC(O)OR8, -(CH2)nC(O)N(R8)2, -(CH2)nNR8C(O)N(R8)2, -(CH2)nNR8C(O)heteroaryl, -(CH2)nheteroaryl, -(CH2)nNR8S(O)PR8, -(CH2)nSR8, and -(CH2)nS(O)PR8, wherein heteroaryl is unsubstituted or substituted with one to three substituents selected from (C1-C4) alkyl; and any methylene (CH2) in R7is unsubstituted or substituted with one to two substituents independently selected from halogen, hydroxyl, oxo, and (C1-C4) alkyl, or two (C1-C4) alkyl substituents on any methylene (CH2) in R7together with the atom to which they are attached form a 3, 4, 5, or 6-membered ring optionally containing an additional heteroatom selected from O, S, -NH, and -N(CI-C4) alkyl; each R8is independently selected from the group consisting of: hydrogen, -(Ci-Cs) alkyl, -(C2-C8) alkenyl, -(CH2)n(C3-C?) cycloalkyl, -(CH2)nheterocycloalkyl, -(CH2)n-phenyl, and -(CH2)n-heteroaryl; each R9is independently selected from the group consisting of: -(Ci-Cs) alkyl, -(C2-C8) alkenyl, -(CH2)n-phenyl, -(CH2)n-naphthyl, -(CH2)n-heteroaryl, -(CH2)nheterocycloalkyl, -(CH2)n(C3-C?) cycloalkyl, halogen, -OR8, -(CH2)nC(O)R8, -

[0445]

[0446] (CH2)nS(O)PN(R8)2, -(CH2)nS(O)pR8, -O(CH2)nC(O)N(R8)2, -(CH2)nCF3, and -O(CH2)nCF3, wherein alkenyl, phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, (C1-C4) alkyl, trifluoromethyl, and (C1-C4) alkoxy, and wherein alkyl, cycloalkyl, heterocycloalkyl, and any methylene (CH2) carbon atom in R9are unsubstituted or substituted with one or two substituents independently selected from halogen, hydroxy, oxo, (C1-C4) alkyl, trifluoromethyl, and (C1-C4) alkoxy, or two R9substituents on the same carbon atom are taken together with the carbon atom to form a cyclopropyl group; r is 1 or 2; s is 0, 1 or 2; n is 0, 1, 2, 3, or 4; and p is 0, 1, or 2.

[0447] In some embodiments, the MC4R agonist is a compound described in WO 2007 / 015157, which is incorporated herein by reference in its entirety.

[0448] In one aspect, the MC4R agonist is a compound of Formula (XII):

[0449]

[0450] racemic or enantiomeric form or any combinations of these forms and wherein: A represents -CH2-, -C(O)-, -C(O)-C(Ra)(Rb)-; X represents -CH- or -N-; Raand Rbrepresent, independently, the hydrogen atom or a (Ci-Ce)alkyl radical;

[0451] R1represents the hydrogen atom, a (Ci-Cs)alkyl radical optionally substituted by hydroxy or one or more identical or different halo radicals, (C2-Ce)alkenyl, or a radical of formula -(CH2)n-X1; R2represents a (Ci-Cs)alkyl radical optionally substituted by hydroxy or one or more identical or different halo radicals, (C2-Ce)alkenyl, or a radical of formula -(CH^-X1; each X1independently represents (Ci-Ce)alkoxy, (C3-C7)cycloalkyl, adamantyl, heterocycloalkyl, aryl or heteroaryl, the (C3-C?)cycloalkyl, heterocycloalkyl, aryl and heteroaryl radicals being optionally substituted by one or more identical or different substituents chosen from: -(CH2)n-V1-Y1halo, nitro, cyano and aryl; V1represents -O-, -S- or a covalent bond; Y1represents a (Ci-Ce)alkyl radical optionally substituted by one or more identical or different halo radicals; n represents an integer from 0 to 6 and n' an integer from 0 to 2 (it being understood that when n is equal to 0, then X1does not represent the alkoxy radical); or R1and R2form together with the nitrogen atom to which they are attached, a heterobicycloalkyl or a heterocycloalkyl optionally substituted by one or more identical or different substituents chosen from: hydroxy, (Ci-Ce)alkyl optionally substituted by hydroxy, (Ci-Ce)alkoxy-carbonyl, heterocycloalkyl and -C(O)NV1Y1with V1and Y1independently representing the hydrogen atom or a (Ci-C6)alkyl; or R1and R2together form a

[0452] radical of one of the following formulas:

[0453]

[0454] R3represents -Z3, - C(R73)(R73)-Z3, -C(R73)(R73)-(CH2)p-Z3or -C(O)-Z3; R73and R73represent, independently, the hydrogen atom or a (Ci-Ce)alkyl radical; Z3represents Z3a, Z3b, Z3c, Z3d, orZ3e; Z3arepresents a (Ci-Cs)alkyl radical; Z3brepresents a (Ci-C6)alkoxy, (Ci-Ce)alkylthio, (Ci-C6)alkylamino or di((Ci-C6)alkyl)amino radical; Z3erepresents an aryl or heteroaryl radical; Z3drepresents a (Ci- Ce) alkoxy-carbonyl, amino-carbonyl, (Ci-C6)alkylamino-carbonyl, di((Ci-Cs)alkyl)amino-carbonyl, (Ci-Ce)alkyl-C(O)-NH-, (C3-C?)cycloalkyl, heterocycloalkyl radical; the (C3-C?)cycloalkyl and heterocycloalkyl radicals being optionally substituted by one or more identical or different substituents chosen from: halo, nitro, (Ci-Ce)alkoxy optionally substituted by one or more identical or different halo radicals, (Ci-Ce)alkyl optionally substituted by one or more identical or different halo radicals, (Ci-Ce)alkyl-carbonyl, (Ci-C6)alkoxy-carbonyl, aminocarbonyl, (Ci-C6)alkylamino-carbonyl, di((C-C6)alkyl)amino-carbonyl and oxy, the aryl and heteroaryl radicals being optionally substituted by one or more identical or different substituents chosen from: halo, cyano, nitro, azido, oxy, (Ci-C6)alkoxy-carbonyl-(Ci-C6)alkenyl, (Ci-C6)alkylamino-carbonyl-(Ci-C6)alkenyl, -SO2-NR31R32, heterocycloalkyl, heteroaryl or -(CH2)P'-V3-Y3; R31and R32form together with the nitrogen atom to which they are attached, a heterocycloalkyl; V3 represents -O-, -S-, -C(O)-, -C(O)-O-, -O-C(O)-, -SO2-, -SO2NH-, -NR3-SO2-, -NR3, -NR3-C(O)-, -C(O)-NR3-, -NH-C(O)-NR3- or a covalent bond. Y3represents the hydrogen atom, a (Ci-C6)alkyl radical optionally substituted by one or more identical or different halo radicals, an aryl radical optionally substituted by one or more identical or different substituents chosen from: halo, nitro, (Ci-Ce)alkyl and (Ci-Ce)alkoxy, or an aryl-(Ci-C6)alkyl radical optionally substituted by one or more identical or different substituents chosen from: halo, nitro, (Ci-C6)alkyl and (Ci-Ce)alkoxy; Z3erepresents a radical of one of the following

[0455]

[0456] formulas:7~1 21 = 1, 2, Z'3represents an aryl radical optionally substituted by one or more identical or different substituents chosen from: halo, nitro and -(CH2)p"-V3-Y3; V’3represents -O-, -C(O)-, -C(O)-O-, -C(O)-NR3-, -NH-C(O)-NR3- or a covalent bond; Y3represents the hydrogen atom or a (Ci-Cfi)alkyl radical optionally substituted by one or more identical or different halo radicals; R3represents the hydrogen atom, a (Ci-Ce)alkyl or (Ci-Ce)alkoxy radical; p represents an integer from 1 to 4; p' and p" represent, independently, an integer from 0 to 4; R4represents a radical of formula -(CH2)s-R4where R4represents the guanidine radical, a heterocycloalkyl containing at least one nitrogen atom and optionally substituted by (Ci-Ce)alkyl or aralkyl, a heteroaryl containing at least one nitrogen atom and optionally substituted by (Ci-Ce)alkyl, or a radical of formula -NW4W4where W4represents the hydrogen atom or (Ci-Cs)alkyl; W4represents a radical of formula -(CH2)s'-Z4; Z4represents the hydrogen atom, (Ci-Cx)alkyl optionally substituted by one or more identical or different substituents chosen from: (Ci-Ce)alkoxy, (Ci-Ce)alkylthio and hydroxy; (C2-Ce)alkenyl; (C3-C?)cycloalkyl optionally substituted by one or more identical or different (Ci-Ce)alkyl substituents; cyclohexene; heteroaryl and aryl; the aryl and heteroaryl radicals being optionally substituted by one or more identical or different radicals chosen of formula: -(CH2)s"-V4-Y4, hydroxy, halo, nitro and cyano; V4represents -O-, -S-, -NH-C(O)-, -NV4'- or a covalent bond; Y4represents a hydrogen atom or a (Ci-C6)alkyl radical optionally substituted by one or more identical or different halo radicals; V4represents a hydrogen atom or a (Ci-C6)alkyl; s"

[0457]

[0458] represents an integer from 0 to 4; or Z4represents a radical of formula:r'■2; s and s' represent, independently, an integer from 0 to 6; and i) when R3represents -C(O)-Z3and R4represents a radical of formula -(CH2)s-NW4W4and W4and W4represent, independently, the hydrogen atom or the (Ci-C6)alkyl radical, then -(CH2)s represents neither the ethylene radical nor the -(CH2)-CH((Ci-C4)alkyl)-radical and ii) when R3represents -Z3cand Z3crepresents a phenyl or naphthyl radical, then phenyl and naphthyl are not substituted by cyano; and it being understood that when R3represents -Z3dthen Z3donly represents one (C3-C?)cycloalkyl or heterocycloalkyl radical; or a pharmaceutically acceptable salt thereof.

[0459] In some embodiments, preferred compounds of Formula (XII) include:

[0460] R1and R2represent, independently, a (Ci-Cs)alkyl radical; R3represents -Z3e, -(RZ3)(RZ3)-Z3c, -C(RZ3)(R’Z3)-Z3d, -C(RZ3)(R'Z3)-(CH2)P-Z3d; R4represents a radical of formula -(CH2)s-R4; R4represents a heterocycloalkyl containing at least one nitrogen atom and optionally substituted by (Ci-Ce)alkyl; or a radical of formula -NW4W4; W4represents the hydrogen atom or (Ci-Cs)alkyl; W4represents a radical of formula -(CH2)s'-Z4; Z4represents the hydrogen atom; s represents an integer from 2 to 4; s' represents an integer from 0 to 4; and preferably the heterocycloalkyl represented by R4is the piperidine ring; RZ3and RZ3represent the hydrogen atom; Z3represents the thienyl, furyl or phenyl radical, the phenyl radical being substituted by one or more identical or different substituents chosen from: halo and -(CH2)P-V3-Y3;

[0461] V3represents -O-, -C(O)-, -C(O)-O-, -C(O)-NR3- or a covalent bond; R3represents the hydrogen atom or a (Ci-Ce)alkyl radical; Y3represents the hydrogen atom; a (Ci-Ce)alkyl radical optionally substituted by one or more identical or different halo radicals; Z3drepresents the (Ci-Ce)alkoxy-carbonyl or heterocycloalkyl radical, and preferably the heterocycloalkyl is imidazolidine; or a pharmaceutically acceptable salt thereof. Preferably, the invention also relates to compounds of Formula (XII) as defined above, characterized in that X represents -CH- and A represents -C(O)-C(Ra)(Rb)- with Raand Rbrepresenting the methyl radical; and more particularly R1and R2represent, independently, a (Ci-Cs)alkyl radical; R3represents -Z3c, -C(RZ3)(R'Z3)-Z3C, -C(RZ3)(R'Z3)-Z3dor -C(RZ3)(R'Z3)-(CH2)P-Z3d; R4represents a radical of formula -(CH2)s-R4; R4represents a heterocycloalkyl containing at least one nitrogen atom and optionally substituted by (Ci-C6)alkyl; or a radical of formula -NW4W4; W4represents the hydrogen atom or (Ci-C8)alkyl; W4represents a radical of formula -(CH2)s'-Z4; Z4represents the hydrogen atom, the phenyl radical or a heteroaryl; s represents an integer from 2 to 4; s' represents an integer from 0 to 4; and preferably RZ3and RZ3represent, independently, the hydrogen atom; Z3crepresents a thienyl radical optionally substituted by (Ci-Ce)alkoxy-carbonyl; or phenyl substituted by one or more identical or different substituents chosen from: halo, nitro or -(CH2)p'-V3-Y3;

[0462] V3represents -O-, -C(O)-, -C(O)-O-, -C(O)-NR3- or a covalent bond; Y3represents the hydrogen atom; a (Ci-Ce)alkyl radical optionally substituted by one or more identical or different halo radicals; R3represents the hydrogen atom; Z3drepresents a (Ci-C6)alkoxy-carbonyl radical; the heterocycloalkyl represented by R4is piperidine; the heteroaryl represented by Z4is pyridine; or a pharmaceutically acceptable salt thereof.

[0463] Preferably, the invention also relates to compounds of Formula (XII) as defined above, characterized in that X represents -CH- and A represents -C(O)-, and more particularly R3represents -C(O)-Z3; R1and R2represent, independently, a (Ci-Cs)alkyl radical; Z3represents a phenyl radical optionally substituted by one or more identical or different substituents chosen from: halo, nitro and -(CH2)P'-V'3-Y'3, where V'3represents -O-, -C(O)-O- or a covalent bond; Y3represents the hydrogen atom or a (Ci-Ce)alkyl radical;

[0464] p" represents the integer 0; R4represents a radical of formula -(CH2)s-R4where R4represents a radical of formula -NW4W'4where W4represents the hydrogen atom or (Ci-Cs)alkyl;

[0465] W4represents a radical of formula -(CH2)s'-Z4and Z4represents the hydrogen atom; s represents an integer from 2 to 4; s' represents an integer from 0 to 4; or a pharmaceutically acceptable salt thereof.

[0466] Preferably, the invention also relates to compounds of Formula (XII) as defined above, characterized in that X represents -CH- and A represents -C(O)-, and R1represents a hydrogen atom, a (Ci-Cs)alkyl radical optionally substituted by hydroxy, (C2-Ce)alkenyl or a radical of formula -(CH2)n-X1; R2represents a (Ci-Cs)alkyl radical optionally substituted by hydroxy, (C2-Ce)alkenyl or a radical of formula -(CH2)n-X1; each X1represents, independently, (Ci-C6)alkoxy, (C3-C?)cycloalkyl, aryl or heteroaryl, the aryl radical being optionally substituted by one or more identical or different substituents chosen from: -(CH2)n-V1-Y1, halo; V1represents -O- or a covalent bond; Y1represents a (Ci-Ce)alkyl radical optionally substituted by one or more identical or different halo radicals; or aryl;

[0467] or R1and R2form together with the nitrogen atom to which they are attached, a heterocycloalkyl optionally substituted by one or more identical or different substituents chosen from: hydroxy, (Ci-Cs)alkyl optionally substituted by hydroxy, (Ci-C6)alkoxy-carbonyl, heterocycloalkyl and -C(O)NV1Y1with V1and Y1' independently representing the hydrogen atom or a (Ci-Ce)alkyl, or R1and R2together form a radical of formula:

[0468]

[0469] represents -Z3, -C(RZ3)(RZ3)-Z3or -C(RZ3)(R'Z3)-(CH2)P-Z3; R4represents a radical of formula -(CH2)S-R4, where R4represents a heterocycloalkyl containing at least one nitrogen atom and optionally substituted by (Ci-C6)alkyl or aralkyl; a heteroaryl containing at least one nitrogen atom and optionally substituted by (Ci-C6)alkyl; or a radical of formula -NW4W4, where W4represents the hydrogen atom or (Ci-C8)alkyl; W4represents a radical of formula -(CH2)S'-Z4; Z4represents the hydrogen atom, (C3-C7)cycloalkyl or aryl; s represents an integer from 0 to 5; s' represents an integer from 0 to 4; and more particularly characterized in that they have at least one of the following characteristics: the (C3-C7)cycloalkyl radical represented by X1is cyclopropyl; the aryl radical represented by X1the phenyl radical; the heteroaryl radical represented by X1is pyridine; the heterocycloalkyl that R1and R2form together with the nitrogen atom to which they are attached is chosen from: pyrrolidine, piperidine, azepane, azacyclooctane, morpholine, piperazine and decahydroisoquinoline; the heterocycloalkyl radical represented by R4, optionally substituted by (Ci-C6)alkyl or benzyl, is chosen from: pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl; the heteroaryl radical represented by R4is the imidazolyl radical; the cycloalkyl represented by Z4is chosen from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; the aryl represented by Z4is phenyl; or a pharmaceutically acceptable salt thereof.

[0470] Very preferably, the invention relates to compounds of Formula (XII) as defined above, characterized in that R4represents a radical of formula -(CH2)s-R4with R4representing the pyrrolidinyl or piperidinyl radical; or a radical of formula -NW4W4, where W4represents the hydrogen atom or (Ci-Cs)alkyl; W4represents a radical of formula -(CH2)s'-Z4with

[0471] Z4representing the hydrogen atom; s represents an integer from 2 to 4; s' represents an integer from 0 to 4; or a pharmaceutically acceptable salt thereof.

[0472] Very preferably also, the invention relates to compounds of Formula (XII) as defined above, characterized in that R1and R2represent, independently, a (Ci-Cs)alkyl radical; or a pharmaceutically acceptable salt thereof. Preferably, the invention also relates to compounds of Formula (XII) as defined above, characterized in that X represents -CH-, A represents -C(O)-, and R3represents -Z3and Z3represents Z3c, Z3dor Z3e; Z3drepresents a (C3-C7)cycloalkyl or heterocycloalkyl radical; and more particularly Z3crepresents a heteroaryl radical chosen from thienyl, furyl, indolyl, dihydroindolyl, pyridyl, benzothienyl and benzofuryl; or an aryl radical chosen from phenyl, naphthyl and fluorenyl; the heteroaryl radical being optionally substituted by one or more identical or different substituents chosen from: (Ci-Ce)alkyl-carbonyl and (Ci-Ce)alkoxy-carbonyl; the aryl radical being optionally substituted by one or more identical or different substituents chosen from: halo, cyano, nitro, azido, (Ci-C6)alkoxy-carbonyl-(Ci-Ce)alkenyl, oxy, -SO2-NR31R32, heterocycloalkyl, heteroaryl, or -(CH2)P'-V3-Y3; R31and R32form together with the nitrogen atom to which they are attached, the piperidine ring; V3represents -O-, -S-, -C(O)-, -C(O)-O-, -SO2-, -SO2NH-, -NR'3-, -NR'3-C(0)-, -C(O)-NR'3-, -NH-C(O)-NR'3- or a covalent bond; Y3represents the hydrogen atom; a (Ci-C6)alkyl radical optionally substituted by one or more identical or different halo radicals; phenyl; or benzyl; R3represents the hydrogen atom, a (Ci-Ce)alkyl or (Ci-Ce)alkoxy radical; Z3drepresents the cyclopropyl, cyclohexyl or piperidinyl radical, each being able to be substituted by a (Ci-C6)alkoxy-carbonyl radical; or a pharmaceutically acceptable salt thereof.

[0473] Preferably, the invention also relates to compounds of Formula (XII) as defined above, characterized in that X represents -CH-, A represents -C(O)-, and R3represents -Z3and

[0474] Z3represents Z3c, Z3dor Z3e; Z3drepresents a (C3-C?)cycloalkyl or heterocycloalkyl radical; and more particularly Z3crepresents a heteroaryl radical chosen from thienyl, indolyl and benzothienyl; or an aryl radical chosen from phenyl and naphthyl; the heteroaryl radical being optionally substituted by one or more oxy radicals; the aryl radical being optionally substituted by one or more identical or different substituents chosen from: halo, nitro, heteroaryl or -(CH2)P-V3-Y3; V3represents -O-, -S-, -C(O)-, -C(O)-O-, -SO2-, -SO2NH-, -NR'3-C(O)-, -C(O)-NR'3-, -NH-C(O)-NR3- or a covalent bond; Y3represents the hydrogen atom; a (Ci-Ce)alkyl radical optionally substituted by one or more identical or different halo radicals; a phenyl radical; or a benzyl radical; R3represents the hydrogen atom, a (Ci-Ce)alkyl or (Ci-Ce)alkoxy radical;

[0475] Z3drepresents the cyclopropyl or piperidinyl radical, each optionally substituted by (Ci-Ce)alkoxy-carbonyl; and preferably Z3represents Z3cor Z3e; Z3crepresents a phenyl being optionally substituted by one or more identical or different substituents chosen from nitro and -(CH2)P'-V3-Y3; V3represents -O-, -S-, -C(O)-, -C(O)-O-, -SO2-, -SO2NH-, -NR'3-C(O)-, -C(O)-NR3- or a covalent bond; Y3represents the hydrogen atom; a (Ci-Ce)alkyl radical; a phenyl

[0476]

[0477] radical; or a benzyl radical; R3represents the hydrogen atom; Z3crepresents r - 1, 2; or a pharmaceutically acceptable salt thereof.

[0478] Preferably, the invention also relates to compounds of Formula (XII) as defined above, characterized in that X represents -CH-, A represents -C(O)-; R3represents -C(RZ3)(R'Z3)-Z3and Z3represents Z3b, Z3c, Z3dor Z3e; or a pharmaceutically acceptable salt thereof. Very preferably, the invention also relates to compounds of Formula (XII) as defined above, characterized in that X represents -CH-, A represents -C(0)-, and R3represents -C(RZ3)(RZ3)-Z3and Z3represents Z3bor Z3e; RZ3and RZ3represent the hydrogen atom; and more particularly Z3brepresents a (Ci-Ce)alkoxy radical; Z3crepresents a heteroaryl radical chosen from thienyl, furyl, pyridyl, benzothienyl and dihydrobenzofuryl; or an aryl radical chosen from phenyl and naphthyl, the aryl radical being optionally substituted by one or more identical or different substituents chosen from: halo or -(CH2)P-V3-Y3; V3represents -O-, -S-, -C(O)-, -C(O)-O-, -SO2-, -SO2NH-, -NR3-C(O)-, -C(O)-NR3-; Y3represents the hydrogen atom, a (Ci-Ce)alkyl radical optionally substituted by one or more identical or different halo radicals; R3represents the hydrogen atom; or a pharmaceutically acceptable salt thereof. Very preferably, the invention relates to compounds of Formula (XII) as defined above, characterized in that X represents -CH-, A represents -C(O)-, and R3represents -C(RZ3)(R'Z3)-Z3and Z3represents Z3bor Z3c; RZ3and RZ3represent the hydrogen atom; and more particularly Z3brepresents a (Ci-Ce)alkoxy radical Z3crepresents a heteroaryl radical chosen from thienyl, furyl, dihydrobenzofuryl; or a phenyl radical; the phenyl radical being optionally substituted by one or more identical or different substituents chosen from: nitro or -(CH2)P-V3-Y3; V3represents -O-, -S-, -C(O)-, -C(O)-O-, -SO2-, -SO2NH-, -C(O)-NR3-; Y3represents the hydrogen atom, or a (Ci-C6)alkyl radical optionally substituted by one or more identical or different halo radicals; R3represents the hydrogen atom; and preferably Z3represents Z3c; Z3crepresents a furyl or phenyl radical, the phenyl radical being optionally substituted by one or more identical or different substituents of formula -(CH2)P'-V3-Y3; V3represents -O-, -S-, -C(O)-, -C(O)-O-, -SO2-, -SO2NH-, -C(O)-NR'3-; Y3represents the hydrogen atom; or a (Ci-Ce)alkyl radical optionally substituted by one or more identical or different halo radicals; R3represents the hydrogen atom; or a pharmaceutically acceptable salt thereof. Very preferably, the invention also relates to compounds of Formula (XII) as defined above, characterized in that X represents -CH-, A represents -C(O)-, and R3represents -C(RZ3)(RZ3)-Z3and Z3represents Z3dor Z3e; RZ3and RZ3represent the hydrogen atom or (Ci-Ce)alkyl; Z3drepresents a (Ci-C6)alkoxy-carbonyl, (C3-C?)cycloalkyl or heterocycloalkyl radical;

[0479] Z3erepresents

[0480]

[0481] more particularly Z3drepresents a (Ci-Ce)alkoxy-carbonyl, cyclohexyl or a tetrahydrofuranyl radical; or a pharmaceutically acceptable salt thereof. Very preferably, the invention also relates to compounds of Formula (XII) as defined above, characterized in that X represents -CH-; A represents -C(O)-, and R3represents -C(RZ3)(RZ3)- Z3and Z3represents Z3dor Z3e; Z3drepresents a (Ci-Ce)alkoxy-carbonyl radical; Z3erepresents

[0482]

[0483] ; and preferably Z3represents

[0484]

[0485] pharmaceutically acceptable salt thereof.

[0486] Preferably, the invention also relates to compounds of Formula (XII) as defined above, characterized in that X represents -CH-; A represents -C(O)-; R3represents -C(RZ3)(RZ3)-(CH2)P- Z3and Z3represents Z3b, Z3cor Z3d; or a pharmaceutically acceptable salt thereof. Very preferably, the invention relates to compounds of Formula (XII) as defined above, characterized in that X represents -CH-; A represents -C(O)-; and R3represents -C(RZ3)(R'Z3)-(CH2)P-Z3and Z3represents Z3b; and more particularly RZ3and RZ3represent, independently, the hydrogen atom or a (Ci-Ce)alkyl radical; Z3brepresents a (Ci-Ce)alkoxy, (Ci-Ce)alkylthio or di((Ci- C6)alkyl)amino radical; or a pharmaceutically acceptable salt thereof. Very preferably, the invention also relates to compounds of Formula (Xll) as defined above, characterized in that X represents -CH-; A represents -C(O)-; and R3represents -C(RZ3)(RZ3)-(CH2)P-Z3and

[0487] Z3represents Z3b; and more particularly RZ3and RZ3represent, independently, the hydrogen atom or a (Ci-Ce)alkyl radical; Z3brepresents a (Ci-Ce)alkoxy or (Ci-Ce)alkylthio radical; or a pharmaceutically acceptable salt thereof. Very preferably, the invention also relates to compounds of Formula (XII) as defined above, characterized in that X represents -CH-; A represents -C(O)-; and R3represents -C(RZ3)(RZ3)-(CH2)P-Z3and Z3represents Z3cor Z3d; and more particularly RZ3and RZ3represent, independently, the hydrogen atom or a (Ci-Ce)alkyl radical; Z3crepresents an indolyl or phenyl radical; the phenyl radical being optionally substituted by one or more identical or different substituents chosen from: halo and -(CH2)P-V3- Y3; V3represents -SO2NH-; Y3represents the hydrogen atom, or a (Ci-Ce)alkyl radical;

[0488] Z3drepresents a (Ci-Cfi)alkoxy-carbonyl, amino-carbonyl, (Ci-C6)alkyl-amino-carbonyl, (Ci- Ce)alkyl-C(O)-NH-, or heterocycloalkyl radical optionally substituted by oxy, and preferably piperidinyl, morpholinyl, pyrrolidine or imidazolidinyl; or a pharmaceutically acceptable salt thereof. Very preferably, the invention also relates to compounds of Formula (XII) as defined above, characterized in that X represents -CH-; A represents -C(O)-; and R3represents - C(RZ3)(RZ3)-(CH2)P-Z3and Z3represents Z3cor Z3d; and more particularly Z3represents Z3d; RZ3and RZ3represent, independently, the hydrogen atom or a (Ci-Cs)alkyl radical; Z3drepresents a (Ci-C6)alkoxy-carbonyl, amino-carbonyl, (Ci-C6)alkylamino-carbonyl, (Ci-C6)alkyl-C(O)-NH-or heterocycloalkyl radical, and preferably pyrrolidine or imidazolidine, optionally substituted by oxy; or a pharmaceutically acceptable salt thereof.

[0489] In some embodiments, the MC4R agonist is a compound described in US 7,816,539, which is incorporated herein by reference in its entirety. In some embodiments, the MC4R agonist is a compound described in US 9,785,549, which is incorporated herein by reference in its entirety. In some embodiments, the MC4R agonist is a compound described in US 8,349,797, which is incorporated herein by reference in its entirety.

[0490] In one aspect, the MC4R agonist is a compound consisting of:

[0491]

[0492] In some embodiments, the MC4R agonist is a compound described in US 8,129,413, which is incorporated herein by reference in its entirety.

[0493] In one aspect, the MC4R agonist is a compound of Formula (XIII):

[0494] (CH2)^ - Z - Y - (CH2)n

[0495]

[0496] C(O)-His— D-Phe(X)— Arg-W— N~ C~C(O)NH2

[0497] H (XIII), wherein His is L-hi stidyl; D-Phe(X) is D-phenylalanyl unsubstituted or optionally para-substituted with a group selected from F, CI, Br, Me, OMe; Arg is L-arginyl; W is L-tryptophanyl or 2-naphthyl-L-alanyl; one of Y and Z is -C(O)- and the other is -NH-; m is 1 to 4; n is 1 to 4, provided that n+m is 4 to 6; or a pharmaceutically acceptable salt thereof. In an embodiment of Formula (XIII), Z is -C(O)- and Y is -NH-. In an embodiment, m is 2. In another subset thereof, n is 2 to 4. In an embodiment, D-Phe(X) is D-phenylalanyl optionally para-substituted with chlorine. In another embodiment Y is -C(0)- and Z is -NH-. In an embodiment, n is 2. In an embodiment, m is 2 to 4. In some embodiments, W is L-tryptophanyl and D-Phe(X) is D-phenyl alanyl. In an embodiment, the MC4R agonist is selected from the group consisting of: cyclo(NH-CH2-CH2-CO-His-D-Phe-Arg-Trp-Glu)-NH2 (SEQ ID NO: 892) and pharmaceutically acceptable salts thereof.

[0498] In some embodiments, compounds of Formula (XIII) have the following combinations of Z, Y, X, W, m, and n:

[0499]

[0500] The MC4R agonists in the provided in the table above refer to SEQ ID NOs: 893-901, respectively.

[0501] In some embodiments, the MC4R agonist is a compound described in US WO 2005 / 060985, which is incorporated herein by reference in its entirety.

[0502] In one aspect, the MC4R agonist is a compound from the group consisting of:

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510]

[0511] and pharmaceutically acceptable salts thereof.

[0512] In some embodiments, the MC4R agonist is a compound described in EP 1534074, which is incorporated herein by reference in its entirety.

[0513] In one aspect, the MC4R agonist is a compound of Formula (XIV):

[0514]

[0515] pharmaceutically acceptable salt thereof,

[0516]

[0517] or 2; each n is independently 0, 1, or 2; R1is selected from the group consisting of hydrogen, (Ci-Q) alkyl, (CHR7)n-(C3-C6) cycloalkyl, (CHR7)n-O(CHR7)aryl, (CHR7)n-aryl, and (CHR7)n-heteroaryl; in which aryl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R6; and alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R6and oxo; R2is selected from the group consisting of hydrogen, (Ci-Cs) alkyl, (CH2)n(C3-Ce) cycloalkyl, and (CH2)naryl; each R3is independently selected from the group consisting of hydrogen, (Ci-Cs) alkyl, (CH2)n-aryl, (CH2)n(C3-C6) cycloalkyl, (CH2)n-heteroaryl, and (CH2)n-heterocyclyl; in which aryl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R6; and alkyl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three groups independently selected from R6and oxo; or R3and R5aand the carbons to which they are attached form a 5- to 7-membered ring optionally containing an additional heteroatom selected from O, S, and NR7; R4aand R4bare each independently selected from the group consisting of hydrogen, (Ci-Cs) alkyl, (CH2)n-aryl, (CH2)n(C3-C6)-cycloalkyl, (CH2)n -heteroaryl, (CH2)n-heterocyclyl, COC(R7)2NH2, COR7, (CH2)nOR7, (CH2)nCO2R7, CH2CVCH. CO2R7, CH2CHF2, CONR7R7, and S(O)2R7, in which aryl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R6; and alkyl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three groups independently selected from R6and oxo; or R4aand R2and the carbons to which they are attached form a 5- to 7-membered ring optionally containing an additional heteroatom selected from O, S, and NR7; or R4aand R4band the atoms to which they are attached form a 5- to 7-membered ring; R5aand R5bare each independently selected from the group consisting of hydrogen, (Ci-Cs) alkyl, (CH2)n-aryl, and (Cs-Cs)-cycloalkyl; wherein alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from Re and oxo; aryl is unsubstituted or substituted with one to three groups independently selected from R6; or R5and R5btogether with the carbons to which they are attached form a 5- to 7- membered ring; R6is selected from the group consisting of hydrogen, (Ci-Cs) alkyl, (CH2)n-aryl, (CH2)n(C3-C7)-cycloalkyl, (CH2)n-heteroaryl, halogen, OR7, NHSO2R7, N(R7)2, ON, CO2R7, C(R7)(R7)N(R7)2, NO2, SO2N(R7)2, S(0)O-2R7, CF3, and OCF3; or two R6substituents, when on the same carbon atom, can be taken together with the carbon atom to which they are attached to form a cyclopropyl group; each R7is independently selected from the group consisting of hydrogen, (Ci-Cs) alkyl, (CH2)n-aryl, and (CH2)n(C3-C7)-cycloalkyl; each R8is independently selected from the group consisting of: hydrogen, (Ci-Cs)-alkyl, (CH2)n-aryl, (CH2)n-heteroaryl, (CH2)n-heterocyclyl, and (CH2)n(C3-C7)-cycloalkyl; wherein aryl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R6; and alkyl, cycloalkyl, heterocyclyl, and (CH2)n are unsubstituted or substituted with one to three groups independently selected from R6and oxo; or two R8groups together with the atoms to which they are attached form a 5- to 8- membered mono- or bi-cyclic ring system optionally containing an additional heteroatom selected from O, S, NR7, NBoc, and NCbz; each R9is independently selected from the group consisting of hydrogen, (Ci-Cs) alkyl, (CH2)n-aryl, (CH2)n(C3-C6) cycloalkyl, (CH2)n-heteroaryl, halogen, OR7, NHSO2R7, N(R7)2, ON, CO2R7, C(R7)(R7)N(R7)2, NO2, SO2N(R7)2, S(0)O-2R7, CF3, and OCF3; X is selected from the group consisting of (Ci-Cs) alkyl, (CH2)n(C3-Cs) cycloalkyl, (CH2)naryl, (CH2)nheteroaryl,

[0518]

[0519] (CH2)nN(R8)(R8), and (CH2)nNR8SO2N(R8)(R8); wherein aryl and heteroaryl are unsubstituted or substituted with one to three groups selected from R6; and alkyl, (CH2)n, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three groups independently selected from R6and oxo; Y is selected from the group consisting of hydrogen, (Ci-Cs)-alkyl, (CH2)n(C3-Cs)-cycloalkyl, (CH2)naryl, (CH2)nheterocyclyl, and (CH2)nheteroaryl; wherein aryl and heteroaryl are unsubstituted or substituted with one to three groups selected from R6; and alkyl, (CH2)n, cycloalkyl, and heterocyclyl are optionally substituted with one to three groups selected from R6and oxo.

[0520] In some embodiments, compounds of Formula (XIV) include: Q is

[0521]

[0522] , wherein Z is O or NR4b;and R2, R3, R4a, R4b, R5a, R5band R9are as defined herein.

[0523] In some embodiments, compounds of Formula (XIV) include: Q is

[0524]

[0525] , wherein R2, R3, R4a, R4b, R5a, R5bare as defined herein. In some embodiments, compounds of Formula (XIV) include: R4aand R4bare each independently selected from the group consisting of hydrogen, (Ci-Cs)-alkyl, (CH2)n-aryl, (CH2)n-heteroaryl, (CH2)n-heterocyclyl, (CH2)n(C3-C6) -cycloalkyl, (CH2)nCO2R7, (CH2)„OR7, COC(R7)NH2, CH2C=CH, and CH2CHF2; or R4aand R4band the atoms to which they are attached form a 6-membered ring;

[0526] R3, R5a, and R5bare each independently hydrogen, (Ci-C4)-alkyl, (Ca-Ce) cycloalkyl, or aryl; wherein aryl is unsubstituted or substituted with one to three groups independently selected from R6; or R3and R3and the carbons to which they are attached form a 6-membered ring optionally containing an additional heteroatom selected from O, S, and NR7.

[0527] In some embodiments, R4aand R4bare each independently selected from the group consisting of hydrogen, (C1-C4) alkyl, CH2-aryl, CH2-heteroaryl, CH2-heterocyclyl, (CH2)O-I(C3-C6) cycloalkyl, CH2CO2R7, (CH2)2OR7, COC(R7)NH2, CH2OCH, and CH2CHF2; or R4aand R4band the atoms to which they are attached form a 6-membered ring; R3, R5a, and R5bare each independently hydrogen, (C1-C4) alkyl, (Ca-Ce) cycloalkyl, or phenyl; wherein phenyl is unsubstituted or substituted with one to three groups independently selected from R6; or R3and R3aand the carbons to which they are attached form a 6-membered ring optionally containing an additional heteroatom selected from O, S, and NR7.

[0528] In some embodiments, compounds of Formula (XIV) include: R1is CHR7-aryl, CHR7OCHR7-aryl, or CHR7-heteroaryl wherein aryl and heteroaryl are optionally substituted with one or two R6groups. In some embodiments, R1is benzyl optionally substituted with one or two groups selected from halogen, (C1-C4) alkyl, (C1-C4) alkoxy, CN, CF3, and OCF3. In some embodiments, R1is 4-chlorobenzyl; 4-fluorobenzyl; 3,4-difluorobenzyl; 3,5-difluorobenzyl; 2-cyano-4-fluorobenzyl; or 4-methoxybenzyl. In some embodiments,

[0529] compounds of Formula (XIV) include R2is H or CH3.

[0530] In some embodiments, compounds of Formula (XIV) include: X is (Ci-Ce) alkyl, (CH2)n-aryl, (CH2)n-heteroaryl, (CH2)n-heterocyclyl, (CH2)nC(O)N(R8)(R8), (CH2)nCO2R8, (CH2)nOR8, (CH2)nS(0)o-2R8, (CH2)nNHC(O)R8, (CH2)nOC(O)NR8R8, or (CH2)nNR8SO2R8; wherein aryl and heteroaryl are optionally substituted with one to three groups selected from R6; heterocyclyl is optionally substituted with one to three groups selected from R6and oxo; the (CH2)ngroup is optionally substituted with one to three groups selected from R7, halogen, S(0)o-2R7, N(R7)2, and OR7; and R8is each independently selected from H, (Ci-Cs) alkyl, and (C3-C6) cycloalkyl optionally substituted with one to three groups selected from R6and oxo; or two R8groups together with the atoms to which they are attached form a 5- to 8-membered mono- or bi-cyclic ring system optionally containing an additional heteroatom selected from O, S, NR7, NBoc, and NCbz. In some embodiments, X is (Ci-Ce) alkyl, (CH2)O-I heteroaryl, CH2-heterocyclyl, CO2R8, CH2OR8, CH2S(0)O-2R8, NHC(O)R8, CH2NR8SO2R8, CH2OC(O)NR8R8, CH2NR8SO2R8, or C(O)N(R8)(R8); wherein heteroaryl is optionally substituted with one to three groups selected from R6; heterocyclyl is optionally substituted with one to three groups selected from R6and oxo; and R8is each independently selected from H, (Ci-Cs) alkyl, and (C3-C6) cycloalkyl optionally substituted with one to three groups selected from R6and oxo; or two R8groups together with the atoms to which they are attached form a 5- to 8-membered mono- or bi-cyclic ring system optionally containing an additional heteroatom selected from O, S, NR7, NBoc, and NCbz.

[0531] In some embodiments, compounds of Formula (XIV) include: Y is (Ci-Cs) alkyl, (CH2)n(C -C?) cycloalkyl, (CH2)n-aryl, (CH2)n-heterocyclyl, or (CH2)n-heteroaryl; wherein aryl and heteroaryl are optionally substituted with one to three groups selected from R6; and (CH2)n, alkyl, cycloalkyl, and heterocyclyl are optionally substituted with one to three groups selected from R6and oxo. In a class of this embodiment, Y is cyclohexyl, cycloheptyl, cyclopentyl, or (Ci-Ce) alkyl, unsubstituted or substituted with one to three groups selected from R6and oxo. In some embodiments, Y is cyclohexyl or (Ci-Ce) alkyl, wherein the cyclohexyl and alkyl groups are unsubstituted or substituted with one to three groups selected from R6and oxo. In some embodiments, the carbon atom marked with * has the R configuration.

[0532] In some embodiments, compounds of Formula (XIV) include:

[0533] X is selected from the group consisting of:

[0534]

[0535]

[0536] -C(O)NHCH2tBu; -CH2SCH(CH3)2; -CH2S(O)CH(CH3)2; -CH2S(O)2CH(CH3)2; - C(O)NHCH2CH2N(CH3)2; C(O)CH(CH3)2; -CH2NHCOtBu; -CH2OC(O)NMe2; -CH2C(O)NEt2; -CH2OC(Me)2CO2H; -C(O)NHC(Me)2CO2Me; -C(O)NHC(Me)2CO2H; -CH2N(CH3)COtBu; - CH2N(iPr)COMe; -CH2N(iPr)SO2Me; -C(O)NHC(Me)2CH2OMe; -C(O)NHC(Me)2CH2OH; -CH2CH2C(Me)2OH;

[0537]

[0538] In some embodiments, compounds of Formula (XIV) include compounds of Formula (XTVa) with the indicated stereochemistry at the stereogenic center marked with ** are:

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556] In some embodiments, compounds of Formula (XIV) include compounds of Formula (XlVb) with the indicated stereochemistry at the stereogenic center marked with ** are:

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565] In some embodiments, compounds of Formula (XIV) include compounds of Formula (XIVc) with the indicated stereochemistry at the stereogenic center marked with ** are:

[0566]

[0567]

[0568]

[0569] In some embodiments, the MC4R agonist is a compound described in WO 2001 / 070708, which is incorporated herein by reference in its entirety.

[0570] In one aspect, the MC4R agonist is a compound of Formula (XV):

[0571]

[0572] pharmaceutically acceptable salt thereof; wherein: r is 1 or 2; s is 0, 1, or 2; n is 0, 1 or 2; p is 0, 1, or 2; R1is selected from the group consisting of hydrogen, amidino, (C1-C4) alkyliminoyl, (Ci-Cio)alkyl, (CH2)n-(C3-C?) cycloalkyl, (CH2)n-phenyl, (CH2)n-naphthyl, and (CH2)n -heteroaryl, wherein heteroaryl is selected from the group consisting of pyridinyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, benzimidazolyl, benzofuryl, benzothienyl, indolyl, benzthiazolyl, and benzoxazolyl; in which phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3; and alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R3and oxo; R2is selected from the group consisting of phenyl, naphthyl, and heteroaryl wherein heteroaryl is selected from the group consisting of pyridinyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, benzimidazolyl, benzofuryl, benzothienyl, indolyl, benzthiazolyl, and benzoxazolyl; in which phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3; each R3is independently selected from the group consisting of (Ci-Ce) -alkyl, (CH2)n-phenyl, (CH2)n-naphthyl, (CH2)n-heteroaryl, (CH2)n-heterocyclyl, (CH2)n(C3-C7)-cycloalkyl, halogen, OR4, (CH2)nN(R4 CO2R4, NO2, (CH2)nNR4SO2R4, (CH2)nSO2N(R4)2, (CH2),1S(O)PR4,2, (CH2)nC(O)N(R4)2, (CH2)nNR4C(O)R4, (CH2)nNR4C heteroaryl, (CH2)nC(O)NR4N(R4)2, (CH2)nC(O)NR4NR4C(O)R4,

[0573]

[0574] CF3, CH2CF3, OCF3, and OCH2CF3; in which heteroaryl is as defined above; phenyl, naphthyl, heteroaryl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, (C1-C4) alkyl, trifluoromethyl, and (C1-C4) alkoxy; and wherein any methylene (CH2) carbon atom in R3is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and (C1-C4) alkyl; or two substituents when on the same methylene (CH2) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group; each R4is independently selected from the group consisting of hydrogen, (Ci-Ce) alkyl, (CH2)n-phenyl, (CH2)n-heteroaryl, (CH2)n-naphthyl, (CH2)n-heterocyclyl, (CH2)n(C3-C?) cycloalkyl, and (CFF n Cs-C?) bicycloalkyl; wherein alkyl, phenyl, heteroaryl, heterocyclyl, and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from halogen, (C1-C4) alkyl, hydroxy, and (C1-C4) alkoxy; or two R4groups together with the atom to which they are attached form a 4- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and N(Ci-C4)alkyl; each R3is independently selected from the group consisting of hydrogen, (Ci-Cs) alkyl, (CH2)n-phenyl, (CH2)n-naphthyl, (CH2)n-heteroaryl, and (CH2)n(C3-C?) cycloalkyl; wherein heteroaryl is as defined above; phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3; alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R3and oxo; and wherein any methylene (CH2) in R3is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and (C1-C4) alkyl; or two R3groups together with the atom to which they are attached form a 5- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and N(CI-C4) alkyl; X is selected from the group consisting of (Ci-Cs) alkyl, (CH2)n(C3-Cs) cycloalkyl, (CH2)n-phenyl,

[0575]

[0576] (CH2)nOC(O)OR5, (CH2)nOC(O)N(R5)2, (CH2)nN(R5)2, and (CH2)nNR5SO2N(R5)(R5);wherein heteroaryl is as defined above; phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3; alkyl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three groups independently selected from R3and oxo; and wherein any methylene (CH2) in X is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and (C1-C4) alkyl; and Y is selected from the group consisting of hydrogen, (Ci-Cs) alkyl, (C2-Ce)alkenyl, (CH2)n(C3-Cs) cycloalkyl, (CH2)n-phenyl, (CH2)n-naphthyl, (CH2)n-heteroaryl, and (CH2)n-heterocyclyl; wherein heteroaryl is as defined above, and phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3; alkyl, cycloalkyl, and heterocyclyl are optionally substituted with one to three groups independently selected from R3and oxo; and wherein any methylene (CH2) in Y is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and (C1-C4) alkyl.

[0577] In some embodiments, compounds of Formula (XV) include: R1is selected from the group consisting of hydrogen, (Ci-Ce) alkyl, (CH2)O-I(C3-C6) cycloalkyl, and (CH2)o-i-phenyl wherein phenyl is unsubstituted or substituted with one to three groups independently selected from R3; and alkyl and cycloalkyl are optionally substituted with one to three groups independently selected from R3and oxo. In some embodiments, R2is phenyl or thienyl optionally substituted with one to three groups independently selected from R3. In some embodiments, R2is phenyl optionally substituted with one to three groups independently selected from R3. In some embodiments, X is selected from the group consisting of (CH2)n-phenyl, (CH2)n-naphthyl, (CH2)n-heteroaryl, (CH2)n(C3-Cs) cycloalkyl, and (CH2)n-heterocyclyl, wherein heteroaryl is as defined above, and phenyl, naphthyl, and heteroaryl are optionally substituted with one to three groups independently selected from R3; cycloalkyl and heterocyclyl are optionally substituted with one to three groups independently selected from R3and oxo; and wherein any methylene (CH2) group in X is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and (C1-C4) alkyl. In some embodiments, X is selected from the group consisting of (CH2)o-i-phenyl, (CH2)o-i-heteroaryl, (CH2)o-i-heterocyclyl; wherein phenyl and heteroaryl are optionally substituted with one to three groups independently selected from R3; heterocyclyl is optionally substituted with one to three groups independently selected from R3and oxo; and CH2is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and (C1-C4) alkyl. In some embodiments, X is phenyl optionally substituted with one to three groups independently selected from R3. In a specific embodiment, Y is hydrogen, r is 1 or 2 and s is 1.

[0578] In one aspect, the MC4R agonist is a compound of Formula (XVa) or (XVb) having the trans orientation of the R2 and piperidinecarbonyl substituents:

[0579]

[0580] (XVa) (XVb)

[0581] or a pharmaceutically acceptable salt thereof; wherein r is 1 or 2; n is 0, 1, or 2; p is 0, 1, or 2; R1is hydrogen, amidino, (C1-C4) alkyliminoyl, (Ci-Ce) alkyl, (Cs-Ce) cycloalkyl, (CH2)o-i phenyl, (CH2)O-I heteroaryl; wherein phenyl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3, and alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R3and oxo; R2is phenyl or thienyl optionally substituted with one to three groups independently selected from R3;each R3is independently selected from the group consisting of (Ci-Ce) alkyl, (CH2)n-heteroaryl, (CH2)n-heterocyclyl, halogen, OR4, (CH2)nN(R4)2, (CH2)nC=N, (CH2)nCO2R4, (CH2)nNR4SO2R4, (CH2)nSO2N(R4)2, (CH2)nS(O)PR4, (CH2)nNR4C(O)N(R4)2, (CH2)nC(O)N(R4)2, (CH2)nNR4C(O)R4, (CH2)nNR4CO2R4, (CH2)nNR4C(O)-heteroaryl, (CH2)nC(O)NR4N(R4)2, (CH2)nC(O)NR4NR4C(O)R4, O(CH2)nC(O)N(R4)2, CF3, CH2CF3, OCF3, and OCH2CF3; in which heteroaryl is as defined above; phenyl, naphthyl, heteroaryl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, (C1-C4) alkyl, trifluoromethyl, and (C1-C4) alkoxy; and wherein any methylene (CH2) group in R3is unsubstituted or substituted, with one to two groups independently selected from halogen, hydroxy, and (C1-C4) alkyl; or two substituents when on the same methylene (CH2) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group; each R4is independently selected from the group consisting of hydrogen, (Ci-Cs) alkyl, phenyl, heteroaryl, (CH2)o-i heterocyclyl, and (C3-Cs) cycloalkyl; wherein alkyl, phenyl, heteroaryl, heterocyclyl, and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from halogen, (C1-C4) alkyl, hydroxy, and (C1-C4) alkoxy; or two R groups together with the atom to which they are attached form a 4- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and N(Ci-C4)alkyl; and X is phenyl or heteroaryl each of which is optionally substituted with one to three groups independently selected from R3.

[0582] In one aspect, the MC4R agonist is a compound of Formula (XVc) or (XVd) having the trans orientation of the phenyl and piperidinecarbonyl substituents:

[0583]

[0584] or a pharmaceutically acceptable salt thereof; wherein r is 1 or 2; R1is hydrogen, (C1-C4) alkyl, or (CH2)O-I phenyl; each R3is independently selected from the group consisting of (Ci-Ce) alkyl, (CH2)o-i-heteroaryl, (CH2)o-i-heterocyclyl, halogen, OR4, (CH2)O-IN(R4)2, (CH2)o-iC=N, (CH2)o-1CO2R4, (CH2)o-iNR4S02R4, (CH2)O-IS02N(R4)2, (CH2)O-IS(0)PR4, (CH2)O-INR4C(0)N(R4)2, (CH2)O-IC(0)N(R4)2, (CH2)O-INR4C(0)R4, (CH2)O-INR4C02R4, (CH2)O- iNR4C(O)-heteroaryl, (CH2)O-IC(0)NR4N(R4)2, (CH2)O-IC(0)NR4NR4C(0)R4, 0(CH2)O-IC(0)N(R4)2, CF3, CH2CF3, OCF3, and OCH2CF3; in which phenyl, naphthyl, heteroaryl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to two substituents independently selected from halogen, hydroxy, oxo, (C1-C4) alkyl, trifluoromethyl, and (C1-C4) alkoxy; and wherein any methylene (CH2) group in R3is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and (C1-C4) alkyl; or two substituents when on the same methylene (CH2) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group; and each R4is independently selected from the group consisting of hydrogen, (Ci-Cs) alkyl, phenyl, heteroaryl, (CH2)O-I heterocyclyl, and (Cs-Ce) cycloalkyl; wherein alkyl, phenyl, heteroaryl, heterocyclyl, and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from halogen, (C1-C4) alkyl, hydroxy, and (C1-C4) alkoxy; or two R4groups together with the atom to which they are attached form a 4- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and N(Ci-C4)alkyl.

[0585] In some embodiments, compounds of any of Formulas (XV), (XVa), (XVb), (XVc), and (XVd) include:

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592]

[0593]

[0594]

[0595] or a pharmaceutically acceptable salt thereof.

[0596] In some embodiments, the MC4R agonist is a compound described in WO 2002 / 068388, which is incorporated herein by reference in its entirety.

[0597] In one aspect, the MC4R agonist is a compound of Formula (XV):

[0598]

[0599] pharmaceutically acceptable salt thereof; wherein: r is 1 or 2; s is 0, I, or 2; n is 0, I or 2; p is 0, l, or 2; R1is NR6R7wherein R6and R7are independently selected from the group consisting of: hydrogen, amidino, (C1-C4) alkyliminoyl, (C1-C4) alkyl, (CH2)n-(C3-C?) cycloalkyl, (CH2)n-phenyl, (CH2)n-naphthyl, and (CH2)n-heteroaryl wherein heteroaryl is selected from the group consisting of: pyridinyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyriridinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, benzimidazolyl, benzofuryl, benzothienyl, indolyl, benzthiazolyl, and benzoxazolyl; in which phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3; and (CH2)n, alkyl, and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R3and oxo; or R6and R7together with the nitrogen atom to which they are attached form a 4-8 membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and N(Ci-C4)alkyl; R2is selected from the group consisting of: phenyl, naphthyl, and heteroaryl wherein heteroaryl is selected from the group consisting of: pyridinyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, benzimidazolyl, benzofuryl, benzothienyl, indolyl, benzthiazolyl, and benzoxazolyl; in which phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3; R3is selected from the group consisting of: (Ci-Ce) alkyl, (CH2)n-phenyl, (CH2)n-naphthyl, (CH2)n-heteroaryl, (CH2)n(C3-C7) cycloalkyl, halogen, OR4, N(R4)2, C=N, CO2R4, C(R4)(R4)N(R4)2, NO2, (CH2)nNR4SO2R4, (CH2)nSO2N(R4)2, (CH2)„S(O)PR4, (CH2)nNR4C(O)N(R4)2, (CH2)nC(O)N(R4)2, (CH2)nNR4C(O)R4, (CH2)nNR4CO2R4, CF3, CH2CF3, OCF3, and OCH2CF3; in which heteroaryl is as defined above and phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from halogen, (C1-C4) alkyl, trifluoromethyl, and (C1-C4) alkoxy; and (CH2)nis unsubstituted or substituted with one to two groups independently selected from halogen and (C1-C4) alkyl; each R4is independently selected from the group consisting of: hydrogen, (Ci-Ce) alkyl, (CH2)n-phenyl, (CH2)n-naphthyl, and (CH2)n(C3-C?) cycloalkyl; or two R4groups together with the atom to which they are attached form a 5- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and N(Ci-C4)alkyl; each R5is independently selected from the group consisting of: hydrogen, (Ci-Cs) alkyl, (CH2)n-phenyl, (CH2)n-naphthyl, (CH2)n-heteroaryl, and (CH2)n(C3-C?) cycloalkyl; wherein heteroaryl is as defined above; phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3; and alkyl, cycloalkyl, and (CH2)nare unsubstituted or substituted with one to three groups independently selected from R3and oxo; or two R?groups together with the atom to which they are attached form a 5- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and N(CI-C4) alkyl; X is selected from the group consisting of: (Ci-Cs) alkyl, (CH2)n(C3-Cs) cycloalkyl, (CH2)n-phenyl, (CH2)n-naphthyl, (CH2)n-heteroaryl, (CH2)nheterocyclyl, (CH2)nON, (CH2)nCON(R5R5), (CH2)nCO2R5, (CH2)nCOR5, (CH2)nNR5C(O)R5, (CH2)nNR5CO2R5, (CH2)nNR5C(O)N(Rs)2, (CH2)nNR5SO2R5, (CH2)nS(O)PR5, (CH2)nSO2NR5)(R5), (CH2)nOR5, (CH2)„OC(O)R5, (CH2)nOC(O)OR5, (CH2)nOC(O)N(R5)2, (CH2)nN(R5)(R5), and (CH2)nNR5SO2N(R5)(R5); wherein heteroaryl is as defined above, and phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3; and alkyl, (CH2)n, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three groups independently selected from R3and oxo; Y is selected from the group consisting of: hydrogen, (Ci-Cs) alkyl, (C2-C6)alkenyl,

[0600] (CH2)nC3- cycloalkyl, (CH2)n-phenyl, (CH2)n-naphthyl, (CH2)n-heteroaryl, and (CH2)n-heterocyclyl; wherein heteroaryl is as defined above, and phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3; and alkyl, (CH2)n, cycloalkyl, and heterocyclyl are optionally substituted with one to three groups independently selected from R3and oxo.

[0601] In some embodiments, compounds of Formula (XV) include: R1is selected from the group consisting of hydrogen, (Ci-Ce) alkyl, (CH2)O-I(C3-C?) cycloalkyl, and (CH2)o-i-phenyl; wherein phenyl is unsubstituted or substituted with one to three groups independently selected from R3; and alkyl and cycloalkyl are optionally substituted with one to three groups independently selected from R3and oxo; R2is phenyl or thienyl optionally substituted with one to three groups independently selected from R3or R2is phenyl optionally substituted with one to three groups independently selected from R3; X is selected from the group consisting of (Ci-Ce) alkyl, (CH2)n-phenyl, (CH2)n-naphthyl, (CH2)n-heteroaryl, (CH2)n-heterocyclyl, (CH2)nC(O)N(R5)(R5), (CH2)nCO2R5, (CH2)nS(O)PR5, (CH2)nOR5, (CH2)nNR5C(O)R5, and (CH2)nNR5SO2R5; wherein heteroaryl is as defined above, and phenyl, naphthyl, and heteroaryl are optionally substituted with one to three groups independently selected from R3; alkyl and heterocyclyl are optionally substituted with one to three groups independently selected from R3and oxo; and the (CH2)ngroup is optionally substituted with one to three groups independently selected from R4, halogen, S(O)PR4, N(R4)2, and OR4or X is selected from the group consisting of (Ci-Ce) alkyl, (CH2)o-i-phenyl, (CH2)o-i-heteroaryl, (CH2)o-i-heterocyclyl, (CH2)O-INHC(0)R3, (CH2)o-iC02R5, and (CH2)o-iC(0)N(R5)(R3); wherein phenyl and heteroaryl are optionally substituted with one to three groups independently selected from R3; and alkyl and heterocyclyl are optionally substituted with one to three groups independently selected from R3and oxo. In a subclass of this class, heteroaryl is selected from the group consisting of pyridyl, pyrazinyl, pyrimidinyl, triazolyl, tetrazolyl, thiadiazolyl, oxadiazolyl, pyrazolyl, and imidazolyl; Y is selected from the group consisting of hydrogen, (Ci-Cs) alkyl, (C2-Ce)alkenyl, (CH2)n(C5-C?) cycloalkyl, (CH2)n-phenyl, (CH2)n-naphthyl, (CH2)n-heterocyclyl, and (CH2)n-heteroaryl, wherein phenyl, naphthyl, and heteroaryl are optionally substituted with one to three groups independently selected from R3; and (CH2)n, alkyl, cycloalkyl, and heterocyclyl are optionally substituted with one to three groups independently selected from R3and oxo, Y is selected from the group consisting of hydrogen, (Ci-Cs) alkyl, (C2-C6) alkenyl, (C5-C7) cycloalkyl, and phenyl; wherein phenyl is unsubstituted or substituted with one to three groups independently selected from R3; and alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R3and oxo. Y is cyclohexyl or (Ci-Ce) alkyl; wherein the cyclohexyl and alkyl groups are unsubstituted or substituted with one to three groups independently selected from R3and oxo, or Y is hydrogen; r is 1 or 2 and s is 1.

[0602] In one aspect, the MC4R agonist is a compound of Formula (XVa) or (XVb) having the trans orientation of the R2and piperidinecarbonyl substituents:

[0603]

[0604] pharmaceutically acceptable salt thereof; wherein: r is 1 or 2; n is 0, 1, or 2; p is 0, 1, or 2; R1is NR6R7wherein R6and R7are each independently selected from the group consisting of hydrogen, (Ci-Ce) alkyl, (C -Ce) cycloalkyl, (CH2)O-I phenyl, (CH2)O-I heteroaryl; wherein phenyl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3, and alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R3and oxo; R2is phenyl or thienyl optionally substituted with one to three groups independently selected from R3; R3is selected from the group consisting of: (Ci-Ce) alkyl, (CH2)n-phenyl, (CH2)n-naphthyl, (CH2)n-heteroaryl, ( cycloalkyl, halogen, OR4, N(R4)2, ON, CO2R4, C(R4)(R4)N(R4)2, NO2, (CH2)n H2)nSO2N(R4)2, (CH2)nS(O)PR4(CH2)nNR4C(O)N(R4)2, (CH2)nC(O)

[0605]

[0606] NR4C(O)R4, (CH2)nNR4CO2R4, CF3, CH2CF3, OCF3, and OCH2CF3; in which heteroaryl is as defined above; phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to two substituents independently selected from halogen, (C1-C4) alkyl, trifluoromethyl, and (C1-C4) alkoxy; and (CH2)nis unsubstituted or substituted with one to two groups independently selected from halogen and (C1-C4) alkyl; each R4is independently selected from the group consisting of: hydrogen, (Ci-Cs) alkyl, and (C3-C6) cycloalkyl; or two R4groups together with the atom to which they are attached form a 5- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and N(Ci-C4)alkyl; each R5is independently selected from the group consisting of hydrogen, C1-5 alkyl, phenyl, naphthyl, heteroaryl, and (Cs-Ce) cycloalkyl; wherein heteroaryl is as defined above; phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3; and alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R3and oxo; or two R5groups together with the atom to which they are attached form a 5- to 8-membered mono- or bicyclic ring optionally containing an additional heteroatom selected from O, S, and NR4; Y is selected from the group consisting of: hydrogen, (Ci-Cs) alkyl, (C2-C6) alkenyl, (CH2)O-I(C5-C?) cycloalkyl, (CH2)O-I -phenyl, (CH2)o-i-naphthyl, and (CH2)o-i-heteroaryl; wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3; and alkyl, (CH2), and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R3and oxo; and X is selected from the group consisting of: 661

[0607]

[0608]

[0609]

[0610] In one aspect, the MC4R agonist is a compound of Formula (XVc) or (XVd) having the trans orientation of the phenyl and piperidinecarbonyl substituents:

[0611]

[0612] pharmaceutically acceptable salt thereof; wherein: r is 1 or 2; R1is NR6R7wherein R6and R7are each independently hydrogen, (C1-C4) alkyl, (CH2)o-i(C3-Ce) cycloalkyl, or (CH2)O-I phenyl; in which phenyl is unsubstituted or substituted with one to three groups independently selected from R3; and alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R3and oxo; each R3is independently selected from the group consisting of hydrogen, halo, (C1-C4) alkyl, trifluoromethyl, and (C1-C4) alkoxy; Y is cyclohexyl or phenyl; and X is selected from the group consisting of:

[0613]

[0614] In one aspect, the MC4R agonist is a compound of Formula (XVe) or (XVf) having the trans orientation of the phenyl and piperidinecarbonyl substituents:

[0615]

[0616] pharmaceutically acceptable salt thereof; wherein: r is 1 or 2; R1is NR6R7wherein R6and R7are each independently hydrogen or (C1-C4) alkyl; and R3is selected from the group consisting of: (Ci-Ce) alkyl, (CH2)n-phenyl, (CH2)n-naphthyl, (CH2)n-heteroaryl, (CH2)n(C3-C7) cycloalkyl, halogen, OR4, N(R4)2, ON, CO2R4, C(R4)(R4)N(R4)2, NO2, (CH2)nNR4SO2R4, (CH2)nSO2N(R4)2, (CH2)nS(O)PR4, (CH2)nNR4C(O)N(R4)2, (CH2)nC(O)N(R4)2, (CH2)nNR4C(O)R4, (CH2)nNR4CO2R4, CF3, CH2CF3, OCF3, and OCH2CF3; in which heteroaryl is as defined above; phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from halogen, (C1-C4) alkyl, trifluorom ethyl, and (Ci-C4) alkoxy; and (CH2)nis unsubstituted or substituted with one to two groups independently selected from halogen and (C1-C4) alkyl; and each R4is independently selected from the group consisting of: hydrogen, (Ci-Ce) alkyl, (CH2)n-phenyl, (CH2)n-naphthyl, and (CH2)n(C3-C?) cycloalkyl; or two R4groups together with the atom to which they are attached form a 5- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and N(Ci-C4)alkyl.

[0617] In some embodiments, compounds of Formulas (XV), (XVa), (XVb), (XVe), (XVd), (XVe), and (XVf) include following:

[0618]

[0619]

[0620] or a pharmaceutically acceptable salt thereof.

[0621] In some embodiments, the MC4R agonist is a compound described in US 7,012,084, which is incorporated herein by reference in its entirety.

[0622] In one aspect, the MC4R agonist is a compound of Formula (XVI) or Formula (XVIa):

[0623]

[0624] or a pharmaceutically acceptable salt thereof; wherein: a, b and c are all single bonds or all double bonds; X and Y taken together form -C(R6)=C(R6)-, or one of X and Y is C(R6)2and the other is selected from the group consisting of C(R6)2, N(R6), C(O), C=N(R6), oxygen, sulfur, S(O), and S(O)2, or one of X and Y is N(R9) and the other is selected from the group consisting of: C(R6)2, N(R9), C(O), C=N(R6), oxygen, sulfur, S(O), and S(O)2, or one of X and Y is C(O) and the other is selected from the group consisting of: C(R6)2, N(R6), C(O), C=N(R6), oxygen, and sulfur; Z is independently selected from the group consisting of: CH, C(R1), and N; R1is selected from the group consisting of: hydrogen, -(CH2)n-NR7R8, amidino, (C1-C4) alkyliminoyl, (Ci-Cio)alkyl, -(CH2)n-(C3-C?) cycloalkyl, -(CH2)n-phenyl, -(CH2)n-naphthyl, and -(CH2)n-heteroaryl, wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3, and wherein alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R3and oxo; R2is selected from the group consisting of: phenyl, naphthyl, and heteroaryl, wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3; each R3is independently selected from the group consisting of: (Ci-Ce) alkyl, — (CH2)n-phenyl, -(CH2)n-naphthyl, -(CH2)n-heteroaryl, -(CH2)n(C2-C7)heterocycloalkyl, -(CH2)n(C3-C?)

[0625]

[0626] 0CF3, and OCH2CF3; wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, (C1-C4) alkyl, trifluoromethyl, and (C1-C4) alkoxy, and wherein alkyl, cycloalkyl, heterocycloalkyl, and (CH2) are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, (C1-C4) alkyl, trifluoromethyl, and (C1-C4) alkoxy, or wherein two substituents when on the same methylene (CH2) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group; each R4is independently selected from the group consisting of: hydrogen, (Ci-Cs) alkyl, -(CH2)n-phenyl, -(CH2)n-naphthyl, -(CH2)n-heteroaryl, -(CH2)n(C2-C7)heterocycloalkyl, -(CH2)n(C3-C?) cycloalkyl, halogen, OR5, - , -

[0627]

[0628] OCF3, and OCH2CF3; wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, (C1-C4) alkyl, trifluoromethyl, and (C1-C4) alkoxy, and wherein alkyl, cycloalkyl, heterocycloalkyl, and (CH2) are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, (C1-C4) alkyl, trifluoromethyl, and (C1-C4) alkoxy, or wherein two substituents when on the same methylene (CH2) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group; each R5is independently selected from the group consisting of: hydrogen, (Ci-Cs) alkyl, -(CH2)n(C3-C7) cycloalkyl, -(CH2)n(C2-C7) heterocycloalkyl, -(CH2)n-phenyl, -(CH2)n-naphthyl, -(CH2)n-heteroaryl, and -(CH2)n(C3-C7) bicycloalkyl; wherein alkyl, phenyl, heteroaryl, heterocycloalkyl, naphthyl, cycloalkyl, bicycloalkyl and (CH2) are unsubstituted or substituted with one to three groups independently selected from halogen, (C1-C4) alkyl, hydroxy, and (C1-C4) alkoxy, or wherein two R5groups together with the atom to which they are attached form a 4- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and -N(Ci-C4)alkyl; each R6is independently selected from the group consisting of: hydrogen, (Ci-Ce) alkyl, -(CH2)n(C3-C7) cycloalkyl, -(CH2)n(C2-C7) heterocycloalkyl, -(CH2)n-phenyl, -(CH2)n-naphthyl, -(CH2)n-heteroaryl, -(CH2)nC(O)R5, -(CH2)nC(O)OR5, -(CH2)nC(OH)R5, -(CH2)nC(O)(CH2)n-N(R5)2, -(CH2)nC(O)(CH2)n-NR7R8, -(CH2)„-OR5, -(CH2)n-OC(O)R5, -(CH2)n-O-(CH2)n-N(R5)2, -(CH2)nCN, -(CH2)nN(R5)2, -(CH2)nN(R5)C(O)R5, -(CH2)nN(C(O)R5)2, -(CH2)nN(R5)C(O)OR5, -(CH2)nN(C(O)OR5)2, -(CH2)nN(R5)C(O)(CH2)nN(R5)2, -(CH2)nN(R5)-S(O)- (Ci-Cs) alkyl, -(CH2)nN(R5)-S(O)2-(C1-C8) alkyl, -(CH2)n-S-R5, -(CH2)n-S(O)-R5, and -(CH2)n-S(O)2-R5, wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3, and wherein alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with one to three groups independently selected from R3and oxo, and wherein any methylene (CH2) in R6is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and (C1-C4) alkyl; or wherein two R6groups together with the atoms to which they are attached form a 3- to 7-membered monocyclic ring optionally containing an additional heteroatom selected from O, S, and N, wherein the monocyclic ring is unsubstituted or substituted on carbon or nitrogen with one to three groups independently selected from R3and oxo; each R7and R8is independently selected from the group consisting of: hydrogen, amidino, (C1-C4) alkyliminoyl, (Ci-Cio)alkyl, -(CH2)n-(C3-C?) cycloalkyl, -(CH2)n-phenyl, -(CH2)n-naphthyl, and -(CH2)n-heteroaryl, wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3, and wherein alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R3and oxo; each R9is independently selected from the group consisting of: hydrogen, C1-C10alkyl, -(CH2)n(C3-C?) cycloalkyl, -(CH2)n(C2-C7)heterocycloalkyl, -(CH2)n-phenyl, -(CH2)n-naphthyl, -(CH2)n-heteroaryl, -(CH2)nC(O)R5, -(CH2)nC(O)OR5, -(CH2)nC(OH)R5, -(CH2)nC(O)(CH2)n-N(R5)2, -(CH2)nC(O)(CH2)n-NR7R8, -(CH2)m-OR5, -(CH2)m-OC(O)R5, -(CH2)m-O-(CH2)n-N(R5)2, -(CH2)mCN, -(CH2)mN(R5)2, -(CH2)mN(R5)C(O)R5, -(CH2)mN(C(O)R5)2, -(CH2)mN(R5)C(O)OR5, -(CH2)mN(C(O)OR5)2, -(CH2)mN(R5)C(O)(CH2)nN(R5)2, -(CH2)mN(R5)-S(O)-(Ci-Cs) alkyl, -(CH2)mN(R5)-S(O)2-(Ci-Cs) alkyl, -(CH2)m-S-R5, -(CH2)n-S(O)-R5, and -(CH2)n-S(O)2-R5, wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3, and wherein alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with one to three groups independently selected from R3and oxo, and wherein any methylene (CH2) in R9is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and (C1-C4) alkyl; or wherein two R9groups together with the atoms to which they are attached form a 3- to 7-membered monocyclic ring optionally containing an additional heteroatom selected from O, S, and N, wherein the monocyclic ring is unsubstituted or substituted on carbon or nitrogen with one to three groups independently selected from R3and oxo; r is 1 or 2; s is 1 or 2; n is 0, 1, 2, or 3; m is 1, 2, or 3; and p is 0, 1, or 2.

[0629] In some embodiments, compounds of Formula (XVI) and Formula (XVIa) include: R1is selected from the group consisting of hydrogen, (Ci-Ce) alkyl, -(CH2)o-i-(C3-Ce) cycloalkyl, -(CH2)O-I -phenyl, and -(CH2)o-i-NR7R8; wherein phenyl is unsubstituted or substituted with one to three groups independently selected from R3, and wherein alkyl and cycloalkyl are optionally substituted with one to three groups independently selected from R3and oxo. In a class of this embodiment, R1is selected from the group consisting of hydrogen, and (Ci-Ce) alkyl, and alkyl is optionally substituted with one to three groups independently selected from R3and oxo. In another class of this embodiment, R1is -(CH2)O-I-NR7R8; R2is phenyl or thienyl optionally substituted with one to three groups independently selected from R3. In a class of this embodiment, R2is phenyl optionally substituted with one to three groups independently selected from R3; R3is selected from the group consisting of (Ci-Ce) alkyl, -(CH2)n-phenyl, -(CH2)n-heteroaryl, -(CH2)n(C2-C7) heterocycloalkyl, -(CH2)n(C3-C?) cycloalkyl, halogen, OR5, -(CH2)nN(R5)2, -(CH2)nCO2R5, NO2, and CF3, wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, (C1-C4) allyl, trifluoromethyl, and (C1-C4) alkoxy, and wherein alkyl, cycloalkyl, heterocycloalkyl, and (CH2) are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, (C1-C4) alkyl, trifluoromethyl, and (C1-C4) alkoxy, or wherein two substituents when on the same methylene (CH2) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group. In a class of this embodiment, R3is selected from the group consisting of (Ci-Ce) alkyl, halogen, and OR5, wherein alkyl is unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, (C1-C4) alkyl, trifluoromethyl, and (C1-C4) alkoxy; R4is selected from the group consisting of hydrogen, (Ci-Ce) alkyl, halogen, OR5, -(CH2)nN(R:>)2, -(CH2)nON, -(CH2)nNR5SO2R5, -(CH2)nN(S(O)2R5)2, and -(CH2)nNR5C(O)R5, wherein alkyl, and (CH2) are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, (C1-C4) alkyl, trifluoromethyl, and (C1-C4) alkoxy, or wherein two substituents when on the same methylene (CH2) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group; R6is independently selected from the group consisting of: hydrogen, (Ci-Ce) alkyl, -(CH2)n(C3-C7) cycloalkyl, -(CH2)n-phenyl, -(CH2)n-

[0630]

[0631] R5, and -(CH2)n-S(O)2-R5, wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3, and wherein alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R3and oxo, and wherein any methylene (CH2) in R6is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and (C1-C4) alkyl, or wherein two R6groups together with the atoms to which they are attached form a 3- to 7-membered monocyclic ring optionally containing an additional heteroatom selected from O, S, and N, wherein the monocyclic ring is unsubstituted or substituted on carbon or nitrogen with one to three groups independently selected from R3and oxo; X and Y are independently selected from the group consisting of oxygen, C(R6)2, N(R9), and C(O), or X and Y taken together form - C(R6)=C(R6)-. In a class of this embodiment, X and Y are independently selected from the group consisting of C(R6)2, N(R9), and C(O), or X and Y taken together form -C(R6)=C(R6)-. In some embodiments, X is selected from the group consisting of N(R9), C(R6)2, and C(O), or X and Y taken together form -C(R6)=C(R6)-. In some embodiments, Y is selected from the group consisting of C(R6)2, and N(R9), or X and Y taken together form -C(R6)=C(R6)-. In some embodiments of Formula (XVI) and Formula (XVIa), Z is N. In a class of this embodiment, Z is N and R1is selected from the group consisting of hydrogen, amidino, (C1-C4) alkyliminoyl, (Ci- Cio)alkyl, -(CH2)n-(C3-C7) cycloalkyl, -(CH2)n-phenyl, -(CH2)n-naphthyl, and -(CH2)n-heteroaryl. In some embodiments of Formula (XVI) and Formula (XVIa), Z is CH. In a class of this embodiment, Z is CH and R1is -(CH2)n-NR7R8.

[0632] In one aspect, the MC4R agonist is a compound of Formula (XVIb) or Formula (XVIc) having the trans orientation of the R2and piperidinecarbonyl substituents:

[0633]

[0634] pharmaceutically acceptable salt thereof; wherein: a, b and c are all single bonds or all double bonds; X and Y taken together form -C(R6)=C(R6)-, or one of X and Y is C(R6)2and the other is selected from the group consisting of C(R6)2, N(R6), C(O), C=N(R6), oxygen, sulfur, S(O), and S(O)2, or one of X and Y is N(R9) and the other is selected from the group consisting of: C(R6)2, N(R9), C(O), C=N(R6), oxygen, sulfur, S(O), and S(O)2, or one of X and Y is C(O) and the other is selected from the group consisting of: C(R6)2, N(R6), C(O), C=N(R6), oxygen, and sulfur; Z is independently selected from the group consisting of: CH, C(R1), and N; R1is selected from the group consisting of hydrogen, amidino, (C1-C4) alkyliminoyl, (Ci-Ce) alkyl, (C5-C6)cycloalkyl, -(CH2)O-I phenyl, -(CH2)O-I heteroaryl, and -(CH2)O-I-NR7R8; wherein phenyl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3, and wherein alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R3and oxo; R2is phenyl or thienyl optionally substituted with one to three groups independently selected from R3; each R3is independently selected from the group consisting of: (Ci-Ce) alkyl, -(CH2)n-phenyl, -(CH2)n-naphthyl, -(CH2)n-heteroaryl, -(CH2)n(C2-C7)heterocycloalkyl, -(CH2)n(C3-C?) cycloalkyl, halogen, OR5, -(CH2)nN(R5)2, -(CH2)nC=N, -(CH2)nCO2R5, NO2, -(CH2)nNR5S(O)pR5, -(CH2)nS(O)pN(R5)2, -(CH2)nS(O)pR5, -(CH2)nNR5C(O)N(R5)2, -(CH2)nC(O)N(R5)2, -(CH2)nNR5C(O)R5, -(CH2)nNR5CO2R5, -(CH2)nNR5C(O)-heteroaryl, -(CH2)nC(O)NR5N(R5)2, -(CH2)nC(O)NR5NR5C(O)R5, O(CH2)nC(O)N(R5)2, CF3, CH2CF3, OCF3, and OCH2CF3; wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, (C1-C4) alkyl, trifluoromethyl, and (C1-C4) alkoxy, and wherein alkyl, cycloalkyl, heterocycloalkyl, and (CH2) are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, (C1-C4) alkyl, trifluoromethyl, and (C1-C4) alkoxy, or wherein two substituents when on the same methylene (CH2) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group; each R4is independently selected from the group consisting of: hydrogen, (Ci-Cs) alkyl, -(CH2)n-phenyl, -(CH2)n-naphthyl, -(CH2)n-heteroaryl, -(CH2)n(C2-C7)heterocycloalkyl, -(CH2)n(C3-C7) cycloalkyl, halogen, OR5, -(CH2)nN(R5)2, -(CH2)nC=N, -(CH2)nC(O)OR5, -(CH2)nOC(O)R5, NO2, -(CH2)nNR5S(O)pR5, -(CH2)nN(S(O)pR5)2, -(CH2)nS(O)pN(R5)2, -(CH2)„S(O)PR5, -(CH2)nNR5C(O)N(R5)2, -(CH2)nC(O)N(R5)2, -(CH2)nNR5C(O)R5, -(CH2)nNR5CO2R5, -(CH2)nNR5C(O)-heteroaryl, -(CH2)nC(O)NR5N(R5)2, -(CH2)nC(O)NR5NR5C(O)R5, O(CH2)nC(O)N(R5)2, CF3, CH2CF3, OCF3, and OCH2CF3; wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, (C1-C4) alkyl, trifluoromethyl, and (C1-C4) alkoxy, and wherein alkyl, cycloalkyl, heterocycloalkyl, and (CH2) are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, (C1-C4) alkyl, trifluoromethyl, and (C1-C4) alkoxy, or wherein two substituents when on the same methylene (CH2) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group; each R5is independently selected from the group consisting of: hydrogen, (Ci-Cs) alkyl, -(CH2)n(C3-C?) cycloalkyl, -(CH2)n(C2-C7)heterocycloalkyl, -(CH2)n-phenyl, -(CH2)n-naphthyl, -(CH2)n-heteroaryl, and -(CH2)n(C3-C?) bicycloalkyl; wherein alkyl, phenyl, heteroaryl, heterocycloalkyl, naphthyl, cycloalkyl, bicycloalkyl and (CH2) are unsubstituted or substituted with one to three groups independently selected from halogen, (C1-C4) alkyl, hydroxy, and (Ci-C4) alkoxy, or wherein two R5groups together with the atom to which they are attached form a 4-to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and -N(Ci-C4)alkyl; each R6is independently selected from the group consisting of: hydrogen, (Ci-Ce) alkyl, -(CH2)n(C3-C?) cycloalkyl, -(CH2)n(C2-C?) heterocycloalkyl, -(CH2)n-phenyl, -(CH2)n-naphthyl, -(CH2)n-heteroaryl, -(CH2)nC(O)R5, -(CH2)nC(O)OR5, -(CH2)nC(OH)R5, -(CH2)nC(O)(CH2)n-N(R5)2, -(CH2)nC(O)(CH2)n-NR7R8, -(CH2)n-OR5, -(CH2)n-OC(O)R5, -(CH2)n-O-(CH2)n-N(R5)2, -(CH2)nCN, -(CH2)nN(R5)2, -(CH2)nN(R5)C(O)R5, -(CH2)nN(C(O)R5)2, -(CH2)nN(R5)C(O)OR5, -(CH2)nN(C(O)OR5)2, -(CH2)nN(R5)C(O)(CH2)nN(R5)2, -(CH2)nN(R5)-S(O)-(Ci-C8) alkyl, -(CH2)nN(R5)-S(O)2-(Ci-C8) alkyl, -(CH2)n-S-R5, -(CH2)n-S(O)-R5, and -(CH2)n-S(O)2-R5, wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3, and wherein alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with one to three groups independently selected from R3and oxo, and wherein any methylene (CH2) in R6is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and (C1-C4) alkyl, or wherein two R6groups together with the atoms to which they are attached form a 3- to 7-membered monocyclic ring optionally containing an additional heteroatom selected from O, S, and N, wherein the monocyclic ring is unsubstituted or substituted on carbon or nitrogen with one to three groups independently selected from R3and oxo; each R7and R8is independently selected from the group consisting of: hydrogen, amidino, (C1-C4) alkyliminoyl, C1-10 alkyl, -(CH2)n-(C3-C?) cycloalkyl, -(CH2)n-phenyl, -(CH2)n-naphthyl, and (CH2)n-heteroaryl, wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3, and wherein alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R3and oxo; each R9is independently selected from the group consisting of: hydrogen, (Ci-Ce) alkyl, -(CH2)n(C3-C7) cycloalkyl, -(CH2)n(C2-C?) heterocycloalkyl, -(CH2)n-phenyl, -(CH2)n-naphthyl, -(CH2)n-heteroaryl, -(CH2)nC(O)R5, -(CH2)nC(O)OR5, -(CH2)nC(OH)R5, -(CH2)nC(O)(CH2)n-N(R5)2, -(CH2)nC(O)(CH2)n-NR7R8, -(CH2)m-OR5, -(CH2)m-OC(O)R5, -(CH2)m-O-(CH2)n-N(R5)2, -(CH2)mCN, -(CH2)mN(R5)2, -(CH2)mN(R5)C(O)R5, -(CH2)mN(C(O)R5)2, -(CH2)mN(R5)C(O)OR5, -(CH2)mN(C(O)OR5)2, -(CH2)mN(R5)C(O)(CH2)nN(R5)2, -(CH2)mN(R5)-(O)-(Ci-Cs) alkyl, -(CH2)mN(R5)-S(O)2-(Ci-C8)alkyl, -(CH2)m-S-R5, -(CH2)n-S(O)-R5, and -(CH2)n-S(O)2-R5, wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3, and wherein alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with one to three groups independently selected from R3and oxo, and wherein any methylene (CH2) in R9is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and (C1-C4) alkyl; or wherein two R9groups together with the atoms to which they are attached form a 3- to 7-membered monocyclic ring optionally containing an additional heteroatom selected from O, S, and N, wherein the monocyclic ring is unsubstituted or substituted on carbon or nitrogen with one to three groups independently selected from R3and oxo; r is 1 or 2; s is 1 or 2; n is 0, 1, 2, or 3; m is 1, 2, or 3; and p is 0, 1, or 2.

[0635] In one aspect, the MC4R agonist is a compound of Formula (XVId) or Formula (XVIe) having the trans orientation of the phenyl and piperidinecarbonyl substituents:

[0636]

[0637] thereof; wherein a, b and c are all single bonds or all double bonds; X and Y taken together form -C(R6)=C(R6)-, or one of X and Y is C(R6)2 and the other is selected from the group consisting of C(R6)2, N(R6), C(O), C=N(R6), oxygen, sulfur, S(O), and S(O)2, or one of X and Y is N(R9) and the other is selected from the group consisting of: C(R6)2, N(R9), C(O), C=N(R6), oxygen, sulfur, S(O), and S(O)2, or one of X and Y is C(O) and the other is selected from the group consisting of: C(R6)2, N(R6), C(O), C=N(R6), oxygen, and sulfur; Z is independently selected from the group consisting of: CH, C(R1), and N; R1is selected from the group consisting of hydrogen, (C1-C4) alkyl, -(CH2)O-I -phenyl, and -(CH2)O-I-NR7R8; each R3is independently selected from the group consisting of: (Ci-Ce) alkyl, -(CH2)O-I -phenyl, -(CH2)O-I -naphthyl, -(CH2)o-i-heteroaryl, -(CH2)o-i-(C2-C7)heterocycloalkyl, -(CH2)O-I-(C3-C7) cycloalkyl, halogen,

[0638]

[0639] (CH2)O-I-NR5C(0)R5, -(CH2)O-I-NR5C02R5, -(CH2)o-i-NR5C(0)-heteroaryl, -(CH2)O-I-C(O)NR5N(R5)2, -(CH2)O-!-C(0)NR5NR5C(0)R5, 0(CH2)O-I-C(0)N(R5)2, CF3, CH2CF3, OCF3, and OCH2CF3; wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, (C1-C4) alkyl, trifluoromethyl, and (C1-C4) alkoxy, and wherein alkyl, cycloalkyl, heterocycloalkyl, and (CH2) are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, (C1-C4) alkyl, trifluoromethyl, and (C1-C4) alkoxy, or wherein two substituents when on the same methylene (CH2) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group; each R4is independently selected from the group consisting of: hydrogen, (Ci-Cs) alkyl, -(CH2)o-i-phenyl, -(CH2)o-i-naphthyl, -(CH2)O-I-heteroaryl, -(CH2)O-I-(C2-C7) heterocycloalkyl, -(CH2)O-I-(C3-C7) cycloalkyl, halogen, OR3, -(CH2)O-I-N(R5)2, -(CH2)O-I-C=N, -(CH2)O-I-C(0)OR5, -(CH2)O-I-OC(0)R5, NO2, -(CH2)O-I-NR5S(O)I-2-R5, -(CH2)O-I-N(S(0)I-2-R5)2, -(CH2)O-I-S(0)I-2-N(R5)2, -(CH2)O-I-S(0)O-2-R5, -(CH2)O-I-NR5C(O)N(R5)2, -(CH2)O-I-C(0)N(R5)2, -(CH2)O-I-NR5C(0)R5, -(CH2)O-I-NR5C02R5, -(CH2)O-I-NR5C(O)-heteroaryl, -(CH2)o-i-C(0)NR5N(R5)2, -(CH2)o-i-C(0)NR5NR5C(0)R5, 0(CH2)o-i-C(O)N(R3)2, CF3, CH2CF3, OCF3, and OCH2CF3; wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, (C1-C4) alkyl, trifluoromethyl, and (C1-C4) alkoxy, and wherein alkyl, cycloalkyl, heterocycloalkyl, and (CH2) are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, (C1-C4) alkyl, trifluoromethyl, and (C1-C4) alkoxy, or wherein two substituents when on the same methylene (CH2) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group; each R5is independently selected from the group consisting of: hydrogen, (Ci-Cs) alkyl, -(CH2)O-I-(C3-C7) cycloalkyl, -(CH2)O-I-(C2-C7) heterocycloalkyl, -(CH2)o-i-phenyl, -(CH2)O-I -naphthyl, -(CH2)O-I- heteroaryl, and -(CH2)O-I-(C3-C?) bicycloalkyl; wherein alkyl, phenyl, heteroaryl, heterocycloalkyl, naphthyl, cycloalkyl, bicycloalkyl and (CH2) are unsubstituted or substituted with one to three groups independently selected from halogen, (C1-C4) alkyl, hydroxy, and (Ci-C4) alkoxy, or wherein two R5groups together with the atom to which they are attached form a 4-to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and -N(Ci-C4)alkyl; each R6is independently selected from the group consisting of: hydrogen, (Ci-Ce) alkyl, -(CH2)O-I-(C3-C?) cycloalkyl, -(CH2)O-I-(C2-C?) heterocycloalkyl, -(CH2)O-I -phenyl, -(CH2)o-i-naphthyl, -(CH2)o-i-heteroaryl, -(CH2)O-I-C(0)R5, -(CH2)O-I-C(0)OR5, -(CH2)O-I-C(OH)R5, -(CH2)O-I-(0)(CH2)O-I-N(R5)2, -(CH2)O-IC(0)(CH2)O-I-NR7R8, -(CH2)O-I-OR5, -(CH2)O-I-OC(0)R5, -(CH2)O-I-0-(CH2)I-2-N(R5)2, -(CH2)O-I-CN, -(CH2)O-3-N(R5)2, -(CH2)O-3-N(R5)C(0)R5, -(CH2)O-3-N(C(0)R5)2, -(CH2)O-3-N(R5)C(0)OR5, -(CH2)O-I-N(C(O)OR5)2, -(CH2)O-I-N(R5)C(0)(CH2)O-IN(R5)2, -(CH2)O-3-N(R5)-S(0)- (CI-CS) alkyl, -(CH2)O-3-N(R5)-S(0)2-(CI-CS) alkyl, -(CH2)O-I-S-R5, -(CH2)o-i-S(0)-R5, and -(CH2)O-I-S(0)2-R5, wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3, and wherein alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with one to three groups independently selected from R3and oxo, and wherein any methylene (CH2) in R6is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and (C1-C4) alkyl, or wherein two R6groups together with the atoms to which they are attached form a 3- to 7-membered monocyclic ring optionally containing an additional heteroatom selected from O, S, and N, wherein the monocyclic ring is unsubstituted or substituted on carbon or nitrogen with one to three groups independently selected from R3and oxo; each R7and R8is independently selected from the group consisting of: hydrogen, amidino, (C1-C4) alkyliminoyl, Ci-ioalkyl, -(CH2)O-I-(C3-C?) cycloalkyl, -(CH2)o-i-phenyl, -(CH2)O-I -naphthyl, and -(CH2)o-i-heteroaryl, wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3, and wherein alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R3and oxo; each R9is independently selected from the group consisting of: hydrogen, (Ci-Ce) alkyl, -(CH2)O-I-(C3-C?) cycloalkyl, -(CH2)O-I-(C2-C?) heterocycloalkyl, -(CH2)O-I -phenyl, -(CH2)o-i-naphthyl, -(CH2)O-I -heteroaryl, -(CH2)O-I-C(0)R5, -(CH2)O-I-C(0)OR5, -(CH2)O-I-C(OH)R5, -(CH2)O-I-C(0)(CH2)O-I-N(R5)2, -(CH2)O-I-C(0)(CH2)O-I-NR7R8, -(CH2)I-3-OR5, -(CH2)I-3-OC(O)R5, -(CH2)I-3-O-(CH2)I-2-N(R5)2, -(CH2)I-3-CN, -(CH2)I- 3-N(R5)2, -(CH2)I-3-N(R5)C(O)R5, -(CH2)I-3-N(C(O)R5)2, -(CH2)I-3-N(R5)C(O)OR5, -(CH2)I-3-N(C(O)OR5)2, -(CH2)I-3-N(R5)C(0)(CH2)O-IN(R5)2, -(CH2)I-3-N(R5)-S(O)-(CI-CS) alkyl, -(CH2)I-3-N(R5)-S(O)2-(CI-C8) alkyl, -(CH2)I-3-S-R5, -(CH2)o-i-S(0)-R5, and -(CH2)O-I-S(0)2-R5, wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3, and wherein alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with one to three groups independently selected from R3and oxo, and wherein any methylene (CH2) in R9is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and (C1-C4) alkyl; or wherein two R9groups together with the atoms to which they are attached form a 3- to 7-membered monocyclic ring optionally containing an additional heteroatom selected from O, S, and N, wherein the monocyclic ring is unsubstituted or substituted on carbon or nitrogen with one to three groups independently selected from R3and oxo; r is 1 or 2; and s is 1 or 2.

[0640] In one aspect, the MC4R agonist is a compound of Formula (XVIf):

[0641]

[0642] wherein R1, R2, R4, X, Y, r, and s are defined as above.

[0643] In some embodiments, compounds of Formula (XVI), (XVIa), (XVIb), (XVIc), (XVId), (XVIe), and (XVIf) include:

[0644]

[0645]

[0646]

[0647]

[0648]

[0649]

[0650]

[0651]

[0652]

[0653] n

[0654]

[0655]

[0656]

[0657] or a pharmaceutically acceptable salt thereof.

[0658] In one aspect, the MC4R agonist is a compound of Formula (XVII):

[0659]

[0660] pharmaceutically acceptable salt thereof; wherein: a, b and c are all single bonds or all double bonds; W is independently selected from the group consisting of: C(O), N(R10), and C(R10)2; X and Y taken together form -C(R6)=C(R6)-, or one of X and Y is C(R6)2 and the other is selected from the group consisting of: C(R6)2, N(R6), C(O), C=N(R6), oxygen, sulfur, S(O), and S(O)2, or one of X and Y is N(R9) and the other is selected from the group consisting of: C(R6)2, C(O), C=N(R6), S(O), and S(O)2, or one of X and Y is C(O) and the other is selected from the group consisting of: C(R6)2, N(R6), oxygen, and sulfur; Z is independently selected from the group consisting of: CH, C(R1), and N; R1is selected from the group consisting of: hydrogen, -(CH2)n-NR7R8, amidino, (C1-C4) alkyliminoyl, (Ci-Cio)alkyl, -(CH2)n-(C3-C?) cycloalkyl, -(CH2)n-phenyl, -(CH2)n-naphthyl, and -(CH2)n-heteroaryl, wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3, and wherein alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R3and oxo; R2is selected from the group consisting of: phenyl, naphthyl, and heteroaryl, wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3; each R3is independently selected from the group consisting of: (Ci-Ce) alkyl, -(CH2)n-phenyl, -(CH2)n-naphthyl, -(CH2)n-heteroaryl, -(CH2)n(C2-C7)heterocycloalkyl, -(CH2)n(C3-C?)

[0661]

[0662] OCF3, and OCH2CF3; wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, (C1-C4) alkyl, trifluoromethyl, and (C1-C4) alkoxy, and wherein alkyl, cycloalkyl, heterocycloalkyl, and (CH2) are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, (C1-C4) alkyl, trifluoromethyl, and (C1-C4) alkoxy, or wherein two substituents when on the same methylene (CH2) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group; each R4is independently selected from the group consisting of: hydrogen, (Ci-Cs) alkyl, -(CH2)n-phenyl, -(CH2)n-naphthyl, -(CH2)n-heteroaryl, heterocycloalkyl, -(CH2)n(C3-C?) cycloalkyl, halogen, OR5, -(CH2)nN(R N. -(CH2)nC(O)OR5, -(CH2)nOC(O)R5, NO2, -(CH2)nNR5S(O)pR5, -(CH2)nN(S( )nS(O)PN(R5)2, -(CH2)nS(O)pR5, -(CH2)nNR5C(O)N(R5)2, -(CH2)nC(O „NR5C(O)R5, -(CH2)nNR5CO2R5, -(CH2)nNR5C(O)-heteroaryl, -(CH2)nC(O

[0663]

[0664] H2)nC(O)NR5NR5C(O)R5, O(CH2)nC(O)N(R5)2, CF3, CH2CF3, OCF3, and OCH2CF3; wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, (C1-C4) alkyl, trifluoromethyl, and (C1-C4) alkoxy, and wherein alkyl, cycloalkyl, heterocycloalkyl, and (CH2) are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, (C1-C4) alkyl, trifluoromethyl, and (C1-C4) alkoxy, or wherein two substituents when on the same methylene (CH2) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group; each R5is independently selected from the group consisting of: hydrogen, (Ci-Cs) alkyl, -(CH2)n(C3-C7) cycloalkyl, -(CH2)n(C2- C7) heterocycloalkyl, -(CH2)n-phenyl, -(CH2)n-naphthyl, -(CH2)n-heteroaryl, and -(CH2)n(C3-C7) bicycloalkyl; wherein alkyl, phenyl, heteroaryl, heterocycloalkyl, naphthyl, cycloalkyl, bicycloalkyl and (CH2) are unsubstituted or substituted with one to three groups independently selected from halogen, (C1-C4) alkyl, hydroxy, and (C1-C4) alkoxy, or wherein two R5groups together with the atom to which they are attached form a 4- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and -N(Ci-C4)alkyl; each R6is independently selected from the group consisting of: hydrogen, (Ci-Ce) alkyl, -(CH2)n(C3-C?) cycloalkyl, -(CH2)n(C2-C7) heterocycloalkyl, -(CH2)n-phenyl, -(CH2)n-naphthyl, -(CH2)n-heteroaryl, -(CH2)nC(O)R5, -(CH2)nC(O)OR5, -(CH2)nC(OH)R5, -(CH2)nC(O)(CH2)n-N(R5)2, -(CH2)nC(O)(CH2)n-NR7R8, -(CH2)n-OR5, -(CH2)n-OC(O)R5, -(CH2)n-O-(CH2)n-N(R5)2, -(CH2)„CN, -(CH2)„N(R5)2, -(CH2)nN(R5)C(O)R5, -(CH2)nN(C(O)R5)2, -(CH2)nN(R5)C(O)OR5, -(CH2)nN(C(O)OR5)2, -(CH2)nN(R5)C(O)(CH2)nN(R5)2, -(CH2)nN(R5)-S(O)- (C1-C8) alkyl, -(CH2)nN(R5)-S(O)2-(Ci-Cs) alkyl, -(CH2)n-S-R5, -(CH2)n-S(O)-R5, and -(CH2)n-S(O)2-R5, wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3, and wherein alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with one to three groups independently selected from R3and oxo, and wherein any methylene (CH2) in R6is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and (C1-C4) alkyl; or wherein two R6groups together with the atoms to which they are attached form a 3- to 7-membered monocyclic ring optionally containing an additional heteroatom selected from O, S, and N, wherein the monocyclic ring is unsubstituted or substituted on carbon or nitrogen with one to three groups independently selected from R3and oxo; each R7and R8is independently selected from the group consisting of: hydrogen, amidino, (C1-C4) alkyliminoyl, (Ci-Cio)alkyl, -(CH2)n-(C3-C7) cycloalkyl, -(CH2)n-phenyl, -(CH2)n-naphthyl, and -(CH2)n-heteroaryl, wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3, and wherein alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R3and oxo; each R9is independently selected from the group consisting of: hydrogen, (Ci-Ce) alkyl, -(CH2)n(C3-C?) cycloalkyl, -(CH2)n(C2- C7) heterocycloalkyl, -(CH2)n-phenyl, -(CH2)n-naphthyl, -(CH2)n-heteroaryl, -(CH2)nC(O)R5, -(CH2)nC(O)OR5, -(CH2)nC(OH)R5, -(CH2)nC(O)(CH2)n-N(R5)2, -(CH2)nC(O)(CH2)n-NR7R8, -(CH2)m-OR5, -(CH2)m-OC(O)R5, -(CH2)m-O-(CH2)„-N(R5)2, -(CH2)mCN, -(CH2)mN(R5)2, -(CH2)mN(R5)C(O)R5, -(CH2)mN(C(O)R5)2, -(CH2)mN(R5)C(O)OR5, -(CH2)mN(C(O)OR5)2, -(CH2)raN(R5)C(O)(CH2)nN(R5)2, -(CH2)mN(R5)-S(O)- (Ci-Cs) alkyl, -(CH2)mN(R5)-S(O)2-(Ci-Cs) alkyl, -(CH2)m-S-R5, -(CH2)n-S(O)-R5, and -(CH2)n-S(O)2-R5, wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3, and wherein alkyl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with one to three groups independently selected from R3and oxo, and wherein any methylene (CH2) in R9is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and (C1-C4) alkyl; or wherein two R9groups together with the atoms to which they are attached form a 3- to 7-membered monocyclic ring optionally containing an additional heteroatom selected from O, S, and N, wherein the monocyclic ring is unsubstituted or substituted on carbon or nitrogen with one to three groups independently selected from R3and oxo; each R10is independently selected from the group consisting of hydrogen, -(Ci-Ce) alkyl, -C(O)- (Ci-Ce) alkyl, and -S(O)2-(Ci-C6) alkyl; r is 1 or 2; s is 1 or 2; n is 0, 1, 2, or 3; m is 1, 2, or 3; and p is 0, 1, or 2.

[0665]

[0666]

[0667]

[0668] In some embodiments, the MC4R agonist is a compound described in US 7,329,673, which is incorporated herein by reference in its entirety.

[0669] In one aspect, the MC4R agonist is a compound of Formula (XVIII):

[0670]

[0671] pharmaceutically acceptable salt thereof; wherein is selected from the group consisting of: hydrogen, amidino, (C1-C4) alkyliminoyl; (Ci-Cio)alkyl; -(CH2)n-NR7R8, -(CH2)n-(C3-C?) cycloalkyl; -(CH2)n-phenyl; -(CH2)n-naphthyl and -(CH2)n-heteroaryl wherein phenyl, naphthyl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3, and wherein alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R3and oxo; R2is selected from the group consisting of: phenyl, naphthyl and heteroaryl wherein phenyl, naphthyl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3; each R3is independently selected from the group consisting of: hydrogen, (Ci-Ce) alkyl, - (CH2)n-phenyl, -(CH2)n-naphthyl, -(CH2)n-heteroaryl, -(CH2)n-heterocycloalkyl, -(CH2)n(C3-C7) cycloalkyl, halogen, OR6, -(CH2)nN(R6)2, -(CH2)nC=N, -(CH2)nCO2R6, NO2, -(CH2)nNR6SO2R6, -(CH2)nSO2N(R6)2, -(CH2)nS(O)PR6, -(CH2)nNR6C(O)N(R6)2, -(CH2)nC(O)N(R6)2, -(CH2)nNR6C(O)R6, -(CH2)nNR6CO2R6, -(CH2)nNR6C(O)-heteroaiyl, -(CH2)nC(O)NR6N(R6)2, -(CH2)nC(O)NR6NR6C(O)R6, O(CH2)nC(O)N(R6)2, CF3, CH2CF3, OCF3, and OCH2CF3, wherein phenyl, naphthyl heteroaryl, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, (C1-C4) alkyl trifluoromethyl and (C1-C4) alkoxy, and wherein any methylene (CH2) carbon atom in R3is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and (C1-C4) alkyl or wherein two substituents when on the same methylene (CH2) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group; R4is selected from the group consisting of -(CH2)n-N(R5)-NR3R6; -(CH2)n-N(R5)-(CH2)q-NR5R6, -(CH2)n-N(R5)-C(=NR5)-NR5R6, -(CH2)n-N(R5)-(CH2)q-N(R5)-(C=NR5)-NR5R6, -(CH2)n-N(R5) -(CH2)n-C(R5)(N(R5)2)-(CH2)q-OR6, -(CH2)n-N(R5)-(CH2)n-C(R5)(N(R5)2)(CH2)n-R6, -(CH2)11-N(R5)-(CH2)n-C(R5)(N(R5)2)(CH2)q-S(O)p-R6, -(CH2)n-N(R5)-(CH2)n-C(R5)(N(R5)2)(CH2)q-NR5R6, -(CH2)n-N(R5)-C(O)(CH2)n-C(R5)(N(R5)2)(CH2)n-R6, -(CH2)n-N(R5)-C(O)(CH2)n-C(R5)(N(R5)2)(CH2)q-S(O)p-R6, -(CH2)n-N(R5)-C(O)(CH2)n-C(R5)(N(R5)2)(CH2)q-NR5R6, -(CH2)n-N(R5)-C(O)(CH2)n-C(R5)(N(R5)2)(CH2)qOR6, and -(CH2)n-N(R5)-R9, wherein (CH2)n is unsubstituted or substituted with one to three groups independently selected from halogen, (C1-C4) alkyl hydroxy, oxo, and (C1-C4) alkoxy; R5is selected from the group consisting of: hydrogen, (Ci-Ce) alkyl and C(O) (Ci-Ce) alkyl wherein alkyl is unsubstituted or substituted with one to three groups independently selected from halogen, (Ci-C4) alkyl hydroxy, oxo, and (C1-C4) alkoxy; R6is selected from the group consisting of: hydrogen, (Ci-Ce) alkyl C(O)Ci-6 alkyl -(CH2)n(C3-C?) cycloalkyl -(CH2)n(C2-C7)heterocycloalkyl -(CH2)n-phenyl -(CH2)n-naphthyl -(CH2)n-heteroaryl and -(CH2)n(C3-C?) bicycloalkyl wherein alkyl phenyl heteroaryl heterocycloalkyl naphthyl cycloalkyl bicycloalkyl and (CH2)n are unsubstituted or substituted with one to three groups independently selected from halogen, (C1-C4) alkyl, hydroxy, and (C1-C4) alkoxy, or wherein two R6groups together with the atom to which they are attached form a 4- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and -N(Ci-C4)alkyl; each R7and R8is independently selected from the group consisting of: hydrogen, amidino, (C1-C4) alkyliminoyl (Ci-Cio)alkyl -(CH2)n-(C3-C?) cycloalkyl -(CH2)n-phenyl -(CH2)n-naphthyl and -(CH2)n-heteroaryl wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R3, and wherein alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R3and oxo; R9is selected from the group consisting of: alanine, glycine, proline, cysteine, histidine, glutamine, aspartic acid, isoleucine, arginine, glutamic acid, lysine, serine, phenylalanine, leucine, threonine, tryptophan, methionine, valine, tyrosine, asparagine, 2-aminoadipic acid, beta-alanine, 2-aminoheptanedioic acid, 2-aminobutyric acid, 4-aminobutyric acid, 2,4-diaminobutyric acid, citrulline, cycloserine, norvaline, norleucine, ornithine, penicillamine, phenylglycine, phenylisoserine, phenyl statine, pipecolic acid, piperidine carboxylic acid, pyroglutamic acid, sarcosine, statine, allo-threonine, t-leucine, 2-aminoisobutyric acid, and 3 -aminoisobutyric acid; Z is selected from the group consisting of: C(R'), and N; r is 1 or 2; s is 0, 1, or 2; n is 0, 1, 2, or 3; p is 0, 1, or 2; and q is 1, 2, 3, or 4.

[0672] In an embodiment of Formula (XVIII), R1is selected from the group consisting of: hydrogen, (C1-C4) alkyl-(CH2)o-i(C3-Ce) cycloalkyl and -(CH2)o-i-phenyl wherein phenyl is unsubstituted or substituted with one to three groups independently selected from R3, and wherein alkyl and cycloalkyl are optionally substituted with one to three groups independently selected from R3and oxo. In an embodiment, R1is selected from the group consisting of: hydrogen, and (C1-C4) alkyl, and alkyl is optionally substituted with one to three groups independently selected from R3and oxo. In another class of this embodiment, R1is -(CH2)o-INR7R8.

[0673] In some embodiments of Formula (XVIII), R2is phenyl or thienyl optionally substituted with one to three groups independently selected from R3. In a class of this embodiment, R2is phenyl optionally substituted with one to three groups independently selected from R3. In some embodiments of Formula (XVIII), R3is selected from the group consisting of: (C1-C4) alkyl -(CH2)n-phenyl-(CH2)n-heteroaryl, -(CH2)n(C2-C?) heterocycloalkyl-(CH2)n(C3-C7) cycloalkyl, halogen, OR5, -(CH2)nN(R5)2, -(CH2)nCO2R5, NO2, and CF3, wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, (C1-C4) alkyl, trifluoromethyl, and (C1-C4) alkoxy, and wherein alkyl, cycloalkyl, heterocycloalkyl, and (CH2) are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, (C1-C4) alkyl trifluoromethyl and (C1-C4) alkoxy, or wherein two substituents when on the same methylene (CH2) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group. In a class of this embodiment, R3is selected from the group consisting of: (C1-C4) alkyl, halogen, and OR5, wherein alkyl is unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, (C1-C4) alkyl, trifluoromethyl, and (C1-C4) alkoxy.

[0674] In some embodiments of Formula (XVIII), R3is selected from the group consisting of: -(CH2)n-N(R5)-NH2, -(CH2)n-N(R5)-(CH2)q-NH2, -(CH2)n-N(R5)-(CH2)n-NR5R6, -(CH2)n-N(R5)-(CH2)n-NH(Ci-C6) alkyl, -(CH2)n-N(R5)-(CH2)n-N((Ci-C6) alkyl)2, -(CH2)n-N(R5)-(CH2)n-NHC(O) (Ci-C6) alkyl, -(CH2)n-N(R5)-(CH2)n-N(R5)C(O) (Ci-C6) alkyl -(CH2)n-N(R5)-(CH2)n-N(C(O) (Ci-C6) alkyl)2, -(CH2)n-N(R5)-C(=NH)-NH2, -(CH2)n-N(R5)-(CH2)q-NH(C=NH)-NH2, -(CH2)n-N(R5)-(CH2)n-C(R5)(NH2)(CH2)q-OH, -(CH2)n-N(R5)-(CH2)„-C(R5)(NH2)(CH2)q-O(Ci-C6) alkyl -(CH2)n-N(R5)-(CH2)n-C(R5)(NH2)(CH2)q-OR6, -(CH2)n-N(R5)-(CH2)n-C(R5)(NH2)(CH2)n-heteroaryl -(CH2)n-N(R5)-(CH2)n-C(R5)(NH2)(CH2)„-R6, -(CH2)„-N(R5)-(CH2)n-C(R5)(NH2)(CH2)q-SH, -(CH2)n-N(R5)-(CH2)n-C(R5)(NH2)(CH2)q-S-(Ci-C6) alkyl -(CH2)n-N(R5)-(CH2)n-C(R5)(NH2)(CH2)q-S-R6, -(CH2)n-N(R5)-(CH2)n-C(R5)(NH2)(CH2)q-NH2, -(CH2)n-N(R5)-(CH2)n-C(R5)(NH2)(CH2)q-NHR6, -(CH2)n-N(R5)-(CH2)n-C(R5)(NH2)(CH2)q-NR5R6, -(CH2)n-N(R5)-C(O)(CH2)n-C(R5)(NH2)(CH2)n-heteroaryl -(CH2)n-N(R5)-C(O)(CH2)n-C(R5)(NH2)(CH2)q-SH, -(CH2)n-N(R5)-C(O)(CH2)n-C(R5)(NH2)(CH2)q-S-(Ci-C6) alkyl -(CH2)n-N(R5)-C(O)(CH2)n-C(R5)(NH2)(CH2)q-NR5R6, and -(CH2)n-N(R5)-R9, wherein alkyl and (CH2)nare unsubstituted or substituted with one to three groups independently selected from halogen, (C1-C4) alkyl, hydroxy, oxo, and (C1-C4) alkoxy, and heteroaryl is unsubstituted or substituted with one to three groups independently selected from halogen, (C1-C4) alkyl hydroxy, and (Ci-C4) alkoxy.

[0675] In some embodiments of Formula (XVIII), R4is selected from the group consisting of: -(CH2)n-N(R5)-NH2, -(CH2)n-N(R5)-(CH2)q-NH2, -(CH2)n-N(R5)-(CH2)q-NH(Ci-C6) alkyl -(CH2)n N(R5)-(CH2)q-N((Ci-C6) alkyl)2, -(CH2)n-N(R5)-(CH2)q-NHC(O)(Ci-C6) alkyl -(CH2)n-N(R5)-C(=NH)-NH2, -(CH2)n-N(R5)-(CH2)q-NH(C=NH)-NH2, -(CH2)n-N(R5)-(CH2)n-C(R5)(NH2)(CH2)q-OH, -(CH2)„-N(R5)-(CH2)n-C(R5)(NH2)(CH2)q-O(Ci-C6) alkyl -(CH2)n-N(R5)-C(O)(CH2)n-C(R5)(NH2)(CH2)n-heteroaryl -(CH2)n-N(R5)-C(O)(CH2)n-C(R5)(NH2)(CH2)q-S-(Ci-C6) alkyl -(CH2)„-N(R5)-C(O)(CH2)„-C(R5)(NH2)(CH2)q-NR5R6, and -(CH2)n-N(R5)-R9, wherein alkyl and (CH2)nare unsubstituted or substituted with one to three groups independently selected from halogen, (C1-C4) alkyl hydroxy, oxo, and (C1-C4) alkoxy, and heteroaryl is unsubstituted or substituted with one to three groups independently selected from halogen, (C1-C4) alkyl, hydroxy, and (C1-C4) alkoxy.

[0676] In some embodiments of the compounds of Formula (XVIII), R6is selected from the group consisting of hydrogen, (Ci-Ce) alkyl, C(O) (Ci-Ce) alkyl and -(CH2)n-heteroaryl wherein alkyl, heteroaryl, and (CH2) are unsubstituted or substituted with one to three groups independently selected from halogen, (C1-C4) alkyl, hydroxy, and (C1-C4) alkoxy, or wherein two R6groups together with the atom to which they are attached form a 4- to 8-membered mono- or bicyclic ring system o...

Claims

CLAIMS1. A method of treating a disease or disorder, e.g., obesity, in a subject comprising administering to the subject:(i) a G-protein coupled hormone receptor (GCHR) modulator; and(ii) a melanocortin receptor 4 (MC4R) agonist;thereby treating obesity in the subject.

2. The method of claim 1, wherein the MC4R agonist is a small molecule.

3. The method of claim 1, wherein the GCHR modulator is a peptide or small molecule.

4. The method of claim 1, wherein the GCHR modulator comprises a glucagon-like peptide- 1 receptor (GLP1R) agonist, a dual GLP1R, or a triple GLP1R.

5. The method of claim 1, wherein the GCHR modulator is a GLP1R agonist.

6. The method of claim 5, wherein the GLP1R agonist comprises semaglutide, orforglipron, albiglutide, dulaglutide, extendin-4, tirzepatide, liraglutide, exenatide, or lixisenatide.

7. The method of claim 1, wherein the GCHR modulator comprises a dual GLP1R and gastric inhibitory peptide agonist.

8. The method of claim 7, wherein the dual GLP1R and gastric inhibitory peptide agonist comprises survodutide, pemvidutide, or cotadutide.

9. The method of claim 1, wherein the GCHR modulator comprises a triple GLP1R, gastric inhibitory peptide, and glucose-dependent insulinotropic polypeptide agonist.

10. The method of claim 9, wherein the triple GLP1R, gastric inhibitory peptide, and glucose-dependent insulinotropic polypeptide agonist comprises retatrutide.

11. The method of claim 1, wherein the MC4R agonist is a compound of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), XX), (XXI), (XXII), or a pharmaceutically acceptable salt thereof.

12. The method of claim 11, wherein the MC4R agonist is a compound of Formula (III):wherein R1is C1-C12 alkyl (e.g., C2-C5 alkyl).

13. The method of claim 12, wherein R1is C2-C5 alkyl.

14. The method of claim 12, wherein R1is ethyl.

15. The method of claim 12, wherein R1is n-propyl.

16. The method of claim 12, wherein R1is isopropyl.

17. The method of claim 12, wherein R1is w-butyl.

18. The method of claim 12, wherein R1is / e / V-butyl.

19. The method of claim 12, wherein R1is sec-butyl.

20. The method of claim 12, wherein R1is isobutyl.

21. The method of claim 12, wherein R1is C5 alkyl.

22. The method of claim 12, wherein the MC4R agonist is a compound of Formula (III) selected from any of the following structural formulas:pharmaceutically acceptable salt thereof.

23. The method of claim 12, wherein the compound of Formula (III) is represented by the following structural formula:or a pharmaceutically acceptable salt thereof.

24. The method of claim 12, wherein the compound of Formula (III) is represented by the following structural formula:or a pharmaceutically acceptable salt thereof.

25. The method of claim 12, wherein the compound of Formula (III) is represented by the following structural formula:or a pharmaceutically acceptable salt thereof.

26. The method of claim 12, wherein the compound of Formula (III) is represented by the following structural formula:or a pharmaceutically acceptable salt thereof.

27. The method of claim 11, wherein the MC4R agonist is a compound of Formula (IV), or a pharmaceutically acceptable salt thereof:wherein:R1is C1-C12 alkyl (e.g., C2-C5 alkyl);R2is halo;R3is hydrogen or halo;R4is C2-C5 alkyl;and n is an integer of 1 or 2.

28. The method of claim 27, wherein R1is C2-C5 alkyl.

29. The method of claim 27, wherein R1is ethyl.

30. The method of claim 27, wherein R1is n-propyl.

31. The method of claim 27, wherein R1is isopropyl.

32. The method of claim 27, wherein R1is / 7-butyl.

33. The method of claim 27, wherein R1is tert-butyl.

34. The method of claim 27, wherein R1is sec-butyl.

35. The method of claim 27, wherein R1is isobutyl.

36. The method of claim 27, wherein R1is C5 alkyl.

37. The method of claim 27, where R2is fluorine, chlorine, bromine, or iodine.

38. The method of claim 27, wherein R2is fluorine.

39. The method of claim 27, wherein R2is chlorine.

40. The method of claim 27, wherein R2is bromine.

41. The method of claim 27, wherein R2is iodine.

42. The method of claim 27, wherein R3is hydrogen.

43. The method of claim 27, wherein R3is halo, e.g., fluorine, chlorine, bromine, or iodine.

44. The method of claim 27, wherein R3is fluorine.

45. The method of claim 27, wherein R3is chlorine.

46. The method of claim 27, wherein R3is bromine.

47. The method of claim 27, wherein R3is iodine.

48. The method of claim 27, wherein n is 1.

49. The method of claim 27, wherein n is 2.

50. The method of claim 27, wherein the MC4R agonist is a compound of Formula (IV) selected from any of the following structural formulas:or a pharmaceutically acceptable salt thereof.

51. The method of claim 27, wherein the compound of Formula (IV) is represented by the following structural formula:or a pharmaceutically acceptable salt thereof.

52. The method of claim 27, wherein the compound of Formula (IV) is represented byor a pharmaceutically acceptable salt thereof.

53. The method of claim 27, wherein the compound of Formula (IV) is represented by the following structural formula:or a pharmaceutically acceptable salt thereof.

54. The method of claim 27, wherein the compound of Formula (IV) is represented by the following structural formula:or a pharmaceutically acceptable salt thereof.

55. The method of claim 12, wherein the MC4R agonist is a compound of Formula (III) and the GCHR is selected from semaglutide, orforglipron, albiglutide, dulaglutide, extendin-4, tirzepatide, liraglutide, exenatide, lixisenatide, survodutide, pemvidutide, retatrutide, cotadutide, mazdutide, efpegerglucagon, efoci pegtruti de, MOD-6031, DR10624, DD01, XTL6001, NA-931, JNJ-64565111, NNC9204-0530, HM15275, SAR441255, MK-0893, PF-06291874, LY2409021, and LGD-6972.

56. The method of claim 1, wherein each of the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof is independently formulated as a pharmaceutical composition.

57. The method of claim 1, wherein each of the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof is formulated together as a single pharmaceutical composition.

58. The method of claim 1, wherein each of the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof is administered concomitantly to the human subject.

59. The method of claim 1, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered within 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, or more of each other.

60. The method of claim 1, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered within 30 minutes of each other.

61. The method of claim 1, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered within 1 hour of each other.

62. The method of claim 1, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered within 2 hours of each other.

63. The method of claim 1, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered within 6 hours of each other.

64. The method of claim 1, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered within 12 hours of each other.

65. The method of claim 1, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered within 24 hours of each other.

66. The method of claim 1, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof is administered sequentially to the human subject.

67. The method of claim 66, wherein administered sequentially comprises administration of the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof within 24 hours.

68. The method of claim 1, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof is administered first to the human subject, followed by the MC4R agonist or a pharmaceutically acceptable salt thereof.

69. The method of claim 1, wherein the MC4R agonist or a pharmaceutically acceptable salt thereof is administered first to the human subject, followed by the GCHR modulator or a pharmaceutically acceptable salt thereof.

70. The method of claim 1, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof is administered for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, or more prior to administration of the MC4R agonist or a pharmaceutically acceptable salt thereof.

71. The method of claim 1, wherein the MC4R agonist or a pharmaceutically acceptable salt thereof is administered for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, or more prior to administration of the GCHR modulator or a pharmaceutically acceptable salt thereof.

72. The method of claim 1, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof is administered at a dosage of between 0.1 to 500 mg.

73. The method of claim 72, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof is administered at a dosage of 0.1 mg.

74. The method of claim 72, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof is administered at a dosage of 1 mg.

75. The method of claim 72, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof is administered at a dosage of 10 mg.

76. The method of claim 72, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof is administered at a dosage of 50 mg.

77. The method of claim 72, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof is administered at a dosage of 100 mg.

78. The method of claim 72, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof is administered at a dosage of 200 mg.

79. The method of claim 72, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof is administered at a dosage of 250 mg.

80. The method of claim 72, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof is administered at a dosage of 500 mg.

81. The method of claim 1, wherein the MC4R agonist or a pharmaceutically acceptable salt thereof is administered at a dosage of between 0.1 to 10 mg.

82. The method of claim 81, wherein the MC4R agonist or a pharmaceutically acceptable salt thereof is administered at a dosage of 0.1 mg.

83. The method of claim 81, wherein the MC4R agonist or a pharmaceutically acceptable salt thereof is administered at a dosage of 0.5 mg.

84. The method of claim 81, wherein the MC4R agonist or a pharmaceutically acceptable salt thereof is administered at a dosage of 1 mg.

85. The method of claim 81, wherein the MC4R agonist or a pharmaceutically acceptable salt thereof is administered at a dosage of 2.5 mg.

86. The method of claim 81, wherein the MC4R agonist or a pharmaceutically acceptable salt thereof is administered at a dosage of 5 mg.

87. The method of claim 81, wherein the MC4R agonist or a pharmaceutically acceptable salt thereof is administered at a dosage of 10 mg.

88. The method of claim 1, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered orally.

89. The method of claim 1, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered subcutaneously.

90. The method of claim 1, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof is administered orally and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered subcutaneously.

91. The method of claim 1, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof is administered subcutaneously and the MC4R agonist or a pharmaceutically acceptable salt thereof are administered orally.

92. The method of claim 1, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof is administered orally.

93. The method of claim 1, wherein the GCHR modulator or a pharmaceutically acceptable salt thereof is administered subcutaneously.

94. The method of claim 1, wherein the MC4R agonist or a pharmaceutically acceptable salt thereof is administered orally.

95. The method of claim 1, wherein the MC4R agonist or a pharmaceutically acceptable salt thereof is administered subcutaneously.

96. The method of claim 1, wherein the obesity is a genetic obesity or a non-genetic obesity.

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

98. The method of claim 1, wherein the subject has a body mass index (BMI) greater than 30.

99. The method of claim 1, wherein the subject has a waist circumference of greater than 40 cm.

100. The method of claim 1, wherein the subject has a waist-to-hip circumference ratio of greater than 2.

101. The method of claim 1, wherein the subject has a mutation in an MC4R pathway agonizable gene.

102. The method of claim 101, wherein the MC4R pathway agonizable gene comprises ARL6, RAI1, SRC1, BBS19, BBS21, CEP290, IFT74, LZTFL1, MKS1, TRIM32, WDPCP, RPS6KA3, HTR2C, KSR2, PROK2, RAB23, MRAP2, AFF4, ADCY3, TUB, OTP, GPR101, or TBX3.

103. The method of claim 101, wherein the subject has a mutation in POMC, LEPR, PCSK1, SRC1, or SH2B1.

104. The method of claim 1, wherein the efficacy of the combination of the GCHR modulator or a pharmaceutically acceptable salt thereof and the MC4R agonist or a pharmaceutically acceptable salt thereof is at least Xi-fold greater than the efficacy of the hypericin alone at the molar amount used in the combination, wherein Xi is 1, 1.25, 1.5, 1.75, 2, 2.5, or greater.

105. The method of claim 1, wherein the GCHR modulator and the MC4R agonist are administered in an alternating manner or in phases, wherein during each phase, only one of the GCHR modulator and the MC4R agonist are administered.

106. The method of claim 105, wherein the phases comprise periods of time.

107. The method of claim 105, wherein the phases comprise administration of different doses of the GCHR modulator and the MC4R agonist.

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