WO2024108198A2 - Methods of treating obesity with an mc4r agonist - Google Patents

Abstract

The disclosure is related to a method of treating a disease, disorder, or condition (e.g., obesity, such as hypothalamic obesity) in a subject using a melanocortin-4 receptor (MC4R) agonist.

Description

METHODS FOR TREATING OBESITY WITH AN MC4R AGONIST CLAIM OF PRIORITY The instant application claims priority to U.S. Application No.63/426,612, filed on November 18, 2022; U.S. Application No.63/426,642, filed on November 18, 2022; and U.S. Application No.63/426,647, filed on November 18, 2022. The contents of the foregoing applications are incorporated herein by reference in their entirety. BACKGROUND There is a need for treatment of obesity and obesity-related disorders, including non- genetic obesity and related disorders. SUMMARY OF THE INVENTION The present disclosure features, inter alia, treatments for a disease or disorder, such as obesity, e.g., a non-genetic obesity, e.g., hypothalamic obesity, with a compound (e.g., an MC4R agonist) or compositions thereof. In some embodiments, 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), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI) (e.g., as described herein), or a pharmaceutically acceptable salt thereof. The MC₄R agonists may be used to treat a subject diagnosed or identified as having a disease or disorder, e.g., a disease or disorder described herein, such as obesity (e.g., hypothalamic obesity), a cancer, or a metabolic disorder. The MC₄R agonist, e.g., 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), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI), or a pharmaceutically acceptable salt thereof, may be provided as a composition (e.g., a pharmaceutical composition) with a pharmaceutically acceptable excipient. In an embodiment, the pharmaceutically acceptable excipient comprises a polyethylene glycol (e.g., a modified polyethylene glycol), a lipid (e.g., a neutral lipid or a phospholipid). In an embodiment, the pharmaceutically acceptable excipient comprises a modified polyethylene glycol. In an embodiment, the pharmaceutically acceptable excipient comprises a lipid, such as a neutral diacyl lipid or a phospholipid. In another embodiment, the pharmaceutically acceptable excipient is an oil. In yet another embodiment, the pharmaceutically acceptable excipient is an excipient that is capable of forming a depot or other long-acting composition, e.g., in order to extend the release of the MC₄R agonist from the composition. The MC₄R agonist or composition thereof may be provided in a unit dosage form. For example, the unit dosage form may comprise between about 0.01 mg to 100 mg of the MC₄R agonist. In an embodiment, the unit dosage form comprises between 0.1 mg and 100 mg, e.g., between 0.1 mg and 50 mg, 0.1 mg and 25 mg, 0.1 mg and 10 mg, 1 mg and 100 mg, 1 mg and 50 mg, 1 mg and 25 mg, 1 mg and 10 mg, 5 mg and 100 mg, 5 mg and 50 mg, 5 mg and 25 mg, 5 mg and 15 mg, or 5 mg and 10 mg. The MC₄R agonist or composition thereof may be administered to a subject daily, weekly or monthly. In an embodiment, the MC₄R agonist or composition thereof is administered daily, e.g., once daily, twice daily, or three times daily. In an embodiment, the MC₄R agonist or composition thereof is administered weekly, e.g., once every week, once every two weeks, once every three weeks. In embodiments, the MC4R agonist or composition thereof is administered daily over a period of at least 3 weeks, e.g., at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 weeks or more, or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months or more, or at least 1, 2, 3, 4 years or more. In embodiments, the method comprises administering the MC4R agonist or composition thereof in a unit dosage form suitable for injection, e.g., subcutaneous injection, to the subject. In embodiments, the unit dosage form is disposed within a delivery device, e.g., a syringe (e.g., prefilled syringe), an implantable device, a needleless hypodermic injection device, an infusion pump (e.g., implantable infusion pump), or an osmotic delivery system. In embodiments, the MC4R agonist is administered subcutaneously, e.g., by subcutaneous injection. In another embodiment, the MC4R agonist is administered orally, e.g., as a tablet, capsule, pill, liquid, or other oral dosage form. In embodiments, the subject is obese, e.g., severely obese. In embodiments, the subject has early onset severe obesity. In embodiments, the subject is hyperphagic. In embodiments, the subject experiences severe hunger. In embodiments, the subject has a body mass index (BMI) greater than 25 kg/m² (e.g., ≥25, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg/m² or greater) prior to administration of the MC4R agonist, e.g., at the time the MC4R agonist is prescribed, or at the time of the first administration. In embodiments, the subject has a body mass index (BMI) greater than 35 kg/m² (e.g., ≥36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg/m² or greater) prior to administration of the MC4R agonist, e.g., at the time the MC4R agonist is prescribed, or at the time of the first administration. In embodiments, the subject has a body mass index (BMI) greater than 40 kg/m² (e.g., ≥41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 kg/m² or greater) prior to administration of the MC4R agonist, e.g., at the time the MC4R agonist is prescribed, or at the time of the first administration. In embodiments, the subject has a body mass index (BMI) greater than 45 kg/m² (e.g., ≥46, 47, 48, 49, 50, 51, 52, 53, 54, 55 kg/m² or greater) prior to administration of the MC4R agonist, e.g., at the time the MC4R agonist is prescribed, or at the time of the first administration. In embodiments, the subject has a BMI higher than the 85-95th percentile prior to administration of the MC4R agonist or composition thereof, e.g., at the time the MC4R agonist is prescribed, or at the time of the first administration. In embodiments, the subject has failed one or more previous therapies, e.g., exercise, diet, or behavioral therapies, prior to administration of the MC4R agonist or composition thereof, e.g., at the time the agonist is prescribed, or at the time of the first administration. In embodiments, the subject has a lower body weight after administration of the MC4R agonist or composition thereof than before administration of the agonist. In embodiments, administration of the MC4R agonist or composition thereof results in a reduction of weight in the subject compared to the weight of the subject before treatment of about 1 kg to 3 kg after 1 week of treatment, or about 1 kg to 6 kg after 2 weeks of treatment, or about 2 kg to 12 kg after 4 weeks of treatment, or about 4 kg to 24 kg after 8 weeks of treatment, or about 8 kg to 48 kg after 16 weeks of treatment. In embodiments, administration of the MC4R agonist or composition thereof results in a reduction of BMI by about 1%, 2%, 3%, 5%, 6%, 7%, 8%, 9%, 10%, or more, e.g., by at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 weeks or longer. In embodiments, administration of the MC4R agonist or composition thereof results in no detectable/significant decrease in resting energy expenditure (REE) in the subject, e.g., over a period of 24 hours, one week, or 30 days or longer, e.g., as compared to a control REE (e.g., the REE in the subject prior to treatment or a predetermined REE, e.g., in subjects of similar pre-treatment BMI, e.g., when expressed as REE per kg of lean body mass). In embodiments, administration of the MC4R agonist or composition thereof results in a reduction in food intake of at least 5 kcal/kg/day, e.g., 5, 10, 20, 30, 40, 50, 60, 70, 80, or 90 or more kcal/kg/day. In embodiments, the reduction in food intake is relative to the food intake at baseline. In embodiments, the baseline food intake is at least 100 kcal/kg/day, e.g., for a pediatric subject at about 1 year of age. In embodiments, the baseline food intake is at least 40 kcal/kg/day, e.g., for a pediatric subject, e.g., in late adolescence. In embodiments, administration of the MC4R agonist or composition thereof results in a reduction in waist circumference of the subject compared to a control (e.g., the waist circumference of the subject prior to treatment), as measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more after initiation of treatment. In embodiments, administration of the MC4R agonist or composition thereof results in no detectable increase in blood pressure (e.g., diastolic and/or systolic blood pressure) of the subject compared to the blood pressure of the subject prior to treatment, as measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more after initiation of treatment. In embodiments, administration of the MC4R agonist or composition thereof results in a reduction in blood pressure (e.g., diastolic and/or systolic blood pressure) of the subject compared to the blood pressure of the subject prior to treatment, as measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more after initiation of treatment. In embodiments, administration of the MC4R agonist or composition thereof results in a reduction in systolic blood of the subject of at least 3 mmHg (e.g., at least 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7 mmHg or more) compared to the blood pressure of the subject prior to treatment, as measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more after initiation of treatment. In embodiments, administration of the MC4R agonist or composition thereof results in a reduction in diastolic blood pressure of the subject of at least 4 mmHg (e.g., at least 4, 7, 7.5, 8, 8.5, 9, 9.5, 10 mmHg or more) compared to the blood pressure of the subject prior to treatment, as measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more after initiation of treatment. In embodiments, administration of the MC4R agonist or composition thereof results in a reduction of hunger in a subject. The reduction of hunger may result in a reduction of food intake, decrease in resting energy expenditure (REE), reduction of weight, reduction in waist circumference, and/or reduction in blood pressure in the subject. In embodiments, the subject is a mammal, e.g., a human. In an embodiment, the subject is an adult (e.g., 18 years of age or older). In an embodiment, the subject is a pediatric subject, e.g., a child. In embodiments, the method further comprises acquiring knowledge of the genotype of the subject, e.g., acquiring knowledge of the genotype of an MC4R pathway agonizable gene, e.g., a gene listed in Table 1. In embodiments, the knowledge is acquired directly, e.g., from a sample (e.g., a blood, serum, urine, or tissue (e.g., biopsy) sample) from the subject. In embodiments, the MC4R agonist or composition thereof is administered in response to the detection of a predetermined sequence, e.g., a mutation, MC4R pathway agonizable gene, e.g., a gene listed in Table 1. In embodiments, the predetermined sequence, e.g., mutation, is detected in a nucleic acid by a method chosen from one or more of: a nucleic acid hybridization assay, an amplification-based assay, a PCR-RFLP assay, real-time PCR, sequencing (e.g., DNA sequencing, e.g., next generation sequencing or Sanger method sequencing, bisulfite sequencing, or pyrosequencing), screening analysis, FISH, spectral karyotyping or MFISH, comparative genomic hybridization, in situ hybridization, SSP, HPLC, or mass-spectrometric genotyping. In embodiments, the predetermined sequence, e.g., mutation, is detected in the subject. In embodiments, the predetermined sequence, e.g., mutation, is detected in a nucleic acid molecule or a polypeptide in a sample from the subject. In embodiments, the sample comprises cells from blood, serum, urine, or tissue (e.g., biopsy) from the subject. In embodiments, the method comprises acquiring knowledge of the genotype of the subject, e.g., acquiring knowledge of the genotype of, e.g., of a mutation in a gene listed in In some embodiments, the compound is a peptide-based MC4R agonist. In some embodiments, the compound is a small molecule-based MC4R agonist. In some embodiments, the compound is a peptidomimetic MC4R agonist. In some embodiments, the compound 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), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of any one of Formulas (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is not Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂ (SEQ ID NO: 140; Compound NO.1014) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is not Hydantoin(C(O)-(Arg-Gly))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp- Cys)-NH₂ (SEQ ID NO:13) or a pharmaceutically acceptable salt thereof. In some embodiments, the 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), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI), is formulated as a pharmaceutical composition. 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. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. 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 limiting. Other features, objects, and advantages of the disclosure will be apparent from the description and drawings, and from the claims. DETAILED DESCRIPTION Described herein are methods for treating a disease or disorder, such as obesity (e.g., hypothalamic obesity) in a subject by administering a therapeutic agent targeting the melanocortin 4 receptor (MC4R) pathway, e.g., an MC4R agonist. In an embodiment, the subject has hypothalamic obesity. In an embodiment, the subject has been identified as having or diagnosed with hypothalamic obesity. In an embodiment, administering an MC4R agonist to a subject leads to significant weight loss, decrease in hunger, and/or an increase in energy expenditure in the subject. Exemplary MC4R agonists, as well as related formulations and methods of use are described in further detail herein. Definitions As used herein “about” and "approximately" generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given value or range of values. “Acquire” or “acquiring” as the terms are used herein, refer to obtaining possession of a physical entity, or a value, e.g., a numerical value, or knowledge of (e.g., knowledge of the sequence or mutational state of) a genotype or a nucleic acid or polypeptide, by “directly acquiring” or “indirectly acquiring” the physical entity, value, or knowledge. “Directly acquiring” means performing a physical process (e.g., performing a synthetic or analytical method) to obtain the physical entity, value, or knowledge. “Indirectly acquiring” refers to receiving the physical entity, value, or knowledge from another party or source (e.g., a third- party laboratory that directly acquired the physical entity, value, or knowledge). Directly acquiring a physical entity includes performing a process that includes a physical change in a physical substance, e.g., a starting material. Exemplary changes include making a physical entity from two or more starting materials, shearing or fragmenting a substance, separating or purifying a substance, combining two or more separate entities into a mixture, performing a chemical reaction that includes breaking or forming a covalent or non-covalent bond. Directly acquiring a value or knowledge includes performing a process that includes a physical change in a sample or another substance. Examples include performing an analytical process which includes a physical change in a substance, e.g., a sample, analyte, or reagent (sometimes referred to herein as “physical analysis”), performing an analytical method, e.g., a method which includes one or more of the following: separating or purifying a substance, e.g., an analyte, or a fragment or other derivative thereof, from another substance; combining an analyte, or fragment or other derivative thereof, with another substance, e.g., a buffer, solvent, or reactant; or changing the structure of an analyte, or a fragment or other derivative thereof, e.g., by breaking or forming a covalent or non-covalent bond, between a first and a second atom of the analyte; or by changing the structure of a reagent, or a fragment or other derivative thereof, e.g., by breaking or forming a covalent or non-covalent bond, between a first and a second atom of the reagent. 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. 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. 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. 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. 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 (Sim1). In an embodiment, the MC4R pathway agonizable gene does not comprise any gene disclosed in WO2013/102047 or WO 2017/059076, the full contents of each of which is incorporated herein by reference in its entirety. 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. 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. 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. In an embodiment, an epigenetic modification, e.g., a histone modification, e.g., acetylation or nucleobase methylation, e.g., cytosine methylation, is present and is associated with the MC4R pathway agonizable gene phenotype, e.g., hyperphagia, appetite, unwanted appetite, obesity, weight, body mass, or a metabolic syndrome (e.g., diabetes) In an embodiment, the epigenetic modification is associated with an MC4R pathway agonizable gene. In an embodiment, the epigenetic modification is associated with MC4R. In an embodiment, the epigenetic modification is associated with an MC4R pathway agonizable gene other than MC4R. 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 (Sim1). In an embodiment, the MC4R pathway agonizable gene does not comprise any gene disclosed in WO2013/102047 or WO 2017/059076, the full contents of each of which is incorporated herein by reference in its entirety. As used herein, the term “obese” refers to a subject having a body mass index (BMI) within the ranges defined as “obese” by the Center for Disease Control (see, e.g., URL.cdc.gov/obesity/ defining.html and www.cdc.gov/obesity/childhood-/defining.html, last accessed on August 26, 2012) or as defined by “Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults” from the National Institutes of Health. BMI is obtained by dividing a subject’s weight, e.g., in kilograms (kg) by the square of the subject’s height, e.g., in meter (m). For example, an adult who has a BMI of 30 kg/m² or higher is considered obese. For example, an adult with a BMI of 25.0 to 29.9 kg/m² is considered overweight; an adult with a BMI of 18.5 to 24.9 kg/m² is considered to have a normal or healthy weight range; and an adult with a BMI of less than 18.5 kg/m² is considered to be underweight. For example, an adult having a height of 5 feet, 9 inches with a body weight of 203 pounds or more is considered obese. For children and teens, obese refers to a subject having a BMI at or above the 85^th to 95^th percentile for children and teens of the same age and sex. A “severely obese” subject or a subject having “severe obesity” refers to a subject having a BMI of 35 kg/m² or higher, e.g., 40 kg/m² or higher. For example, a severely obese subject is over 100% over the ideal (normal, healthy) body weight. As used herein “early onset”, e.g., as in early onset obesity, refers to an onset (e.g., first occurrence of one or more symptoms of a disorder, e.g., a disorder described herein, e.g., obesity) that occurs in a subject before adulthood, e.g., during childhood, e.g., when the subject is less 18 years of age or younger (e.g., 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 year of age or younger, or during adolescence, e.g., when the child is younger than 12 years of age or when the child is younger than 6 years of age). 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; 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. As used herein, the term “agonist” refers to any chemical compound, either naturally occurring or synthetic, that, upon interacting with (e.g., binding to) its target, e.g., MC4R, raises the signaling activity of MC4R above its basal level. An agonist can be a superagonist (i.e. a compound that is capable of producing a greater maximal response than the endogenous agonist for the target receptor, and thus has an efficacy of more than 100%), a full agonist (i.e. a compound that elicits a maximal response following receptor occupation and activation) or a partial agonist (i.e. a compounds that can activate receptors but are unable to elicit the maximal response of the receptor system). 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., a compound of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), or (XXXIII) (e.g., as described herein) or a pharmaceutically acceptable salt thereof. 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., hypothalamic obesity), Prader Willi Syndrome, Smith-Magenis syndrome, type-II diabetes, a pre-diabetic condition, blood level of hemoglobin A1C (Hb1Ac) 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. 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%. “Prophylactic treatment” refers to treatment before onset of obesity to prevent, inhibit or reduce its occurrence. 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). 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). 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. 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. As used herein “null genotype” refers to the presence of two non-functional alleles of a gene in a subject. 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. 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. Selected Chemical Definitions 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, 75^th Ed., 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, March’s Advanced Organic Chemistry, 5^th Edition, 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, 3^rd Edition, Cambridge University Press, Cambridge, 1987. 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. 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. When a range of values is listed, it is intended to encompass each value and sub– range within the range. For example, “C₁-C₆ alkyl” is intended to encompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁-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. 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. 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, including ¹H, ²H (D or deuterium), and ³H (T or tritium); C may be in any isotopic form, including ¹²C, ¹³C, and ¹⁴C; O may be in any isotopic form, including ¹⁶O and ¹⁸O; N may be in any isotopic form, including ¹⁴N and ¹⁵N; F may be in any isotopic form, including ¹⁸F, ¹⁹F; and the like. 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. 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. 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. 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. 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 R⋅x 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⋅0.5 H₂O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R⋅2 H₂O) and hexahydrates (R⋅6 H₂O)). 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 π 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. Symbol Meaning Abu α-aminobutyric acid Ac acyl group Acc 1-amino-1-cyclo(C₃-C₉)alkyl carboxylic acid A3c 1-amino-1cyclopropanecarboxylic acid A5c 1-amino-1-cyclopentanecarboxylic acid A6c 1-amino-1-cyclohexanecarboxylic acid Aha 7-aminoheptanoic acid Ahx 6-aminohexanoic acid Aib α-aminoisobutyric acid Aic 2-aminoindan-2-carboxylic acid Ala or A Alanine β-Ala β-alanine Apc denotes the structure:

Apn 5-aminopentanoic acid (HN—(CH₂)₄—C(O) Arg or R Arginine hArg Homoarginine Asn or N Asparagine Asp or D aspartic acid Atc Bal 3-benzothienylalanine Bip 4,4’-biphenylalanine, represented by the structure H N Bpa 4-benzoylphen

y 4-Br-Phe 4-bromo-phenylalanine Cha β –cyclohexylalanine hCha homo-cyclohexylalanine Chg Cyclohexylglycine sChp Cya α‐amino acid cysteic acid Cys or C Cysteine hCys Homocysteine Dab 2,4-diaminobutyric acid Dap 2,3-diaminopropionic acid Dip β,β-diphenylalanine Doc 8-amino-3,6-dioxaoctanoic acid with the structure of: Dpr 2,3-Diam

noproponc ac Gaba 4-aminobutyric acid Gln or Q Glutamine Glu or E glutamic acid Gly or G Glycine His or H Histidine 3-Hyp trans-3-hydroxy-L-proline, i.e., (2S,3S)-3-hydroxy-pyrrolidine-2- carboxylic acid 4-Hyp 4-hydroxyproline, i.e., (2S,4R)-4-hydorxypyrrolidine-2-carboxylic acid Ile or 1 Isoleucine Leu or L Leucine hLeu Homoleucine Lys or K Lysine Met or M Methionine β-hMet β-homomethionine 1-Nal β-(1-naphthyl)alanine 2-Nal β-(2-naphthyl)alanine Nip nipecotic acid Nle Norleucine Oic Octahydroindole-2-carboxylic Acid Orn Ornithine 2-Pal β-(2-pyridiyl)alanine 3-Pal β-(3-pyridiyl)alanine 4-Pal β-(4-pyridiyl)alanine Pen Penicillamine Pff (S)-pentafluorophenylalanine Phe or F Phenylalanine hPhe Homophenylalanine Pro or P Proline hPro Homoproline Sar Sarcosine (N-methylglycine) Ser or S Serine Tle tert-Leucine Taz β-(4-thiazolyl)alanine 2-Thi β-(2-thienyl)alanine 3-Thi β-(3-thienyl)alanine Thr or T Threonine Trp or W Tryptopham Tyr or Y Tyrosine D-(Et) Tyr has a structure of Val or V Valine

Certain other abbreviations used herein are defined as follows: Boc: tert-butyloxycarbonyl OtBu oxy-tert-butyl tBu: tert-butyl 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 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═CH₃ and R′═H for Ala), or R and R′ may be joined to form a ring system. For the N-terminal amino acid, the abbreviation stands for the structure of:

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. “-c(Cys-Cys)-” or “-cyclo(Cys-Cys)-” denotes the structure:

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

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

The following abbreviations are used throughout the disclosure: “Hydantoin-(C(O)-(A^a-A^b))” denotes the structure: amino acid “A^a ” has t

he structure: and amino acid “A^b” the structure:

For example, “Hydantoin-(C(O)-Arg-A^b))” would have the following structure:

For example, “Hydantoin-(C(O)-(Arg-Gly))” would have the following structure:

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

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

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

, whereas “c[Hydantoin(C(O)-(Dap-A^b))-A¹-A²-A³-A⁴-Asp]-” has the following formula:

“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, “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 (“C₁-C₈ alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C₁-C₆ 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 (“C₁ alkyl”). Examples of C₁-C₆alkyl groups include methyl (C₁), ethyl (C₂), n–propyl (C₃), isopropyl (C₃), n–butyl (C₄), tert–butyl (C₄), sec–butyl (C₄), iso–butyl (C₄), n–pentyl (C₅), 3–pentanyl (C₅), amyl (C₅), neopentyl (C₅), 3–methyl–2–butanyl (C₅), tertiary amyl (C₅), and n–hexyl (C₆). Additional examples of alkyl groups include n–heptyl (C₇), n–octyl (C₈) 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 C_1–C₁₀ alkyl (e.g., – CH₃). In certain embodiments, the alkyl group is substituted C₁–C₆ alkyl. “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, -NH CH₃), -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)₀-20-COOH. In different embodiments 1, 2, 3 or 4 substituents are present. The presence of -(CH₂)_0-20-COOH results in the production of an alkyl acid. Non- limiting examples of alkyl acids containing, or consisting of, -(CH₂)_0-20-COOH include 2- norbornane acetic acid, tert-butyric acid, 3-cyclopentyl propionic acid, and the like. As used herein, the term “halogen” or “halo” encompasses fluoro, chloro, bromo and iodo. As used herein, the term “hydroxy” refers to -OH. 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. “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-O-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, –NR^CR^D, or the like, it will be understood that the terms heteroalkyl and –CH₂O or – NR^CR^D are 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, –NR^CR^D, or the like. “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)₀-20-COOH. In different embodiments 1, 2, 3 or 4 substituents are present. “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 carbon– carbon 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- C₆ alkenyl groups include the aforementioned C_2–4 alkenyl groups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and the like. Additional examples of alkenyl include heptenyl (C₇), octenyl (C₈), octatrienyl (C₈), and the like. “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 bel substituted with one or more substituents selected, independently for each occurrence, from the group consisting of halogens, —CF₃, —OCH₃, —OCF₃, and —(CH₂)_0-20—COOH. In different embodiments 1, 2, 3 or 4 substituents are present. 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 C_2–10 alkynyl. In certain embodiments, the alkynyl group is substituted C_2–6 alkynyl. “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 14 π 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 (“C₆ aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C₁₀ aryl”; e.g., naphthyl such as 1– naphthyl and 2–naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C₁₄ aryl”; e.g., anthracyl). An aryl group may be described as, e.g., a C₆-C₁₀- 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, —NO ₂-(C₁-C₂₀) alkyl substituted with halogens, —CF₃, —OCF₃, and —(CH₂)_0-20— COOH. In different embodiments the aryl contains 0, 1, 2, 3, or 4 substituents. 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 π 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. 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. “Alkylaryl” refers to an “alkyl” joined to an “aryl”. The term “(C₁-₁₂)hydrocarbon moiety” encompasses alkyl, alkenyl and alkynyl and in the case of alkenyl and alkynyl there is C₂-C₁₂. 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 (“C₃-C₈ 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- C₇-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 (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like. ExemplaryC₃-C₈ cycloalkyl groups include, without limitation, the aforementioned C₃-C₆ cycloalkyl groups as well as cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C₈), cubanyl (C₈), bicyclo[1.1.1]pentanyl (C₅), bicyclo[2.2.2]octanyl (C₈), bicyclo[2.1.1]hexanyl (C₆), bicyclo[3.1.1]heptanyl (C₇), and the like. Exemplary C₃-C₁₀ cycloalkyl groups include, without limitation, the aforementioned C₃-C₈ cycloalkyl groups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl (C₁₀), octahydro–1H–indenyl (C₉), decahydronaphthalenyl (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. “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, i.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. “Heterocyclyl” as used herein refers to a radical of a 3– to 16–membered non– aromatic 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. 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., 1-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 C₆ 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, octahydropyrrolopyrrolyl (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. 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., (1,5)-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). 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., C≡N. As used herein, the term “nitro” refers to a substituent having two oxygen atoms bound to a nitrogen atom, e.g., -NO₂. As used herein, “oxo” refers to a carbonyl, i.e., -C(O)-. The symbol “ ed herein in relation to a compound of Formula (I) or (II) refers to an attachment p

oint to another moiety or functional group within the compound. 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. Designation “(amino acid)n” means that an amino acid is repeated n times. For example, designation “(Pro)₂” or “(Arg)₃” mean that proline or arginine residues are repeated, respectively, two or three times. MC4R Hmc4R is a protein encoded by a genomic sequence having GenBank 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. 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). 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, I317V, L325F, and 750DelGA, as described in Xiang et al., “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. 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; SER58CYS; ILE102SER; ASN274SER; 1-BP INS, 112A; 4-BP DEL, 211CTCT; 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. 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 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, and the cloned sequence analyzed using commercially available sequencers and software. 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. α- MSH), and the intracellular level of Camp, the secondary messenger of MC4R, measured by an electrochemiluminescence assay described, e.g., in Roubert et al., 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. 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. Melanocortin-4 Receptor (MC4R) pathway genes 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 (α-MSH), β-MSH, γ-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 POMC-MC4R pathway increases energy expenditure and decreases food intake. See, e.g., Fan et al. Nature 1997;385:165-68. The POMC-MC4R pathway includes a number of proteins, such as melanocortins (MCs), MC4 receptor (MC4R), 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 (Sim1), that together contribute to the regulation of energy homeostasis, e.g., by regulating appetite and energy expenditure. MC4R and other components of the POMC-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 POMC-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 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 (Sim1). 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 WO2013/102047 or WO 2017/059076, the full contents of each of which is incorporated herein by reference in its entirety. In an embodiment, 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), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI), 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. ADP Ribosylation Factor-like GTPase 6 (ARL6) ADP Ribosylation Factor-like GTPase 6 (ARL6), also known as BBS3, is a member of the ARF-like (ADP ribosylation factor-like) sub-family of the ARF family of GTP-binding proteins, which are involved in the regulation of intracellular traffic. ARL6 is involved in membrane protein trafficking at the base of the ciliary organelle and mediates recruitment onto plasma membrane of the BBSome complex. Together with BBS1, ARL6 is necessary for correct trafficking of PKD1 to primary cilia. Together with the BBSome complex and LTZL1, ARL6 controls SMO ciliary trafficking and contributes to the sonic hedgehog (SHH) pathway regulation. It is believed that ARL6 may regulate cilia assembly and disassembly and subsequent ciliary signaling events such as the Wnt signaling cascade. ARL6 isoform 2 may be required for proper retinal function and organization. A vision-specific transcript, encoding long isoform BBS3L, has also been described. Mutations in the ARL6 gene are associated with Bardet-Biedl syndrome (BBS), a genetically heterogeneous disorder. BBS is a form of Laurence-Moon-Beidl syndrome and is characterized by obesity, retinopathy, learning disability, polydactyly, hypogenitalism, and retinitis pigmentosa 55. (See, e.g., Young et al. Am. J. Med. Genet.78(5):461-7 (2002)). The human ARL6 gene sequence is provided in GenBank Accession No. NG_008119.2, incorporated herein by reference. An exemplary human ARL6 nucleic acid sequence is provided in GenBank Accession No. NM_001278293.3, incorporated herein by reference. An exemplary amino acid sequence of human ARL6 is provided by Q9H0F7, incorporated herein by reference. Retinoic Acid Induced 1 (RAI1) Retinoic Acid Induced 1 (RAI1) is a transcription factor that regulates the circadian clock components: CLOCK, ARNTL/BMAL1, ARNTL2/BMAL2, PER1/3, CRY1/2, NR1D1/2, and RORA/C. RAI1 positively regulates the transcriptional activity of CLOCK, a core component of the circadian clock. (See, e.g., Williams et al. Am. J. Hum. Genet. 90(6):941-9 (2012)). RAI1 also regulates transcription through chromatin remodeling by interacting with other proteins in chromatin as well as proteins in the basic transcriptional machinery. It is believed that RAI1 may be important for embryonic and postnatal development and may be involved in neuronal differentiation. Mutations in RAI1 (e.g., leading to haploinsufficiency) are associated with Smith- Magenis Syndrome, a disorder characterized by cognitive and behavioral abnormalities, including self-injurious behaviors and sleep disturbance, obesity, and distinct craniofacial and skeletal anomalies, that has been associated with deletions involving chromosome 17p11.2. (See, e.g., Slager et al. Nat Genet.33(4):466‐468 (2003)). The human RAI1 gene sequence is provided in GenBank Accession No. NG_007101.2, incorporated herein by reference. An exemplary human RAI1 nucleic acid sequence is provided in GenBank Accession No. NM_030665.4, incorporated herein by reference. An exemplary amino acid sequence of human RAI1 is provided by Q7Z5J4-1, incorporated herein by reference. Steroid Receptor Coactivator 1 (SRC1) Steroid Receptor Coactivator 1 (SRC₁), also known as Nuclear Receptor Coactivator 1 (NCOA1), is a transcriptional coactivator for steroid and nuclear hormone receptors. SRC₁ is a member of the p160/SRC family, and like other family members, has histone acetyltransferase activity and contains a nuclear localization signal, as well as Bhlh and PAS domains. SRC1 binds nuclear receptors directly and stimulates the transcriptional activities in a hormone-dependent fashion. SRC1 is involved in the coactivation of different nuclear receptors, such as for steroids, retinoids, thyroid hormone, and prostanoids. SRC1 is also involved in coactivation mediated by STAT3, STAT5A, STAT5B, and STAT6 transcription factors. SRC1 plays a central role in creating multi-subunit coactivator complexes that act via remodeling of chromatin, and possibly acts by participating in both chromatin remodeling and recruitment of general transcription factors. It is required with NCOA2 to control energy balance between white and brown adipose tissues and for mediating steroid hormone response. Alternatively spliced transcript variants encoding different isoforms have also been identified. Mutations in SRC1 has been linked to obesity. Without wishing to be bound by theory, it is believed that SRC-1 modulates the function of hypothalamic Pro- opiomelanocortin (Pomc) neurons, which regulate food intake and body weight. Rare heterozygous variants of SRC1 were found in severely obese individuals that impaired leptin mediated Pomc reporter activity in cells. (See, e.g., Yang et al. Nat. Commun.10(1):1718 (2019)). The human SRC1 gene sequence is provided in GenBank Accession No. NG_029014.2, incorporated herein by reference. An exemplary human SRC1 nucleic acid sequence is provided in GenBank Accession No. NM_003743.5, incorporated herein by reference. An exemplary amino acid sequence of human SRC1 is provided by Q15788-1, incorporated herein by reference. Bardet-Biedl Syndrome 19 (BBS19) Bardet-Biedl Syndrome 19 (BBS19), also known as intraflagellar transport protein 27 homolog (IFT27), is a small GTPase-like component of the intraflagellar transport complex B, which is essential for cilia biogenesis and maintenance. BBS19 promotes the exit of the BBSome complex from cilia via its interaction with ARL6. BBS19 forms a subcomplex within the IFT complex B with IFT25 and prevents aggregation of GTP-free ARL6 but is not believed to be involved in entry of the BBSome complex into cilium. (See, e.g., Liew et al. Dev. Cell 31(3):265-278 (2014)). BBS19 is also required for hedgehog signaling. Its role in intraflagellar transport is mainly seen in tissues rich in ciliated cells such as kidney and testis. BBS19 is essential for male fertility, spermiogenesis and sperm flagella formation, plays a role in the early development of the kidney, and may be involved in the regulation of ureteric bud initiation. Mutations in the BBS19 gene have been associated with Bardet-Biedl syndrome (See, e.g., Aldahmesh et al. Hum. Mol. Genet.23(12):3307-15 (2014)). The human BBS19 gene sequence is provided in GenBank Accession No. NG_034205.1, incorporated herein by reference. An exemplary human BBS19 nucleic acid sequence is provided in GenBank Accession No. NM_001177701.3, incorporated herein by reference. An exemplary amino acid sequence of human BBS19 is provided by Q9BW83-1, incorporated herein by reference. Bardet-Biedl Syndrome 21 (BBS21) The Bardet-Biedl syndrome 21 (BBS21) gene, also known as chromosome 8 open reading frame 37 (C8orf37), encodes a broadly expressed protein of unknown function. High levels of BBS21 Mrna can be found in the brain, heart, and retina. The protein has been shown to co-localize with polyglutamylated tubulin at the base of the primary cilium in human retinal pigment epithelial cells. Mutations in the BBS21 gene have been associated with Bardet-Biedl syndrome, autosomal recessive cone-rod dystrophy (arCRD), and retinitis pigmentosa (See, e.g., Heon et al. Hum. Mol. Genet.25(11):2283-2294 (2016)). The human BBS21 gene sequence is provided in GenBank Accession No. NG_032804.1, incorporated herein by reference. An exemplary human BBS21 nucleic acid sequence is provided in GenBank Accession No. NM_177965.4, incorporated herein by reference. An exemplary amino acid sequence of human BBS21 is provided by Q96NL8-1, incorporated herein by reference. Centrosomal Protein 290 (CEP290) Centrosomal Protein 290 (CEP290), also known as BBS14, encodes a protein with thirteen putative coiled-coil domains, a region with homology to SMC chromosome segregation ATPases, six KID motifs, three tropomyosin homology domains, and an ATP/GTP binding site motif A. The protein is localized to the centrosome and cilia and has sites for N-glycosylation, tyrosine sulfation, phosphorylation, N-myristoylation, and amidation. CEP290 is involved in early and late steps in cilia formation and its association with CCP110 is required for inhibition of primary cilia formation by CCP110. CEP290 may play a role in early ciliogenesis in the disappearance of centriolar satellites and in the transition of primary ciliar vesicles (PCVs) to capped ciliary vesicles (CCVs). CEP290 is also required for the centrosomal recruitment of RAB8A and for the targeting of centriole satellite proteins to centrosomes such as of PCM1. It is required for the correct localization of ciliary and phototransduction proteins in retinal photoreceptor cells and may play a role in ciliary transport processes. Required for efficient recruitment of RAB8A to primary cilium. In the ciliary transition zone, CEP290 is part of the tectonic-like complex, which is required for tissue-specific ciliogenesis and may regulate ciliary membrane composition. CEP290 is involved in regulation of the BBSome complex integrity, specifically for presence of BBS2, BBS5, and BBS8/TTC8 in the complex, and in ciliary targeting of selected BBSome cargos. CEP290 may play a role in controlling entry of the BBSome complex to cilia. Mutations in this gene have been associated with several ciliopathies including Bardet-Biedl syndrome, isolated retinal degeneration, nephronophthisis (NPHP), Joubert syndrome, Senior–Loken syndrome (SLSN), and neonatal lethal Meckel-Gruber syndrome (MKS). (See, e.g., Zhang et al. Hu. Mol. Genet.23(1):40-51 (2014) and Leitch et al. Nat. Genet.40(4):443-448 (2008)). The human CEP290 gene sequence is provided in GenBank Accession No. NG_008417.2, incorporated herein by reference. An exemplary human CEP290 nucleic acid sequence is provided in GenBank Accession No. NM_025114.4, incorporated herein by reference. An exemplary amino acid sequence of human CEP290 is provided by O15078-1, incorporated herein by reference. Intraflagellar Transport 74 (IFT74) Intraflagellar Transport 74 (IFT74) is a core component of the intraflagellar transport (IFT), a multi-protein complex involved in the transport of ciliary proteins along axonemal microtubules. IFT proteins are found at the base of the cilium as well as inside the cilium, where they assemble into long arrays between the ciliary base and tip. Specifically, IFT74, together with IFT81, forms a tubulin-binding module that specifically mediates transport of tubulin within the cilium. IFT74 binds beta-tubulin via its basic region and is required for ciliogenesis. Naturally occurring mutations in this gene are associated with Bardet-Biedl Syndrome and amyotrophic lateral sclerosis–frontotemporal dementia. (See, e.g., Lindstrand et al. Am. J. Hum. Genet.99(2):318-336 (2016)). The human IFT74 gene sequence is provided in GenBank Accession No. NG_053083.1, incorporated herein by reference. An exemplary human IFT74 nucleic acid sequence is provided in GenBank Accession No. NM_001099222.2, incorporated herein by reference. An exemplary amino acid sequence of human IFT74 is provided by Q96LB3-1, incorporated herein by reference. Leucine Zipper Transcription Factor Like 1 (LZTFL1) Leucine Zipper Transcription Factor Like 1 (LZTFL1), also known as BBS17, encodes a ubiquitously expressed protein that localizes to the cytoplasm. The protein interacts with Bardet-Biedl Syndrome (BBS) proteins and, through its interaction with BBS protein complexes, regulates protein trafficking to the ciliary membrane. LZTFL1 regulates ciliary localization of the BBSome complex and, together with the BBSome complex, controls SMO ciliary trafficking and contributes to the sonic hedgehog (SHH) pathway regulation. Nonsense mutations in this gene are associated with a form of Bardet-Biedl Syndrome. (See, e.g., Deffert et al. Am. J. Med. Genet. A.143A(2):208-213 (2007)). LZTFL1 may also function as a tumor suppressor; possibly by interacting with E-cadherin and the actin cytoskeleton and thereby regulating the transition of epithelial cells to mesenchymal cells. Alternative splicing of LZTFL1 results in multiple transcript variants. The human LZTFL1 gene sequence is provided in GenBank Accession No. NG_033917.1, incorporated herein by reference. An exemplary human LZTFL1 nucleic acid sequence is provided in GenBank Accession No. NM_020347.4, incorporated herein by reference. An exemplary amino acid sequence of human LZTFL1 is provided by Q9NQ48-1, incorporated herein by reference. MKS Transition Zone Complex Subunit 1 (MKS1) MKS Transition Zone Complex Subunit 1 (MKS1), also known as BBS13, is a component of the tectonic-like complex, a complex localized at the transition zone of primary cilia and acting as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes. MKS1 localizes to the basal body and is involved in centrosome migration to the apical cell surface during early ciliogenesis, is required for formation of the primary cilium in ciliated epithelial cells, and is required for ciliary structure and function, including a role in regulating length and appropriate number through modulating centrosome duplication. MKS1 is also required for cell branching morphology. Mutations in this gene result in Meckel syndrome type 1 and in Bardet-Biedl syndrome type 13. (See, e.g., Xing et al. PloS One 9(3):e90599 (2014)). Multiple transcript variants encoding different isoforms have been identified for this gene. The human MKS1 gene sequence is provided in GenBank Accession No. NG_013032.1, incorporated herein by reference. An exemplary human MKS1 nucleic acid sequence is provided in GenBank Accession No. NM_017777.4, incorporated herein by reference. An exemplary amino acid sequence of human MKS1 is provided by Q9NXB0-1, incorporated herein by reference. Tripartite Motif Containing 32 (TRIM32) Tripartite Motif Containing 32 (TRIM32), also known as BBS11, is a member of the tripartite motif (TRIM) family. The protein encoded by the TRIM32 gene contains three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. The protein encoded by TRIM32 localizes to cytoplasmic bodies and to the nucleus, where it interacts with the activation domain of the HIV-1 Tat protein. The TRIM32 protein also has E3 ubiquitin ligase activity and has been shown to ubiquitinate DTNBP1 (dysbindin) and promotes its degradation. It may also ubiquitinate BBS2. Mutations in TRIM32 have been associated with muscular dystrophy, limb-girdle, autosomal recessive 8, and Bardet-Biedl syndrome (See, e.g., Chiang et al. Proc. Natl. Acad. Sci. U.S.A.103(16):3287-92 (2006)). The human TRIM32 gene sequence is provided in GenBank Accession No. NG_011619.1, incorporated herein by reference. An exemplary human TRIM32 nucleic acid sequence is provided in GenBank Accession No. NM_012210.4, incorporated herein by reference. An exemplary amino acid sequence of human TRIM32 is provided by Q13049-1, incorporated herein by reference. WD Repeat Containing Planar Cell Polarity Effector (WDPCP) WD Repeat Containing Planar Cell Polarity Effector (WDPCP), also known as BBS15, is a cytoplasmic WD40 repeat protein. WDPCP is proposed to act as a planar cell polarity protein, which plays a critical role in collective cell movement and ciliogenesis by mediating septin localization. Together with FUZ, WDPCP is proposed to function as core component of the CPLANE (ciliogenesis and planar polarity effectors) complex involved in the recruitment of peripheral IFT-A proteins to basal bodies. Mutations in this gene are associated with Bardet-Biedl syndrome and may also play a role in Meckel-Gruber syndrome. (See, e.g., Kim et al. Science 329(5997):1337-40 (2010)). Alternative splicing results in multiple transcript variants. The human WDPCP gene sequence is provided in GenBank Accession No. NG_028144.2, incorporated herein by reference. An exemplary human WDPCP nucleic acid sequence is provided in GenBank Accession No. NM_001042692.3, incorporated herein by reference. An exemplary amino acid sequence of human WDPCP is provided by O95876-1, incorporated herein by reference. Ribosomal Protein S6 Kinase A3 (RPS6KA3) Ribosomal Protein S6 Kinase A3 (RPS6KA3) is a member of the RSK (ribosomal S6 kinase) family of serine/threonine kinases that acts downstream of ERK (MAPK1/ERK2 and MAPK3/ERK1) signaling and mediates mitogenic and stress-induced activation of the transcription factors CREB1, ETV1/ER81, and NR4A1/NUR77, regulates translation through RPS6 and EIF4B phosphorylation, and mediates cellular proliferation, survival, and differentiation by modulating Mtor signaling and repressing pro-apoptotic function of BAD and DAPK1. In fibroblasts, RPS6KA3 is required for EGF-stimulated phosphorylation of CREB1 and histone H3 at ‘Ser-10’, which results in the subsequent transcriptional activation of several immediate-early genes. In response to mitogenic stimulation (EGF and PMA), RPS6KA3 phosphorylates and activates NR4A1/NUR77 and ETV1/ER81 transcription factors and the cofactor CREBBP. Upon insulin-derived signal, RPS6KA3 acts indirectly on the transcription regulation of several genes by phosphorylating GSK3B at ‘Ser-9’ and inhibiting its activity. RPS6KA3 also phosphorylates RPS6 in response to serum or EGF via an mTOR-independent mechanism and promotes translation initiation by facilitating assembly of the preinitiation complex. In response to insulin, RPS6KA3 phosphorylates EIF4B, enhancing EIF4B affinity for the EIF3 complex and stimulating cap-dependent translation. RPS6KA3 is involved in the Mtor nutrient-sensing pathway by directly phosphorylating TSC2 at ‘Ser-1798’, which potently inhibits TSC2 ability to suppress Mtor signaling, and mediates phosphorylation of RPTOR, which regulates Mtorc1 activity and may promote rapamycin-sensitive signaling independently of the PI3K/AKT pathway. RPS6KA3 mediates cell survival by phosphorylating the pro-apoptotic proteins BAD and DAPK1 and suppressing their pro-apoptotic function. RPS6KA3 promotes the survival of hepatic stellate cells by phosphorylating CEBPB in response to the hepatotoxin carbon tetrachloride (CCl4). RPS6KA3 is also involved in cell cycle regulation by phosphorylating the CDK inhibitor CDKN1B, which promotes CDKN1B association with 14-3-3 proteins and prevents its translocation to the nucleus and inhibition of G1 progression. In LPS-stimulated dendritic cells, RPS6KA3 is involved in TLR4-induced macropinocytosis, and in myeloma cells, it acts as effector of FGFR3-mediated transformation signaling, after direct phosphorylation at Tyr-529 by FGFR3. RPS6KA3 negatively regulates EGF-induced MAPK1/3 phosphorylation via phosphorylation of SOS1. RPS6KA3 phosphorylates SOS1 at ‘Ser-1134’ and ‘Ser-1161’ that create YWHAB and YWHAE binding sites and which contribute to the negative regulation of MAPK1/3 phosphorylation and phosphorylates EPHA2 at ‘Ser-897’, the RPS6KA-EPHA2 signaling pathway controls cell migration. Mutations in this gene have been associated with Coffin-Lowry syndrome (CLS), a rare X-linked semi-dominant syndrome characterized by severe psychomotor retardation, facial dysmorphism, digit abnormalities, and progressive skeletal deformations. (See, e.g., Delaunoy et al. Clin. Genet.70(2): 161-6 (2006)). The human RPS6KA3 gene sequence is provided in GenBank Accession No. NG_007488.1, incorporated herein by reference. An exemplary human RPS6KA3 nucleic acid sequence is provided in GenBank Accession No. NM_004586.3, incorporated herein by reference. An exemplary amino acid sequence of human RPS6KA3 is provided by P51812-1, incorporated herein by reference. 5-Hydroxytryptamine Receptor 2C (HTR2C) 5-Hydroxytryptamine Receptor 2C (HTR2C) is a seven-transmembrane G-protein- coupled receptor for 5-hydroxytryptamine (serotonin). HTR2C also functions as a receptor for various drugs and psychoactive substances, including ergot alkaloid derivatives, 1-2,5,- dimethoxy-4-iodophenyl-2-aminopropane (DOI) and lysergic acid diethylamide (LSD). Ligand binding causes a conformational change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Beta-arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways. Signaling activates a phosphatidylinositol-calcium second messenger system that modulates the activity of phosphatidylinositol 3-kinase and down- stream signaling cascades and promotes the release of Ca^2- ions from intracellular stores. HTR2C also regulates neuronal activity via the activation of short transient receptor potential calcium channels in the brain, and thereby modulates the activation of pro-opiomelacortin neurons and the release of CRH that then regulates the release of corticosterone. HTR2C plays a role in the regulation of appetite and eating behavior, responses to anxiogenic stimuli and stress, and also plays a role in insulin sensitivity and glucose homeostasis. The mRNA of HTR2C is subject to multiple RNA editing events, where adenosine residues encoded by the genome are converted to inosines. RNA editing is predicted to alter the structure of the second intracellular loop, thereby generating alternate protein forms with decreased ability to interact with G proteins. Abnormalities in RNA editing of HTR2C have been detected in victims of suicide that suffer from depression. In addition, naturally occurring variation in the promoter and 5’ non-coding and coding regions of HTR2C may show statistically significant association with mental illness and behavioral disorders. Alternative splicing results in multiple different transcript variants. Mutations in HTR2C have been linked to hyperphagia, hyperactivity, and obesity. (See, e.g., Xu et al. Neuron. 60(4):582-9 (2008)). The human HTR2C gene sequence is provided in GenBank Accession No. NG_012082.2, incorporated herein by reference. An exemplary human HTR2C nucleic acid sequence is provided in GenBank Accession No. NM_001256760.2, incorporated herein by reference. An exemplary amino acid sequence of human HTR2C is provided by P28335-1, incorporated herein by reference. Kinase Suppressor of Ras 2 (KSR2) Kinase Suppressor of Ras 2 (KSR2) is an intracellular scaffolding protein involved in multiple signaling pathways. In particular, KSR2is a location-regulated scaffold connecting MEK to RAF. KSR2has been shown to have very low protein kinase activity and can phosphorylate MAP2K1 at several Ser and Thr residues with very low efficiency in vitro. KSR2acts as MAP2K1/MEK1-dependent allosteric activator of BRAF; upon binding to MAP2K1/MEK1, KSR2dimerizes with BRAF and promotes BRAF-mediated phosphorylation of MAP2K1/MEK1 (See, e.g., Lavoie et al. Nature 554:549-553(2018)). Interaction with BRAF enhances KSR2-mediated phosphorylation of MAP2K1 in vitro. KSR2blocks MAP3K8 kinase activity and MAP3K8-mediated signaling. KSR2also acts as a negative regulator of MAP3K3-mediated activation of ERK, JNK and NF-kappa-B pathways, inhibiting MAP3K3-mediated interleukin-8 production. Mutations in KSR2are linked to hyperphagia in childhood, low heart rate, reduced basal metabolic rate and severe insulin resistance, suggesting that KSR2 is an important regulator of energy intake, energy expenditure, and substrate utilization in humans. (See, e.g., Pearce et al. Cell.155(4):765-77 (2013)). The human KSR2 gene sequence is provided within GenBank Accession No. NC_000012.12, incorporated herein by reference. An exemplary human KSR2 nucleic acid sequence is provided in GenBank Accession No. NM_173598.6, incorporated herein by reference. An exemplary amino acid sequence of human KSR2 is provided by Q6VAB6-1, incorporated herein by reference. Prokineticin 2 (PROK2) The prokineticin 2 (PROK2) gene encodes a protein expressed in the suprachiasmatic nucleus (SCN) circadian clock that may function as the output component of the circadian clock. The secreted form of the encoded protein may also serve as a chemoattractant for neuronal precursor cells in the olfactory bulb. Proteins from other vertebrates which are similar to the PROK2 gene product were isolated based on homology to snake venom; secretions from frog skin and have been shown to have diverse functions. Mutations in PROK2 are associated with hypogonadotropic hypogonadism 4 with or without anosmia and Kallmann syndrome. Multiple transcript variants encoding different isoforms have been found for this gene. (See, e.g., Dodé et al. PloS Genet.2(10):e175 (2006)). The human PROK2 gene sequence is provided in GenBank Accession No. NG_008275.1, incorporated herein by reference. An exemplary human PROK2 nucleic acid sequence is provided in GenBank Accession No. NM_001126128.2, incorporated herein by reference. An exemplary amino acid sequence of human PROK2 is provided by Q9HC23-1, incorporated herein by reference. Ras-Related Protein Rab-23 (RAB23) Ras-Related Protein Rab-23 (RAB23) is a small GTPase of the Ras superfamily. The small GTPases Rab are involved in the regulation of diverse cellular functions associated with intracellular membrane trafficking, including autophagy and immune response to bacterial infection. Rabs cycle between an inactive GDP-bound form and an active GTP- bound form that is able to recruit to membranes different set of downstream effectors directly responsible for vesicle formation, movement, tethering, and fusion. Together with SUFU, the protein encoded by RAB23 prevents nuclear import of GLI1, and thereby inhibits GLI1 transcription factor activity. RAB23 also regulates GLI1 in differentiating chondrocytes, regulates GLI3 proteolytic processing, and modulates GLI2 and GLI3 transcription factor activity. RAB23 also plays a role in autophagic vacuole assembly, and mediates defense against pathogens, such as S.aureus, by promoting their capture by autophagosomes that then merge with lysosomes. RAB23 may play a role in central nervous system development by antagonizing sonic hedgehog signaling. Mutations in RAB23 have been associated with cancer and Carpenter syndrome, a pleiotropic disorder with autosomal recessive inheritance, the cardinal features of which include craniosynostosis, polysyndactyly, obesity, and cardiac defects. (See, e.g., Jenkins et al. Am. J. Hum. Genet.80(6):1162-70 (2007)). Alternative splicing results in multiple transcript variants. The human RAB23 gene sequence is provided in GenBank Accession No. NG_012170.1, incorporated herein by reference. An exemplary human RAB23 nucleic acid sequence is provided in GenBank Accession No. NM_016277.5, incorporated herein by reference. An exemplary amino acid sequence of human RAB23 is provided by Q9ULC₃-1, incorporated herein by reference. Melanocortin 2 Receptor Accessory Protein 2 (MRAP2) Melanocortin 2 Receptor Accessory Protein 2 (MRAP2) is a G-protein-coupled receptor accessory protein that modulates melanocortin receptor signaling and is involved in energy homeostasis. The encoded protein has been shown to interact with all known melanocortin receptors and may regulate both receptor trafficking and activation in response to ligands. MRAP2 is thought to play a central role in the control of energy homeostasis and body weight regulation by increasing ligand-sensitivity of MC4R and MC4R-mediated generation of Camp. MRAP2 may also act as a negative regulator of MC2R (e.g., by competing with MRAP for binding to MC2R and impairs the binding of corticotropin (ACTH) to MC2R). MRAP2 may also regulate activity of other melanocortin receptors (MC1R, MC3R and MC5R). MRAP2 has been implicated in energy control in rodents, notably via the melanocortin-4 receptor. Deficiencies in MRAP2 have been associated with obesity (e.g., monogenic hyperphagic obesity, hyperglycemia, and hypertension) in both children and adults. (See, e.g., Baron et al. Nat. Med.25(11):1733-1738 (2019)). The human MRAP2 gene sequence is provided in GenBank Accession No. NG_051944.1, incorporated herein by reference. An exemplary human MRAP2 nucleic acid sequence is provided in GenBank Accession No. NM_138409.4, incorporated herein by reference. An exemplary amino acid sequence of human MRAP2 is provided by Q96G30-1, incorporated herein by reference. AF4/FMR2 Family Member 4 (AFF4) AF4/FMR2 family member 4 (AFF4) is a component of the positive transcription elongation factor b (P-TEFb) complex, a core component of the super elongation complex (SEC), which is required to increase the catalytic rate of RNA polymerase II transcription by suppressing transient pausing by the polymerase at multiple sites along the DNA. In the SEC complex, AFF4 acts as a central scaffold that recruits other factors through direct interactions with ELL proteins (e.g., ELL, ELL2, or ELL3) and the P-TEFb complex. In case of infection by HIV-1 virus, the SEC complex is recruited by the viral Tat protein to stimulate viral gene expression. Chromosomal aberrations involving ATF4 have been found in acute lymphoblastic leukemia (ALL). Missense mutations in AFF4 have been associated with CHOPS syndrome (C for cognitive impairment and coarse facies, H for heart defects, O for obesity, P for pulmonary involvement and S for short stature and skeletal dysplasia). (See, e.g., Izumi et al. Nat. Genet.47(4):338-44 (2015)). The human AFF4 gene sequence is provided in GenBank Accession No. NG_030340.1, incorporated herein by reference. An exemplary human AFF4 nucleic acid sequence is provided in GenBank Accession No. NM_014423.4, incorporated herein by reference. An exemplary amino acid sequence of human AFF4 is provided by Q9UHB7-1, incorporated herein by reference. Adenylate Cyclase 3 (ADCY3) Adenylate cyclase 3 (ADCY3) is a membrane-associated enzyme and catalyzes the formation of the secondary messenger cyclic adenosine monophosphate (Camp). ADCY3 catalyzes the formation of the signaling molecule Camp in response to G-protein signaling and participates in signaling cascades triggered by odorant receptors via its function in Camp biosynthesis. ADCY3 is required for the perception of odorants, for normal sperm motility, and normal male fertility. ADCY3 also plays a role in regulating insulin levels and body fat accumulation in response to a high fat diet. ADCY3 is widely expressed in various human tissues and may be involved in a number of physiological and pathophysiological metabolic processes. Two transcript variants encoding different isoforms have been identified for ADCY3. Loss of function mutations in ADCY4 have been associated with monogenic severe obesity. (See, e.g., Saeed et al. Nat. Genet.50(2):175-179 (2018)). The human ADCY3 gene sequence is provided within GenBank Accession No. NC_000002.12, incorporated herein by reference. An exemplary human ADCY3 nucleic acid sequence is provided in GenBank Accession No. NM_001320613.2, incorporated herein by reference. An exemplary amino acid sequence of human ADCY3 is provided by O60266-1, incorporated herein by reference. TUB Bipartite Transcription Factor (TUB) TUB Bipartite Transcription Factor (TUB) is a member of the Tubby family of bipartite transcription factors that functions in signal transduction from heterotrimeric G protein-coupled receptors. The crystal structure has been determined for a similar protein in mouse, which functions as a membrane-bound transcription regulator that translocates to the nucleus in response to phosphoinositide hydrolysis. TUB binds to membranes containing phosphatidylinositol 4,5-bisphosphate and has been shown to bind DNA in vitro. TUB may contribute to the regulation of transcription in the nucleus and could be involved in the hypothalamic regulation of body weight. TUB contributes to stimulation of phagocytosis of apoptotic retinal pigment epithelium (RPE) cells and macrophages. Two transcript variants encoding distinct isoforms have been identified for this gene. Mutations in TUB have been associated with obesity and retinal dystrophy (e.g., characterized by obesity, night blindness, decreased visual acuity, and electrophysiological features of a rod cone dystrophy). (See, e.g., Borman et al. Hum. Mutat.35(3):289-93 (2014)). The human TUB gene sequence is provided in GenBank Accession No. NG_029912.1, incorporated herein by reference. An exemplary human TUB nucleic acid sequence is provided in GenBank Accession No. NM_003320.4, incorporated herein by reference. An exemplary amino acid sequence of human TUB is provided by P50607-1, incorporated herein by reference. Orthopedia Homeobox (OTP) Orthopedia Homeobox (OTP) is a member of the homeodomain (HD) family. HD family proteins are helix-turn-helix transcription factors that play key roles in the specification of cell fates. OTP may function during brain development, specifically in the differentiation of hypothalamic neuroendocrine cells. OTP is also believed to be involved in mammalian energy homeostasis and behavior. Disruption of OTP has been associated with obesity, marasmus, Kwashiorkor, and anxiety (See, e.g., Moir et al. Mol. Metab.6(11):1419-1428 (2017)). The human OTP gene sequence is provided within GenBank Accession No. NC_000005.10, incorporated herein by reference. An exemplary human OTP nucleic acid sequence is provided in GenBank Accession No. NM_032109.3, incorporated herein by reference. An exemplary amino acid sequence of human OTP is provided by Q5XKR4-1, incorporated herein by reference. G-Protein Coupled Receptor 101 (GPR101) G-Protein Coupled Receptor 101 (GPR101) is an orphan G protein-coupled receptor of largely unknown function. The encoded protein is a member of a family of proteins that contain seven transmembrane domains and transduce extracellular signals through heterotrimeric G proteins. Diseases associated with GPR101 include Pituitary Adenoma 2, Growth Hormone- Secreting and Chromosome Xq26.3 Duplication Syndrome. Neuronal GLP1Rs has been shown to mediate body weight and anorectic effects of liraglutide but are not required for glucose-lowering effects. (See, e.g., Sisley et al. J. Clin. Invest.124(6):2456-63 (2014)). The human GPR101 gene sequence is provided in GenBank Accession No. NG_016367.1, incorporated herein by reference. An exemplary human GPR101 nucleic acid sequence is provided in GenBank Accession No. NM_054021.2, incorporated herein by reference. An exemplary amino acid sequence of human GPR101 is provided by Q96P66-1, incorporated herein by reference. T-Box Transcription Factor 3 (TBX3) T-Box Transcription Factor 3 (TBX3) is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. TBX3 is a transcriptional repressor and is thought to play a role in the anterior/posterior axis of the tetrapod forelimb. TBX3 acts as a negative regulator of PML function in cellular senescence. TBX3 may also play a role in limb pattern formation. Alternative splicing of this gene results in three transcript variants encoding different isoforms. Mutations that disrupt the DNA-binding domain of TBX3 have been associated with Ulnar-mammary syndrome (UMS), a pleiotropic disorder affecting limb, apocrine-gland, tooth, hair, and genital development. (See, e.g., Bamshad et al. Am. J. Hum. Genet. 64(6):1550-62 (1999)). The human TBX3 gene sequence is provided in GenBank Accession No. NG_008315.1, incorporated herein by reference. An exemplary human TBX3 nucleic acid sequence is provided in GenBank Accession No. NM_016569.4, incorporated herein by reference. An exemplary amino acid sequence of human TBX3 is provided by O15119-1, incorporated herein by reference. 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

Additional MC4R pathway agonizable genes Additional MC4R pathway agonizable genes useful in the methods disclosed herein are described as follows: Acyl-CoA Binding Domain Containing 7 (ACBD7), also known as BA455B2.2, has been associated with food intake, energy expenditure, and body weight in preclinical models. (See, e.g., Lanfray et al. Elife.15;5:e11742 (2016)). Agouti Related Neuropeptide (AGRP), also known as ASIP2, has been associated with hyperphagia and obesity. (See, e.g., Carroll et al. Clin. Dermatol. 22(4):345-9 (2004)). Cell Adhesion Molecule 1 (CADM1), also known as TSLC1 or IGSF4, has been associated with obesity. (See, e.g., Rathjen et al. Nat. Neurosci.20(8):1096-1103 (2017)). Cell Adhesion Molecule 2 (CADM2), also known as IGSF4D, has been associated with obesity. (See e.g., Li et al. Hum. Genet.132(7):793-801 (2013)). Cocaine and Amphetamine-Regulated Transcript Protein (CARTPT), also known as CART, has been associated with obesity. (See, e.g., Asnicar et al. Endocrinology. 42(10):4394-400 (2001)). Coiled-Coil Domain Containing 28B (CCDC₂8B) has been associated with Bardet- Biedl syndrome. (See, e.g., Novas et al. Sic. Rep.14;8(1):3019 (2018)). Cholecystokinin (CCK), also known as Prepro-Cholecystokinin, has been associated with obesity and body mass index. (See, e.g., Namjou et al. Front. Genet.3;4:268 (2013)). Cannabinoid Receptor 1 (CNR1), also known as CNR, has been associated with obesity and body fat mass and distribution. (See, e.g., Russo et al. J. Endocrinol. Metab. 92(6):2382-6 (2007)). CREB Binding Protein (CREBBP), also known as RSTS, has been associated with Rubinstein-Taybi syndrome. (See, e.g., Stevens et al. Am. J. Med. Genet. A.155A(7):1680-4 (2011)). CREB3 Regulatory Factor (CREBRF), also known as C5orf41, has been associated with obesity and diabetes. (See, e.g., Hanson et al. Diabetologia.62(9):1647-1652 (2019)). Cullin 4B (CUL4B), also known as KIAA0695, MRXHF2, MRXS15, MRXSC, and SFM2, has been associated with mental retardation, X-linked, syndromic 15 (Cabezas type). (See, e.g., Tarpey et al. Am. J. Hum. Genet.80(2):345-52 (2007)). DNA Methyltransferase 3 Alpha (DNMT3A), also known as HESJAS and TBRS, encodes a protein involved in de novo methylation. (See, e.g., Xie S. et al. Gene 236(1):87- 95 (1999)). Dual Specificity Tyrosine Phosphorylation Regulated Kinase 1B (DYRK1B), also known as Minibrain-related kinase, has been associated with abdominal obesity-metabolic syndrome 3. (See, e.g., Keramati et al. N. Engl. J. Med.15;370(20):1909-1919 (2014)). Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1), also known as NPPS, M6S1, and PDNP1, has been associated with obesity. (See, e.g., Valli-Jaakola et al. Obesity. 16(9):2113-9 (2008)). E1A Binding Protein P300 (EP300), also known as Histone Acetyltransferase P300, has been associated with Rubinstein-Taybi syndrome. (See, e.g., Stevens et al. Am. J. Med. Genet. A.155A(7):1680-4 (2011)). FMRP Translational Regulator 1 (FMR1), also known as POF1 and POF, has been associated with Fragile X Syndrome. (See, e.g., Raspa et al. Am. J. Intelelct. Devv. Disabil.115(6):482-95 (2010)). FTO Alpha-Ketoglutarate Dependent Dioxygenase (FTO), also known as FTO Alpha-Ketoglutarate Dependent Dioxygenase, has been associated with obesity- related traits including body mass index, hip circumference, and weight. (See e.g., Scuteri et al. PloS. Genet.3(7):e115 (2007)). Ghrelin and Obestatin Prepropeptide (GHRL), also known as Prepro-Appetite Regulatory Hormone, has been associated with obesity. (See, e.g., J. Clin. Endocrinol. Metab.87(8):4005-8 (2002)). Gastric Inhibitory Polypeptide Receptor (GIPR), also known as GIP-R and PGQTL2, has been associated with body mass index and energy intake and expenditure pathways in obesity. (See, e.g., Turcot et al. Nat. Genet.50(1):26-41 (2018)). Glucagon Like Peptide 1 Receptor (GLP1R), also known as GLP-1, has been associated with food intake and body weight regulation. (See, e.g., Sisley et al. J. Clin. Invest.124(6):2456-63 (2014). Inositol Polyphosphate-5-Phosphatase E (INPP5E), also known as JBTS1, has been associated with Jourbert syndrome and MORM syndrome, an autosomal recessive congenital disorder characterized by mental retardation, truncal obesity, retinal dystrophy, and micropenis. (See, e.g., Jacoby et al. Nat. Genet.41(9):1027-31 (2009)). Insulin (INS), also known as IDDM2 and IDDM1, has been associated with body mass index and obesity. (See, e.g., Antúnez-Ortiz et al. Biomed. Res. Int. 2017:2432957 (2017)). Insulin Induced Gene 2 (INSIG2), also known as Insulin Induced Protein 2, has been associated with feedback control of lipid synthesis and obesity in children. (See, e.g., Kaulfers et al. PloS One 10(1):e0116340 (2015)). Insulin Receptor Substrate 1(IRS1), also known as HIRS-1, has been associated with obesity, type II diabetes, and susceptibility to insulin resistance. (See, e.g., Clausen et al. Lancet.346(8972):397-402 (1995)). Insulin Receptor Substrate 4 (IRS4), also known as Pp160, CHNG9, PY160, and Py160, has been associated with obesity, hyperglycemia, and insulin resistance. (See, e.g., Sadagurski et al. Mol. Metab.23;3(1):55-63 (2013)). Insulin Gene Enhancer Protein (ISL1), also known as Islet-1 and Isl-1, is a member of the LIM/homeodomain family of transcription factors, and mutations in this gene have been associated with, inter alia, maturity-onset diabetes. (See, e.g., Tanizawa Y et al. Diabetes (1994)). Methyl-CpG Binding Protein 2 (MeCP2), also known as AUTSX3, MRXS13, MRX16, RTS, and RTT, encodes a nuclear protein related to onset of Rett syndrome, a progressive neurologic developmental disorder. Amir, R.E. et al. Nat Genet 23(2):185-8 (1999) Neuropilin 1 (NRP1), also known as CD304 and BDCA4, encodes one of two neuropilins involved in signaling pathways that control cell migration. NRP1 is associated with cerebral arteriopathy, autosomal dominant, and neuroma. (See, e.g., Soker, S. et al Cell 92(6):735-745). Neuropilin 2 (NRP2), also known as NPN2, NP2, and PRO2714, may play a role in cardiovascular development, axon guidance, and tumorigenesis. (See, e.g., Chen, H. et al. Neuron 19(3):547-549 (1997)). RPGRIP1L Like (RPGRIP1L), also known as FTM, PPP1R134, CORS3, MKS5, JBTS7, and KIAA1005, has been found to interact with neprocystin-4. Defects in this gene have been associated with Joubert syndrome type 7 and Meckel syndrome type 5 (Nagase, T et al DNA Res 6(1):63-70 (1999)). Plexin A1 (PLXNA1), also known as NOV and PLXN1, is associated with hereditary congenital facial paresis and nephronophthisis 4. (See, e.g., Maestrini, E. et al. Proc Natl Acad Sci USA 93(2):674-678 (1996)). Plexin A2 (PLXNA2), also known as OCT, KIAA0463, and FLJ11751, is a plexin-A family member believed to be related to signal transduction from semaphorin-3A and semaphorin-3B. (See, e.g., also Coric, V. et al. Depress Anxiety 27(5):417-425 (2010)). Plexin A3 (PLXNA3), also known as XAP-6, is involved in cytoskeletal remodeling and apoptosis. This gene has been shown to be important in axon pathfinding in developing nervous systems and is associated with tumor progression. (See, e.g., Maestrini, L. et al. Proc Natl Acad Sci USA 93(2):674-678 (1996)). Plexin A4 (PLXNA4), also known as FAYV2820, KIAA1550, and PRO34003, is associated with various signal transduction pathways, particularly involving semaphorin-3A and semaphorin-3B. (See, e.g., Imboden, M. J Allergy Clin Immunol 129(5):1218-1228 (2012)). Potassium Channel Tetramerization Domain Containing 15 (KCTD15), also known as BTB/POZ Domain-Containing Protein KCTD15, has been associated with body mass index and obesity in children. (See, e.g., Zhao et al. Obesity 17(12):2254-7 (2009)). Kinase D Interacting Substrate 220 (KIDINS220), also known as ARMS, KIAA1250, and SINO, has been associated with spastic paraplegia, intellectual disability, nystagmus, and obesity. (See, e.g., Josifova et al. Hum. Mol. Genet. 25(11):2158-2167 (2016)). Melanin Concentrating Hormone Receptor 1 (MCHR1), also known as GPR24, has been associated with regulation of food intake and body weight. (See, e.g., Marsh et al. Proc. Natl. Acad. Sci. U.S.A.5;99(5):3240-5 (2002)). Methionine Sulfoxide Reductase A (MSRA), also known as PMSR, has been associated with several obesity-related traits in children. (See, e.g., Albuquerque et al. J. Hum. Genet.59(6):307-13 (2014)). Necdin, MAGE Family Member (NDN), also known as PWCR, has been associated with Prader-Willi syndrome. (See, e.g., Jay et al. Nat. Genet.17(3):357-61 (1997)). Neuronal Growth Regulator 1 (NEGR1), also known as Neurotractin, IGLON4, DMML2433, KILON, and Ntra, has been associated with body mass index. (See, e.g., Zhao et al. Obesity.17(12):2254-7 (2009)). Neuroligin 2 (NLGN2), also known as KIAA1366, has been associated with anxiety, autism, intellectual disability, hyperphagia, and obesity. (See, e.g., Am. J. Med. Genet. A.173(1):213-216 (2017)). Neuropeptide Y (NPY), also known as PYY4, has been associated with obesity. (See, e.g., van Rossum et al. Int. J. Obes.30(10):1522-8 (2006)). Nuclear Receptor Subfamily 0 Group B Member 2 (NR0B2), also known as SHP1, has been associated with mild and early-onset obesity. (See, e.g., Nishigori et al. PNAS. 16;98(2):575-80 (2001)). Neurotrophic Receptor Tyrosine Kinase 2 (NTRK2), also known as Trk-B, has been associated with severe obesity and developmental delay (e.g., NTRK2 deficiency obesity). (See, e.g., Yeo et al. Nat. Neurosci.7(11):1187-9 (2004)). Opioid Receptor Mu 1 (OPRM1), also known as MOR1, MOP, LMOR, OPRM, and HMOP, has been associated with associated with metabolism and the MC4R pathway (See, e.g., Olszewski et al. Neuroreport 12(8):1727-1730 (2001)). Pericentrin (PCNT), also known as Kendrin and PCNT2, has been associated with Majewski osteodysplastic primordial dwarfism type II. (See, e.g., Rauch et al. Science. 8;319(5864):816-9 (20008)). Pleckstrin Homology Domain Interacting Protein (PHIP), also known as WDR11, Ndrp, DCAF14, BRWD2. (See, e.g., Webster et al. Cold Spring Harb Mol Case Stud 2(6):a001172 (2016). Proprotein Convertase Subtilisin/Kexin Type 2 (PCSK2), also known as NEC₂, has been associated with glucose homeostasis, food intake, ultimately body mass. (See, e.g., Anini et al. Int. J. Obes.34(11):1599-607 (2010)). PHD Finger Protein 6 (PHF6), also known as BFLS and BORJ, has been associated with Börjeson-Forssman-Lehman syndrome, a syndrome characterized by moderate to severe mental retardation, epilepsy, hypogonadism, hypometabolism, obesity with marked gynecomastia, swelling of subcutaneous tissue of the face, narrow palpebral fissure, and large but not deformed ears. (See, e.g., Lower et al. Nat. Genet.32(4):661-5 (2002)). Pro-Melanin Concentrating Hormone (PMCH), also known as MCH and PpMCH, has been associated with regulation of food intake and body weight. (See, e.g., Shimada et al. Nature.396(6712):670-4 (1998)). Peroxisome Proliferator Activated Receptor Gamma (PPARG), also known as NR1C3, PPARG1, PPARG2, CIMT1, and GLM1, has been associated with obesity in children and adolescents. (See, e.g., Ochoa et al. Int. J. Obes. Relat. Metab. Disord.28 Suppl 3:S37-41 (2004)). Peptide YY (PYY), also known as Peptide Tyrosine Tyrosine, has been associated with regulation of food intake and obesity. (See, e.g., Ahituv et al. Hum. Mol. Genet.1;15(3):387-91 (2006)). Syndecan 3 (SDC3), also known as SDCN, has been associated with energy balance, obesity, body mass index, and LHDL cholesterol. (See, e.g., Chang et al. Int. J. Endocrinol.30;2018:9282598 (2018)). SEC16 Homolog B, Endoplasmic Reticulum Export Factor (SEC16B), also known as LZTR2, has been associated with body mass index. (See, e.g., Felix et al. Hum. Mol. Genet.15;25(2):389-403 (2016)). Solute Carrier Family 6 Member 14 (SLC₆A14), also known as BMIQ11, has been associated with body mass index and obesity. (See, e.g., Suviolahti et al. J. Clin. Invest.112(11):1762-72 (2003)). Small Nuclear Ribonucleoprotein Polypeptide N (SNRPN), also known as PWCR, has been associated with Prader-Willi Syndrome. (See, e.g., Kuslich et al. Am. J. Hum. Genet.64(1):70-6 (1999)). Thyroid Hormone Receptor Beta (THRB), also known as ERBA2 and PRTH, has been associated with regulation of food intake and body weight. (See e.g., Amorim et al. J. Endocrinol.203(2):291-9 (2009)). Transient Receptor Potential Cation Channel Subfamily C Member 5 (TRPC5), also known as PPP1R159, TRP-5, HTRP5. (see, e.g., Sossey-Alaoui, K et al. Genomics 60(3):330-3340 (1999)). Transmembrane Protein 18 (TMEM18), also known as LncND, has been associated with body mass index and body weight regulation. (See, e.g., Willer et al. Nat. Genet.41(1):25-34 (2009)). Transmembrane Protein 67 (TMEM67), also known as MKS3, has been associated with Bardet-Biedl Syndrome. (See, e.g., Leitch et al. Nat. Genet. 40(4):443-8 (2008)). Trafficking Protein Particle Complex 9 (TRAPPC9), also known as NIBP, has been associated with mental retardation, autosomal recessive 13. (See, e.g., Marangi et al. Eur. J. Hum. Genet.21(2):229-32 (2013)). Uncoupling Protein 1 (UCP1), also known as thermogenin, SLC25A7, and UCP, has been associated with obesity. (See, e.g., Ramos et al. BMC Med. Genet.7;13:101 (2012)). Uncoupling Protein 3 (UCP3), also known as SLC25A9, has been associated with metabolic fuel partitioning and obesity. (See, e.g., Argyropoulos et al. J. Clin. Invest. 1;102(7):1345-51 (1998)). Vacuolar Protein Sorting 13 Homolog B (VPS13B), also known as CHS1 and COH1, has been associated with Cohen syndrome, an autosomal recessive disorder with variability in the clinical manifestations, characterized by mental retardation, postnatal microcephaly, facial dysmorphism, pigmentary retinopathy, myopia, and intermittent neutropenia. (See, e.g., Seifert et al. J. Med. Genet.43(5):e22 (2006)). In an embodiment, the MC4R pathway agonizable gene comprises POMC, PCSK1, LEPR, LEP, SDCCAG8, SH2B1, CPE, ALMS1, BBS1, BBS2, BBS4, BBS5, BBS6, BBS7, BBS8, BBS9, BBS10, BBS12, BBS18, BBS20, GNAS, MC3R, NHLH2, SIM1, BDNF, NTRK2, MAGEL2, or a 16p11.2 deletion. Methods of Use Disclosed herein are methods for treating and/or preventing a disease, disorder or condition with an MC4R agonist, such as 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), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI), or a pharmaceutically acceptable salt thereof. Exemplary diseases or disorders may include obesity or an obesity-related disorder (e.g., hypothalamic obesity), a metabolic disorder (e.g., hyperphagia, congenital hyperinsulinism), cancer, a neurological disorder, a cardiovascular disorder, a pulmonary disorder, an integumentary disorder, a sexual disorder, a urinary disorder, or a symptom thereof. In some embodiments, the disease, disorder or condition is a metabolic disorder. In some embodiments, the metabolic disorder is hyperinsulinism (HI), congenital hyperinsulinism (CHI), persistent hyperinsulinism, or transient hyperinsulinism. In some embodiments, the metabolic disorder is a hyperinsulism-related syndrome, e.g., Beckwith- Wiedemann syndrome, hyperinsulinism-hyperammonaemia (HIHA) syndrome, Sotos syndrome, Turner syndrome, Costello syndrome, Kabuki syndrome, and the like. In some embodiments, the disease, disorder, or condition is obesity, e.g., hypothalamic obesity. In some embodiments, the disease, disorder, or condition is diabetes, e.g., Type 1 or Type 2 diabetes, or first-phase diabetes or a pre-diabetes syndrome. In some embodiments, the disease, disorder, or condition is a genetic or epigenetic disorder, e.g., Prader-Willi syndrome, Alström syndrome, Bardet-Biedl syndrome, or Smith-Magenis syndrome. In some embodiments, the disease, disorder, or condition is Prader-Willi syndrome. In some embodiments, the disease, disorder, or condition is Alström syndrome. In some embodiments, the disease, disorder, or condition is Bardet-Biedl syndrome. In some embodiments, the metabolic disorder is Smith-Magenis syndrome. In an embodiment, the disease, disorder, or condition is ischemia. In an embodiment, any one of obesity (e.g., hypothalamic obesity), diabetes, or a genetic or epigenetic disorder, e.g., Prader-Willi syndrome, Alström syndrome, Bardet-Biedl syndrome, or Smith-Magenis syndrome, is treated with 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), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI), or a pharmaceutically acceptable salt thereof. In some embodiments, the disease, disorder, or condition is alopecia or baldness. In an embodiment, the disease, disorder, or condition is a behavioral disorder or a psychological disorder. In some embodiments, the methods described herein directly or indirectly reduce or alleviate at least one symptom of a disease, disorder, or condition (e.g., a disease or disorder described herein). In some embodiments, the methods described herein may treat or alleviate at least one symptom of disease, disorder, or condition, e.g., an increase in waist circumference of at least 2 cm relative to a reference (e.g., the waist circumference of a subject before onset of the metabolic disorder); an increase in blood pressure relative to a reference (e.g., the blood pressure of a subject before onset of the metabolic disorder); hyperglycemia or an increase in fasting blood sugar relative to a reference (e.g., the fasting blood sugar of a subject before the onset of the metabolic disorder); an increase in thirst (e.g., an increase in thirst relative to a reference, e.g., the level of thirst of a subject before the onset the metabolic disorder); an increase in fatigue (e.g., an increase in fatigue relative to a reference, e.g., the level of fatigue of a subject before the onset of a metabolic disorder); or an increase in urination (e.g., an increase in urination relative to a reference, e.g., the frequency or amount of urination of a subject before the onset of a metabolic disorder). In some embodiments, the methods described herein prevents or slows the onset of a disease, disorder, or condition, e.g., a hypothalamic obesity. In some embodiments, the subject has a comorbidity, e.g., obesity, hyperphagia or hyperphagia-related syndromes, unwanted appetite, hypoglycemia, hyperglycemia, hyperlipidemia, hypercholesterolemia, or hypertriglyceridemia. In some embodiments, the metabolic disorder is hyperinsulinemia, e.g., chronic hyperinsulinemia (CHI). In some embodiments, the metabolic disorder is pre-diabetes, type I diabetes, or type II diabetes. In some embodiments, the metabolic disorder is a diabetological condition. In some embodiments, the subject has had interventional surgery, e.g., bariatric surgery. In some embodiments, the subject has had brain surgery, e.g., a hypothalamic surgery. In some embodiments, the subject has a brain tumor, e.g., a craniopharyngioma, germinoma, glioma, hamartoma, pituitary adenoma. In some embodiments, the methods described herein may treat a metabolic disorder. In some embodiments, the methods described herein may provide a counterregulatory response to hypoglycemia in subject with diabetes, e.g., type I or type II diabetes. In some embodiments, the methods described herein may be useful in combination with a second agent, e.g., a sulfonylurea prior to a bolus to restore normal insulin levels in a subject, e.g., a subject with diabetes, e.g., type I or type II diabetes. In some embodiments, the disease, disorder, or condition is a cancer. In some embodiments, the cancer is a gastrointestinal cancer, e.g., oesophageal cancer, gastric cancer, pancreatic cancer, liver cancer, gallbladder cancer, colorectal cancer, anal cancer, or a gastrointestinal carcinoid tumour. In some embodiments, the gastrointestinal cancer is oesophageal cancer. In some embodiments, the gastrointestinal cancer is gastric cancer. In some embodiments, the gastrointestinal cancer is pancreatic cancer. In some embodiments, the gastrointestinal cancer is a pancreatic cancer, wherein the pancreatic cancer is an insulinoma. In some embodiments, the gastrointestinal cancer is liver cancer. In some embodiments, the gastrointestinal cancer is gallbladder cancer. In some embodiments, the gastrointestinal cancer is colorectal cancer. In some embodiments, the gastrointestinal cancer is anal cancer. In some embodiments, the gastrointestinal cancer is a gastrointestinal cancer. In some embodiments, the disease, disorder, or condition is a neurological disorder, e.g., Alzheimer’s Disease, Parkinson’s Disease, Multiple Sclerosis, migraine (e.g., chronic migraine), epilepsy and epilepsy-related syndromes. In some embodiments, the methods as described herein directly or indirectly reduce or alleviate at least one symptom of a disease, disorder, or condition, e.g., a neurological disease or disorder described herein. In some embodiments, the methods directly or indirectly reduce or alleviate pain or aid in pain management, i.e., the methods as described herein directly or indirectly function in analgesia of a disease, disorder, or condition, e.g., a neurological disorder. In some embodiments, the methods as described herein directly or indirectly alleviate a symptom of a disease, disorder, or condition, e.g., a neurological disorder. In some embodiments, the methods as described herein provide neuroprotection in a subject in need thereof, e.g., in a subject with a neurological disorder, e.g., Alzheimer’s Disease, Parkinson’s Disease, or Multiple Sclerosis. In some embodiments, the disease, disorder, or condition is a cardiovascular disorder, e.g., ischemia, ischemia-reperfusion injury, hypertension, coronary spasm, ocular pressure, peripheral vascular disease. In some embodiments, the cardiovascular disorder is angina, cardioplegia, a ventricular septal defect, atrial fibrillation, arrythmia, coronary artery disease, or myocardial stunning. In some embodiments. the methods as described herein provide cardiooprotection in a subject in need thereof, e.g., in a subject with a cardiovascular disorder, e.g., angina, cardioplegia, a ventricular septal defect, atrial fibrillation, arrythmia, coronary artery disease, or myocardial stunning. In some embodiments, the disease, disorder, or condition is a pulmonary disorder, e.g., pulmonary hypertension or asthma. In some embodiments, the disease, disorder, or condition is an integumentary disorder, e.g., a disorder of the hair, skin, and nails, inter alia. In some embodiments, the disease or disorder is alopecia, baldness, e.g., male-pattern baldness, or disorders of hair follicular growth. In some embodiments, the disease, disorder, or condition is a sexual disorder, e.g., male impotence. In some embodiments, the disease, disorder, or condition is a urinary disorder, e.g., detrusor hyperreactivity. In an embodiment, the subject is a mammal, e.g., a human. In an embodiment, the subject is an adult (e.g., over the age of 18 years old) or a child (e.g., under the age of 18, 12, 10, 8, 6, 4, or 2 years old). In an embodiment, the subject has been treated for a disease, disorder, or condition (e.g., obesity or a metabolic disorder) previously. For example, the subject may be a bariatric surgery patient. Obesity The present disclosure features methods for treating a subject having obesity, e.g., a non-genetic obesity. In an embodiment, the obesity is hypothalamic obesity. In an embodiment, the obesity is due to a disease, disorder, or condition relating to an MC4R pathway agonizable gene. In an embodiment, the disease, disorder, or condition is characterized by a mutation (e.g., a substitution mutation, a deletion mutation, or a polymorphism) in the MC4R pathway agonizable gene. In embodiments, the methods comprise administering to the subject an MC4R agonist or compositions described herein, e.g., a compound of any one of of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI), or a pharmaceutically acceptable salt thereof (e.g., as described herein). Hypothalamic obesity is a form of obesity caused by physical or inherited damage to the hypothalamus, resulting in symptoms such as uncontrollable hunger, rapid and/or excessive weight gain, and a low metabolic rate. Causes for this condition include the presence of a tumor, swelling in the brain, head trauma, radiotherapy, brain surgery, or the presence of certain genetic mutations. For example, hypothalamic obesity may be caused by craniopharyngioma, a rare non-cancerous tumor. Removal of this tumor can result in damage to the hypothalamus, leading to symptoms of hypothalamic obesity. Genetic mutations in the LEP, LEPR, POMC, MC4R, and CART genes may also lead to this disease (see, e.g., Kim et al. Ann Pediatr Endocrinol Metab (2013) 18(4): 161-167). Hypothalamic obesity has also been linked to diminished α-MSH levels (see, e.g., Roth et al. Metabol Clin Exper (2010) 59:186-194). In an embodiment, 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), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI), or a pharmaceutically acceptable salt thereof is used in a method to treat a subject having (e.g., diagnosed) as having hypothalamic obesity. In an embodiment, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is used in a method to treat a subject having (e.g., diagnosed as having) hypothalamic obesity. In an embodiment, a compound of Formula (II), or a pharmaceutically acceptable salt thereof, is used in a method to treat a subject having (e.g., diagnosed as having) hypothalamic obesity. In an embodiment, a compound of Formula (III), or a pharmaceutically acceptable salt thereof, is used in a method to treat a subject having (e.g., diagnosed as having) hypothalamic obesity. In an embodiment, a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, is used in a method to treat a subject having (e.g., diagnosed as having) hypothalamic obesity. In an embodiment, a compound of Formula (V), or a pharmaceutically acceptable salt thereof, is used in a method to treat a subject having (e.g., diagnosed as having) hypothalamic obesity. In an embodiment, a compound of Formula (VI), or a pharmaceutically acceptable salt thereof, is used in a method to treat a subject having (e.g., diagnosed as having) hypothalamic obesity. In an embodiment, a compound of Formula (VII), or a pharmaceutically acceptable salt thereof, is used in a method to treat a subject having (e.g., diagnosed as having) hypothalamic obesity. In an embodiment, a compound of Formula (VIII), or a pharmaceutically acceptable salt thereof, is used in a method to treat a subject having (e.g., diagnosed as having) hypothalamic obesity. In an embodiment, a compound of Formula (IX), or a pharmaceutically acceptable salt thereof, is used in a method to treat a subject having (e.g., diagnosed as having) hypothalamic obesity. In an embodiment, a compound of Formula (X), or a pharmaceutically acceptable salt thereof, is used in a method to treat a subject having (e.g., diagnosed as having) hypothalamic obesity. In an embodiment, a compound of Formula (XI), or a pharmaceutically acceptable salt thereof, is used in a method to treat a subject having (e.g., diagnosed as having) hypothalamic obesity. In an embodiment, a compound of Formula (XII), or a pharmaceutically acceptable salt thereof, is used in a method to treat a subject having (e.g., diagnosed as having) hypothalamic obesity. In an embodiment, a compound of Formula (XIII), or a pharmaceutically acceptable salt thereof, is used in a method to treat a subject having (e.g., diagnosed as having) hypothalamic obesity. In an embodiment, a compound of Formula (XIV), or a pharmaceutically acceptable salt thereof, is used in a method to treat a subject having (e.g., diagnosed as having) hypothalamic obesity. In an embodiment, a compound of Formula (XV), or a pharmaceutically acceptable salt thereof, is used in a method to treat a subject having (e.g., diagnosed as having) hypothalamic obesity. In an embodiment, a compound of Formula (XVI), or a pharmaceutically acceptable salt thereof, is used in a method to treat a subject having (e.g., diagnosed as having) hypothalamic obesity. In an embodiment, a compound of Formula (XVII), or a pharmaceutically acceptable salt thereof, is used in a method to treat a subject having (e.g., diagnosed as having) hypothalamic obesity. In an embodiment, a compound of Formula (XVIII), or a pharmaceutically acceptable salt thereof, is used in a method to treat a subject having (e.g., diagnosed as having) hypothalamic obesity. In an embodiment, a compound of Formula (XIX), or a pharmaceutically acceptable salt thereof, is used in a method to treat a subject having (e.g., diagnosed as having) hypothalamic obesity. In an embodiment, a compound of Formula (XX), or a pharmaceutically acceptable salt thereof, is used in a method to treat a subject having (e.g., diagnosed as having) hypothalamic obesity. In an embodiment, a compound of Formula (XXI), or a pharmaceutically acceptable salt thereof, is used in a method to treat a subject having (e.g., diagnosed as having) hypothalamic obesity. In an embodiment, a compound of Formula (XXII), or a pharmaceutically acceptable salt thereof, is used in a method to treat a subject having (e.g., diagnosed as having) hypothalamic obesity. In an embodiment, a compound of Formula (XXIII), or a pharmaceutically acceptable salt thereof, is used in a method to treat a subject having (e.g., diagnosed as having) hypothalamic obesity. In an embodiment, a compound of Formula (XXVI), or a pharmaceutically acceptable salt thereof, is used in a method to treat a subject having (e.g., diagnosed as having) hypothalamic obesity. In an embodiment, a compound of Formula (XXV), or a pharmaceutically acceptable salt thereof, is used in a method to treat a subject having (e.g., diagnosed as having) hypothalamic obesity. In an embodiment, a compound of Formula (XXVI), or a pharmaceutically acceptable salt thereof, is used in a method to treat a subject having (e.g., diagnosed as having) hypothalamic obesity. In an embodiment, a compound of Formula (XXVII), or a pharmaceutically acceptable salt thereof, is used in a method to treat a subject having (e.g., diagnosed as having) hypothalamic obesity. In an embodiment, a compound of Formula (XXVIII), or a pharmaceutically acceptable salt thereof, is used in a method to treat a subject having (e.g., diagnosed as having) hypothalamic obesity. In an embodiment, a compound of Formula (XXIX), or a pharmaceutically acceptable salt thereof, is used in a method to treat a subject having (e.g., diagnosed as having) hypothalamic obesity. In an embodiment, a compound of Formula (XXX), or a pharmaceutically acceptable salt thereof, is used in a method to treat a subject having (e.g., diagnosed as having) hypothalamic obesity. In an embodiment, a compound of Formula (XXXI), or a pharmaceutically acceptable salt thereof, is used in a method to treat a subject having (e.g., diagnosed as having) hypothalamic obesity. In an embodiment, a compound of Formula (XXXII), or a pharmaceutically acceptable salt thereof, is used in a method to treat a subject having (e.g., diagnosed as having) hypothalamic obesity. In an embodiment, a compound of Formula (XXXIII), or a pharmaceutically acceptable salt thereof, is used in a method to treat a subject having (e.g., diagnosed as having) hypothalamic obesity. In an embodiment, a compound of Formula (XXIV), or a pharmaceutically acceptable salt thereof, is used in a method to treat a subject having (e.g., diagnosed as having) hypothalamic obesity. In an embodiment, a compound of Formula (XXV), or a pharmaceutically acceptable salt thereof, is used in a method to treat a subject having (e.g., diagnosed as having) hypothalamic obesity. In an embodiment, a compound of Formula (XXVI), or a pharmaceutically acceptable salt thereof, is used in a method to treat a subject having (e.g., diagnosed as having) hypothalamic obesity. Additional diseases, disorders, or conditions that may be treated by administration of an MC4R agonist or compositions described herein, e.g., 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), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI), or a pharmaceutically acceptable salt thereof, include 5p3 microduplication syndrome, Angelman syndrome, Chudley Lowry syndrome, Cornelia de Lange syndrome, Laron syndrome, Kleefstra syndrome/9q34.3, Camera-Marugo-Cohen syndrome, Clark and Baraitser XLMR syndrome, DiGeorge syndrome, velocardiofacial syndrome, conotruncal anomaly face syndrome, 22q11.2 deletion syndrome, rapid onset obesity with hypothalamic dysfunction (ROHHAD), rapid onset obesity with hypothalamic dysfunction, hypoventilation, autonomic dysregulation and neural crest tumor (ROHHAD NET), Shashi XLMR syndrome, mental retardation, epileptic seizures, hypogonadism and -genitalism, microcephaly, obesity (MEHMO) syndrome, mandibular prognathism with eye and skin anomalies (MOMES) syndrome, and MOMO syndrome. Additional diseases, disorders, or conditions that may be treated by administration of an MC4R agonist, e.g., an MC4R agonist described herein, include those summarized in Kaur et al (2017) Obesity Reviews 18:603- 634. Outcomes In embodiments, methods described herein result in one or more outcomes, including a reduction of weight (e.g., body weight), a reduction in hunger level, no detectable decrease in energy expenditure (e.g., resting energy expenditure), an increase in energy expenditure (e.g., resting energy expenditure), a reduction in daily/weekly/monthly food intake, a reduction in waist circumference, no detectable increase in blood pressure, or a reduction in blood pressure in a subject, e.g., relative to a control. In embodiments, the control is the measurement of the parameter in the subject prior to administration of (treatment with) a MC4R agonist, e.g., 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), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI), or a pharmaceutically acceptable salt thereof, is used in a method to treat a subject having (e.g., diagnosed) as having hypothalamic obesity . In embodiments, the control is a predetermined value, e.g., the value of the parameter in an average obese human population, e.g., of like age and gender as the subject; or the value of the parameter measured in the subject at a previous time point (e.g., at a previous visit, e.g., to a physician, medical facility or laboratory). In embodiments, the outcome (e.g., the reduction, increase, no detectable decrease, or no detectable increase in a given parameter) is measured in the subject 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more after initiation of treatment with a MC4R agonist. In other embodiments, the outcome (e.g., the reduction, increase, no detectable decrease, or no detectable increase in a given parameter) is measured in the subject over a period of time (e.g., over a period of 1-2 weeks, 2-4 weeks, 4-6 weeks, 6-8 weeks, 8-12 weeks, or 12-16 weeks) during a course of treatment. In embodiments, methods described herein result in a reduction of weight (e.g., body weight) in the subject compared to a control (e.g., weight of the subject before treatment or a predetermined value, e.g., average weight of an obese human population of like age and gender as the subject not subjected to therapeutic intervention, or the weight of the subject at a previous measurement, e.g., at a previous visit). In embodiments, the reduction is about 1 kg to 3 kg after 1 week of treatment, about 1 kg to 6 kg after 2 weeks of treatment, about 2 kg to 12 kg after 4 weeks of treatment, about 4 kg to 24 kg after 8 weeks of treatment, or about 8 kg to 48 kg after 16 weeks of treatment. In embodiments, the reduction is at a rate of loss of about 1-2 kg/week, e.g., about 2 kg/week, e.g., over a period of 1-2 weeks of treatment or longer, 2-4 weeks of treatment or longer, 4-8 weeks of treatment or longer, 8-16 weeks of treatment, or 16-32 weeks of treatment, or longer. Measurement of weight, e.g., body weight, can be performed using standard methods in the art. In embodiments, methods described herein result in a reduction in hunger level in the subject compared to a control (e.g., hunger level of the subject before treatment or a predetermined hunger level, e.g., average hunger level of an obese human population of like age and gender as the subject or the hunger level of the subject at a previous measurement, e.g., at a previous visit). In embodiments, the methods described herein result in abolishment of hunger in the subject. In embodiments, hunger is measured by a scale, such as a Likert hunger scale, which ranges from 0 to 10 and is described herein. In embodiments, methods described herein result in a reduction in hunger score in the subject compared to a control (e.g., hunger level of the subject before treatment or a predetermined hunger level, e.g., average hunger level of an obese human population of like age and gender as the subject or the hunger level of the subject at a previous measurement, e.g., at a previous visit). In embodiments, methods described herein result in a lower score on the Likert hunger scale, e.g., a lower score by at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 points, compared to the control (e.g., hunger level of the subject before treatment or a predetermined hunger level, e.g., average hunger level of an obese human population of like age and gender as the subject or the hunger level of the subject at a previous measurement, e.g., at a previous visit). In embodiments, methods described herein result in a score of 0 on the Likert hunger scale after treatment. In embodiments, the reduction in hunger level is measured/observed after 1 to 2 weeks of treatment or longer, 2-4 weeks of treatment or longer, 4-8 weeks of treatment or longer, or 8-16 weeks of treatment or longer. REE is a measure of the basal metabolic rate of the subject and can be determined using methods such as those described in Chen et al. J. Clin. Endocrinol. Metab. 100.4(2015):1639-45. In embodiments, the REE can be determined by placing the subject in a whole-room indirect calorimeter (also called a metabolic chamber) at a certain time after treatment (e.g., after 3, 4, 5, 6, 7 days, or 1, 2, 3, 4, or more weeks). In embodiments, the REE is measured in 30-minute measurements periods, and in some cases, REE values from several 30-minute periods are averaged to generate an average REE. In embodiments, the REE can be determined after a 10-12 hour fasting period, at thermoneutrality (e.g., around 25 deg C), where the subject is awake without psychological or physical stress. In embodiments, REE is measured in units of energy per unit time (e.g., kcal/h or kcal/day). In embodiments, the REE is measured relative to kg lean body mass in a subject (e.g., REE/kg lean mass), e.g., as described in the Examples. In embodiments, methods described herein result in no change or no decrease in energy expenditure, e.g., resting energy expenditure (REE), in the subject over an hourly, daily (e.g., in 24 hours), weekly (e.g., in 7 days), or monthly (e.g., in 30 days) period compared to a control REE (e.g., the REE in the subject prior to treatment or a predetermined REE, e.g., average REE of an obese human population of like age and gender and normalized for weight as the subject or the REE of the subject at a previous measurement, e.g., previous visit), e.g., as measured after 3, 4, 5, 6, 7 days, or 1, 2, 3, 4, or more weeks of treatment. In embodiments, methods described herein result in no detectable change or no detectable decrease in energy expenditure, e.g., resting energy expenditure (REE) per kg lean body mass, in the subject over an hourly, daily (e.g., in 24 hours), weekly (e.g., in 7 days), or monthly (e.g., in 30 days) period compared to the control REE (e.g., the REE in the subject prior to treatment or a predetermined REE, e.g., average REE of an obese human population of like age and gender as the subject or the REE of the subject at a previous measurement, e.g., previous visit), e.g., as measured after 3, 4, 5, 6, 7 days, or 1, 2, 3, 4, or more weeks of treatment. In embodiments, methods described herein result in an increase in energy expenditure, e.g., resting energy expenditure (REE), in the subject over a hourly, daily (e.g., in 24 hours), weekly (e.g., in 7 days), or monthly (e.g., in 30 days) period compared to a control REE (e.g., the REE in the subject prior to treatment or a predetermined REE, e.g., average REE of an obese human population of like age and gender and normalized for weight as the subject or the REE of the subject at a previous measurement, e.g., previous visit), e.g., as measured after 3, 4, 5, 6, 7 days, or 1, 2, 3, 4, or more weeks of treatment. In embodiments, the increase in REE in the subject is at least 20 kcal/day (e.g., at least 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150 kcal/day or more), e.g., as measured after 3, 4, 5, 6, 7 days, or 1, 2, 3, 4, or more weeks of treatment. In embodiments, the increase in REE in the subject is at least 2% (e.g., at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or more), e.g., as measured after 3, 4, 5, 6, 7 days, or 1, 2, 3, 4, or more weeks of treatment, compared to the REE in the subject prior to treatment. In embodiments, the REE in the subject (e.g., adult subject) after treatment with a MC4R agonist (e.g., after 3, 4, 5, 6, 7 days, or 1, 2, 3, 4, or more weeks of treatment) is at least 1800 kcal/day (e.g., at least 1800, 1825, 1850, 1875, 1900, 1925, 1950, 1975, 2000, 2025, 2050, 2100, 2150, 2200, 2250, 2300, 2400 kcal/day, or more), e.g., for an adult subject. In embodiments, the REE in the subject (e.g., pediatric subject) after treatment with a MC4R agonist (e.g., after 3, 4, 5, 6, 7 days, or 1, 2, 3, 4, or more weeks of treatment) is at least 200 kcal/day (e.g., at least 200, 225, 250, 275, 300, 325, 350, 375, 400, 450, 500 kcal/day or more), e.g., for pediatric patients. In embodiments, methods described herein result in a reduction in food intake by the subject compared to a control (e.g., the food intake of the subject prior to treatment or a predetermined food intake level, e.g., the food intake of an average human obese population or the food intake of the subject at a previous measurement, e.g., at a previous visit), e.g., where the food intake is measured as daily food intake or food intake over a period of 24 hours, or one week,. In embodiments, the reduction is at least 100 kilocalories, e.g., at least 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 1000 kilocalories or more, e.g., for daily food intake or food intake over a period of 24 hours, or one week, or 30 days or for longer time periods, e.g., for an adult subject. In embodiments, mean food intake can decrease from a baseline at or above about 100 kcal/kg/day to about 90, 80, 70, 60, 50, 40, 30, 20 or 10 kcal/kg/day or lower after treatment with a MC4R agonist, e.g., setmelanotide, e.g., in a pediatric subject at about 1 year of age. In embodiments, mean food intake can decrease from a baseline at or above about 40 kcal/kg/day to about 35, 30, 20 or 10 kcal/kg/day or lower after treatment with a MC4R agonist, e.g., setmelanotide, e.g., in a pediatric subject in late adolescence. Food intake can be determined by standard methods, e.g., as described in Rutishauser. Pub. Health Nutr.8.7A(2005):1100-07. In embodiments, methods described herein result in a reduction in waist circumference of the subject compared to a control (e.g., the waist circumference of the subject prior to treatment or the waist circumference of the subject at a previous measurement, e.g., previous visit), as measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more after initiation of treatment. In embodiments, the reduction in waist circumference is at least 2 cm (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10 cm or more) in the subject (e.g., adult subject) compared to a control (e.g., the waist circumference of the subject prior to treatment or a predetermined waist circumference, e.g., the waist circumference of an average obese human population of like age and gender or the waist circumference of the subject at a previous measurement, e.g., previous visit), as measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more after initiation of treatment. In embodiments, the waist circumference is measured using standard methods. In embodiments, the waist circumference is the largest circumference around a subject’s mid- section, e.g., around a subject’s abdomen. In other embodiments, the waist circumference is measured around the natural waist (e.g., in between the lowest rib and the top of the hip bone), the umbilicus, or at the narrowest point of the midsection. In embodiments, methods described herein result in no detectable increase in blood pressure (e.g., diastolic and/or systolic blood pressure) of the subject compared to a control blood pressure (e.g., the blood pressure of the subject prior to treatment or a predetermined blood pressure, e.g., the blood pressure of an average obese human population of like age and gender or the blood pressure of the subject at a previous measurement, e.g., previous visit), as measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more after initiation of treatment. In embodiments, methods described herein result in a reduction in blood pressure (e.g., diastolic and/or systolic blood pressure) of the subject a control blood pressure (e.g., the blood pressure of the subject prior to treatment or a predetermined blood pressure, e.g., the blood pressure of an average obese human population of like age and gender or the blood pressure of the subject at a previous measurement, e.g., previous visit), as measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more after initiation of treatment. In embodiments, the reduction in blood pressure, e.g., systolic blood pressure, is at least 3 mmHg (e.g., at least 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7 mmHg or more) compared to the blood pressure of the subject prior to treatment, as measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more after initiation of treatment. In embodiments, the reduction in blood pressure, e.g., diastolic blood pressure, is at least 4 mmHg (e.g., at least 4, 7, 7.5, 8, 8.5, 9, 9.5, 10 mmHg or more) compared to the blood pressure of the subject prior to treatment, as measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more after initiation of treatment. In embodiments, the methods described herein do not result in an adverse effect on heart rate or blood pressure. Patient Selection In accordance with any method described herein, in certain embodiments, the subject is obese, e.g., prior to administration of an MC4R agonist described herein, e.g., 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), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI), or a pharmaceutically acceptable salt thereof, at the time the MC4R agonist is prescribed, or at the time of the first administration of the MC4R agonist. In embodiments, the subject is a severely obese, pediatric or adult patient e.g., prior to administration of an MC4R agonist described herein, e.g., at the time the MC4R agonist is prescribed or at the time of the first administration of the MC4R agonist. In embodiments, the subject is hyperphagic, e.g., prior to administration of an MC4R agonist described herein, e.g., at the time the MC4R agonist is prescribed, or at the time of the first administration of the MC4R agonist. In embodiments, the subject (e.g., adult subject) has a body mass index (BMI) greater than 25 kg/m² or 30 kg/m² (e.g., ≥ 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg/m² or greater) prior to administration of the MC4R agonist, e.g., at the time the MC4R agonist is prescribed, or at the time of the first administration. In embodiments, the subject (e.g., pediatric subject) has a body mass index (BMI) higher than 85-95 percentile prior to administration of the MC4R agonist, e.g., at the time the MC4R agonist is prescribed, or at the time of the first administration. In embodiments, the subject has a body weight of at least about 5 kg, e.g., at least about 5 kg, 10 kg, 20kg, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140,145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200, 205, 210, 215, 220 kg or greater, e.g., prior to administration of the MC4R agonist, e.g., at the time the MC4R agonist is prescribed, or at the time of the first administration. In embodiments, the subject has a body weight of a least 20 kg, at least 60 kg, or at least 100 kg, e.g., prior to administration of the MC4R agonist, e.g., at the time the MC4R agonist is prescribed, or at the time of the first administration. In embodiments, the subject has received intervention in the gastrointestinal system. For example, the subject may have received a gallbladder surgery, an intestinal surgery, a gastric surgery (e.g., a bariatric surgery), or other survival procedure. In an embodiment, the subject has received a gastric bypass surgery. In an embodiment, the subject has received a surgery resulting in a restriction of the total amount of food capable of being held or processed at one time, e.g., the stomach, small intestine, large intestine, or colon. In an embodiment, the subject has undergone a surgery, e.g., a tumor resection surgery. In an embodiment, the subject has a proliferative brain disease. The proliferative brain disease may include a benign tumor, benign lesion, or a malignant tumor, e.g., cancer. In an embodiment, the proliferative brain disease is present in the hypothalamus. In an embodiment, the proliferative brain disease is present in the paraventricular hypothalamic nucleus, ventromedial hypothalamic nucleus, or arcuate hypothalamic nucleus. In an embodiment, the proliferative brain disease is a benign brain tumor or benign brain lesion. Exemplary types of benign tumors or brain lesions include a meningioma, pituitary adenoma, craniopharyngioma, Schwannoma, nasopharyngeal angiofibroma, choroid plexus tumor, dysembryoplastic neuroepithelial tumor, neurofibroma, hemangioblastoma, chondroma, giant cell tumor, osteoma, arachnoid cyst, colloid cyst, dermoid cyst, epidermoid cyst, fibrous dysplasia, Rathke’s cleft cyst, and petrous apex lesion. In an embodiment, the proliferative brain disease is a craniopharyngioma. In an embodiment, the subject has a malignant tumor or a cancer, e.g., a cancer of the central nervous system or peripheral nervous system. In an embodiment, the cancer is present in the hypothalamus. In an embodiment, the cancer is present in the paraventricular hypothalamic nucleus, ventromedial hypothalamic nucleus, or arcuate hypothalamic nucleus. In an embodiment, the subject has a brain cancer. Exemplary brain cancers include glioblastoma, oligodendroglioma, and astrocytoma. In an embodiment, the cancer comprises astrocytoma. In embodiments, the subject is an adult, e.g., 18 years of age or older, e.g., 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, or older. In embodiments, the subject is a pediatric subject, e.g., less 18 years of age or younger (e.g., 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 year of age or younger. In embodiments, the subject has or is identified as having a defect, e.g., genetic defect, or a mutation, in an MC4R pathway agonizable gene. In embodiments, the subject has or is identified as having a mutation a gene selected from n the ARL6, RAI1, SRC1, BBS19, BBS21, CEP290, IFT74, LZTFL1, MKS1, TRIM32, WDPCP, RPS6KA3, HTR2C, KSR2, PROK2, RAB23, MRAP2, AFF4, ADCY3, TUB, OTP, GPR101, TBX3, ACBD7, AGRP, CADM1, CADM2, CARTPT, CCDC28B, CCK, CNR1, CREBBP, CREBRF, CUL4B, DYRK1B, ENPP1, EP300, FMR1, FTO, GHRL, GIPR, GLP1R, INPP5E, INS, INSIG2, IRS1, IRS4, KCTD15, KIDINS220, MCHR1, MSRA, NDN, NEGR1, NLGN2, NPY, NR0B2, NTRK2, PCNT, PCSK2, PHF6, PMCH, PPARG, PYY, SDC3, SEC16B, SLC6A14, SNRPN, THRB, TMEM18, TMEM67, TRAPPC9, UCP1, UCP3, VPS13B, NRP1, NRP2, PLXNA1, PLXNA2, PLXNA3, PLXNA4, SEMA3A, SEMA3B, SEMA3D, SEMA3E, SEMA3F, SEMA3G, DNMT3A, RPGRIP1L, ISL1, or MeCP2 genes. In embodiments, the subject has a disease or disorder associated with a gene in Table 1. In embodiments, the subject has or is identified as having a loss of function mutation in one or more genes in Table 1. In embodiments, methods herein can comprise identifying or selecting a subject having a defect e.g., genetic defect, or a mutation, in one or more genes listed in Table 1. In embodiments, methods herein can comprise acquiring knowledge of the genotype, predetermined sequence, or mutation. In embodiments, the methods herein can comprise acquiring knowledge of the genotype of, e.g., of a mutation in one or more of ARL6, RAI1, SRC1, BBS19, BBS21, CEP290, IFT74, LZTFL1, MKS1, TRIM32, WDPCP, RPS6KA3, HTR2C, KSR2, PROK2, RAB23, MRAP2, AFF4, ADCY3, TUB, OTP, GPR101, TBX3, ACBD7, AGRP, CADM1, CADM2, CARTPT, CCDC28B, CCK, CNR1, CREBBP, CREBRF, CUL4B, DYRK1B, ENPP1, EP300, FMR1, FTO, GHRL, GIPR, GLP1R, INPP5E, INS, INSIG2, IRS1, IRS4, KCTD15, KIDINS220, MCHR1, MSRA, NDN, NEGR1, NLGN2, NPY, NR0B2, NTRK2, PCNT, PCSK2, PHF6, PMCH, PPARG, PYY, SDC3, SEC16B, SLC6A14, SNRPN, THRB, TMEM18, TMEM67, TRAPPC9, UCP1, UCP3, or VPS13B, NRP1, NRP2, PLXNA1, PLXNA2, PLXNA3, PLXNA4, SEMA3A, SEMA3B, SEMA3D, SEMA3E, SEMA3F, SEMA3G, DNMT3A, RPGRIP1L, ISL1, or MeCP2 genes. In embodiments, the MC4R agonist is administered in response to acquiring knowledge, e.g., detection or identification, of a predetermined sequence, e.g., a mutation, in a gene described herein, one or more of ARL6, RAI1, SRC1, BBS19, BBS21, CEP290, IFT74, LZTFL1, MKS1, TRIM32, WDPCP, RPS6KA3, HTR2C, KSR2, PROK2, RAB23, MRAP2, AFF4, ADCY3, TUB, OTP, GPR101, TBX3, ACBD7, AGRP, CADM1, CADM2, CARTPT, CCDC28B, CCK, CNR1, CREBBP, CREBRF, CUL4B, DYRK1B, ENPP1, EP300, FMR1, FTO, GHRL, GIPR, GLP1R, INPP5E, INS, INSIG2, IRS1, IRS4, KCTD15, KIDINS220, MCHR1, MSRA, NDN, NEGR1, NLGN2, NPY, NR0B2, NTRK2, PCNT, PCSK2, PHF6, PMCH, PPARG, PYY, SDC3, SEC16B, SLC6A14, SNRPN, THRB, TMEM18, TMEM67, TRAPPC9, UCP1, UCP3, or VPS13B, NRP1, NRP2, PLXNA1, PLXNA2, PLXNA3, PLXNA4, SEMA3A, SEMA3B, SEMA3D, SEMA3E, SEMA3F, SEMA3G, DNMT3A, RPGRIP1L, ISL1, or MeCP2 genes. In embodiments, identification or selection of a subject as having a certain genotype or predetermined sequence, e.g., mutation, in a gene, can comprise acquiring knowledge of the certain genotype or predetermined sequence, e.g., mutation. Knowledge of the sort can be acquired in a number of ways, as described in detail in the Definitions section. In some embodiments, a sequence is acquired, e.g., by obtaining possession of a nucleotide sequence, by “directly acquiring” or “indirectly acquiring” the sequence. “Directly acquiring a sequence” means performing a process (e.g., performing a synthetic or analytical method) to obtain the sequence, such as performing a sequencing method (e.g., a Next Generation Sequencing (NGS) method). “Indirectly acquiring a sequence” refers to receiving information or knowledge of, or receiving, the sequence from another party or source (e.g., a third-party laboratory that directly acquired the sequence). The sequence acquired need not be a full sequence, e.g., sequencing of at least one nucleotide, or obtaining information or knowledge, that identifies a genotype or predetermined sequence, e.g., mutation, disclosed herein as being present in a subject constitutes acquiring a sequence. In embodiments, the sequence can be directly acquired. Directly acquiring a sequence includes performing a process that includes a physical change in a physical substance, e.g., a starting material, such as a tissue sample, e.g., a blood sample or tissue biopsy, or analysis of an isolated nucleic acid (e.g., DNA or RNA) sample. Exemplary changes include making a physical entity from two or more starting materials, shearing or fragmenting a substance, such as a genomic DNA fragment; separating or purifying a substance (e.g., isolating a nucleic acid sample from a tissue); combining two or more separate entities into a mixture, performing a chemical reaction that includes breaking or forming a covalent or non-covalent bond. Directly acquiring a value includes performing a process that includes a physical change in a sample or another substance as described above. In some embodiments, acquiring knowledge of the certain genotype or predetermined sequence, e.g., mutation, can comprise acquiring a sample, e.g., from which the genotype or predetermined sequence, e.g., mutation, is determined. “Acquiring a sample” as the term is used herein, refers to obtaining possession of a sample, e.g., a tissue sample or nucleic acid sample, by “directly acquiring” or “indirectly acquiring” the sample. “Directly acquiring a sample” means performing a process (e.g., performing a physical method such as a surgery or extraction) to obtain the sample. “Indirectly acquiring a sample” refers to receiving the sample from another party or source (e.g., a third-party laboratory that directly acquired the sample). Directly acquiring a sample includes performing a process that includes a physical change in a physical substance, e.g., a starting material, such as a tissue, e.g., a tissue in a human patient or a tissue that has was previously isolated from a patient. Exemplary changes include making a physical entity from a starting material, dissecting or scraping a tissue; separating or purifying a substance (e.g., a sample tissue or a nucleic acid sample); combining two or more separate entities into a mixture; performing a chemical reaction that includes breaking or forming a covalent or non-covalent bond. Directly acquiring a sample includes performing a process that includes a physical change in a sample or another substance, e.g., as described above. In some aspects, provided herein is also a method of evaluating a subject, e.g., for likely responsiveness to a MC4R agonist, e.g., a MC4R agonist described herein, e.g., 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), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI), or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises acquiring information about the genotype of the subject. In embodiments, the method comprises acquiring information about the presence or absence of a defect, e.g., genetic defect, in one or more genes listed in Table 1 in the subject. In embodiments, the subject can be identified as having a defect, e.g., genetic defect, e.g., mutation, in one or more genes listed in Table 1, using methods described herein. In embodiments, the identification of the subject having a defect, e.g., genetic defect, e.g., mutation, indicates that the subject is likely to respond (e.g., with an improvement in one or more symptoms) to a MC4R agonist, e.g., a MC4R agonist described herein, e.g., 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), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI), or a pharmaceutically acceptable salt thereof. In embodiments, an improvement in a symptom can include an outcome described herein. For example, an improvement in a symptom can include a reduction of weight (e.g., body weight), a reduction in hunger level, no detectable decrease in energy expenditure (e.g., resting energy expenditure), an increase in energy expenditure (e.g., resting energy expenditure), a reduction in daily/weekly/monthly food intake, or a reduction in waist circumference, e.g., relative to a control. In embodiments, the identification of the subject having the defect, e.g., genetic defect, e.g., mutation, indicates that the subject is more likely to respond to (or is likely to have a greater response to) a MC4R agonist, e.g., a MC4R agonist described herein, e.g., 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), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI), or a pharmaceutically acceptable salt thereof, than a subject (e.g., obese subject, e.g., of like age and/or pre-treatment weight) lacking a genetic defect in one or more genes listed in Table 1, e.g., a wild-type obese subject. In embodiments, a subject that is more likely to respond is more likely to have one or more improved symptoms, such as symptoms described herein, e.g., compared to a control, e.g., a subject (e.g., obese subject, e.g., of like age and/or pre- treatment weight) lacking a genetic defect in one or more genes listed in Table 1, e.g., a wild- type obese subject. In embodiments, a subject that is likely to have a greater response is likely to have a greater improvement in symptoms, e.g., symptoms described herein, e.g., greater weight loss, greater decrease in waist circumference, greater increase in resting energy expenditure, greater decrease in food intake, greater decrease in hunger level, e.g., compared to a control, e.g., a subject (e.g., obese subject, e.g., of like age and/or pre- treatment weight) lacking a genetic defect in one or more genes listed in Table 1, e.g., a wild- type obese subject. In embodiments, methods described herein further comprise providing a report that identifies the presence or absence of the genetic defect and in some cases an identifier for the subject. In embodiments, the report provides a recommendation on potential therapeutic options, likely effectiveness of a therapeutic option, and/or recommendations/instructions for administration of the therapeutic option (e.g., MC4R agonist, e.g., MC4R agonist described herein, e.g., 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), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI), or a pharmaceutically acceptable salt thereof). MC4R agonists Described herein are methods for treating a disease, disorder, or condition in a subject, comprising administering to a subject a melanocortin 4 receptor (MC4R) agonist. Examples of naturally occurring MC4R agonists include α-MSH, β-MSH, γ-MSH and adrenocorticotropic hormone (ACTH) or a functional fragment thereof. Examples of synthetic MC4R agonists are described in detail below. In some embodiments, an MC4R agonist can be any known agonist of MC4R. In some example embodiment, the MC4R agonist is not an adrenocorticotropic hormone (ACTH) or a fragment thereof. Exemplary MC4R agonists include those described in WO2011104378; WO2011104379; WO201060901; WO200887189, WO200887188, WO200887187, WO200887186; US20110065652; WO2010144341; WO2010144344; WO201065799; WO201065800; WO201065801; WO201065802; WO201037081; WO2009152079; WO2009151383; US20100311648; US20100280079; WO201081666; WO201034500; WO200910299; WO2008116665; WO201052256; WO201052255; WO201126015; US20100120783; WO201096854; US20100190793; WO201025142; WO2014144260; WO2017059075; and WO201015972. Further examples of MC4R agonists are found in U.S. Pat. No.8,263,608; U.S. Pat. No.8,247,530; U.S. Pat. No.8,114,844; and U.S. Pat. No.7,968,548. The entire teachings of these publications are incorporated herein by reference. In some embodiments, 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), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI), or a pharmaceutically acceptable salt thereof as described herein. In some embodiments, the MC4R agonist is not a compound of any one of Formulas (I) or (II), or a pharmaceutically acceptable salt thereof as described herein. In one embodiment, the MC4R agonist is not a compound of Formula (I). In one embodiment, the MC4R agonist is not a compound of Formula (II). In one example embodiment, the agonist of MC4R is not a tripeptide D-Phe-Arg-Trp (SEQ ID NO: 560) or a pharmaceutical salt thereof. In another example, the agonist is any peptide that does not include SEQ ID NO: 560 or a pharmaceutical salt thereof. In yet another example, the MC4R agonist is not an acetylated tripeptide Ac-D-Phe-Arg-Trp-NH₂ (SEQ ID NO: 561) or a pharmaceutical salt thereof. Described herein are methods for a disease, disorder, or condition in a subject, comprising administering to a subject a melanocorin 4 receptor (MC4R) agonist. Examples of naturally occurring MC4R agonists include α-MSH, β-MSH, γ-MSH and adenocorticitropic hormone (ACTH) or a functional fragment thereof. Examples of synthetic MC4R agonists are described in detail below. In some embodiments, an MC4R agonist can be any known agonist of MC4R. In some example embodiment, the MC4R agonist is not an adrenocorticotropic hormone (ACTH) or a fragment thereof. Exemplary MC4R agonists include those described in WO2011104378; WO2011104379; WO201060901; WO200887189, WO200887188, WO200887187, WO200887186; US20110065652; WO2010144341; WO2010144344; WO201065799; WO201065800; WO201065801; WO201065802; WO201037081; WO2009152079; WO2009151383; US20100311648; US20100280079; WO201081666; WO201034500; WO200910299; WO2008116665; WO201052256; WO201052255; WO201126015; US20100120783; WO201096854; US20100190793; WO201025142; WO2014144260; WO2017059075; and WO201015972. Further examples of MC4R agonists are found in U.S. Pat. No.8,263,608; U.S. Pat. No.8,247,530; U.S. Pat. No.8,114,844; and U.S. Pat. No.7,968,548. The entire teachings of these publications are incorporated herein by reference. In some embodiments, 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), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI), or a pharmaceutically acceptable salt thereof, as described herein. In some embodiments, the MC4R agonist is a compound of Formula (I): (R²R³)-A¹-c(A²-A³-A⁴-A⁵-A⁶-A⁷-A⁸-A⁹)-A¹⁰-R¹ (I) or a pharmaceutically acceptable salt thereof, wherein A¹ is Acc, HN—(CH₂)_m—C(O), L- or D-amino acid, or deleted; A² is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp, or Glu; A³ is Gly, Ala, β-Ala, Gaba, Aib, D-amino acid, or deleted; A⁴ is His, 2-Pal, 3-Pal, 4-Pal, Taz, 2- Thi, 3-Thi, or (X¹, X², X³, X⁴, X⁵)Phe; A⁵ is D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal, D-(X¹, X², X³, X⁴, X⁵)Phe, L-Phe or D-(Et)Tyr; A⁶ is Arg, hArg, Dab, Dap, Lys, Orn, or HN-CH((CH₂ )n-N(R⁴ R⁵))-C(O); A⁷ is Trp, 1-Nal, 2-Nal, Bal, Bip, D-Trp, D-2-Nal, D-Bal or D-Bip; A⁸ is Gly, D-Ala, Acc, Ala, 13-Ala, Gaba, Apn, Ahx, Aha, HN-(CH₂ )_s-C(O), or deleted; A⁹ is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab, Dap, Orn, or Lys; A¹⁰ is Acc, HN-(CH₂)t-C(O), L- or D-amino acid, or deleted; R¹ is OH or NH₂; each of R² and R³ is, independently for each occurrence, selected from the group consisting of H,(C₁-C₃₀)alkyl, (C₁-C₃₀)heteroalkyl, (C₁-C₃₀)acyl, (C₂-C₃₀)alkenyl, (C₂-C₃₀)alkynyl, aryl(C₁-C₃₀)alkyl, aryl(C₁-C₃₀)acyl, substituted (C₁-C₃₀)alkyl, substituted (C₁-C₃₀)heteroalkyl, substituted (C₁- C₃₀)acyl, substituted (C₂-C₃₀)alkenyl, substituted (C₂-C₃₀)alkynyl, substituted aryl(C₁- C₃₀ )alkyl, and substituted aryl(C₁-C₃₀)acyl; each of R⁴ and R⁵ is, independently for each occurrence, H, (C₁-C₄₀)alkyl, (C₁-C₄₀)heteroalkyl, (C₁-C₄₀)acyl, (C₂-C₄₀)alkenyl, (C₂- C₄₀)alkynyl, aryl(C₁-C₄₀)alkyl, aryl(C₁-C₄₀)acyl, substituted (C₁-C₄₀)alkyl, substituted (C₁- C₄₀)heteroalkyl, substituted (C₁-C₄₀)acyl, substituted (C₂-C₄₀)alkenyl, substituted (C₂- C₄₀)alkynyl, substituted aryl(C₁-C₄₀)alkyl, substituted aryl(C₁-C₄₀)acyl, (C₁- C₄₀)alkylsulfonyl, or -C(NH)-NH₂; m is, independently for each occurrence, 1, 2, 3, 4, 5, 6 or 7; n is, independently for each occurrence, 1, 2, 3, 4 or 5; s is, independently for each occurrence, 1, 2, 3, 4, 5, 6, or 7; t is, independently for each occurrence, 1, 2, 3, 4, 5, 6, or 7; X′, X², X³, X⁴, and X⁵ each is, independently for each occurrence, H, F, Cl, Br, I, -(C₁-C₁₀) alkyl, substituted (C₁-C₁₀) alkyl, (C₂-C₁₀) alkenyl, substituted (C₂-C₁₀) alkenyl, (C₂-C₁₀) alkynyl, substituted (C₂-C₁₀) alkynyl, aryl, substituted aryl, OH, NH₂ , NO2 , or CN. In some embodiments, for Formula (I), when R⁴ is (C₁-C₄₀)acyl, aryl(C₁-C₄₀)acyl, substituted (C₁-C₄₀)acyl, substituted aryl(C₁-C₄₀)acyl, (C₁-C₄₀)alkylsulfonyl, or -C(NH)-NH₂, then R⁵ is H or (C₁-C₄₀)alkyl, (C₁-C₄₀)heteroalkyl, (C₂-C₄₀)alkenyl, (C₂-C₄₀)alkynyl, aryl(C_1- C₄₀)alkyl, substituted (C₁-C₄₀)alkyl, substituted (C₁-C₄₀)heteroalkyl, substituted (C₂- C₄₀)alkenyl, substituted (C₂-C₄₀)alkynyl, or substituted aryl(C₁-C₄₀)alkyl. In some embodiments, for Formula (I), when R² is (C₁-C₃₀)acyl, aryl(C₁-C₃₀)acyl, substituted (C₁-C₃₀)acyl, or substituted aryl(C₁-C₃₀)acyl, then R³ is H, (C₁-C₃₀)alkyl, (C₁- C₃₀)heteroalkyl, (C₂-C₃₀)alkenyl, (C₂-C₃₀)alkynyl, aryl(C₁-C₃₀)alkyl, substituted (C₁- C₃₀)alkyl, substituted (C₁-C₃₀)heteroalkyl, substituted (C₂-C₃₀)alkenyl, substituted (C₂- C₃₀)alkynyl, or substituted aryl(C₁-C₃₀)alkyl; In some embodiments, for Formula (I), either A³ or A⁸ or both must be present in said compound. In some embodiments, for Formula (I) when A² is Cys, D-Cys, hCys, D-hCys, Pen, or D-Pen, then A⁹ is Cys, D-Cys, hCys, D-hCys, Pen, or D-Pen. In some embodiments, for Formula (I), when A² is Asp or Glu, then A⁹ is Dab, Dap, Orn, or Lys. In some embodiments, for Formula (I), when A⁸ is Ala or Gly, then A¹ is not NIe. In some embodiments, for Formula (I), when A¹ is deleted, then R² and R³ cannot both be H. In some embodiments, for Formula (I): A¹ is A6c, Arg, D-Arg, Cha, D-Cha, hCha, Chg, D-Chg, Gaba, Ile, Leu, hLeu, Met, β-hMet, 2-Nal, D-2-Nal, Nip, Nle, Oic, Phe, D-Phe, hPhe, hPro, Val, or deleted; A² is Asp, Cys, D-Cys, hCys, D-hCys, Glu, Pen, or D-Pen; A³ is D-Abu, Aib, Ala, β-Ala, D-Ala, D-Cha, Gaba, D-Glu, Gly, D-Ile, D-Leu, D-Tle, D-Val, or deleted;A⁴ is His or 3-Pal; A⁵ is D-Bal, D-1-Nal, D-2-Nal, D-Phe, D-Trp, or D-(Et)Tyr; A⁶ is Arg, or hArg; A⁷ is Bal, Bip, 1-Nal, 2-Nal, Trp, D-Trp; A⁸ is A6c, D-Ala, Aha, Ahx, Ala, β- Ala, Apn, Gaba, Gly or deleted; A⁹ is Cys, D-Cys, hCys, D-hCys, Lys, Pen, or D-Pen; and A¹⁰ is Thr, or deleted, wherein at least one of A³ or A⁸ is deleted, but not both. In some embodiments, the compound of Formula (I) is a compound disclosed in International Patent Application Publication Number WO 2007/008704, which is incorporated herein by reference in its entirety. In some embodiments, the compound of Formula (I) is selected from: (SEQ ID NO: 1) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-NH₂; (SEQ ID NO: 2) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-A6c-Lys)-NH₂; (SEQ ID NO: 3) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-NH₂; (SEQ ID NO: 4) D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-NH₂; (SEQ ID NO: 5) D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-NH₂; (SEQ ID NO: 6) D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-NH₂; (SEQ ID NO: 7) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH₂; (SEQ ID NO: 8) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-NH₂; (SEQ ID NO: 9) Ac-A6c-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 10) Ac-D-2-Nal-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 11) Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 12 ) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 13) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 14) Ac-Nle-c(Cys-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 15) Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 16) Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 17) Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 18) Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 19) Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 20) Ac-Nle-c(D-Cys-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 21) Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 22) Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 23) Ac-Nle-c(D-Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 24) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH₂; (SEQ ID NO: 25) Ac-Nle-c(Cys-β-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH₂; (SEQ ID NO: 26) Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH₂; (SEQ ID NO: 27) Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH₂; (SEQ ID NO: 28) Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-D-Cys)-NH₂; (SEQ ID NO: 29) Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH₂; (SEQ ID NO: 30) Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH₂; (SEQ ID NO: 31) Ac-Nle-c(D-Cys-β-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH₂; (SEQ ID NO: 32) Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH₂; (SEQ ID NO: 33) Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH₂; (SEQ ID NO: 34) Ac-Oic-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 35) Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 36) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 37) Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 38) Ac-D-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 39) Ac-Nip-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 40) Ac-hPro-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 41) Ac-hLeu-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 42) Ac-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 43) Ac-D-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 44) Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 45) n-butanoyl-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 46) n-butyryl-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 47) Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 48) Ac-β-hMet-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 49) Ac-Gaba-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 50) Ac-Cha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH₂; (SEQ ID NO: 51) Ac-hCha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH₂; (SEQ ID NO: 52) Ac-Leu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH₂; (SEQ ID NO: 53) Ac-hLeu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH₂; (SEQ ID NO: 54) Ac-Phe-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH₂; (SEQ ID NO: 55) Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-D-Ala-Lys)-NH₂; (SEQ ID NO: 56) Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-β-Ala-Lys)-NH₂; (SEQ ID NO: 57) Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 58) Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Aha-Lys)-NH₂; (SEQ ID NO: 59) Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Apn-Lys)-NH₂; (SEQ ID NO: 60) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Apn-Cys)-NH₂; (SEQ ID NO: 61) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-NH₂; (SEQ ID NO: 62) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-NH₂; (SEQ ID NO: 63) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-NH₂; (SEQ ID NO: 64) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)-NH₂; (SEQ ID NO: 65) Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 66) Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-NH₂; (SEQ ID NO: 67) Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-1-Nal-Cys)-NH₂; (SEQ ID NO: 68) n-butanoyl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH₂; (SEQ ID NO: 69) n-butanoyl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 70) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH₂; (SEQ ID NO: 71) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-1-Nal-Cys)-NH₂; (SEQ ID NO: 72) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Bal-Cys)-NH₂; (SEQ ID NO: 73) Ac-Nle-c(Cys-D-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 74) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-D-Ala-Lys)-NH₂; (SEQ ID NO: 75) Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-NH₂; (SEQ ID NO: 76) Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 77) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 78) Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 79) D-Phe-c(Cys-His-D-Phe-hArg-Trp-β-Ala-D-Cys)-Thr-NH₂; (SEQ ID NO: 80) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH₂; (SEQ ID NO: 81) D-Phe-c(Cys-His-D-Phe-Arg-Bip-β-Ala-D-Cys)-Thr-NH₂; (SEQ ID NO: 82) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-NH₂; (SEQ ID NO: 83) D-Phe-c(Cys-His-D-Phe-hArg-Bip-β-Ala-D-Cys)-Thr-NH₂; (SEQ ID NO: 84) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-NH₂; (SEQ ID NO: 85) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH₂; (SEQ ID NO: 86) Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Trp-Lys)-NH₂; (SEQ ID NO: 87) Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Lys)-NH₂; (SEQ ID NO: 88) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 89) Ac-Nle-c(Cys-D-Abu-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 90) Ac-Nle-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)- NH₂; (SEQ ID NO: 91) Ac-Nle-c(Cys-D-Ile-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 92) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 93) Ac-Nle-c(Cys-D-Tle-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 94) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 95) Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂; (SEQ ID NO: 96) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH₂; (SEQ ID NO: 97) Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Pen)-NH₂; (SEQ ID NO: 98) Ac-Leu-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂; (SEQ ID NO: 99) Ac-Cha-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂; (SEQ ID NO: 100) Ac-Ile-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂; (SEQ ID NO: 101) Ac-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂; (SEQ ID NO: 102) Ac-Val-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂; (SEQ ID NO: 103) Ac-2-Nal-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂; (SEQ ID NO: 104) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂; (SEQ ID NO: 105) Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂; (SEQ ID NO: 106) Ac-Nle-c(Cys-3-Pal-D-Phe-Arg-Trp-Gaba-Cys)-NH₂; (SEQ ID NO: 107) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; (SEQ ID NO: 108) Ac-Nle-c(Cys-His-Phe-Arg-D-Trp-Gaba-Cys)- NH₂; (SEQ ID NO: 109) Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Ala-Lys)-NH₂; (SEQ ID NO: 110) Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-β-Ala-Lys)-NH₂; (SEQ ID NO: 111) Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Gaba-Cys)-NH₂; (SEQ ID NO: 112) Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Ahx-Cys)-NH₂; (SEQ ID NO: 113) Ac-hPhe-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 114) Ac-Cha-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 115) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-OH; (SEQ ID NO: 116) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-OH; (SEQ ID NO: 117) D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-OH; (SEQ ID NO: 118) D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-OH; (SEQ ID NO: 119) D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-OH; (SEQ ID NO: 120) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-OH; (SEQ ID NO: 121) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-OH; (SEQ ID NO: 122) Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; (SEQ ID NO: 123) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; (SEQ ID NO: 124) Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; (SEQ ID NO: 125) Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; (SEQ ID NO: 126) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; (SEQ ID NO: 127) Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; (SEQ ID NO: 128) Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; (SEQ ID NO: 129) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-OH; (SEQ ID NO: 130) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-OH; (SEQ ID NO: 131) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-OH; (SEQ ID NO: 132) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)-OH; (SEQ ID NO: 133) Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-OH; (SEQ ID NO: 134) Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-OH; (SEQ ID NO: 135) Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-1-Nal-Cys)-OH; (SEQ ID NO: 136) Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-OH; (SEQ ID NO: 137) Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; (SEQ ID NO: 138) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-OH; (SEQ ID NO: 139) Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 140) Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 141) Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 142) Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 143) Ac-D-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH₂; (SEQ ID NO: 144) Ac-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH₂; (SEQ ID NO: 145) Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 146) Ac-D-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH₂; and (SEQ ID NO: 147) Ac-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH₂, or a pharmaceutically acceptable salt thereof. In embodiments, the compound of Formula (I) is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂ (SEQ ID NO: 140) or a pharmaceutically acceptable salt thereof. Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)- NH₂ (SEQ ID NO: 140), also known as RM-493 and setmelanotide, is a peptide that retains the specificity and functionality of the naturally occurring hormone that activates MC4R and has not been shown to adversely affect blood pressure in clinical trials (see, e.g., Chen et al. J. Clin. Endocrinol. Metab.2015;100(4):1639-45. The structure of Ac-Arg-c(Cys-D-Ala- His-D-Phe-Arg-Trp-Cys)-NH₂ (SEQ ID NO: 140) is shown below:

In some embodiments, the MC4R agonist is a compound of Formula (I-a): H-A¹-c(A²-A³-A⁴-A⁵-A⁶-A⁷-A⁸-A⁹)-A¹⁰-NH₂ (I-a) or a pharmaceutically acceptable salt thereof, wherein: A¹ is Phe, D-Phe, or Nle; A² is Cys; A³ is deleted; A⁴ is His; A⁵ is D-Phe or D-(Et)Tyr; A⁶ is Arg or hArg; A⁷ is Trp or Bip; A⁸ is Ala, β-Ala, Gaba, or Apn; A⁹ is D-Cys; and A¹⁰ is Thr or deleted. In some embodiments, the compound of Formula (I-a) is selected from: (SEQ ID NO: 4) D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-NH₂; (SEQ ID NO: 5) D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-NH₂; (SEQ ID NO: 6) D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-NH₂; (SEQ ID NO: 79) D-Phe-c(Cys-His-D-Phe-hArg-Trp-β-Ala-D-Cys)-Thr-NH₂; (SEQ ID NO: 80) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH₂; (SEQ ID NO: 81) D-Phe-c(Cys-His-D-Phe-Arg-Bip-β-Ala-D-Cys)-Thr-NH₂; (SEQ ID NO: 82) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-NH₂; (SEQ ID NO: 83) D-Phe-c(Cys-His-D-Phe-hArg-Bip-β-Ala-D-Cys)-Thr-NH₂; (SEQ ID NO: 84) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-NH₂; (SEQ ID NO: 85) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH₂; and (SEQ ID NO: 105) Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂. In some embodiments, the MC4R agonist is a compound of Formula (I-b): Ac-A¹-c(A²-A³-A⁴-A⁵-A⁶-A⁷-A⁸-A⁹)-A¹⁰-NH₂ (I-b) or a pharmaceutically acceptable salt thereof, wherein: A¹ is Nle, A6c, D-2-Nal, Cha, Oic, Chg, hCha, D-Cha, D-hCha, Nip, hPro, hLeu, Phe, D- Phe, D-Chg, hPhe, β-hMet, Gaba, Leu, Ile, Val, 2-Nal, Arg or D-Arg; A² is Asp, Cys, D-Cys, or Pen; A³ is D-Ala, β-Ala, Gaba, Aib, Gly, Ala, D-Glu, D-Abu, D-Val, D-Ile, D-Leu, D-Tle, D-Cha, deleted; A⁴ His or 3-Pal; A⁵ is Phe, D-Phe, or D-2-Nal; A⁶ is Arg; A⁷ is Trp, 1-Nal, 2-Nal, Bal, or D-Trp; A⁸ is β-Ala, A6c, Ahx, Apn, Gaba, Ala, Aha, D-Ala or deleted; A⁹ is Lys, Cys, D-Cys, or Pen; A¹⁰ is deleted. wherein A² and A⁹ are pairwise selected to form a disulfide or lactam bridge. In some embodiments, the compound of Formula (I-b) is selected from: (SEQ ID NO: 1) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-NH₂; (SEQ ID NO: 2) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-A6c-Lys)-NH₂; (SEQ ID NO: 3) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-NH₂; (SEQ ID NO: 7) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH₂; (SEQ ID NO: 8) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-NH₂; (SEQ ID NO: 9) Ac-A6c-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 10) Ac-D-2-Nal-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 11) Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 12 ) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 13) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 14) Ac-Nle-c(Cys-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 15) Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 16) Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 17) Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 18) Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 19) Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 20) Ac-Nle-c(D-Cys-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 21) Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 22) Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 23) Ac-Nle-c(D-Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 24) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH₂; (SEQ ID NO: 25) Ac-Nle-c(Cys-β-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH₂; (SEQ ID NO: 26) Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH₂; (SEQ ID NO: 27) Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH₂; (SEQ ID NO: 28) Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-D-Cys)-NH₂; (SEQ ID NO: 29) Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH₂; (SEQ ID NO: 30) Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH₂; (SEQ ID NO: 31) Ac-Nle-c(D-Cys-β-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH₂; (SEQ ID NO: 32) Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH₂; (SEQ ID NO: 33) Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH₂; (SEQ ID NO: 34) Ac-Oic-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 35) Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 36) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 37) Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 38) Ac-D-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 39) Ac-Nip-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 40) Ac-hPro-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 41) Ac-hLeu-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 42) Ac-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 43) Ac-D-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 44) Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 47) Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 48) Ac-β-hMet-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 49) Ac-Gaba-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 50) Ac-Cha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH₂; (SEQ ID NO: 51) Ac-hCha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH₂; (SEQ ID NO: 52) Ac-Leu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH₂; (SEQ ID NO: 53) Ac-hLeu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH₂; (SEQ ID NO: 54) Ac-Phe-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH₂; (SEQ ID NO: 55) Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-D-Ala-Lys)-NH₂; (SEQ ID NO: 56) Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-β-Ala-Lys)-NH₂; (SEQ ID NO: 57) Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 58) Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Aha-Lys)-NH₂; (SEQ ID NO: 59) Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Apn-Lys)-NH₂; (SEQ ID NO: 60) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Apn-Cys)-NH₂; (SEQ ID NO: 61) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-NH₂; (SEQ ID NO: 62) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-NH₂; (SEQ ID NO: 63) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-NH₂; (SEQ ID NO: 64) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)-NH₂; (SEQ ID NO: 65) Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 66) Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-NH₂; (SEQ ID NO: 67) Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-1-Nal-Cys)-NH₂; (SEQ ID NO: 70) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH₂; (SEQ ID NO: 71) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-1-Nal-Cys)-NH₂; (SEQ ID NO: 72) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Bal-Cys)-NH₂; (SEQ ID NO: 73) Ac-Nle-c(Cys-D-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 74) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-D-Ala-Lys)-NH₂; (SEQ ID NO: 75) Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-NH₂; (SEQ ID NO: 76) Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 77) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 78) Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 86) Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Trp-Lys)-NH₂; (SEQ ID NO: 87) Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Lys)-NH₂; (SEQ ID NO: 89) Ac-Nle-c(Cys-D-Abu-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 90) Ac-Nle-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)- NH₂; (SEQ ID NO: 91) Ac-Nle-c(Cys-D-Ile-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 92) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 93) Ac-Nle-c(Cys-D-Tle-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 94) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 95) Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂; (SEQ ID NO: 96) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH₂; (SEQ ID NO: 97) Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Pen)-NH₂; (SEQ ID NO: 98) Ac-Leu-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂; (SEQ ID NO: 99) Ac-Cha-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂; (SEQ ID NO: 100) Ac-Ile-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂; (SEQ ID NO: 101) Ac-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂; (SEQ ID NO: 102) Ac-Val-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂; (SEQ ID NO: 103) Ac-2-Nal-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂; (SEQ ID NO: 106) Ac-Nle-c(Cys-3-Pal-D-Phe-Arg-Trp-Gaba-Cys)-NH₂; (SEQ ID NO: 108) Ac-Nle-c(Cys-His-Phe-Arg-D-Trp-Gaba-Cys)- NH₂; (SEQ ID NO: 109) Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Ala-Lys)-NH₂; (SEQ ID NO: 110) Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-β-Ala-Lys)-NH₂; (SEQ ID NO: 111) Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Gaba-Cys)-NH₂; (SEQ ID NO: 112) Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Ahx-Cys)-NH₂; (SEQ ID NO: 113) Ac-hPhe-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 114) Ac-Cha-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 139) Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 140) Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 141) Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 142) Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 143) Ac-D-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH₂; (SEQ ID NO: 144) Ac-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH₂; (SEQ ID NO: 145) Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 146) Ac-D-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH₂; and (SEQ ID NO: 147) Ac-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH₂. In some embodiments, the MC4R agonist is a compound of Formula (I-c): Ac-Nle-c(A²-A³-A⁴-A⁵-A⁶-A⁷-A⁸-A⁹)-A¹⁰-NH₂ (I-c) or a pharmaceutically acceptable salt thereof, wherein: A² is Asp, Cys, D-Cys, or Pen; A³ is D-Ala, β-Ala, Gaba, Aib, Gly, Ala, Aib, Dl-Glu, D-Abu, D-Val, D-Ile, D-Leu, D-Tle, D-Cha, or deleted; A⁴ is His or 3-Pal; A⁵ is D-Phe, D-2-Nal, or Phe; A⁶ is Arg; A⁷ is Trp, D-Trp, 2-Nal, 1-Nal, Bal; A⁸ is β-Ala, A6c, Ahx, Apn, Gaba, D-Ala, Aha, Ala or deleted; A⁹ is Lys, Cys, D-Cys or Pen; and A¹⁰ is deleted, wherein A² and A⁹ are pairwise selected to form a disulfide or lactam bridge. In some embodiments, the compound of Formula (I-c) is selected from: (SEQ ID NO: 1) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-NH₂; (SEQ ID NO: 2) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-A6c-Lys)-NH₂; (SEQ ID NO: 3) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-NH₂; (SEQ ID NO: 7) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH₂; (SEQ ID NO: 8) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-NH₂; (SEQ ID NO: 12 ) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 13) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 14) Ac-Nle-c(Cys-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 15) Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 16) Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 17) Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 18) Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 19) Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 20) Ac-Nle-c(D-Cys-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 21) Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 22) Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 23) Ac-Nle-c(D-Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 24) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH₂; (SEQ ID NO: 25) Ac-Nle-c(Cys-β-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH₂; (SEQ ID NO: 26) Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH₂; (SEQ ID NO: 27) Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH₂; (SEQ ID NO: 28) Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-D-Cys)-NH₂; (SEQ ID NO: 29) Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH₂; (SEQ ID NO: 30) Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH₂; (SEQ ID NO: 31) Ac-Nle-c(D-Cys-β-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH₂; (SEQ ID NO: 32) Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH₂; (SEQ ID NO: 33) Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH₂; (SEQ ID NO: 55) Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-D-Ala-Lys)-NH₂; (SEQ ID NO: 56) Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-β-Ala-Lys)-NH₂; (SEQ ID NO: 57) Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Gaba-Lys)-NH₂; (SEQ ID NO: 58) Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Aha-Lys)-NH₂; (SEQ ID NO: 59) Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Apn-Lys)-NH₂; (SEQ ID NO: 60) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Apn-Cys)-NH₂; (SEQ ID NO: 61) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-NH₂; (SEQ ID NO: 62) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-NH₂; (SEQ ID NO: 63) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-NH₂; (SEQ ID NO: 64) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)-NH₂; (SEQ ID NO: 65) Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 66) Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-NH₂; (SEQ ID NO: 67) Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-1-Nal-Cys)-NH₂; (SEQ ID NO: 70) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH₂; (SEQ ID NO: 71) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-1-Nal-Cys)-NH₂; (SEQ ID NO: 72) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Bal-Cys)-NH₂; (SEQ ID NO: 73) Ac-Nle-c(Cys-D-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 74) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-D-Ala-Lys)-NH₂; (SEQ ID NO: 75) Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-NH₂; (SEQ ID NO: 76) Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 77) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 78) Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 86) Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Trp-Lys)-NH₂; (SEQ ID NO: 87) Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Lys)-NH₂; (SEQ ID NO: 89) Ac-Nle-c(Cys-D-Abu-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 90) Ac-Nle-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)- NH₂; (SEQ ID NO: 91) Ac-Nle-c(Cys-D-Ile-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 92) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 93) Ac-Nle-c(Cys-D-Tle-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 94) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 95) Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂; (SEQ ID NO: 96) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH₂; (SEQ ID NO: 97) Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Pen)-NH₂; (SEQ ID NO: 106) Ac-Nle-c(Cys-3-Pal-D-Phe-Arg-Trp-Gaba-Cys)-NH₂; (SEQ ID NO: 108) Ac-Nle-c(Cys-His-Phe-Arg-D-Trp-Gaba-Cys)- NH₂; (SEQ ID NO: 109) Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Ala-Lys)-NH₂; (SEQ ID NO: 110) Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-β-Ala-Lys)-NH₂; (SEQ ID NO: 111) Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Gaba-Cys)-NH₂; and (SEQ ID NO: 112) Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Ahx-Cys)-NH₂. In some embodiments, the MC4R agonist is a compound of Formula (I-d): H-D-Phe-c(A²-A³-A⁴-A⁵-A⁶-A⁷-A⁸-A⁹)-A¹⁰-NH₂ (I-d) or a pharmaceutically acceptable salt thereof, wherein: A² is Cys; A³ is deleted; A⁴ is His; A⁵ is D-Phe or D-(Et)Tyr; A⁶ is Arg or hArg; A⁷ is Trp or Bip; A⁸ is Ala, β-Ala, or Gaba; A⁹ is D-Cys; and A¹⁰ is Thr. In some embodiments, the compound of Formula (I-d) is selected from: (SEQ ID NO: 4) D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-NH₂; (SEQ ID NO: 5) D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-NH₂; (SEQ ID NO: 6) D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-NH₂; (SEQ ID NO: 79) D-Phe-c(Cys-His-D-Phe-hArg-Trp-β-Ala-D-Cys)-Thr-NH₂; (SEQ ID NO: 80) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH₂; (SEQ ID NO: 81) D-Phe-c(Cys-His-D-Phe-Arg-Bip-β-Ala-D-Cys)-Thr-NH₂; (SEQ ID NO: 82) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-NH₂; (SEQ ID NO: 83) D-Phe-c(Cys-His-D-Phe-hArg-Bip-β-Ala-D-Cys)-Thr-NH₂; and (SEQ ID NO: 84) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-NH₂. In some embodiments, the MC4R agonist is a compound of Formula (II): ically

acceptable salt thereof, wherein: X ¹ is s, D-Cys, Dab, Dap, Glu, Lys, Orn,

Pen or D-Pen; A² is an L- or D-amino acid; A³ is H is, 2-Pal, 3-Pal, 4-Pal, (X¹, X², X³, X⁴, X⁵)Phe, Taz, 2-Thi or 3-Thi; A⁴ is D-Bal, D-1-Nal, D-2-Nal, D-Phe or D-(X¹, X², X³, X⁴, X⁵)Phe; A⁵ is Arg, hArg, Dab, Dap, Lys or Orn; A⁶ is Bal, 1-Nal, 2-Nal, (X¹, X², X³, X⁴, X⁵)Phe or Trp; A⁷ is Asp, Cys, D-Cys, Dab, Dap, Glu, Lys, Orn, Pen or D-Pen; R¹ is H, (C₁- C₁₀)alkyl or substituted (C₁-C₁₀)alkyl; R² and R³ each is, independently, H, (C₁-C₁₀)alkyl, (C₁-C₁₀)heteroalkyl, aryl(C₁-C₅)alkyl, substituted (C₁-C₁₀)alkyl, substituted (C₁- C₁₀)heteroalkyl or substituted aryl(C₁-C₅)alkyl or R² and R³ may be fused together form a cyclic moiety; R⁴ is OH, NH₂, CO₂ H or C(O)NH₂; R⁵ and R⁶ each is, independently, H, (C₁- C₁₀)alkyl, (C₁-C₁₀)heteroalkyl, aryl(C₁-C₅)alkyl, substituted (C₁-C₁₀)alkyl, substituted (C₁- C₁₀)heteroalkyl or substituted aryl(C₁-C₅)alkyl or R⁵ and R⁶ may be fused together form a cyclic moiety; R⁷ and R⁸ each is, independently, H, (C₁-C₁₀)alkyl, (C₁-C₁₀)heteroalkyl, aryl(C₁-C₅)alkyl, substituted (C₁-C₁₀)alkyl, substituted (C₁-C₁₀)heteroalkyl or substituted aryl(C₁-C₅)alkyl; or R⁷ and R⁸ may be fused together form a cyclic moiety; R⁹ is H, (C₁- C₁₀)alkyl or substituted (C₁-C₁₀)alkyl; and n is, independently for each occurrence thereof, 0, 1, 2, 3, 4, 5, 6 or 7; or a pharmaceutically acceptable salt thereof. In some embodiments of Formula (II), A¹ is Cys; A² is D-Ala, Asn, Asp, Gln, Glu or D-Phe; A³ is H is; A⁴ is D-2-Nal or D-Phe; A⁵ is Arg; A⁶ is Trp; and A⁷ is Cys or Pen; each of R′, R², R³, and R⁹ is, independently, H; R⁴ is C(O)NH₂; each of R⁵ and R⁶ is, independently, H, (C₁-C₁₀)heteroalkyl, substituted (C₁-C₁₀)alkyl or substituted (C₁-C₁₀)heteroalkyl or R⁵ and R⁶ may be fused together form a cyclic moiety; and each of R⁷ and R⁸ is, independently, H, (C₁-C₁₀)alkyl, (C₁-C₁₀)heteroalkyl, substituted (C₁-C₁₀)alkyl or substituted (C₁- C₁₀)heteroalkyl; or pharmaceutically acceptable salts thereof. In some embodiments, the compound of Formula (II) is selected from: (SEQ ID NO: 148) Hydantoin(C(O)-(Arg-Gly))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 149) Hydantoin(C(O)-(Nle-Gly))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 150) Hydantoin(C(O)-(Gly-Gly))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 151) Hydantoin(C(O)-(Nle-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 152) Hydantoin(C(O)-(Gly-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 153) Hydantoin(C(O)-(Nle-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 154) Hydantoin(C(O)-(Gly-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 155) Hydantoin(C(O)-(Ala-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 156) Hydantoin(C(O)-(D-Ala-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)- NH₂; (SEQ ID NO: 157) Hydantoin(C(O)-(Aib-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 158) Hydantoin(C(O)-(Val-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 159) Hydantoin(C(O)-(Ile-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 160) Hydantoin(C(O)-(Leu-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)- NH₂; (SEQ ID NO: 161) Hydantoin(C(O)-(Gly-Gly))-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 162) Hydantoin(C(O)-(Nle-Gly))-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 163) Hydantoin(C(O)-(D-Arg-Gly))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)- NH₂; (SEQ ID NO: 164) Hydantoin(C(O)-(D-Arg-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)- NH₂; (SEQ ID NO: 165) Hydantoin(C(O)-(Arg-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)- NH₂; (SEQ ID NO: 166) Hydantoin(C(O)-(D-Arg-Gly))-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)- NH₂; (SEQ ID NO: 167) Hydantoin(C(O)-(Arg-Gly))-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)- NH₂; (SEQ ID NO: 168) Hydantoin(C(O)-(Ala-Nle))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 169) Hydantoin(C(O)-(Val-Nle))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 170) Hydantoin(C(O)-(Gly-Nle))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 171) Hydantoin(C(O)-(A6c-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)- NH₂; (SEQ ID NO: 172) Hydantoin(C(O)-(Gly-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 173) Hydantoin(C(O)-(Ala-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 174) Hydantoin(C(O)-(D-Ala-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)- NH₂; (SEQ ID NO: 175) Hydantoin(C(O)-(Val-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 176) Hydantoin(C(O)-(Leu-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 177) Hydantoin(C(O)-(Cha-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)- NH₂; (SEQ ID NO: 178) Hydantoin(C(O)-(Aib-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 179) Hydantoin(C(O)-(Gly-Arg))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 180) Hydantoin(C(O)-(Gly-Arg))-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 181) Hydantoin(C(O)-(Gly-Arg))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)- NH₂; (SEQ ID NO: 182) Hydantoin(C(O)-(Gly-Arg))-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)- NH₂; (SEQ ID NO: 183) Hydantoin(C(O)-(Gly-D-Arg))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)- NH₂; (SEQ ID NO: 184) Hydantoin(C(O)-(Gly-D-Arg))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)- NH₂; (SEQ ID NO: 185) Hydantoin(C(O)-(Gly-D-Arg))-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)- NH₂; and (SEQ ID NO: 186) Hydantoin(C(O)-(Nle-Ala))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH₂, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (II) is described in WO2008/147556 or International Patent Application Number PCT/US08/06675, each of which is incorporated herein by reference in its entirety. In embodiments, the compound of Formula (II) is hydantoin(C(O)-(Arg-Gly))-c(Cys- Glu-His-D-Phe-Arg-Trp-Cys)-NH₂ (SEQ ID NO: 148) or a pharmaceutically acceptable salt thereof, also known as RM-511. The structure of hydantoin(C(O)-(Arg-Gly))-c(Cys-Glu-His- D-Phe-Arg-Trp-Cys)-NH₂ (SEQ ID NO:148) is shown below:

In some embodiments, the MC4R agonist is a compound of Formula (III): maceutically acceptable salt thereof,

wherein X is selected from the group consisting of -CH₂-S-S-CH₂-, -C(CH₃)₂-S-S-CH₂-, - CH₂-S-S-C(CH₃)₂-, -C(CH₃)₂-S-S-C(CH₃)₂-, -(CH₂)2-S-S-CH₂-, -CH₂-S-S-(CH₂)2-, -(CH₂)2- S-S-(CH₂)₂-, -C(CH₃)₂-S-S-(CH₂)₂-, -(CH₂)₂-S-S-C(CH₃)₂-, -(CH₂)_t-C(O)-NR⁸-(CH₂)_r-and - (CH₂)r-NR⁸-C(O)-(CH₂)t -; R² each is, independently, H, (C₁-C₁₀)alkyl or substituted (C₁- C₁₀)alkyl; R³ is -OH or -NH₂; R⁴ and R⁵ each is, independently, H, (C₁-C₁₀)alkyl or substituted (C₁-C₁₀)alkyl; X¹ is ; A¹ is H is, 2-Pal, 3-Pal, 4-Pal, (X¹, X², X³, X⁴, X⁵)Phe, Taz, 2-Thi, 3-Thi or is deleted; A² is D-Bal, D-1-Nal, D-2-Nal, D-Phe or D-(X¹, X², X³, X⁴, X⁵)Phe; A³ is Arg, hArg, Dab, Dap, Lys or Orn; A⁴ is Bal, 1-Nal, 2-Nal, (X¹, X², X³, X⁴, X⁵)Phe or Trp; R⁶ and R⁷ each is, independently for each occurrence thereof, H, (C₁- C₁₀)heteroalkyl, aryl(C₁-C₅)alkyl, substituted (C₁-C₁₀)alkyl, substituted (C₁-C₁₀)heteroalkyl or substituted aryl(C₁-C₅)alkyl provided that R⁶ and R⁷ may be joined together to form a ring; R⁸ is H, (C₁-C₁₀)alkyl or substituted (C₁-C₁₀)alkyl; r is, independently for each occurrence thereof, 1, 2, 3, 4 or 5; and t is, independently for each occurrence thereof, 1 or 2. Compounds according to the foregoing formula can include compounds wherein X ¹ is selected from the group consisting of: ,

Compounds of Formula (III) are disclosed in International Patent Publication WO 2008/147556 or International Patent Application Number PCT/US08/06675, each of which is incorporated herein by reference in its entirety. In some embodiments, the compound of Formula (III) is selected from: (SEQ ID NO: 187) c[Hydantoin(C(O)-(Cys-D-Ala))-His-D-Phe-Arg-Trp-Cys]-NH₂; (SEQ ID NO: 188) c[Hydantoin(C(O)-(hCys-D-Ala))-His-D-Phe-Arg-Trp-Cys]-NH₂; (SEQ ID NO: 189) c[Hydantoin(C(O)-(Cys-D-Ala))-His-D-2-Nal-Arg-Trp-Cys]-NH₂; (SEQ ID NO: 190) c[Hydantoin(C(O)-(hCys-D-Ala))-His-D-2-Nal-Arg-Trp-Cys]-NH₂; (SEQ ID NO: 191) c[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Lys]-NH₂; (SEQ ID NO: 192) c[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Orn]-NH₂; (SEQ ID NO: 193) c[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Dab]-NH₂; (SEQ ID NO: 194) c[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Dap]-NH₂; (SEQ ID NO: 195) c[Hydantoin(C(O)-(Asp-His))-D-2-Nal-Arg-Trp-Lys]-NH₂; (SEQ ID NO: 196) c[Hydantoin(C(O)-(Asp-His))-D-Phe-Arg-Trp-Lys]-NH₂; (SEQ ID NO: 197) c[Hydantoin(C(O)-(Asp-A3c))-D-Phe-Arg-Trp-Lys]-NH₂; (SEQ ID NO: 198) c[Hydantoin(C(O)-(Asp-A5c))-D-Phe-Arg-Trp-Lys]-NH₂; (SEQ ID NO: 199) c[Hydantoin(C(O)-(Asp-A6c))-D-Phe-Arg-Trp-Lys]-NH₂; (SEQ ID NO: 200) c[Hydantoin(C(O)-(Asp-A3c))-D-2-Nal-Arg-Trp-Lys]-NH₂; (SEQ ID NO: 201) c[Hydantoin(C(O)-(Asp-A5c))-D-2-Nal-Arg-Trp-Lys]-NH₂; (SEQ ID NO: 202) c[Hydantoin(C(O)-(Asp-A6c))-D-2-Nal-Arg-Trp-Lys]-NH₂; (SEQ ID NO: 203) c[Hydantoin(C(O)-(Asp-Aic))-D-Phe-Arg-Trp-Lys]-NH₂; (SEQ ID NO: 204) c[Hydantoin(C(O)-(Asp-Apc))-D-Phe-Arg-Trp-Lys]-NH₂; (SEQ ID NO: 205) c[Hydantoin(C(O)-(Asp-Aic))-D-2-Nal-Arg-Trp-Lys]-NH₂; (SEQ ID NO: 206) c[Hydantoin(C(O)-(Asp-Apc))-D-2-Nal-Arg-Trp-Lys]-NH₂; (SEQ ID NO: 207) c[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Orn]-NH₂; (SEQ ID NO: 208) c[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Dab]-NH₂; (SEQ ID NO: 209) c[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Dap]-NH₂; (SEQ ID NO: 210) c[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Lys]-NH₂; (SEQ ID NO: 211) c[Hydantoin(C(O)-(Glu-His))-D-Phe-Arg-Trp-Dap]-NH₂; and (SEQ ID NO: 212) c[Hydantoin(C(O)-(Glu-His))-D-Phe-Arg-Trp-Lys]-NH₂, or a pharmaceutically acceptable salt thereof. In some embodiments, the MC4R agonist is a compound of Formula (IV): (R²R³)-A¹-c(A²-A³-A⁴-A⁵-A⁶-A⁷-A⁸-A⁹)-NH₂ (IV) or a pharmaceutically acceptable salt thereof, wherein A¹ is Nle or deleted; A² is Cys or Asp; A³ is Glu or D-Ala; A⁴ is His; A⁵ is D-Phe; A⁶ is Arg; A⁷ is Trp, 2-Nal or Bal; A⁸ is Gly, Ala, D-Ala, 3-Ala, Gaba or Apn; A⁹ is Cys or Lys; each of R² and R³ is independently selected from the group consisting of H or (C₁-C₆))acyl. In exemplary embodiments of Formula (IV): (I) when R² is (C₁-C₆)acyl, then R³ is H; and (II) when A² is Cys, then A⁹ is Cys. Exemplary MC4R agonists of Formula (IV) are disclosed in International Patent Application Publication Number WO 2007/008704, which is incorporated herein by reference in its entirety. In some embodiments, the compound of Formula (IV) is selected from: (SEQ ID NO: 213) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gly-Cys)-NH₂; (SEQ ID NO: 214) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Ala-Cys)-NH₂; (SEQ ID NO: 215) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-β-Ala-Cys)-NH₂; (SEQ ID NO: 216) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys)-NH₂; (SEQ ID NO: 217) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Apn-Cys)-NH₂; (SEQ ID NO: 218) Ac-c(Cys-Glu-His-D-Phe-Arg-Trp-Ala-Cys)-NH₂; (SEQ ID NO: 219) Ac-c(Cys-Glu-His-D-Phe-Arg-2-Nal-Ala-Cys)-NH₂; (SEQ ID NO: 220) Ac-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH₂; (SEQ ID NO: 221) Ac-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Ala-Cys)-NH₂; (SEQ ID NO: 222) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH₂; and (SEQ ID NO: 223) Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Ala-Lys)-NH₂, or a pharmaceutically acceptable salt thereof. In some embodiments, the MC4R agonist is a compound of Formula (V): (R²R³)-B¹-A¹-c(A²-A³-A⁴-A⁵-A⁶-A⁷-A⁸-A⁹)-A¹⁰-A¹¹-A¹²-A¹³-B²-B³-R¹ (V) or a pharmaceutically acceptable salt thereof: B¹ is a peptide moiety which contains 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids, wherein at least 5 amino acids are independently selected from the group consisting of L-Arg, D-Arg, L-hArg and D-hArg, or B¹ is optionally deleted; A¹ is Acc, HN-(CH₂)m-C(O), L- or D-amino acid or deleted; A² is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp or Glu; A³ is Gly, Glu, Ala, β-Ala, Gaba, Aib, D-amino acid or deleted; A⁴ is H is, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi or (X′, X², X³, X⁴, X⁵)Phe; A⁵ is D- Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal, D-(X¹, X², X³, X⁴, X⁵)Phe, D-(Et)Tyr, D-Dip, D-Bip or D-Bpa; A⁶ is Arg, hArg, Dab, Dap, Lys, Orn or HN-CH((CH₂)_n-N(R⁴R⁵))-C(O); A⁷ is Trp, 1-Nal, 2-Nal, Bal, Bip, Dip, Bpa, D-Trp, D-1-Nal, D-2-Nal, D-Bal, D-Bip, D-Dip or D-Bpa; A⁸ is Gly, D-Ala, Acc, Ala, β-Ala, Gaba, Apn, Ahx, Aha, HN-(CH₂)s-C(O) or deleted; A⁹ is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab, Dap, Orn or Lys; A¹⁰ is Acc, HN-(CH₂)_t-C(O), Pro, hPro, 3-Hyp, 4-Hyp, Thr, an L- or D-amino acid or deleted; A¹¹ is Pro, hPro, 3-Hyp, 4- Hyp or deleted; A¹² is Lys, Dab, Dap, Arg, hArg or deleted; A¹³ is Asp, Glu or deleted; B² is a peptide moiety containing 1, 2, 3, 4, or 5 amino acids or deleted, B³ is a peptide moiety which contains 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acids wherein at least 5 amino acids are independently selected from the group consisting of L-Arg, D-Arg, L-hArg and D-hArg, or is deleted; R¹ is OH or NH₂; R² and R³ each is, independently for each occurrence, selected from the group consisting of H, (C₁-C₃₀)alkyl, (C₁-C₃₀)heteroalkyl, (C₁-C₃₀)acyl, (C₂- C₃₀)alkenyl, (C₂-C₃₀)alkynyl, aryl(C₁-C₃₀)alkyl, aryl(C₁-C₃₀)acyl, substituted (C₁-C₃₀)alkyl, substituted (C₁-C₃₀)heteroalkyl, substituted (C₁-C₃₀)acyl, substituted (C₂-C₃₀)alkenyl, substituted (C₂-C₃₀)alkynyl, substituted aryl(C₁-C₃₀)alkyl and substituted aryl(C₁-C₃₀)acyl; R⁴ and R⁵ each is, independently for each occurrence, H, (C₁-C₄₀)alkyl, (C₁-C₄₀)heteroalkyl, (C₁-C₄₀)acyl, (C₂-C₄₀)alkenyl, (C₂-C₄₀)alkynyl, aryl(C₁-C₄₀)alkyl, aryl(C₁-C₄₀)acyl, substituted (C₁-C₄₀)alkyl, substituted (C₁-C₄₀)heteroalkyl, substituted (C₁-C₄₀)acyl, substituted (C₂- C₄₀)alkenyl, substituted (C₂-C₄₀)alkynyl, substituted aryl(C₁-C₄₀)alkyl, substituted aryl(C₁- C₄₀)acyl, (C₁-C₄₀)alkylsulfonyl or C(NH)-NH₂; n is, independently for each occurrence, 1, 2, 3, 4 or 5; m is, independently for each occurrence, 1, 2, 3, 4, 5, 6 or 7; s is, independently for each occurrence, 1, 2, 3, 4, 5, 6 or 7; t is, independently for each occurrence, 1, 2, 3, 4, 5, 6 or 7; X¹, X², X³, X⁴ and X⁵ each is, independently for each occurrence, H, F, Cl, Br, I, -(C₁-C₁₀) alkyl, substituted (C₁-C₁₀) alkyl, (C₂-C₁₀) alkenyl, substituted (C₂-C₁₀) alkenyl, (C₂-C₁₀) alkynyl, substituted (C₂-C₁₀) alkynyl, aryl, substituted aryl, OH, NH₂ , NO2 or CN. In some embodiments of Formula (V): (I) when R⁴ is (C₁-C₄₀)acyl, aryl(C₁-C₄₀)acyl, substituted (C₁-C₄₀)acyl, substituted aryl(C₁-C₄₀)acyl, (C₁-C₄₀)alkylsulfonyl or C(NH)—NH₂ , then R⁵ is H, (C₁-C₄₀)alkyl, (C₁- C₄₀)heteroalkyl, (C₂-C₄₀)alkenyl, (C₂-C₄₀)alkynyl, aryl(C₁-C₄₀)alkyl, substituted (C₁- C₄₀)alkyl, substituted (C₁-C₄₀)heteroalkyl, substituted (C₂-C₄₀)alkenyl, substituted (C₂- C₄₀)alkynyl or substituted aryl(C₁-C₄₀)alkyl; (II) when R² is (C₁-C₃₀)acyl, aryl(C₁-C₃₀)acyl, substituted (C₁-C₃₀)acyl or substituted aryl (C₁-C₃₀)acyl, then R³ is H, (C₁-C₃₀)alkyl, (C₁-C₃₀)heteroalkyl, (C₂-C₃₀)alkenyl, (C₂- C₃₀)alkynyl, aryl(C₁-C₃₀)alkyl, substituted (C₁-C₃₀)alkyl, substituted (C₁-C₃₀)heteroalkyl, substituted (C₂-C₃₀)alkenyl, substituted (C₂-C₃₀)alkynyl or substituted aryl(C₁-C₃₀)alkyl; (III) neither B¹ nor B² contains one or more of the following amino acid sequences: Arg-(Lys)₂-(Arg)₂-Gln-(Arg)₃, Tyr-Ala-Arg-Lys-Ala-(Arg)₂-Gln-Ala-(Arg)₂, Tyr-Ala-Arg- (Ala)2-(Arg)₂-(Ala)2-(Arg)₂, Tyr-Ala-(Arg)9, Tyr-(Ala)3-(Arg)₇, Tyr-Ala-Arg-Ala-Pro- (Arg)₂-Ala-(Arg)₃ or Tyr-Ala-Arg-Ala-Pro-(Arg)₂-Pro-(Arg)₂; (IV) either B¹ or B² or both must be present in said compound; (V) when A² is Cys, D-Cys, hCys, D-hCys, Pen or D-Pen, then A⁹ is Cys, D-Cys, hCys, D-hCys, Pen or D-Pen; and (VI) when A² is Asp or Glu, then A⁹ is Dab, Dap, Orn or Lys. In some embodiments of Formula (V): B¹ is Arg-Lys-Gln-Lys-(Arg)₅, Arg-(Lys)2-Arg-Gln-(Arg)₄, Arg-(Lys)2-(Arg)₃-Gln- (Arg)₂, Arg-(Lys)₂-(Arg)₄-Gln-Arg, Arg-(Lys)₂-(Arg)₅-Gln, Arg-(Lys)₂-Gln-(Arg)₅, Arg-Gln- (Lys)₂-(Arg)₅, Arg-Gln-(Arg)₇, Arg-Gln-(Arg)₈, (Arg)₂-Gln-(Arg)₆, (Arg)₂-Gln-(Arg)₇, (Arg)₃-Gln-(Arg)₅,(Arg)₃-Gln-(Arg)₆, (Arg)₄-Gln- (Arg)₄, (Arg)₄-Gln-(Arg)₅, (Arg)₅, (Arg)₅- Gln-(Arg)₃, (Arg)₅-Gln-(Arg)₄, (Arg)₆, (Arg)₆-Gln-(Arg)₃, (Arg)₇, (Arg)₇-Gln-(Arg)₂, (Arg)₈, (Arg)s-Gln-Arg, (Arg)9, (Arg)9-Gln, (D-Arg)5, (D-Arg)6, (D-Arg)7, (D-Arg)8, (D-Arg)9, Gln- Arg-(Lys)₂-(Arg)₅, Gln-(Arg)₈, Gln-(Arg)₉, Tyr-Gly-Arg-(Lys)₂-(Arg)₂-Gln-(Arg)₃, Tyr-Gly- Arg-(Lys)2-(Arg)₂-Gln-(Arg)₃-Doc; or deleted; B² is β-Ala, β-Ala-Gly, β-Ala-Tyr, β-Ala-Tyr-Gly, (β-Ala)2, (β-Ala)2-Gly, (β-Ala)2- Tyr, (β-Ala)₂-Tyr-Gly, Doc, Doc-Gly, Doc-Tyr, Doc-Tyr-Gly, (Doc)₂, (Doc)₂-Gly, (Doc)₂- Tyr, Doc)₂-Tyr-Gly, or deleted; B³ is Arg-Lys-Gln-Lys-(Arg)₅, Arg-Lys-(Arg)₃-Gln-(Arg)₃, Arg-(Lys)2-Arg-Gln- (Arg)₄, Arg-(Lys)₂-Gln-(Arg)₅, Arg-(Lys)₂-(Arg)₂-Gln-(Arg)₃, Arg-(Lys)₂-(Arg)₃-Gln-(Arg)₂, Arg-(Lys)₂-(Arg)₄-Gln-Arg, Arg-(Lys)₂-(Arg)₅-Gln, Arg-Gln-(Lys)₂-(Arg)₅, Arg-Gln-(Arg)₇, Arg-Gln-(Arg)s, (Arg)₂-Lys-(Arg)₂-Gln-(Arg)₃, (Arg)₂-Gln-(Arg)₆, (Arg)₂-Gln-(Arg)₇, (Arg)₃-Gln-(Arg)₅, (Arg)₃-Gln-(Arg)₆, (Arg)₄-Gln-(Arg)₄, (Arg)₄-Gln-(Arg)₅, (Arg)₅, (Arg)s- Gln-(Arg)₃, (Arg)₅-Gln-(Arg)₄, (Arg)₆, (Arg)₆-Gln-(Arg)₃, (Arg)₇, (Arg)₇-Gln-(Arg)₂, (Arg)₈, (Arg)s-Gln-Arg, (Arg)9, (Arg)9-Gln, (D-Arg)5, (D-Arg)6, (D-Arg)7, (D-Arg)8, (D-Arg)9, Gln- Arg-(Lys)2-(Arg)₅, Gln-(Arg)8, Gln-(Arg)9, or deleted; A¹ is A6c, Cha, hCha, Chg, D-Chg, hChg, Gaba, hLeu, Met, β-hMet, D-2-Nal, Nip, Nle, Oic, Phe, D-Phe, hPhe, hPro, or deleted; A² is Cys; A³ is D-Abu, Aib, Ala, β-Ala, D-Ala, D-Cha, Gaba, Glu, Gly, D-Ile, D-Leu, D-Met, D-Nle, D-Phe, D-Tle, D-Trp, D-Tyr, D-Val, or deleted; A⁴ is H; A⁵ is D-Bal, D-1-Nal, D-2-Nal, D-Phe, D-(X¹, X², X³, X⁴, X⁵)Phe, D-Trp, or D- (Et)Tyr; A⁶ is Arg or hArg; A⁷ is Bal, Bip, 1-Nal, 2-Nal, Trp, or D-Trp; A⁸ is A5c, A6c, Aha, Ahx, Ala, β-Ala, Apn, Gaba, Gly, or deleted; A⁹ is Cys, D-Cys, hCys, D-hCys, Lys, Pen, or D-Pen; A¹⁰ is Pro, Thr or deleted; A¹¹ is Pro or deleted; A¹² is Arg, Lys, or deleted; A¹³ is Asp or deleted; each of R² and R³ is, independently, H or acyl; or pharmaceutically acceptable salts thereof. In some embodiments, the compound of Formula (V) is selected from: (SEQ ID NO: 224) Tyr-Gly-Arg-(Lys)2-(Arg)₂-Gln-(Arg)₃-Nle-c(Asp-His-D-2-Nal-Arg-Trp- Lys)-NH₂; (SEQ ID NO: 225) Tyr-Gly-Arg-(Lys)₂-(Arg)₂-Gln-(Arg)₃-Doc-Nle-c(Asp-His-D-2-Nal- Arg-Trp-Lys)-NH₂; (SEQ ID NO: 226) Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)-β-Ala-Tyr-Gly-Arg-(Lys)2-(Arg)₂- Gln-(Arg)₃-NH₂; (SEQ ID NO: 227) Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)-β-Ala-Tyr-Gly-Arg-(Lys)₂- (Arg)₂-Gln-(Arg)₃-NH₂; (SEQ ID NO: 228) Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)-(Doc)2-Tyr-Gly-Arg-(Lys)2- (Arg)₂-Gln-(Arg)₃-NH₂; (SEQ ID NO: 229) Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)-(Pro)2-Lys-Asp-Tyr-Gly-Arg- (Lys)2-(Arg)₂-Gln-(Arg)₃-NH₂; (SEQ ID NO: 230) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Gly-Cys)-(Pro)₂-Lys-Asp-Tyr-Gly- Arg-(Lys)₂-(Arg)₂-Gln-(Arg)₃-NH₂; (SEQ ID NO: 231) Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)-(β-Ala)2-Tyr-Gly-Arg-(Lys)2- (Arg)₂-Gln-(Arg)₃-NH₂; (SEQ ID NO: 232) Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)-(Pro)₂-Lys-Asp-Doc-Tyr-Gly- Arg-(Lys)2-(Arg)₂-Gln-(Arg)₃-NH₂; (SEQ ID NO: 233) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Gly-Cys)-(Pro)₂-Lys-Asp-Doc-Tyr- Gly-Arg- (Lys)₂-(Arg)₂-Gln-(Arg)₃-NH₂; (SEQ ID NO: 234) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala- Tyr-Gly-Arg-(Lys)2-(Arg)₂-Gln-(Arg)₃-NH₂; (SEQ ID NO: 235) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)₂-Lys-Asp-Doc-Tyr- Gly-Arg-(Lys)2-(Arg)₂-Gln-(Arg)₃-NH₂; (SEQ ID NO: 236) Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)-(Doc)2-Tyr-Gly-Arg-(Lys)2- (Arg)₂-Gln-(Arg)₃-NH₂; (SEQ ID NO: 237) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)₂-Lys-Asp-β-Ala- Tyr-Gly-Arg-(Lys)2-(Arg)₂-Gln-(Arg)₃-NH₂; (SEQ ID NO: 238) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala- (Arg)₅-Gln-(Arg)₃-NH₂; (SEQ ID NO: 239) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)₂-Lys-Asp-β-Ala- Gly-(Arg)₅-Gln-(Arg)₃-NH₂; (SEQ ID NO: 240) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala- Tyr-Gly-(Arg)₅-Gln-(Arg)₃-NH₂; (SEQ ID NO: 241) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)₂-Lys-Asp-β-Ala- Tyr-Gly-Arg-(Lys)2-Arg-Gln-(Arg)₄-NH₂; (SEQ ID NO: 242) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)₂-Lys-Asp-β-Ala- Tyr-Gly-Arg-(Lys)₂-Gln-(Arg)₅-NH₂; (SEQ ID NO: 243) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala- Tyr-Gly-Arg-Lys-Gln-Lys-(Arg)₅-NH₂; (SEQ ID NO: 244) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)₂-Lys-Asp-β-Ala- Tyr-Gly-Arg-(Lys)2-(Arg)₄-Gln-Arg-NH₂; (SEQ ID NO: 245) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala- Tyr-Aib-Arg-(Lys)₂-(Arg)₂-Gln-(Arg)₃-NH₂; (SEQ ID NO: 246) Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)₂-Arg-Asp-β-Ala- (Arg)₅ -Gln-(Arg)₃-NH₂; (SEQ ID NO: 247) Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)₂-Lys-Asp-β-Ala- (Arg)₅-Gln-(Arg)₃-NH₂; (SEQ ID NO: 248) Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala- (Arg)₆-Gln-(Arg)₃-NH₂; (SEQ ID NO: 249) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)₂-Arg-Asp-β-Ala- (Arg)₅-Gln-(Arg)₃-NH₂; (SEQ ID NO: 250) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala- (Arg)₅-Gln-(Arg)₃-NH₂; (SEQ ID NO: 251) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala- (Arg)₆-Gln-(Arg)₃-NH₂; (SEQ ID NO: 252) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)₂-Arg-Asp-β-Ala- (Arg)₆-Gln-(Arg)₃-NH₂; (SEQ ID NO: 253) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Arg-Asp-β-Ala- (Arg)₅-Gln-(Arg)₃-NH₂; (SEQ ID NO: 254) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)₂-Lys-Asp-β-Ala- (Arg)₆-Gln-(Arg)₃-NH₂; (SEQ ID NO: 255) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala- Tyr-Gly-Arg-(Lys)₂-(Arg)₃-Gln-(Arg)₂-NH₂; (SEQ ID NO: 256) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)₂-Lys-Asp-β-Ala- Tyr-Gly-Arg-Gln-(Lys)2-(Arg)₅-NH₂; (SEQ ID NO: 257) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)₂-Lys-Asp-β-Ala- Tyr-Gly-Arg-(Lys)₂-(Arg)₅-Gln-NH₂; (SEQ ID NO: 258) Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala- Tyr-Gly-Arg-(Lys)2-(Arg)₂-Gln-(Arg)₃-NH₂; (SEQ ID NO: 259) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)₂-Lys-Asp-β-Ala- Tyr-Gly-Arg-(Lys)2-(Arg)₂-Gln-(Arg)₃-NH₂; (SEQ ID NO: 260) Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala- (Arg)₂ -Lys-(Arg)₂-Gln-(Arg)₃-NH₂; (SEQ ID NO: 261) Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)₂-Lys-Asp-β-Ala- Arg-Lys-(Arg)₃-Gln-(Arg)₃-NH₂; (SEQ ID NO: 262) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)₂-Lys-Asp-β-Ala- (Arg)₂-Lys-(Arg)₂-Gln-(Arg)₃-NH₂; (SEQ ID NO: 263) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala- Tyr-Gly-(Arg)₂-Lys-(Arg)₂-Gln-(Arg)₃-NH₂; (SEQ ID NO: 264) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)₂-Lys-Asp-β-Ala- Gly-(Arg)₂-Lys-(Arg)₂-Gln-(Arg)₃-NH₂; (SEQ ID NO: 265) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala- Gly-Arg-Lys-(Arg)₃-Gln-(Arg)₃-NH₂; (SEQ ID NO: 266) Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala- Tyr-Gly-(Arg)₂-Lys-(Arg)₂-Gln-(Arg)₃-NH₂; (SEQ ID NO: 267) Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)₂-Lys-Asp-β-Ala- Tyr-Gly-Arg-Lys-(Arg)₃-Gln-(Arg)₃-NH₂; (SEQ ID NO: 268) Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala- Gly-(Arg)₂-Lys-(Arg)₂-Gln-(Arg)₃-NH₂; (SEQ ID NO: 269) Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)₂-Lys-Asp-β-Ala- Gly-Arg-Lys-(Arg)₃-Gln-(Arg)₃-NH₂; (SEQ ID NO: 270) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala- (Arg)₂-Lys-(Arg)₂-Gln-(Arg)₃-NH₂; (SEQ ID NO: 271) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)₂-Lys-Asp-β-Ala- Arg-Lys-(Arg)₃-Gln-(Arg)₃-NH₂; (SEQ ID NO: 272) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)₂-Lys-Asp-β-Ala- Tyr-Gly-Arg-Lys-(Arg)₃-Gln-(Arg)₃-NH₂; (SEQ ID NO: 273) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala- (Arg)₂-Lys-(Arg)₂-Gln-(Arg)₃-NH₂; (SEQ ID NO: 274) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)₂-Lys-Asp-β-Ala- Arg-Lys-(Arg)₃-Gln-(Arg)₃-NH₂; (SEQ ID NO: 275) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala- Tyr-Gly-(Arg)₂-Lys-(Arg)₂-Gln-(Arg)₃-NH₂; (SEQ ID NO: 276) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)₂-Lys-Asp-β-Ala- Tyr-Gly-Arg-Lys-(Arg)₃-Gln-(Arg)₃-NH₂; (SEQ ID NO: 277) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)₂-Lys-Asp-β-Ala- Gly-(Arg)₂-Lys-(Arg)₂-Gln-(Arg)₃-NH₂; (SEQ ID NO: 278) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala- Gly-Arg-Lys-(Arg)₃-Gln-(Arg)₃-NH₂; (SEQ ID NO: 279) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)₂-Lys-Asp-β-Ala- (Arg)₅-Gln-(Arg)₃-NH₂; (SEQ ID NO: 280) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Arg-Asp-β-Ala- (Arg)₅-Gln-(Arg)₃-NH₂; (SEQ ID NO: 281) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala- Tyr-Gly-(Arg)₅-Gln-(Arg)₃-NH₂; (SEQ ID NO: 282) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)₂-Arg-Asp-β-Ala- Tyr-Gly-(Arg)₅-Gln-(Arg)₃-NH₂; (SEQ ID NO: 283) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala- (Arg)₅-Gln-(Arg)₄-NH₂; (SEQ ID NO: 284) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)₂-Arg-Asp-β-Ala- (Arg)₅-Gln-(Arg)₄-NH₂; (SEQ ID NO: 285) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala- Tyr-Gly-(Arg)₅-Gln-(Arg)₄-NH₂; (SEQ ID NO: 286) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)₂-Arg-Asp-β-Ala- Tyr-Gly-(Arg)₅-Gln-(Arg)₄-NH₂; (SEQ ID NO: 287) Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)₂-Lys-Asp-β-Ala- (Arg)₅-Gln-(Arg)₄-NH₂; (SEQ ID NO: 288) Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)2-Arg-Asp-β-Ala- (Arg)₅-Gln-(Arg)₄-NH₂; (SEQ ID NO: 289) Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)₂-Arg-Asp-β-Ala- (Arg)₆-Gln-(Arg)₃-NH₂; (SEQ ID NO: 290) Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala- Tyr-Gly-(Arg)₅-Gln-(Arg)₃-NH₂; (SEQ ID NO: 291) Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)₂-Arg-Asp-β-Ala- Tyr-Gly-(Arg)₅-Gln-(Arg)₃-NH₂; (SEQ ID NO: 292) Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)₂-Lys-Asp-β-Ala- Tyr-Gly-(Arg)₅-Gln-(Arg)₄-NH₂; (SEQ ID NO: 293) Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)2-Arg-Asp-β-Ala- Tyr-Gly-(Arg)₅-Gln-(Arg)₄-NH₂; (SEQ ID NO: 294) Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)₂-Lys-Asp-β-Ala- Tyr-Gly-(Arg)₆-Gln-(Arg)₃-NH₂; (SEQ ID NO: 295) Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)2-Arg-Asp-β-Ala- Tyr-Gly-(Arg)₆-Gln-(Arg)₃-NH₂; (SEQ ID NO: 296) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Arg-Asp-β-Ala- (Arg)₆-Gln-(Arg)₃-NH₂; (SEQ ID NO: 297) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)₂-Lys-Asp-β-Ala- (Arg)₅-Gln-(Arg)₄-NH₂; (SEQ ID NO: 298) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Arg-Asp-β-Ala- (Arg)₅-Gln-(Arg)₄-NH₂; (SEQ ID NO: 299) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)₂-Lys-Asp-β-Ala- Tyr-Gly-(Arg)₅-Gln-(Arg)₃-NH₂; (SEQ ID NO: 300) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Arg-Asp-β-Ala- Tyr-Gly-(Arg)₅-Gln-(Arg)₃-NH₂; (SEQ ID NO: 301) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)₂-Lys-Asp-β-Ala- Tyr-Gly-(Arg)₆-Gln-(Arg)₃-NH₂; (SEQ ID NO: 302) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)₂-Arg-Asp-β-Ala- Tyr-Gly-(Arg)₆-Gln-(Arg)₃-NH₂; (SEQ ID NO: 303) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala- Tyr-Gly-(Arg)₅-Gln-(Arg)₄-NH₂; (SEQ ID NO: 304) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)₂-Arg-Asp-β-Ala- Tyr-Gly-(Arg)₅-Gln-(Arg)₄-NH₂; (SEQ ID NO: 305) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala- (Arg)₅-Gln-(Arg)₄-NH₂; (SEQ ID NO: 306) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)₂-Arg-Asp-β-Ala- (Arg)₅-Gln-(Arg)₄-NH₂; (SEQ ID NO: 307) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)₂-Arg-Asp-β-Ala- Tyr-Gly-(Arg)₅-Gln-(Arg)₃-NH₂; (SEQ ID NO: 308) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala- Tyr-Gly-(Arg)₅-Gln-(Arg)₄-NH₂; (SEQ ID NO: 309) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)₂-Arg-Asp-β-Ala- Tyr-Gly-(Arg)₅-Gln-(Arg)₄-NH₂; (SEQ ID NO: 310) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-β-Ala- Tyr-Gly-(Arg)₆-Gln-(Arg)₃-NH₂; (SEQ ID NO: 311) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Arg-Asp-β-Ala- Tyr-Gly-(Arg)₆-Gln-(Arg)₃-NH₂; (SEQ ID NO: 312) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(Doc)₂-Tyr-Gly-Arg- (Lys)₂-(Arg)₂-Gln-(Arg)₃-NH₂; (SEQ ID NO: 313) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-β-Ala-Tyr-Gly-Arg- (Lys)2-Arg-Gln-(Arg)₄-NH₂; (SEQ ID NO: 314) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Doc-Tyr-Gly-Arg-(Lys)₂ -(Arg)₂-Gln-(Arg)₃-NH₂; (SEQ ID NO: 315) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-β-Ala-(Arg)₅-Gln-(Arg)₃- NH₂; (SEQ ID NO: 316) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-β-Ala-Gly-(Arg)₅-Gln- (Arg)₃-NH₂; (SEQ ID NO: 317) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-β-Ala-Tyr-Gly-(Arg)₅- Gln-(Arg)₃-NH₂; (SEQ ID NO: 318) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-β-Ala-Gly-(Arg)₅-Gln- (Arg)₄-NH₂; (SEQ ID NO: 319) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-β-Ala-Tyr-Gly-(Arg)₂- Lys-(Arg)₂-Gln-(Arg)₃-NH₂; (SEQ ID NO: 320) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-β-Ala-Tyr-Gly-Arg-Lys- (Arg)₃-Gln-(Arg)₃-NH₂; (SEQ ID NO: 321) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-β-Ala-Gly-(Arg)₂-Lys- (Arg)₂-Gln-(Arg)₃-NH₂; (SEQ ID NO: 322) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-β-Ala-Gly-Arg-Lys- (Arg)₃-Gln-(Arg)₃-NH₂; (SEQ ID NO: 323) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-β-Ala-(Arg)₂-Lys-(Arg)₂- Gln-(Arg)₃-NH₂; (SEQ ID NO: 324) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-β-Ala-Arg-Lys-(Arg)₃ - Gln-(Arg)₃-NH₂; (SEQ ID NO: 325) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(β-Ala)2-(Arg)₅-Gln- (Arg)₃-NH₂; (SEQ ID NO: 326) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(β-Ala)2-Gly-(Arg)₅ - Gln-(Arg)₃-NH₂; (SEQ ID NO: 327) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(β-Ala)₂-Tyr-Gly-(Arg)₅ - Gln-(Arg)₃-NH₂; (SEQ ID NO: 328) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Doc-(Arg)₅-Gln-(Arg)₃ - NH₂; (SEQ ID NO: 329) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Doc-Gly-(Arg)₅-Gln- (Arg)₃-NH₂; (SEQ ID NO: 330) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Doc-Tyr-Gly-(Arg)₅ - Gln-(Arg)₃-NH₂; (SEQ ID NO: 331) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(Doc)₂ -(Arg)₅-Gln- (Arg)₃-NH₂; (SEQ ID NO: 332) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(Doc)₂ -Gly-(Arg)₅ -Gln- (Arg)₃-NH₂; (SEQ ID NO: 333) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(Doc)2 -Tyr-Gly-(Arg)₅ - Gln-(Arg)₃-NH₂; (SEQ ID NO: 334) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-β-Ala-(Arg)₅-Gln-(Arg)₄- NH₂; (SEQ ID NO: 335) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-β-Ala-Tyr-Gly-(Arg)₅ - Gln-(Arg)₄ -NH₂; (SEQ ID NO: 336) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(β-Ala)₂-(Arg)₅-Gln- (Arg)₄-NH₂; (SEQ ID NO: 337) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(β-Ala)₂-Gly-(Arg)₅-Gln- (Arg)₄-NH₂; (SEQ ID NO: 338) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(β-Ala)2-Tyr-Gly-(Arg)₅ - Gln-(Arg)₄-NH₂; (SEQ ID NO: 339) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Doc-(Arg)₅ -Gln-(Arg)₄ - NH₂; (SEQ ID NO: 340) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Doc-Gly-(Arg)₅-Gln- (Arg)₄-NH₂; (SEQ ID NO: 341) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Doc-Tyr-Gly-(Arg)₅-Gln- (Arg)₄-NH₂; (SEQ ID NO: 342) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(Doc)₂ -(Arg)₅-Gln- (Arg)₄-NH₂; (SEQ ID NO: 343) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(Doc)2 -Gly-(Arg)₅-Gln- (Arg)₄ -NH₂; (SEQ ID NO: 344) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(Doc)₂ -Tyr-Gly-(Arg)₅ - Gln-(Arg)₄ -NH₂; (SEQ ID NO: 345) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-β-Ala-Tyr-Gly- (Arg)₅ - Gln-(Arg)₃-NH₂; (SEQ ID NO: 346) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-β-Ala-(Arg)₅ -Gln-(Arg)₃ - NH₂; (SEQ ID NO: 347) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-β-Ala-Tyr-Gly-(Arg)₅ -Gln- (Arg)₃ -NH₂; (SEQ ID NO: 348) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-β-Ala-(Arg)₅-Gln-(Arg)₃- NH₂; (SEQ ID NO: 349) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-β-Ala-Tyr-Gly-(Arg)₅-Gln- (Arg)₃-NH₂; (SEQ ID NO: 350) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-β-Ala-Gly-(Arg)₅-Gln-(Arg)₃- NH₂; (SEQ ID NO: 351) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-β-Ala-(Arg)₅ -Gln-(Arg)₃ -NH₂; (SEQ ID NO: 352) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(β-Ala)2-Tyr-Gly-(Arg)₅-Gln- (Arg)₃-NH_2; (SEQ ID NO: 353) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(β-Ala)₂ -Gly-(Arg)₅ -Gln-(Arg)₃ -NH₂; (SEQ ID NO: 354) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(β-Ala)₂-(Arg)₅ -Gln-(Arg)₃ - NH₂; (SEQ ID NO: 355) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-Doc-Tyr-Gly-(Arg)₅-Gln-(Arg)₃ -NH₂; (SEQ ID NO: 356) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-Doc-Gly-(Arg)₅ -Gln-(Arg)₃ - NH₂; (SEQ ID NO: 357) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-Doc-(Arg)₅ -Gln-(Arg)₃ -NH₂; (SEQ ID NO: 358) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(Doc)₂-Tyr-Gly-(Arg)₅-Gln- (Arg)₃-NH₂; (SEQ ID NO: 359) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(Doc)2 -Gly-(Arg)₅-Gln-(Arg)₃ - NH₂; (SEQ ID NO: 360) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(Doc) ₂ -(Arg)₅ -Gln-(Arg)₃ - NH₂; (SEQ ID NO: 361) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-β-Ala-Tyr-Gly-(Arg)₅ -Gln- (Arg)₄ -NH₂; (SEQ ID NO: 362) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-β-Ala-Gly-(Arg)₅-Gln-(Arg)₄ - NH₂; (SEQ ID NO: 363) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-β-Ala-(Arg)₅-Gln-(Arg)₄-NH₂; (SEQ ID NO: 364) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(β-Ala)₂ -Tyr-Gly-(Arg)₅-Gln- (Arg)₄-NH₂; (SEQ ID NO: 365) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(β-Ala)2 -Gly-(Arg)₅-Gln- (Arg)₄-NH₂; (SEQ ID NO: 366) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(β-Ala)2 -(Arg)₅ -Gln-(Arg)₄ - NH₂; (SEQ ID NO: 367) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-Doc-Tyr-Gly-(Arg)₅ -Gln-(Arg)₄ -NH₂; (SEQ ID NO: 368) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-Doc-Gly-(Arg)₅-Gln-(Arg)₄ - NH₂; (SEQ ID NO: 369) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-Doc-(Arg)₅ -Gln-(Arg)₄-NH₂; (SEQ ID NO: 370) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(Doc)2-Tyr-Gly-(Arg)₅-Gln- (Arg)₄-NH₂; (SEQ ID NO: 371) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(Doc)₂ -Gly-(Arg)₅ -Gln-(Arg)₄ - NH₂; (SEQ ID NO: 372) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(Doc)2 -(Arg)₅ -Gln-(Arg)₄ - NH₂; (SEQ ID NO: 373) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-β-Ala-Tyr-Gly-(Arg)₅- Gln-(Arg)₃-NH₂; (SEQ ID NO: 374) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-β-Ala-(Arg)₅ -Gln-(Arg)₃ -NH₂; (SEQ ID NO: 375) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-β-Ala-Tyr-Gly-(Arg)₅ - Gln-(Arg)₃ -NH₂; (SEQ ID NO: 376) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-β-Ala-(Arg)₅ -Gln-(Arg)₃ - NH₂; (SEQ ID NO: 377) D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-β-Ala-Tyr-Gly- (Arg)₅ -Gln-(Arg)₃ - NH₂; (SEQ ID NO: 378) D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-β-Ala-(Arg)₅-Gln- (Arg)₃-NH₂; (SEQ ID NO: 379) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-β-Ala-Tyr-Gly-(Arg)₅-Gln- (Arg)₃ -NH₂; (SEQ ID NO: 380) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-β-Ala-(Arg)₅ -Gln-(Arg)₃ - NH₂; (SEQ ID NO: 381) Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-β-Ala-Tyr-Gly- (Arg)₅ - Gln-(Arg)₃ -NH₂; (SEQ ID NO: 382) Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-β-Ala-(Arg)₅ -Gln-(Arg)₃ -NH₂; (SEQ ID NO: 383) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-β-Ala-Tyr-Gly-(Arg)₅ - Gln-(Arg)₃ -NH₂; (SEQ ID NO: 384) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-β-Ala-(Arg)₅ -Gln-(Arg)₃ - NH₂; (SEQ ID NO: 385) Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-β-Ala-Tyr-Gly-(Arg)₅ - Gln-(Arg)₃ -NH₂; (SEQ ID NO: 386) Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-β-Ala-(Arg)₅ -Gln-(Arg)₃ -NH₂; (SEQ ID NO: 387) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-β-Ala-Tyr-Gly-(Arg)₅ - Gln-(Arg)₃- NH₂; (SEQ ID NO: 388) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-β-Ala-(Arg)₅ -Gln- (Arg)₃ -NH₂; (SEQ ID NO: 389) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(β-Ala)₂ -Tyr-Gly-(Arg)₅ -Gln-(Arg)₃ - NH₂; (SEQ ID NO: 390) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(β-Ala)2-(Arg)₅-Gln- (Arg)₃-NH₂; (SEQ ID NO: 391) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-Doc-Tyr-Gly-(Arg)₅ - Gln-(Arg)₃-NH₂; (SEQ ID NO: 392) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-Doc-(Arg)₅-Gln-(Arg)₃ - NH₂; (SEQ ID NO: 393) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(Doc)₂ -Tyr-Gly-(Arg)₅ - Gln-(Arg)₃-NH₂; (SEQ ID NO: 394) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(Doc)₂ -(Arg)₅ -Gln- (Arg)₃ -NH₂; (SEQ ID NO: 395) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-β-Ala-Tyr-Gly-(Arg)₅ - Gln-(Arg)₄-NH₂; (SEQ ID NO: 396) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-β-Ala-(Arg)₅ -Gln- (Arg)₄ -NH₂; (SEQ ID NO: 397) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(β-Ala)2 -Tyr-Gly-(Arg)₅ -Gln-(Arg)₄ - NH₂; (SEQ ID NO: 398) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(β-Ala)₂-(Arg)₅-Gln- (Arg)₄-NH₂; (SEQ ID NO: 399) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-Doc-Tyr-Gly-(Arg)₅ - Gln-(Arg)₄ -NH₂; (SEQ ID NO: 400) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-Doc-(Arg)₅ -Gln-(Arg)₄ - NH₂; (SEQ ID NO: 401) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(Doc)₂ -Tyr-Gly-(Arg)₅ - Gln-(Arg)₄-NH₂; (SEQ ID NO: 402) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(Doc)2-(Arg)₅-Gln- (Arg)₄-NH₂; (SEQ ID NO: 403) Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-β-Ala-Tyr-Gly-(Arg)₅ - Gln-(Arg)₃-NH₂; (SEQ ID NO: 404) Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-β-Ala-(Arg)₅-Gln- (Arg)₃-NH₂; (SEQ ID NO: 405) Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-β-Ala-Tyr-Gly-(Arg)₅- Gln-(Arg)₃-NH₂; (SEQ ID NO: 406) Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-β-Ala-(Arg)₅-Gln-(Arg)₃- NH₂; (SEQ ID NO: 407) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Apn-Cys)-β-Ala-Tyr-Gly-(Arg)₅ - Gln-(Arg)₃-NH₂; (SEQ ID NO: 408) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Apn-Cys)-β-Ala-(Arg)₅-Gln- (Arg)₃-NH₂; (SEQ ID NO: 409) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-β-Ala-Tyr-Gly-(Arg)₅- Gln-(Arg)₃-NH₂; (SEQ ID NO: 410) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-β-Ala-(Arg)₅ -Gln- (Arg)₃-NH₂; (SEQ ID NO: 411) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-β-Ala-Tyr- Gly-(Arg)₅ -Gln-(Arg)₃-NH₂; (SEQ ID NO: 412) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-β-Ala-(Arg)₅-Gln- (Arg)₃-NH₂; (SEQ ID NO: 413) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-β-Ala-Tyr-Gly -(Arg)₅ - Gln-(Arg)₃-NH₂; (SEQ ID NO: 414) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-β-Ala-Gly-(Arg)₅-Gln- (Arg)₃-NH₂; (SEQ ID NO: 415) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-β-Ala-(Arg)₅-Gln-(Arg)₃- NH₂; (SEQ ID NO: 416) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-(β-Ala)₂-Tyr-Gly-(Arg)₅- Gln-(Arg)₃-NH₂; (SEQ ID NO: 417) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-(β-Ala)2 -Gly-(Arg)₅ - Gln-(Arg)₃-NH₂; (SEQ ID NO: 418) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-(β-Ala)2-(Arg)₅-Gln- (Arg)₃-NH₂; (SEQ ID NO: 419) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-Doc-Tyr-Gly-(Arg)₅ - Gln-(Arg)₃-NH₂; (SEQ ID NO: 420) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-Doc-Gly-(Arg)₅-Gln- (Arg)₃-NH₂; (SEQ ID NO: 421) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-Doc-(Arg)₅-Gln-(Arg)₃- NH₂; (SEQ ID NO: 422) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-(Doc)2-Tyr-Gly-(Arg)₅ - Gln-(Arg)₃-NH₂; (SEQ ID NO: 423) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-(Doc)₂-Gly-(Arg)₅-Gln- (Arg)₃-NH₂; (SEQ ID NO: 424) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-(Doc)₂-(Arg)₅-Gln- (Arg)₃-NH₂; (SEQ ID NO: 425) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-β-Ala-Tyr-Gly- (Arg)₅-Gln-(Arg)₃-NH₂; (SEQ ID NO: 426) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-β-Ala-(Arg)₅ -Gln- (Arg)₃-NH₂; (SEQ ID NO: 427) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-β-Ala-Gly-(Arg)₅ - Gln-(Arg)₃-NH₂; (SEQ ID NO: 428) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-β-Ala-(Arg)₅-Gln- (Arg)₄-NH₂; (SEQ ID NO: 429) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-(β-Ala)₂ -Tyr-Gly- (Arg)₅ -Gln-(Arg)₃-NH₂; (SEQ ID NO: 430) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-(β-Ala)2-(Arg)₅ - Gln-(Arg)₃-NH₂; (SEQ ID NO: 431) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-(β-Ala)₂ -Gly-(Arg)₅ -Gln-(Arg)₃-NH₂; (SEQ ID NO: 432) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-(β-Ala)2-(Arg)₅-Gln- (Arg)₄-NH₂; (SEQ ID NO: 433) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Doc-Tyr-Gly- (Arg)₅-Gln-(Arg)₃-NH₂; (SEQ ID NO: 434) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Doc-(Arg)₅-Gln- (Arg)₃-NH₂; (SEQ ID NO: 435) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Doc-Gly-(Arg)₅ - Gln-(Arg)₃-NH₂; (SEQ ID NO: 436) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Doc-(Arg)₅-Gln- (Arg)₄-NH₂; (SEQ ID NO: 437) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-(Doc)2-Tyr-Gly- (Arg)₅ -Gln-(Arg)₃-NH₂; (SEQ ID NO: 438) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-(Doc)₂ -(Arg)₅ -Gln- (Arg)₃-NH₂; (SEQ ID NO: 439) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-(Doc)₂-Gly-(Arg)₅ - Gln-(Arg)₃-NH₂; (SEQ ID NO: 440) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-(Doc)2-(Arg)₅-Gln- (Arg)₄-NH₂; (SEQ ID NO: 441) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-β- Ala-Tyr- Gly-(Arg)₅-Gln-(Arg)₃-NH₂; (SEQ ID NO: 442) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-β-Ala-(Arg)₅- Gln-(Arg)₃-NH₂; (SEQ ID NO: 443) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-(β-Ala)₂-Tyr- Gly-(Arg)₅-Gln-(Arg)₃-NH₂; (SEQ ID NO: 444) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-(β-Ala)₂- (Arg)₅-Gln-(Arg)₃-NH₂; (SEQ ID NO: 445) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-Doc-Tyr-Gly- (Arg)₅-Gln-(Arg)₃-NH₂; (SEQ ID NO: 446) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-Doc-(Arg)₅ - Gln-(Arg)₃-NH₂; (SEQ ID NO: 447) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-(Doc)2-Tyr- Gly-(Arg)₅-Gln-(Arg)₃-NH₂; (SEQ ID NO: 448) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-β- Ala-Tyr- Gly-(Arg)₅-Gln-(Arg)₄-NH₂; (SEQ ID NO: 449) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-β-Ala-(Arg)₅- Gln-(Arg)₄-NH₂; (SEQ ID NO: 450) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-(β-Ala)2-Tyr- Gly-(Arg)₅-Gln-(Arg)₄-NH₂; (SEQ ID NO: 451) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-(β-Ala)₂- (Arg)₅-Gln-(Arg)₄-NH₂; (SEQ ID NO: 452) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-Doc-Tyr-Gly- (Arg)₅-Gln-(Arg)₄-NH₂; (SEQ ID NO: 453) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-Doc-(Arg)₅- Gln-(Arg)₄-NH₂; (SEQ ID NO: 454) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-(Doc)₂-Tyr- Gly-(Arg)₅-Gln-(Arg)₄-NH₂; (SEQ ID NO: 455) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-(Doc)2-(Arg)₅- Gln-(Arg)₄-NH₂; (SEQ ID NO: 456) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-β-Ala-Tyr- Gly-(Arg)₅-Gln-(Arg)₃-NH₂; (SEQ ID NO: 457) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-β-Ala-Tyr- Gly-(Arg)₅-Gln-(Arg)₄-NH₂; (SEQ ID NO: 458) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-β-Ala-(Arg)₅- Gln-(Arg)₃-NH₂; (SEQ ID NO: 459) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-(β-Ala)₂-Tyr- Gly-(Arg)₅-Gln-(Arg)₃-NH₂; (SEQ ID NO: 460) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-(β-Ala)2- (Arg)₅-Gln-(Arg)₃-NH₂; (SEQ ID NO: 461) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-Doc-Tyr-Gly- (Arg)₅-Gln-(Arg)₃-NH₂; (SEQ ID NO: 462) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-Doc-Tyr-Gly- (Arg)₅-Gln-(Arg)₄-NH₂; (SEQ ID NO: 463) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-Doc-(Arg)₅- Gln-(Arg)₃-NH₂; (SEQ ID NO: 464) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-(Doc)₂-Tyr- Gly-(Arg)₅-Gln-(Arg)₃-NH₂; (SEQ ID NO: 465) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-(Doc)2-(Arg)₅- Gln-(Arg)₃-NH₂; (SEQ ID NO: 466) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gly-Cys)-β-Ala-Tyr-Gly- (Arg)₅-Gln-(Arg)₃-NH₂; (SEQ ID NO: 467) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gly-Cys)-β-Ala-(Arg)₅-Gln- (Arg)₃-NH₂; (SEQ ID NO: 468) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-β-Ala-Tyr-Gly-(Arg)₅-Gln- (Arg)₃-NH₂; (SEQ ID NO: 469) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-β-Ala-(Arg)₅-Gln-(Arg)₃-NH₂; (SEQ ID NO: 470) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(β-Ala)₂-Tyr-Gly-(Arg)₅-Gln- (Arg)₃-NH₂; (SEQ ID NO: 471) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(β-Ala)2-(Arg)₅-Gln-(Arg)₃- NH₂; (SEQ ID NO: 472) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-β-Ala-Tyr-Gly-(Arg)₅-Gln- (Arg)₄-NH₂; (SEQ ID NO: 473) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-β-Ala-(Arg)₅-Gln-(Arg)₄-NH₂; (SEQ ID NO: 474) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(β-Ala)₂-Tyr-Gly-(Arg)₅-Gln- (Arg)₄-NH₂; (SEQ ID NO: 475) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(β-Ala)₂-(Arg)₅-Gln-(Arg)₄- NH₂; (SEQ ID NO: 476) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-Doc-Tyr-Gly-(Arg)₅-Gln- (Arg)₃-NH₂; (SEQ ID NO: 477) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-Doc-(Arg)₅-Gln-(Arg)₃-NH₂; (SEQ ID NO: 478) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(Doc)2-Tyr-Gly-(Arg)₅-Gln- (Arg)₃-NH₂; (SEQ ID NO: 479) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(Doc)₂-(Arg)₅-Gln-(Arg)₃-NH₂; (SEQ ID NO: 480) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-Doc-Tyr-Gly-(Arg)₅-Gln- (Arg)₄-NH₂; (SEQ ID NO: 481) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-Doc-(Arg)₅-Gln-(Arg)₄-NH₂; (SEQ ID NO: 482) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(Doc)₂-Tyr-Gly-(Arg)₅-Gln- (Arg)₄-NH₂; (SEQ ID NO: 483) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(Doc)2-(Arg)₅-Gln-(Arg)₄-NH₂; (SEQ ID NO: 484) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-β-Ala-Tyr-Gly-(Arg)₅- Gln-(Arg)₃-NH₂; (SEQ ID NO: 485) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-β-Ala-(Arg)₅-Gln-(Arg)₃- NH₂; (SEQ ID NO: 486) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(β-Ala)₂-Tyr-Gly-(Arg)₅- Gln-(Arg)₃-NH₂; (SEQ ID NO: 487) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(β-Ala)2-(Arg)₅-Gln- (Arg)₃-NH₂; (SEQ ID NO: 488) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-Doc-Tyr-Gly-(Arg)₅- Gln-(Arg)₃-NH₂; (SEQ ID NO: 489) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-Doc-(Arg)₅-Gln-(Arg)₃- NH₂; (SEQ ID NO: 490) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Tyr-Gly-(Arg)₅- Gln-(Arg)₃-NH₂; (SEQ ID NO: 491) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(Doc)₂-(Arg)₅-Gln- (Arg)₃-NH₂; (SEQ ID NO: 492) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-β-Ala-Tyr-Gly-(Arg)₅- Gln-(Arg)₄-NH₂; (SEQ ID NO: 493) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-β-Ala-(Arg)₅-Gln-(Arg)₄- NH₂; (SEQ ID NO: 494) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(β-Ala)₂-Tyr-Gly-(Arg)₅- Gln-(Arg)₄-NH₂; (SEQ ID NO: 495) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(β-Ala)2-(Arg)₅-Gln- (Arg)₄-NH₂; (SEQ ID NO: 496) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-Doc-Tyr-Gly-(Arg)₅- Gln-(Arg)₄-NH₂; (SEQ ID NO: 497) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-Doc-(Arg)₅-Gln-(Arg)₄- NH₂; (SEQ ID NO: 498) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(Doc)₂-Tyr-Gly-(Arg)₅- Gln-(Arg)₄- NH₂; (SEQ ID NO: 499) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(Doc)2-(Arg)₅-Gln- (Arg)₄-NH₂; (SEQ ID NO: 500) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-β-Ala-Tyr-Gly-(Arg)₅- Gln-(Arg)₃-NH₂; (SEQ ID NO: 501) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-β-Ala-(Arg)₅-Gln-(Arg)₃- NH₂; (SEQ ID NO: 502) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(β-Ala)₂-Tyr-Gly-(Arg)₅- Gln-(Arg)₃-NH₂; (SEQ ID NO: 503) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(β-Ala)₂-(Arg)₅-Gln- (Arg)₃-NH₂; (SEQ ID NO: 504) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-Doc-Tyr-Gly-(Arg)₅- Gln-(Arg)₃-NH₂; (SEQ ID NO: 505) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-Doc-(Arg)₅-Gln-(Arg)₃- NH₂; (SEQ ID NO: 506) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Tyr-Gly-(Arg)₅- Gln-(Arg)₃-NH₂; (SEQ ID NO: 507) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(Doc)₂-(Arg)₅-Gln- (Arg)₃-NH₂; (SEQ ID NO: 508) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-β-Ala-Tyr-Gly-(Arg)₅- Gln-(Arg)₄-NH₂; (SEQ ID NO: 509) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-β-Ala-(Arg)₅-Gln-(Arg)₄- NH₂; (SEQ ID NO: 510) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(β-Ala)₂-Tyr-Gly-(Arg)₅- Gln-(Arg)₄-NH₂; (SEQ ID NO: 511) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(β-Ala)2-(Arg)₅-Gln- (Arg)₄-NH₂; (SEQ ID NO: 512) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-Doc-Tyr-Gly-(Arg)₅- Gln-(Arg)₄-NH₂; (SEQ ID NO: 513) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-Doc-(Arg)₅-Gln-(Arg)₄- NH₂; (SEQ ID NO: 514) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Tyr-Gly-(Arg)₅- Gln-(Arg)₄-NH₂; (SEQ ID NO: 515) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(Doc)₂-(Arg)₅-Gln- (Arg)₄-NH₂; (SEQ ID NO: 516) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-β-Ala-Tyr-Gly-(Arg)₅-Gln- (Arg)₃-NH₂; (SEQ ID NO: 517) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-β-Ala-(Arg)₅-Gln-(Arg)₃-NH₂; (SEQ ID NO: 518) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(β-Ala)2-Tyr-Gly-(Arg)₅-Gln- (Arg)₃-NH₂; (SEQ ID NO: 519) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(β-Ala)₂-(Arg)₅-Gln-(Arg)₃- NH₂; (SEQ ID NO: 520) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-β-Ala-Tyr-Gly-(Arg)₅-Gln- (Arg)₄-NH₂; (SEQ ID NO: 521) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-β-Ala-(Arg)₅-Gln-(Arg)₄-NH₂; (SEQ ID NO: 522) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(β-Ala)2-Tyr-Gly-(Arg)₅-Gln- (Arg)₄-NH₂; (SEQ ID NO: 523) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(β-Ala)₂-(Arg)₅-Gln-(Arg)₄- NH₂; (SEQ ID NO: 524) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-Doc-Tyr-Gly-(Arg)₅-Gln- (Arg)₃-NH₂; (SEQ ID NO: 525) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-Doc-(Arg)₅-Gln-(Arg)₃-NH₂; (SEQ ID NO: 526) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(Doc)₂-Tyr-Gly-(Arg)₅-Gln- (Arg)₃-NH₂; (SEQ ID NO: 527) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(Doc)2-(Arg)₅-Gln-(Arg)₃- NH₂; (SEQ ID NO: 528) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-Doc-Tyr-Gly-(Arg)₅-Gln- (Arg)₄-NH₂; (SEQ ID NO: 529) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-Doc-(Arg)₅-Gln-(Arg)₄-NH₂; (SEQ ID NO: 530) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(Doc)₂-Tyr-Gly-(Arg)₅-Gln- (Arg)₄-NH₂; and (SEQ ID NO: 531) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(Doc)2-(Arg)₅-Gln-(Arg)₄- NH₂, or pharmaceutically acceptable salts thereof. In some embodiments, a compound of Formula (V) is disclosed in International Application Publication Number WO 2007/008684, which is incorporated herein by reference in its entirety. In some embodiments, the MC4R agonist is a compound of Formula (VI): Ac-c(Cys-Glu-His-A¹-Arg-A²-A³-Cys)-(Pro)₂-Lys-Asp-NH₂ (VI) or pharmaceutically acceptable salts thereof, wherein: A¹ is the D-isomer of X-Phe or 2-Nal where X is halogen; A² is Bal, 1-Nal, 2-Nal, or Trp; and A³ is Aib, Ala, β-Ala or Gly. In some embodiments, the compound of Formula (VI) is selected from: (SEQ ID NO: 532) Ac-c(Cys-Glu-His-D-4-Br-Phe-Arg-Trp-Gly-Cys)-(Pro)₂-Lys-Asp-NH₂; (SEQ ID NO: 533) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-NH₂; (SEQ ID NO: 534) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-NH₂; (SEQ ID NO: 535) Ac-c(Cys-Glu-His-D-2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)₂-Lys-Asp-NH₂; (SEQ ID NO: 536) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)₂-Lys-Asp-NH₂; (SEQ ID NO: 537) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-β-Ala-Cys)-(Pro)2-Lys-Asp-NH₂; and (SEQ ID NO: 538) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Aib-Cys)-(Pro)₂-Lys-Asp-NH₂, or pharmaceutically acceptable salts thereof. In an example embodiment, the MC4R agonist is a compound of Formula (VII):

pharmaceutically acceptable salt thereof wherein: X is selected from the group consisting of -CH₂-S-S-CH₂-, -C(CH₃)₂-S-S- CH₂-,-CH₂-S-S-C(CH₃)₂-, -C(CH₃)₂-S-S-C(CH₃)_z-, -(CH₂)₂-S-S-CH₂-, -CH₂-S-S-(CH₂)₂, - (CH₂)2-S-S-(CH₂)2-, -C(CH₃)₂-S-S-(CH₂)2-, -(CH₂)2-S-S-C(CH₃)₂-, -(CH₂)t-C(O)-NR⁸- (CH₂)_r- and -(CH₂)r-NR⁸-C(O)-(CH₂)_t-; each of R¹ and R⁵ is, independently, H, (C₁-C₁₀)alkyl or substituted (C₁-C₁₀)alkyl; each of R² and R³ is, independently, H, (C₁-C₁₀)alkyl, (C₁- C₁₀)heteroalkyl, aryl(C₁-C₅)alkyl, substituted (C₁-C₁₀)alkyl, substituted (C₁-C₁₀)heteroalkyl or substituted aryl(C₁-C₅)alkyl or R² and R³ may be fused together to form a ring; R⁴ is OH or NH₂; each of R⁶ and R⁷ is, independently, H, (C₁-C₁₀)alkyl or substituted (C₁-C₁₀)alkyl; A¹ is an L- or D-amino acid or deleted; A² is H is, 2-Pal, 3-Pal, 4-Pal, (X¹, X², X³, X⁴, X⁵)Phe, Taz, 2-Thi or 3-Thi; A³ is D-Bal, D-1-Nal, D-2-Nal, D-Phe or D-(X¹, X², X³, X⁴, X⁵)Phe; A⁴ is Arg, hArg, Dab, Dap, Lys or Orn; A⁵ is Bal, 1-Nal, 2-Nal, (X¹, X², X³, X⁴, X⁵)Phe or Trp; r is, independently for each occurrence thereof, 1, 2, 3, 4 or 5; and t is, independently for each occurrence thereof, 1 or 2; or pharmaceutically acceptable salts thereof. In some embodiments of the compounds of Formula (VII), A¹ is Ala, D-Ala, Asn, Asp, Gln, Glu or Gly. Example compounds according to Formula (VII) include: (SEQ ID NO: 539) c[Hydantoin(C(O)-(Nle-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂; (SEQ ID NO: 540) c[Hydantoin(C(O)-(Ala-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂; (SEQ ID NO: 541) c[Hydantoin(C(O)-(D-Ala-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂; (SEQ ID NO: 542) c[Hydantoin(C(O)-(Aib-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂; (SEQ ID NO: 543) c[Hydantoin(C(O)-(Val-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂; (SEQ ID NO: 544) c[Hydantoin(C(O)-(Abu-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂; (SEQ ID NO: 545) c[Hydantoin(C(O)-(Leu-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂; (SEQ ID NO: 546) c[Hydantoin(C(O)-(Ile-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂; (SEQ ID NO: 547) c[Hydantoin(C(O)-(Cha-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂; (SEQ ID NO: 548) c[Hydantoin(C(O)-(A6c-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂; (SEQ ID NO: 549) c[Hydantoin(C(O)-(Phe-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂; (SEQ ID NO: 550) c[Hydantoin(C(O)-(Gly-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH₂; and (SEQ ID NO: 551) c[Hydantoin(C(O)-(Gly-Cys))-Glu-His-D-Phe-Arg-Trp-Cys]-NH₂, or pharmaceutically acceptable salts thereof. In some embodiments, a compound of Formula (VII) is disclosed in International Application Publication Number WO2008/147556, which is incorporated herein by reference in its entirety. In some embodiments, the MC4R agonist is a compound of Formula (VIII): (R²R³)-A⁰-A¹-c(A²-A³-A⁴-A⁵-A⁶-A⁷-A⁸-A⁹)-A¹⁰-R¹ (VIII) or a pharmaceutically acceptable salt thereof wherein: A⁰ is an aromatic amino acid; A¹ is Acc, HN-(CH₂)_m-C(O), an L- or D-amino acid; A² is Asp, Cys, D-Cys, hCys, D-hCys, Glu, Pen, or D-Pen; A³ is Aib, Ala, β-Ala, Gaba, Gly or a D-amino acid; A⁴ is H is, 2-Pal, 3-Pal, 4-Pal, (X¹, X², X³, X⁴, X⁵)Phe, Taz, 2-Thi, or 3-Thi; A⁵ is D-Bal, D-1-Nal, D-2-Nal, D-Phe, L-Phe, D-(X¹, X², X³, X⁴, X⁵)Phe, L-Phe, D-Trp or D-(Et)Tyr; A⁶ is Arg, hArg, Dab, Dap, Lys, Orn, or HN-CH((CH₂)_n-N(R⁴R⁵))-C(O); A⁷ is Bal, D-Bal, Bip, D-Bip, 1-Nal, D-1-Nal, 2-Nal, D-2-Nal, or D-Trp; A⁸ is Acc, Aha, Ahx, Ala, D-Ala, β-Ala, Apn, Gaba, Gly, HN- (CH₂)_s-C(O), or deleted; A⁹ is Cys, D-Cys, hCys, D-hCys, Dab, Dap, Lys, Orn, Pen, or D- Pen; A¹⁰ is Acc, HN-(CH₂)_t-C(O), L- or D-amino acid, or deleted; R¹ is OH, or NH₂; each of R² and R³ is, independently for each occurrence selected from the group consisting of H, (C₁- C₃₀)alkyl, (C₁-C₃₀)heteroalkyl, (C₁-C₃₀)acyl, (C₂-C₃₀)alkenyl, (C₂-C₃₀)alkynyl, aryl(C₁- C₃₀)alkyl, aryl(C₁-C₃₀)acyl, substituted (C₁-C₃₀)alkyl, substituted (C₁-C₃₀)heteroalkyl, substituted (C₁-C₃₀)acyl, substituted (C₂-C₃₀)alkenyl, substituted (C₂-C₃₀)alkynyl, substituted aryl(C₁-C₃₀)alkyl, and substituted aryl(C₁-C₃₀)acyl; each of R⁴ and R⁵ is, independently for each occurrence, H, (C₁-C₄₀)alkyl, (C₁-C₄₀)heteroalkyl, (C₁-C₄₀)acyl, (C₂-C₄₀)alkenyl, (C₂- C₄₀)alkynyl, aryl(C₁-C₄₀)alkyl, aryl(C₁-C₄₀)acyl, substituted (C₁-C₄₀)alkyl, substituted (C₁- C₄₀)heteroalkyl, substituted (C₁-C₄₀)acyl, substituted (C₂-C₄₀)alkenyl, substituted (C₂- C₄₀)alkynyl, substituted aryl(C₁-C₄₀)allyl, substituted aryl(C₁-C₄₀)acyl, (C₁-C₄₀)alkylsulfonyl, or -C(NH)-NH_2; m is, independently for each occurrence, 1, 2, 3, 4, 5, 6 or 7; n is, independently for each occurrence, 1, 2, 3, 4 or 5; s is, independently for each occurrence, 1, 2, 3, 4, 5, 6, or 7; t is, independently for each occurrence, 1, 2, 3, 4, 5, 6, or 7; X¹, X², X³, X⁴, and X⁵ each is, independently for each occurrence, H, F, Cl, Br, I, (C₁-C₁₀)alkyl, substituted (C₁-C₁₀)alkyl, (C₂-C₁₀)alkenyl, substituted (C₂-C₁₀)alkenyl, (C₂-C₁₀)alkynyl, substituted (C₂- C₁₀)alkynyl, aryl, substituted aryl, OH, NH₂, NO2, or CN. In an embodiment of Formula (VIII), when R⁴ is (C₁-C₄₀)acyl, aryl(C₁-C₄₀)acyl, substituted (C₁-C₄₀)acyl, substituted aryl(C₁-C₄₀)acyl, (C₁-C₄₀)alkylsulfonyl, or -C(NH)-NH₂, then R⁵ is H or (C₁-C₄₀)alkyl, (C₁-C₄₀)heteroalkyl, (C₂-C₄₀)alkenyl, (C₂-C₄₀)alkynyl, aryl(C₁- C₄₀)alkyl, substituted (C₁-C₄₀)alkyl, substituted (C₁-C₄₀)heteroalkyl, substituted (C₂- C₄₀)alkenyl, substituted (C₂-C₄₀)alkynyl, or substituted aryl(C₁-C₄₀)alkyl. In an embodiment of Formula (VIII), when R² is (C₁-C₃₀)acyl, aryl(C₁-C₃₀)acyl, substituted (C₁-C₃₀)acyl, or substituted aryl(C₁-C₃₀)acyl, then R³ is H, (C₁-C₃₀)alkyl, (C₁- C₃₀)heteroalkyl, (C₂-C₃₀)alkenyl, (C₂-C₃₀)alkynyl, aryl(C₁-C₃₀)alkyl, substituted (C₁- C₃₀)alkyl, substituted (C₁-C₃₀)heteroalkyl, substituted (C₂-C₃₀)alkenyl, substituted (C₂- C₃₀)alkynyl, or substituted aryl(C₁-C₃₀)alkyl. In an embodiment of Formula (VIII), when A² is Cys, D-Cys, hCys, D-hCys, Pen, or D-Pen, then A⁹ is Cys, D-Cys, hCys, D-hCys, Pen, or D-Pen. In an embodiment of Formula (VIII), when A² is Asp or Glu, then A⁹ is Dab, Dap, Orn, or Lys. In an embodiment of Formula (VIII), when A⁸ is Ala or Gly, then A¹ is not Nle; or pharmaceutically acceptable salts thereof. In some embodiments of Formula (VIII), A⁰ is 1-Nal, 2-Nal, H is, Pff, Phe, Trp, or Tyr; A¹ is Arg; A² is Cys; A³ is D-Ala; A⁴ is H; A⁵ is D-Phe; A⁶ is Arg; A⁷ is Trp; A⁸ is deleted; A⁹ is Cys; and A¹⁰ is deleted; or pharmaceutically acceptable salts thereof. Particular compounds of the immediately foregoing group of Formula (VIII) compounds include: (SEQ ID NO: 552) Ac-Tyr-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 553) Ac-2-Nal-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 554) Ac-1-Nal-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 555) Ac-Phe-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 556) Ac-Trp-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 557) Ac-Pff-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 558) H-His-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂; and (SEQ ID NO: 559) Ac-His-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂, or a pharmaceutically acceptable salt thereof. In some embodiments, the MC4R agonist is an agonist described in WO2014/144260 A1, incorporated herein by reference. In one example embodiment, an MC4R agonist is a compound represented by Formula (IX):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, or a (C₁-C₆)acyl; R² is, -NR³R⁴, or –OR⁵ wherein R³, R⁴, and R⁵ are each independently is H or a (C₁-C₆)alkyl; A¹ is an amino acid residue selected from Arg, Lys, Orn, His, Nle, Phe, Val, Leu, Trp, Tyr, Ala, Ser, Thr, Gln, Asn, Asp, Glu, or TzAla; or A¹ is a moiety selected from an optionally substituted -(C₁-C₁₂)-alkyl, an optionally substituted -(C₆-C₁₈)-aryl, an optionally substituted -(C₅-C₁₈)-heteroaryl, an aralkyl wherein the aryl portion is an optionally substituted (C₆- C₁₈)aryl, and the alkyl portion is an optionally substituted (C₁-C₁₂)alkyl, or a heteroaralkyl, wherein the heteroaryl portion is an optionally substituted (C5-C18)heteroaryl, and the alkyl portion is an optionally substituted (C₁-C₁₂)alkyl; A² and A⁸ is each independently an amino acid residue selected from Cys, hCys, Pen, Asp, Glu, Lys, Orn, Dbu, or Dpr, wherein A² and A⁸ are pairwise selected so as to be able to form covalent bond between their respective side chains; A³ is absent or is an amino acid residue selected from Ala, Tle, Val, Leu, Ile, Cha, Pro, Ser, Thr, Lys, Arg, His, Phe, Gln, Sar, Gly, Asn, Aib, or residue Y, wherein Y is an amino acid selected from amino acids represented by the following structural formulas

wherein: R¹¹ and R¹² , each independently, is H, -CH₃, phenyl, or benzyl; R²¹, R²², R²³, and R²⁴, each independently is H, -CH₃, -CF₃, phenyl, benzyl, F, Cl, Br, I, -OCH₃, or -OH; R³¹, R³², R³³, R³⁴, R⁴¹, R⁴², and R⁴³, each independently is H, -CH₃, -CF₃, phenyl, benzyl, F, Cl, Br, I, -OCH₃, or -OH; A⁴ is absent or is an amino acid residue selected from Atc, Ala, QAla, Aib, Sar, Ser, Thr, Pro, Hyp, Asn, Gln, an optionally substituted His, Trp, Tyr, Lys, Arg, sChp, or residue X, where the X is an amino acid selected from amino acids represented by the following formulas:

wherein: R⁵¹ and R⁵², each independently, is H, -CH₃, phenyl, or benzyl; R⁶¹, R⁶², R⁶³, and R⁶⁴, each independently is H, -CH₃, -CF₃, phenyl, benzyl, F, Cl, Br, I, -OCH₃, or -OH; R⁷¹, R⁷², R⁷³, R⁷⁴, R⁸¹, R⁸², and R⁸³, each independently is H, -CH₃, -CF₃, phenyl, benzyl, F, Cl, Br, I, -OCH₃, or -OH; A⁵ is an optionally substituted Phe, an optionally substituted 1-Nal, or an optionally substituted 2-Nal; A⁶ is Arg; and A⁷ is Trp, wherein any amino acid residue is either in L- or in D-configuration. Exemplary compound of Formula (IX) include: (SEQ ID NO: 560) Ac-Arg-c(Cys-D-Ala-His-D-Phe(p-F)-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 561) Ac-Arg-c(Cys-D-Ala-Pro-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 562) Ac-Arg-c(Cys-D-Ala-Pro-D-Phe(p-F)-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 563) Ac-Arg-c(Cys-D-Ala-Pro-D-Phe(p-F)-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 564) Ac-Arg-c(Cys-D-Ala-Ser-D-Phe(p-F)-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 565) Ac-Arg-c(Cys-D-Ala-Thr-D-Phe(p-CN)-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 566) Ac-Arg-c(Cys-D-Ala-Asn-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 567) Ac-Arg-c(Cys-D-Ala-Gln-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 568) Ac-Arg-c(Cys-D-Ala-Trp-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 569) Ac-Arg-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 570) Ac-Arg-c(Cys-D-Val-Gln-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 571) Ac-Arg-c(Cys-D-Val-Pro-D-Phe-Arg-Trp-Cys)-NH₂; and (SEQ ID NO: 572) Ac-Arg-c(Cys-D-Ser-Pro-D-Phe-Arg-Trp-Cys)-NH₂, or a pharmaceutically acceptable salt thereof. In yet another embodiment, the polypeptides of the present invention include any one of the following structural formulas: (SEQ ID NO: 573) Ac-Arg-c(hCys-D-Ala-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 574) Ac-Arg-c(hCys-Ala-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 575) Ac-Arg-c(hCys-Ala-D-Phe-Arg-Trp-Cys)-OH; (SEQ ID NO: 576) Ac-Arg-c(Cys-D-Ala-D-Phe-Arg-Trp-hCys)-NH₂; (SEQ ID NO: 577) Ac-Arg-c(Pen-D-Ala-D-Phe-Arg-Trp-hCys)-NH₂; (SEQ ID NO: 578) Ac-Arg-c(hCys-D-Ala-D-Phe(p-F)-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 579) Ac-Arg-c(hCys-Pro-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 580) Ac-Nle-c(hCys-Pro-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 581) Arg-c(hCys-Pro-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 582) CH₃-(CH₂)4-CO-c(hCys-Pro-D-Phe-Arg-Trp-Cys)-NH₂; and (SEQ ID NO: 583) Benzyl-CO-c(hCys-Pro-D-Phe-Arg-Trp-Cys)-NH₂, or a pharmaceutically acceptable salt thereof. In a further embodiment, the polypeptides of the present invention include the polypeptide represented by any one of the following structural formulas: (SEQ ID NO: 584) Ac-Arg-c(Asp-D-Ala-D-Phe-Arg-Trp-Dbu)-NH₂; (SEQ ID NO: 585) Ac-Arg-c(Glu-D-Ala-D-Phe-Arg-Trp-Dpr)-NH₂; (SEQ ID NO: 586) Ac-Arg-c(Glu-Ala-D-Phe-Arg-Trp-Dpr)-NH₂; (SEQ ID NO: 587) Ac-Arg-c(Dpr-D-Ala-D-Phe-Arg-Trp-Glu)-NH₂; (SEQ ID NO: 588) Ac-Arg-c(Dpr-D-Ala-D-Phe(4-F)-Arg-Trp-Glu)-NH₂; (SEQ ID NO: 589) Ac-Arg-c(Dpr-Ala-D-Phe-Arg-Trp-Glu)-NH₂; (SEQ ID NO: 590) Ac-Arg-c(Dpr-Ala-D-Phe-Arg-Trp-Glu)-OH; (SEQ ID NO: 591) Ac-Nle-c(Dpr-Ala-D-Phe-Arg-Trp-Glu)-NH₂; (SEQ ID NO: 592) Arg-c(Dpr-Ala-D-Phe-Arg-Trp-Glu)-NH₂; (SEQ ID NO: 593) CH₃-(CH₂)₄-CO-c(Dpr-Ala-D-Phe-Arg-Trp-Glu)-NH₂; or (SEQ ID NO: 594) Benzyl-CO-c(Dpr-Ala-D-Phe-Arg-Trp-Glu)-NH₂, or a pharmaceutically acceptable salt thereof. In yet another embodiment, the polypeptides of the present invention include a polypeptide represented by Formula (IX), wherein A⁴ is an amino acid residue selected from Atc, Ala, QAla, Aib, Sar, Ser, Thr, Pro, Hyp, Asn, Gln, a substituted His, Trp, Tyr, Lys, Arg, sChp, or residue X. Examples of such peptides include peptides represented by any one of the following structural formulas: (SEQ ID NO: 595) Ac-Arg-c(Cys-D-Ala-His(3-Me)-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 596) Ac-Arg-c(Cys-D-Ala-His(1-Me)-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 568) Ac-Arg-c(Cys-D-Ala-Trp-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 567) Ac-Arg-c(Cys-D-Ala-Gln-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 566) Ac-Arg-c(Cys-D-Ala-Asn-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 597) Ac-Arg-c(Cys-D-Ala-Arg-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 598) Ac-Arg-c(Cys-D-Ala-Tyr-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 599) Ac-Arg- c(Cys-D-Ala-D-Pro-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 561) Ac-Arg-c(Cys-D-Ala-Pro-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 563) Ac-Arg-c(Cys-D-Ala-Pro-D-Phe(p-F)-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 600) Ac-Arg- c(Cys-D-Ala-Atc-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 601) Ac-Arg- c(Cys-D-Ala-QAla-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 602) Ac-Arg- c(Cys-D-Ala-sChp-D-Phe-Arg-Trp-Cys)-NH₂; or (SEQ ID NO: 603) Ac-Arg- c(Cys-D-Ala-X-D-Phe-Arg-Trp-Cys)-NH₂, or a pharmaceutically acceptable salt thereof. In example embodiments, the polypeptides of the present invention include a polypeptide represented by any one of the following structural formulas: (SEQ ID NO: 574) Ac-Arg-c(hCys-Ala-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 573) Ac-Arg-c(hCys-D-Ala-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 604) Ac-Arg-c(hCys-D-Ala-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 585) Ac-Arg-c(Glu-D-Ala-D-Phe-Arg-Trp-Dpr)-NH₂; (SEQ ID NO: 586) Ac-Arg-c(Glu-Ala-D-Phe-Arg-Trp-Dpr)-NH₂; (SEQ ID NO: 605) Ac-Arg-c(hCys-Aib-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 606) Ac-Arg-c(hCys-Sar-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 607) Ac-Arg-c(hCys-Val-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 608) Ac-Arg-c(hCys-D-Val-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 609) Ac-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 610) Ac-Arg-c(hCys-D-Gln-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 611) Ac-Arg-c(hCys-Ala-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 612) Ac-Arg-c(D-Pen-D-Ala-D-Phe-Arg-Trp-hCys)-NH₂; (SEQ ID NO: 576) Ac-Arg-c(Cys-D-Ala-D-Phe-Arg-Trp-hCys)-NH₂; (SEQ ID NO: 613) Ac-Arg-c(Pen-D-Ala-D-Phe-Arg-Trp-hCys)-NH₂; (SEQ ID NO: 614) Ac-Arg-c(D-hCys-D-Ala-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 579) Ac-Arg-c(hCys-Pro-D-Phe-Arg-Trp-Cys)-NH₂; or (SEQ ID NO: 615) Ac-Arg-c(hCys-D-Pro-D-Phe-Arg-Trp-Cys)-NH₂, or a pharmaceutically acceptable salt thereof. In another embodiment, the polypeptides of the present invention include polypeptides represented by Formula (IX), wherein A³ is an amino acid residue selected from Tle, Val, Leu, Ile, Cha, Pro, Ser, Thr, Lys, Arg, His, Phe, Gln, Sar, Gly, Asn, or Aib; and A⁴ is an amino acid residue selected from Atc, Ala, QAla, Aib, Sar, Ser, Thr, Pro, Hyp, Asn, Gln, a substituted His, Trp, Tyr, Lys, Arg, sChp, or residue X. Examples of such polypeptides are polypeptides represented by any one of the following structural formulas: (SEQ ID NO: 616) Ac-Arg-c(Cys-Val-Gln-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 570) Ac-Arg-c(Cys-D-Val-Gln-D-Phe-Arg-Trp-Cys)-NH₂; or (SEQ ID NO: 617) Ac-Arg-c(Cys-D-Val-His(1-Me)-D-Phe-Arg-Trp-Cys)-NH₂, or a pharmaceutically acceptable salt thereof. In a further embodiment, the polypeptides of the present invention include a polypeptide represented by any one of the following structural formulas: (SEQ ID NO: 618) Ac-TzAla-c(Cys-Ala-Gln-D-Phe-Arg-Trp-Cys)-NH₂; or (SEQ ID NO: 619) Ac-Glu-c(Cys-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂, or a pharmaceutically acceptable salt thereof. In yet another embodiment, the polypeptides of the present invention include a polypeptide represented by any one of the following structural formulas: (SEQ ID NO: 596) Ac-Arg-c(Cys-D-Ala-His(1-Me)-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 567) Ac-Arg-c(Cys-D-Ala-Gln-D-Phe-Arg-Trp-Cys)-NH₂; or (SEQ ID NO: 566) Ac-Arg-c(Cys-D-Ala-Asn-D-Phe-Arg-Trp-Cys)-NH₂, or a pharmaceutically acceptable salt thereof. In a further embodiment, the polypeptides of the present invention include a polypeptide represented by any one of the following structural formulas: (SEQ ID NO: 620) Ac-Arg-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 621) Ac-Arg-c(Cys-D-Ile-His-D-Phe-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 622) Ac-Arg-c(Cys-D-Tle-His-D-Phe-Arg-Trp-Cys)-NH₂; or (SEQ ID NO: 569) Ac-Arg-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)-NH₂, or a pharmaceutically acceptable salt thereof. In a further embodiment, the polypeptides of the present invention include a polypeptide represented by any one of the following structural formulas: (SEQ ID NO: 623) Ac-Arg-c(Cys-D-Ala-His(1-Me)-D-2-Nal-Arg-Trp-Cys)-NH₂; (SEQ ID NO: 624) Ac-Arg-c(Cys-D-Ala-Gln-D-2-Nal-Arg-Trp-Cys)-NH₂; or (SEQ ID NO: 625) Ac-Arg-c(Cys-D-Ala-Asn-D-2-Nal-Arg-Trp-Cys)-NH₂, or a pharmaceutically acceptable salt thereof. In a further embodiment, the polypeptides of the present invention include a polypeptide represented by any one of the following structural formulas: (SEQ ID NO: 626) Ac-Arg-c(Cys-D-Ala-His(1-Me)-D-Phe-Arg-Trp-Cys)-OH; (SEQ ID NO: 627) Ac-Arg-c(Cys-D-Ala-Gln-D-Phe-Arg-Trp-Cys)-OH; or (SEQ ID NO: 628) Ac-Arg-c(Cys-D-Ala-Asn-D-Phe-Arg-Trp-Cys)-OH, or a pharmaceutically acceptable salt thereof. In one example embodiment, an MC4R agonist is a compound represented by Formula (X):

(X), or a pharmaceutically acceptable salt thereof, wherein: R₁ is –NH-C(O)- or –C(O)-NH-; R₂ is –H, –CH₂-, or, R₂ , together with R3, forms a pyrrolidine ring optionally substituted with –OH; R3 is –(CH₂)₂- if R2 is –CH₂-, and otherwise R₃ is selected from

; , R^4b, and R^4c are each independently selected from hydrogen, halo, (C₁-C₁₀)alkyl-halo, (C₁- C₁₀)alkyl-dihalo, (C₁-C₁₀)alkyl-trihalo, (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy, (C₁-C₁₀)alkylthio, aryl, aryloxy, nitro, nitrile, sulfonamide, amino, hydroxyl, carboxy, and alkoxy-carbonyl; R⁵ is – OH or –N(R^6a)(R^6b); R^6a and R^6b are each independently H or C1 to C4 linear, branched or cyclic alkyl chain; R⁷ is –H or –C(O)-NH₂; w is in each instance independently 0 to 5; x is 1 to 5; y is 1 to 5; z is in each instance independently 1 to 5. In one example embodiment, R^4a, R^4b, and R^4c is not hydrogen. An example of a compound of Formula (X) is a cyclic peptide defined by Formula (XI):

armaceutically acceptable salt thereof. In one example embodiment, the MC4R agonist is Ac-Arg-c(Cys-D-Ala-His-D-Phe- Arg-Trp-Cys)-NH₂ (SEQ ID NO: 140) or a pharmaceutically acceptable salt thereof. In another example embodiment, the MC4R agonist is Hydantoin(C(O)-(Arg-Gly))-c(Cys-Glu- His-D-Phe-Arg-Trp-Cys)-NH₂ (SEQ ID NO: 148) or a pharmaceutically acceptable salt thereof. In some embodiments, the MC4R agonist is an agonist described in WO2014/144260 A1, incorporated herein by reference. In one example embodiment, the MC4 agonist is a compound represented by Formula (XII): A1-Yyy-c(Aaa-Xxx-D-Phe-Arg-Trp-Bbb)-A2 (XII), or a pharmaceutically acceptable salt thereof, wherein: Aaa and Bbb are selected from Cys, hCys, Pen capable of establishing a disulfide bridge; or Glu, Asp, Lys, Orn, Dpr, Dbu capable of establishing a lactam bridge; Xxx is Asn, Gln, Ser, Thr; Yyy is Lys, Arg, D-Lys, D-Arg; A1 is H, Ac; A₂ is OH, NH₂. In embodiments, the MC4R agonist is chosen from one or more of the following compounds, (or pharmaceutically acceptable salt thereof): (SEQ ID NO: 629) Ac-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 630) Ac-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 631) Ac-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 632) Ac-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 633) Ac-Arg-c(Glu-Gln-D-Phe-Arg-Trp-Dpr)-NH₂; (SEQ ID NO: 634) Ac-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 635) H-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 636) H-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 637) Ac-D-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 638) H-D-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 639) Ac-D-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 640) H-D-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 641) Ac-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 642) Ac-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 643) H-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 644) H-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 645) Ac-D-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 646) H-D-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 647) Ac-D-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 648) H-D-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 649) Ac-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 650) H-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 651) H-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 652) Ac-D-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 653) H-D-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 654) Ac-D-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 655) H-D-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 656) Ac-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 657) Ac-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 658) H-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 659) H-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 660) Ac-D-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 661) H-D-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 662) Ac-D-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 663) H-D-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 664) Ac-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 665) H-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 666) H-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 667) Ac-D-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 668) H-D-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 669) Ac-D-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 670) H-D-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 671) Ac-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 672) Ac-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 673) H-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 674) H-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 675) Ac-D-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 676) H-D-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 677) Ac-D-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 678) H-D-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 679) Ac-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 680) H-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 681) H-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 682) Ac-D-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 683) H-D-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 684) Ac-D-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 685) H-D-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 686) Ac-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 687) Ac-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 688) H-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 689) H-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 690) Ac-D-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 691) H-D-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 692) Ac-D-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH₂, or (SEQ ID NO: 693) H-D-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH₂. In some embodiments, the MC4R agonist is a compound of Formula (XII-a): H-Yyy-c(Aaa-Xxx-D-Phe-Arg-Trp-Bbb)-NH₂ (XII-a) or a pharmaceutically acceptable salt thereof, wherein: Aaa and Bbb are selected from Cys, hCys, Pen capable of establishing a disulfide bridge; or Glu, Asp, Lys, Orn, Dpr, Dbu capable of establishing a lactam bridge; Xxx is Asn, Gln, Ser, Thr; and Yyy is Lys, Arg, D- Lys, D-Arg. In some embodiments, the compound of Formula (XII-a) is selected from: (SEQ ID NO: 635) H-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 643) H-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 646) H-D-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 650) H-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 653) H-D-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 658) H-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 661) H-D-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 665) H-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 668) H-D-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 673) H-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 676) H-D-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 680) H-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 683) H-D-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 688) H-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 691) H-D-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH₂; and (SEQ ID NO: 693) H-D-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH₂. In some embodiments, the MC4R agonist is a compound of Formula (XII-b): Ac-Yyy-c(Aaa-Xxx-D-Phe-Arg-Trp-Bbb)-NH₂ (XII-b) or a pharmaceutically acceptable salt thereof, wherein: Aaa and Bbb are selected from Cys, hCys, Pen capable of establishing a disulfide bridge; or Glu, Asp, Lys, Orn, Dpr, Dbu capable of establishing a lactam bridge; Xxx is Asn, Gln, Ser, Thr; and Yyy is Lys, Arg, D- Lys, D-Arg. In some embodiments, the compound of Formula (XII-b) is selected from: (SEQ ID NO: 629) Ac-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 630) Ac-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 631) Ac-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 632) Ac-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 633) Ac-Arg-c(Glu-Gln-D-Phe-Arg-Trp-Dpr)-NH₂; (SEQ ID NO: 637) Ac-D-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 641) Ac-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 645) Ac-D-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 652) Ac-D-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 656) Ac-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 660) Ac-D-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 667) Ac-D-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 671) Ac-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 675) Ac-D-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 682) Ac-D-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 686) Ac-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 690) Ac-D-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH₂; and (SEQ ID NO: 692) Ac-D-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH₂. In some embodiments, the MC4R agonist is a compound of Formula (XII-c): A₁-Yyy-c(Aaa-Xxx-D-Phe-Arg-Trp-Bbb)-A₂ (XII-c) or a pharmaceutically acceptable salt thereof, wherein: A1 is H or Ac; A2 is OH or NH₂; Yyy is L-Arg or D-Arg; Aaa and Bbb are selected from Cys, hCys, and Pen capable of establishing a disulfide bridge; or Glu, Asp, Lys, Orn, Dpr, and Dbu capable of establishing a lactam bridge; and Xxx is Asn, Gln, Ser, or Thr. In some embodiments, the compound of Formula (XII-c) is selected from: (SEQ ID NO: 629) Ac-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 630) Ac-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 631) Ac-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 632) Ac-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 633) Ac-Arg-c(Glu-Gln-D-Phe-Arg-Trp-Dpr)-NH₂; (SEQ ID NO: 634) Ac-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 635) H-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 636) H-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 637) Ac-D-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 638) H-D-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 639) Ac-D-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 640) H-D-Arg-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 649) Ac-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 650) H-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 651) H-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 652) Ac-D-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 653) H-D-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 654) Ac-D-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 655) H-D-Arg-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 664) Ac-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 665) H-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 666) H-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 667) Ac-D-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 668) H-D-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 669) Ac-D-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 670) H-D-Arg-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 679) Ac-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 680) H-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 681) H-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 682) Ac-D-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 683) H-D-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 684) Ac-D-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH; and (SEQ ID NO: 685) H-D-Arg-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH. In some embodiments, the MC4R agonist is a compound of Formula (XII-d): A₁-Yyy-c(Aaa-Xxx-D-Phe-Arg-Trp-Bbb)-A₂ (XII-d) or a pharmaceutically acceptable salt thereof, wherein: A1 is H or Ac; A2 is OH or NH₂; Yyy is L-Lys or D-Lys; Aaa and Bbb are selected from Cys, hCys, and Pen capable of establishing a disulfide bridge; or Glu, Asp, Lys, Orn, Dpr, and Dbu capable of establishing a lactam bridge; and Xxx is Asn, Gln, Ser, or Thr. In some embodiments, the compound of Formula (XII-d) is selected from: (SEQ ID NO: 641) Ac-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 642) Ac-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 643) H-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 644) H-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 645) Ac-D-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 646) H-D-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 647) Ac-D-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 648) H-D-Lys-c(hCys-Asn-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 656) Ac-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 657) Ac-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 658) H-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 659) H-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 660) Ac-D-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 661) H-D-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 662) Ac-D-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 663) H-D-Lys-c(hCys-Gln-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 671) Ac-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 672) Ac-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 673) H-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 674) H-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 675) Ac-D-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 676) H-D-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 677) Ac-D-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 678) H-D-Lys-c(hCys-Ser-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 686) Ac-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 687) Ac-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 688) H-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 689) H-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-OH; (SEQ ID NO: 690) Ac-D-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 691) H-D-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH₂; (SEQ ID NO: 692) Ac-D-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH₂, and (SEQ ID NO: 693) H-D-Lys-c(hCys-Thr-D-Phe-Arg-Trp-Pen)-NH₂. In some embodiments, the MC4R agonist is an agonist described in WO2014/144260 or WO2017/059075, each of which is incorporated herein by reference. Administration of a compound or pharmaceutically acceptable salt thereof or a composition comprising a compound or pharmaceutical salt of a compound of the disclosure useful to practice the methods described herein, can be continuous, hourly, four times daily, three time daily, twice daily, once daily, once every other day, twice weekly, once weekly, once every two weeks, once a month, or once every two months, or longer or some other intermittent dosing regimen. Described herein are compounds having activity at the melanocortin receptor 4 (MC4R), specifically those useful for treating a non-genetic obesity (e.g., hypothalamic obesity) in a subject. Examples of naturally occurring MC4R agonists include α-MSH, β- MSH, γ-MSH and adrenocorticotropic hormone (ACTH) or a functional fragment thereof. Examples of synthetic MC4R agonists are described in detail below. In one aspect, the MC4R agonist is a compound of Formula (XIII):

, or a pharmaceutically acceptable salt thereof, wherein: W is Glu, Gln, Asp, Asn, Ala, Gly, Thr, Ser, Pro, Met, Ile, Val, Arg, His, Tyr, Trp, Phe, Lys, Leu, Cya, or is absent; R¹ is -H, - C(O)CH₃, -C(O)(CH₂)1-4CH₃, -C(O)(CH₂)1-4NHC(NH)NH₂, Tyr-βArg-, Ac-Tyr-β-hArg-, gluconoyl-Tyr-Arg-, Ac-diaminobutyryl-, Ac-diaminopropionyl-, N-propionyl-, N-butyryl-, N-valeryl-, N-methyl-Tyr-Arg-, N-glutaryl-Tyr-Arg-, N-succinyl-Tyr-Arg-, R⁶— SO2NHC(O)CH₂CH₂C(O)—, R⁶—SO2NHC(O)CH₂CH₂C(O)Arg-, R⁶— SO₂NHCH₂CH₂CH₂C(O)—, (C₃-C₇)-cycloalkylcarbonyl, phenylsulfonyl, (C₈-C₁₄)-bicyclic arylsulfonyl, phenyl-(CH₂)qC(O)—, (C8-C14)-bicyclic aryl-(CH₂)qC(O)—,

n R² is —H, —NH₂, —NHC(O)CH₃, —NHC(O)(CH₂)1-4CH₃, —

NH-TyrC(O)CH₃, R⁶SO₂NH—, Ac-Cya-NH—, Tyr-NH—, HO—(C₆H₅)— CH₂CH₂C(O)NH—, or CH₃—(C6H5)—C(O)CH₂CH₂C(O)NH—; R³ is C₁-C₄ straight or branched alkyl, NH₂—CH₂—(CH₂)q—, HO—CH₂—, (CH₃)₂CHNH(CH₂)4—, R⁶(CH₂)q—, R⁶SO2NH—, Ser, Ile, R⁶ is a

phenyl or C₈-C₁₄ bicyclic aryl; m is 1 or 2; n is 1, 2, 3, or 4; R⁹ is (CH₂)_p or (CH₃)₂C—; p is 1 or 2; R¹⁰ is NH— or is absent; R⁷ is a 5- or 6-membered heteroaryl or a 5- or 6-membered heteroaryl ring optionally substituted with R⁴; R⁴ is H, C₁-C₄ straight or branched alkyl, phenyl, benzyl, or (C₆H₅)—CH₂—O—CH₂—; R⁸ is phenyl, a phenyl ring optionally substituted with X, or cyclohexyl; X is H, Cl, F, Br, methyl, or methoxy; R¹¹ is —C(O) or — CH₂; R⁵ is —NH₂, —OH, glycinol, NH₂-Pro-Ser-, NH₂-Pro-Lys-, HO-Ser-, HO-Pro-Ser-, HO-Lys-, -Ser alcohol, -Ser-Pro alcohol, -Lys-Pro alcohol, HOCH₂CH₂—O—CH₂CH₂NH— , NH₂-Phe-Arg-, NH₂-Glu-, NH₂CH₂RCH₂NH—, RHN—, or RO— where R is a C₁- C₄ straight or branched alkyl; and L is —S—S— or —S—CH₂—S— In one aspect, the MC4R agonist is a compound of Formula (XIIIa):

eutically

acceptable salts thereof, wherein W is a single bond, Glu, Gln, Asp, Asn, Ala, Gly, Thr, Ser, Pro, Met, Ile, Val, Arg, His, Tyr, Trp, or Phe; R¹ is -H, -C(O)CH₃, -C(O)(CH₂)1-4CH₃, - C(O)(CH₂)_1-4-NHC(NH)NH₂, Tyr-βArg, gluconoyl-Tyr-Arg, Ac-Dab, Ac-Dap, N-succinyl- Tyr-Arg, N-propionyl, N-valeryl, N-glutaryl-Tyr-Arg, N-butyryl,

or , wherein R² is -H, -NH₂, -NHC(O)CH₃, -NHC(O)(CH₂)1-4CH₃, or -NH- TyrC(O)CH₃; R³ is C₁-C₄ straight or branched alkyl, Ser, Ile, ,

q is 0, 1, 2, or 3; m is 1 or 2; p is 1 or 2; R⁴ is H or C₁-C₄ straight or branched alkyl; X is H, Cl, F, Br, methyl, or methoxy; and R⁵ is —NH₂, —OH, glycinol, -Ser-Pro-NH₂, -Lys-Pro-NH₂, -Ser- OH, -Ser-Pro-OH, -Lys-Pro-OH-Arg-Phe-NH₂, -Glu-NH₂, —NHR, or —OR, where R is a C₁- C₄ straight or branched alkyl. In some embodiments, the MC4R agonist is a compound of Formula (XIIIa) with the proviso that the combination of R2=Tyr, R3=Arg, W=Glu, R4=H, X=H, m=1, p=1, and R₅=NH₂ is specifically excluded. In one aspect, the MC4R agonist is a compound of Formula (XIIIb):

pharmaceutically acceptable salts thereof, wherein: W is Glu, Gln, Asp, Asn, Ala, Gly, Thr, Ser, Pro, Met, Ile, Val, Arg, His, Tyr, Trp, Phe, Lys, Leu, Cya, or is absent; R¹ is —H, —C(O)CH₃, —C(O)(CH₂)1-4CH₃, —C(O)(CH₂)1-4NHC(NH)NH₂, Tyr-βArg-, Ac-Tyr-β-hArg-, gluconoyl- Tyr-Arg-, Ac-diaminobutyryl-, Ac-diaminopropionyl-, N-propionyl-, N-butyryl-, N-valeryl-, N- methyl-Tyr-Arg-, N-glutaryl-Tyr-Arg-, N-succinyl-Tyr-Arg-, R⁶—SO2NHC(O)CH₂CH₂C(O)—, R⁶—SO2NHC(O)CH₂CH₂C(O)Arg-, R⁶—SO2NHCH₂CH₂CH₂C(O)—, C₃- C₇ cycloalkylcarbonyl, phenylsulfonyl, C₈-C₁₄ bicyclic arylsulfonyl, phenyl-(CH₂)_qC(O)—, C₈- C₁₄ bicyclic aryl (CH₂) C(O)—

wherein R² is —H, —NH₂, —NHC(O)CH₃, —NHC(O)(CH₂)_1-4CH₃, —NH-TyrC(O)CH₃, R⁶SO2NH—, Ac-Cya-NH—, Tyr-NH—, HO—(C6H5)—CH₂CH₂C(O)NH—, or CH₃— (C6H5)—C(O)CH₂CH₂C(O)NH—; R³ is C₁-C₄ straight or branched alkyl, NH₂—CH₂— (CH₂)_q—, HO—CH₂—, (CH₃)₂CHNH(CH₂)₄—, R⁶(CH₂)_q—, R⁶SO₂NH—, Ser, Ile, 3; R⁶ is a phenyl or C8-

C₁₄ bicyclic aryl; m is 1 or 2; p is 1 or 2; R⁴ is H, C₁-C₄ straight or branched alkyl, phenyl, benzyl, or (C₆H₅)—CH₂—O—CH₂—; X is H, Cl, F, Br, methyl, or methoxy; and R⁵ is — NH₂, —OH, glycinol, NH₂-Pro-Ser-, NH₂-Pro-Lys-, HO-Ser-, HO-Pro-Ser-, HO-Lys-, -Ser alcohol, -Ser-Pro alcohol, -Lys-Pro alcohol, HOCH₂CH₂—O—CH₂CH₂NH—, NH₂-Phe- Arg-, NH₂-Glu-, NH₂CH₂RCH₂NH—, RHN—, or RO— where R is a C₁-C₄ straight or branched alkyl. In some embodiments, the MC4R agonist is a compound of Formula (XIIIb) wherein W is Glu or a single bond (viz., is absent); R₄ is H or CH₃; X is H, Cl, F, or Br; and R₅ is NH₂ or OH. In some embodiments, the MC4R agonist is a compound of Formula (XIIIb) wherein W is Glu or is absent; R¹ is H—, Ac—, Arg-, Ac-Arg-, or Ac-D-Arg-; m is 1 or 2; p is 1; and R⁵ is NH₂ or OH. In some embodiments, the MC4R agonist is a compound of Formula (XIIIb) wherein W is absent; R¹ is Ac—; m is 2; p is 1; and R⁵ is NH₂. In some embodiments, the MC4R agonist is a compound of Formula (XIIIb) wherein W is Glu; R¹ is Ac-Arg-; m is 1; p is 1; and R¹ is NH₂. In some embodiments, the MC4R agonist is a compound of Formula (XIIIb) wherein W is absent; R¹ is H; m is 2; p is 1; and R⁵ is NH₂. In some embodiments, the MC4R agonist is a compound of Formula (XIIIb) wherein W is absent; R¹ is Arg-; m is 2; p is 1; and R is OH. In some embodiments, the MC4R agonist is a compound of Formula (XIIIb) wherein W is Glu; R¹ is Ac-D-Arg-; m is 1; p is 1; and R⁵ is NH₂. In some embodiments, the MC4R agonist is selected from: SE 69 69 69 69 69 69 70 70 70 70



y y y g p y

When a compound represented any of the formulas provided herein has more than one chiral substituent, it may exist in diastereoisomeric forms, different stable conformational forms, and zwitterionic forms. The diastereoisomeric pairs may be separated by methods known to those skilled in the art (for example, chromatography or crystallization), and the individual enantiomers within each pair may be separated using methods familiar to the skilled artisan. The conformational forms may be separable as well. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers. The present invention includes each diastereoisomer, conformational isomer, and zwitterionic form of compounds of any one of the formulas provided herein, and mixtures thereof. In some embodiments, the MC4R agonist, e.g., an MC4R agonist of Structural Formula (XIII), (XIIIa), or (XIIIb), is a compound described in U.S.2007/0105759, which is incorporated herein by reference in its entirety. In some embodiments, the MC4R agonist is a compound described in U.S. 2007/0293223, which is incorporated herein by reference in its entirety. In one aspect, the MC4R agonist is a compound described in US20220289731A1, EP4265255A1, EP4249485A1, EP4249484A1, EP4249483A1, EP4249482A1, EP4219475A1, EP4219474A1, EP4219473A1, EP4219472A1, or EP4219471A1, the teachings of which are incorporated herein by reference in their entirety. 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. In an aspect, the MC4R agonist is a compound described in WO2023153762A1, which is herein incorporated by reference in its entirety. 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. In some embodiments, the MC4R agonist is a compound described in U.S. 2007/0293223, which is incorporated herein by reference in its entirety. In one aspect, the MC4R agonist is a compound of Formula (XIV):

ein: R¹ represents hydrogen, amidino, C₁-C₄- alkylamidino,C₁-C₄-alkanoylamidino, C₁-C₁₀-alkyl, C₃-C₇-cycloalkyl, C₆-C₁₀-aryl, heterocycle, heteroaryl, C₁-C₆-alkylcarbonyl, C₃-C₇-cycloalkylcarbonyl, C₁-C₄- alkoxycarbonyl, C₆-C₁₀-aryl-C₁-C₄-alkoxycarbonyl, -SO₂, -C₁-C₄-alkyl, -C(O)-N(R⁶)(R⁷) or - C(S)-N(R⁶)(R⁷), wherein R⁶ and R⁷ each independently represents hydrogen, C₁-C₆-)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, C₁-C₄-alkyl, trifluoromethyl, hydroxy, C₁-C₄-alkoxy and oxo; R² represents C₆-C₁₀-aryl or heteroaryl, each of which is unsubstituted or mono- or di-substituted with a substituent selected from the group consisting of halogen, hydroxy, C₁-C₄-alkyl, C₁-C₄- alkoxy, cyano and amino; R³ represents hydrogen, cyano, C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₂- C₆-alkenyl, monocyclic heterocycle, monocyclic heteroaryl, -C(O)-R⁸ or -C(S)-R⁸, wherein, R⁸ represents hydroxy, C₁-C₄-alkyl, C₁-C₄-alkyloxy or N(R⁹)(R¹⁰), wherein R⁹ and R¹⁰ each independently represents hydrogen, C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₁-C₄-alkyloxy, phenyl or heteroaryl, or R⁹ and R¹⁰ may 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 (C₁-C₄-alkyl)(C₁-C₄-alkyl)amino; R⁴ represents C₃-C₈-cycloalkyl, C₆-C₁₀- aryl, heteroaryl or heterocycle, wherein, C₆-C₁₀-aryl or heteroaryl is unsubstituted or mono- or poly-substituted with a substituent selected from the group consisting of halogen, hydroxy, C₁-C₄-alkyl, trifluoromethyl, C₁-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, C₁-C₄-alkyl, trifluoromethyl, C₁-C₄-alkoxy and oxo; R⁵ represents hydrogen, C₁-C₆-alkyl, -C(O)-R¹¹, C₁-C₆-alkylsulfonyl, C₆-C₁₀-arylsulfonyl, - (CH₂)p-C₆-)C₁₀-aryl, -(CH₂)p-heteroaryl or -(CH₂)p- C₃-C₈-cycloalkyl, wherein, p represents 1 or 2; R¹¹ represents C₁-C₁₀-alkyl, C₂-C₆-alkenyl, C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl, amino, C₁-C₄-alkylamino, (C₁-C₄-alkyl)(C₁-C₄-alkyl)amino, C₆-C₁₀-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, C₁-C₃-alkylcarboxy, amino, dimethylamino, C₁-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, C₁-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, C₁-C₄-alkyl, trifluoromethyl, C₁-C₄-alkoxy and oxo. In some embodiments, preferred compounds among the compounds of Formula (XIV) above are those wherein i) R¹ represents hydrogen, amidino, C₁-C₄-alkylamidino, C₁-C₄-alkanoylamidino, C₁-C₆-)alkyl, C₃-C₇-cycloalkyl, phenyl, monocyclic heterocycle, monocyclic heteroaryl, C₁-C₆-alkylcarbonyl, trifluoroacetyl, C₁-C₄-alkoxycarbonyl, C₆-C₁₀- aryl-C₁-C₄-alkoxycarbonyl, -SO₂-C₁-C₄-alkyl, carbamoyl, C₁-C₆-alkylcarbamoyl, (C₁-C₆- alkyl)(C₁-C₆)-alkyl)carbamoyl, thiocarbamoyl, C₁-C₆)-alkylthiocarbamoyl or (C₁-C₆)-alkyl)(C₁- 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, ethylcarbamoyl, trifluoroethylcarbamoyl, propylcarbamoyl, iso- propylcarbamoyl, butylcarbamoyl, t-butylcarbamoyl, thiocarbamoyl, methylthio- carbamoyl, ethylthiocarbamoyl or methylethylcarbamoyl; ii) R² represents phenyl unsubstituted or mono- or di-substituted with a substituent selected from the group consisting of F, Cl and methyl, more preferably, R² represents phenyl, 4-fluorophenyl, 4-chlorophenyl, 4- methylphenyl or 2,4-difluorophenyl; iii) R³ represents hydrogen, cyano, C₁-C₄-alkyl, C₂-C₄- alkenyl, -CH₂C(CH₃)₂CH₂OH, oxazolyl, thiazolyl, oxazolynyl, thiazolynyl, carboxy, C₁-C₄- alkylcarbonyl, C₁-C₄-alkyloxycarbonyl, carbamoyl, thiocarbamoyl, C₁-C₄-alkylcarbamoyl, (C₁-C₄-alkyl)(C₁-C₄-alkyl)carbamoyl, (C₁-C₄-alkyl)(C₁-C₄-alkyloxy)carbamoyl, C₁-C₄- alkylthiocarbamoyl or (C₁-C₄-alkyl)(C₁-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, (C₁-C₄-alkyl)amino and (C₁-C₄- alkyl)(C₁-C₄-alkyl)amino, more preferably, R³ represents hydrogen, cyano, methyl, ethyl, propyl, allyl, -CHNOH, hydroxymethyl, -CH(CH₃)OH, aminomethyl, dimethylaminomethyl, oxazolyl, thiazolyl, oxazolynyl, thiazolynyl, carboxy, acetyl, propanoyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl, carbamoyl, thiocarbamoyl, ethylcarbamoyl, t-butylcarbamoyl, dimethylcarbamoyl, methylethylcarbamoyl, methylmethoxycarbamoyl, dimethylthiocarbamoyl, phenylcarbamoyl, heteroarylcarbamoyl, - C(O)NH(CH₂)₂NH , azetidinecarbonyl, pyrrolidinecarbonyl, piperidinecarbonyl or morpholinecarbonyl; iv) R⁴ represents C₄-C₇-cycloalkyl or monocyclic heterocycle unsubstituted or mono- or poly-substituted with a substituent selected from the group consisting of halogen, hydroxy, C₁-C₄-alkyl, trifluoromethyl, C₁-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, C₁-C₄-alkyl, trifluoromethyl, C₁-C₂- alkoxy and amino, more preferably, R⁴ represents cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 4-methylcyclohexyl, 4,4-dimethylcyclohexyl, 4,4-difluorocyclohexyl, 4-trifluoromethylcyclohexyl, 3,4-tetramethylcyclopentyl, 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) R⁵ represents hydrogen, C₁-C₅-alkyl, trifluoromethyl, C₁-C₆-)alkylcarbonyl, trifluoroacetyl, acryloyl, methacryloyl, C₃-C₈-cycloalkylcarbonyl, C₃-C₈-cycloalkenylcarbonyl, carbamoyl, C₁-C₄-alkylcarbamoyl, (C₁-C₄-alkyl)(C₁-C₄-alkyl)carbamoyl, methanesulfonyl, ethanesulfonyl, propanesulfonyl, benzoyl, hydroxybenzoyl, aminobenzoyl, monocyclic heteroarylcarbonyl, heterocyclecarbonyl, benzyl, -CH₂-monocyclic heteroaryl, or -CH₂-C₃- C₈-cycloalkyl, more preferably, R⁵ represents 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 imidazolemethyl. In some embodiments, the MC4R agonist is a compound of Formula (XIV) selected from:

C N 2 2 2

In some embodiments, the MC4R agonist is a compound described in WO 2008/007930, which is incorporated herein by reference in its entirety. In one aspect, the MC4R agonist is a compound of Formula (XV):

R¹ represents 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; R² 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, C₁-C₄-alkoxy, cyano and amino; R³ represents hydrogen, or represents C₁-C₆-)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; R⁴ represents 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, dimethyl carbamoyl 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. In some embodiments, preferred compounds of Formula (XV) include: i) R¹ represents hydrogen, methyl, ethyl, trifluoroethyl, propyl, isopropyl, butyl, isobutyl, tert- 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, R¹ represents 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; ii) R² represents 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, R² represents 4-chlorophenyl or 2,4-difluorophenyl; iii) R³ represents hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl or cyclopentyl, and more preferably, R³ represents hydrogen, methyl, ethyl or isopropyl; iv) R⁴ represents 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 R⁴ represents cyclohexyl, 4-methylcyclohexyl, 4,4-dimethylcyclohexyl, 4,4- difluorocyclcohexyl or 2,4-difluorophenyl; and v) R⁵ represents methyl, trifluoromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, propyl, isopropyl, isobutyl, tert-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, R⁵ represents isopropyl, tert-butyl, -C(CH₃)₂CH₂OH, furanyl or tetrahydrofuranyl. In some embodiments, preferred compounds of Formula (XV) include: R¹ represents 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; R² represents 4-chlorophenyl or 2,4-difluorophenyl; R³ represents hydrogen, methyl, ethyl or isopropyl; R⁴ represents cyclohexyl, 4-methylcyclohexyl, 4,4-dimethylcyclohexyl, 4,4- difluorocyclohexyl or 2,4-difluorophenyl; and R⁵ represents isopropyl, tert-butyl, - C(CH₃)₂CH₂OH, furanyl or tetrahydrofuranyl. In some embodiments, the compound of Formula (XV) is selected from:

^{F F}

C^l

In some embodiments, the MC4R agonist is a compound described in WO 2010/056022, which is incorporated herein by reference in its entirety. In some embodiments, the MC4R agonist is a compound described in US 8,288,386, which is incorporated herein by reference in its entirety. 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. In one aspect the MC4R agonist is a compound of Formula (XVI):

rein R¹ is C₁-C₁₂ alkyl (e.g., C₂-C₅ alkyl). In some embodiments, the compound of Formula (XVI) includes a compound shown in the table below:

In some embodiments, the MC4R agonist is a compound described in WO 2021/091283, which is incorporated herein by reference in its entirety. In another aspect, the MC4R agonist is a compound of Formula (XVII):

wherein: R¹ is C₁-C₁₂ alkyl (e.g., C₂-C₅ alkyl); R² is

halo; R³ is hydrogen or halo; R⁴ is C₂-C₅ alkyl; and n is an integer of 1 or 2. In an embodiment, when R² is chlorine and R³ is hydrogen, n is 2. In some embodiments, the MC4R agonist is selected from a compound shown in the table below:

or a pharmaceutically acceptable salt thereof. 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. In another aspect, the MC4R agonist comprises an H⁰x¹R²W³ motif, e.g., as described in Cell Research (2021) 31:1176-1189. In an embodiment, the MC4R agonist has a structure of Formula (XVIII): harmaceutically acceptable salt thereof,

wherein R¹ is 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 R⁶ and R⁷ is 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 R⁶ and R⁷ is taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclyl ring; each of R², R⁴, and R⁶ is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted; each of R^3a, R^3b, R^5a and R^5b is 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 R^5a and R^5b may be taken together with the carbon atom to which they are attached to form an oxo group; wherein each of R² and R^3a may be taken together with the carbon and nitrogen atoms to which they are attached to form an optionally substituted heterocyclyl group; wherein each of R⁴ and R^3a may be taken together with the carbon and nitrogen atoms to which they are attached to form an optionally substituted heterocyclyl group; wherein each of R⁴ and R^5a may be taken together with the carbon and nitrogen atoms to which they are attached to form an optionally substituted heterocyclyl group; wherein each of R⁶ and R^5a may 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. In an embodiment, the MC4R agonist has a structure of Formula (XIX): thereof, wherein each of R^1a, R^1b, R^6a

and R^6b is 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 R^1a and R^1b or R^6a and R^6b is taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclyl ring; R² is hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted; each of R^3a, R^3b, R^4a, R^4b, R^5a and R^5b is 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 R^5a and R^5b may be taken together with the carbon atom to which they are attached to form an oxo group; and wherein each of R² and R^3a may 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. In an embodiment, R^1a is acyl. In an embodiment, R^1b is optionally substituted cycloalkyl. In an embodiment, z is 0. In an embodiment, z is 1. In another aspect, the MC4R agonist is a compound of Formula (XX):

harmaceutically 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; R¹ is 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; R² is H, F or Cl, with the proviso that when Y is N, R² is 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 ═O substituent, which ring is optionally substituted by one or more substituents independently selected from F, Cl, OH, CN, methyl, ethyl, NH₂, NHCH₃, N(CH₃)₂ and 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. In some embodiments, Het is one of:

In some embodiments, preferred embodiments of Formula (XX) include: Preferably, X is N and Y is CH; preferably R is chloro; preferably R¹ is phenyl optionally substituted by one or more substituents independently selected from F, Cl, CN, methyl and methoxy; more preferably R¹ is phenyl, 4-chlorophenyl or 4-fluorophenyl. In an alternative embodiment. R¹ is preferably C₃-C₆ cycloalkyl, more preferably cyclopropyl or cyclohexyl; preferably R² is H or F; more preferably R² is H. Preferably Het is pyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, 6-oxo-1,6-dihydropyridazin-3-yl, 6-oxo-1,6-dihydropyridin-3-yl, 2-oxo-1,2- dihydropyrimidin-4-yl, 6-oxo-1,6-dihydropyrimidin-4-yl, 2-oxo-1,2-dihydropyridin-4-yl, imidazo[1,2-b]pyridazin-6-yl, [1,2,4]triazolo[4,3-b]pyridazin-6-yl or 6-oxo-1,6- 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-1,6-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. In some embodiments, compounds of Formula (XX) include:

and the pharmaceutically acceptable salts, solvates (including hydrates), and prodrugs thereof. In some embodiments, more preferred compounds of Formula (XX) include: 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. In some embodiments, more preferred compounds of Formula (XX) include: 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. In some embodiments, the MC4R agonist is a compound described in US 8,138,188, which is incorporated herein by reference in its entirety. In one aspect, the MC4R agonist is a compound of Formula (XXI):

harmaceutically acceptable salt, hydrate,

solvate, stereoisomer, geometric isomer or tautomer thereof, wherein: R¹ is selected from: - (C₁-C₆)alkyl, -(C₂-C₆)alkenyl, -(C₂-C₆)alkynyl, -(C₃-C₈)cycloalkyl, -(C₅-C₈)cycloalkenyl, - (C₁-C₂)alkyl(C₃-C₈)cycloalkyl, aryl, -(C₁-C₂)alkylaryl, heterocyclic, or -(C₁- C₂)alkylheterocyclic groups, wherein each of the foregoing R¹ groups is optionally substituted by one or more groups selected from: -(C₁-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; R² is H, OH or OCH₃; R³ is selected from: H, -(C₁-C₆))alkyl, -(C₂-C₆)alkenyl, -(C₂-C₆)alkynyl, -(C₃-C₈)cycloalkyl, -(C₆-C₈)cycloalkenyl, -(C₁- C₂)alkyl(C₃-C₈)cycloalkyl, aryl, -(C₁-C₂)alkylaryl, heterocyclic, or -(C₁-C₂)alkylheterocyclic groups, wherein each of latter ten R³ groups is optionally substituted by one or more groups selected from: OH, -(C₁-C₄)alkyl, -(CH₂)_n(C₃-C₅)cycloalkyl, halogen, CN, -(CH₂)_nOR⁶ or - (CH₂)_nNR⁷R⁸ wherein n = 0, 1 or 2; R⁴ is selected from: H, -(C₁-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; R⁵ is selected from: -(C₁-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; or R⁴ and R⁵ can together form a fused 5- to 7-membered saturated or unsaturated ring; R⁶, R⁷ and R⁸ are each independently selected from H, CH₃ or CH₂CH₃; and wherein the heterocyclic groups of R¹ and R³ are independently selected from 4- to 10-membered ring systems containing up to 4 heteroatoms independently selected from O, N or S. 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. 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 R¹ heterocyclic 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 R¹ heterocyclic rings are monocyclic 5- to 6-membered heteroaryl rings containing one or 2N heteroatoms. Highly preferred R¹ heterocyclic rings herein are monocyclic 6-membered heteroaryl rings containing one or two N heteroatoms such as pyridinyl and pyrimidinyl. An especially preferred R¹ heteroaryl group herein is the pyridinyl group. Preferred R³ heterocyclic 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 R³ heterocyclic rings are monocyclic 5- to 6-membered heteroaryl rings containing one or two N heteroatoms. More preferred still as R³ heterocyclic 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 pyridin- 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 R⁴ and R⁵ together 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 R⁴ and R⁵ may form are: indane, 1,2,3,4-tetrahydronaphthalene, indolyl, indazolyl, naphthyl, quinolyl, benzothiazolyl, benzimidazolyl, benzo[1,3]dioxolane, 2,3- dihydrobenzo[1,4]dioxine, 2,3-dihydrobenzofuran, 2,3-dihydrobenzothiophene and 1,3- dihydroisobenzofuran. In some embodiments, compounds of Formula (XXI) include compounds of one of Formulas (XXI-IA), (XXI-IB), (XXI-IC), (XXI-ID), (XXI-IE), (XXI-IF), (XXI-IG), or (XXI- IH):

wherein R¹, R², R³, R⁴ and R⁵ are as defined above. Also included are compounds having the formulas (XXI-IB), and (XXI-ID), wherein the stereochemistry of the groups at the 3 and 4 positions of the pyrrolidine ring are cis relative to each other. In some embodiments, compounds of Formula (XXI), preferably formula (XXI-IA), more preferably formula (XXI-IC),, more preferably still formula (XXI-IE), and especially formula (XXI-IG),, wherein R¹ is selected from: -(C₁-C₆)alkyl, -(C₃-C₈)cycloalkyl, -(C₁- C₂)alkyl(C₃-C₈)cycloalkyl, phenyl, -(C₁-C₂)alkylaryl, heterocyclic, or -(C₁- C₂)alkylheterocyclic groups and wherein R¹ is optionally substituted by one or more groups selected from -(C₁-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 R¹ is a heterocyclic, or a -(C₁-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. In some embodiments, the present disclosure provides compounds having formula (XXI), preferably formula (XXI-IA), more preferably formula (XXI-IC), more preferably still formula (XXI-IE) and especially formula (XXI-IF), wherein R¹ is selected from: -(C₁- C₆)alkyl, -(C₃-C₈)cycloalkyl, -(C₁-C₂)alkyl(C₃-C₈)cycloalkyl, phenyl, -(C₁-C₂)alkylaryl, heterocyclic, or -(C₁-C₂)alkylheterocyclic groups wherein each of the foregoing R¹ groups is optionally substituted by one or more groups selected from: -(C₁-C₄)alkyl, halogen, - (CH₂)_mOR⁶, CN, CF₃, OCF₃, wherein m = 1 or 2; R² is OH; R³ is selected from: H, -(C₁- C₆)alkyl, -(C₃-C₈)cycloalkyl, -(C₁-C₂)alkyl(C₃-C₈)cycloalkyl, aryl, -(C₁-C₂)alkylaryl, heterocyclic, or -(C₁-C₂)alkylheterocyclic groups wherein each of latter seven R³ groups is optionally substituted by one or more groups selected from: OH, -(C₁-C₄)alkyl, -(CH₂)_n(C₃- C₅)cycloalkyl, halogen, CN, -(CH₂)_nOR⁶ or - (CH₂)_nNR⁷R⁸ wherein n = 0, 1 or 2; R⁴ is selected from: H, -(C₁-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; R⁵ is selected from: -(C₁-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, R⁷ and R⁸ are each independently selected from H, CH₃ or CH₂CH₃; wherein the heterocyclic group of R³ 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; and wherein the heterocyclic group of R¹ is selected from mono-cyclic 5- to 6- membered ring systems containing 1 N heteroatom. In some embodiments, compounds of Formula (XXI), preferably formula (XXI-IA), more preferably formula (XXI-IC), more preferably still formula (XXI-IE), and especially formula (XXI-IF), as defined hereinbefore wherein R³ is H, -(C₁-C₆)alkyl, -(C₃- C₈)cycloalkyl, -(C₁-C₂)alkyl(C₃-C₈)cycloalkyl, -(C₁-C₂)alkylaryl or a heterocyclic group and wherein each of the latter five R³ groups is optionally substituted by one or more groups selected from -OH, -(C₁-C₄)alkyl, -(CH₂)_n(C₃-C₅)cycloalkyl, halogen, -CN or - (CH₂)_nOR⁶ wherein n = 0 or 1 and wherein R⁶ is H, CH₃ or CH₂CH₃ and wherein when R³ is 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 (XXI), preferably formula (XXI-IA), more preferably formula (XXI-IC), more preferably still formula (XXI- IE), and especially formula (XXI-IF), wherein R¹ is selected from -(C₁-C₆))alkyl, -(C₃- C₈)cycloalkyl, phenyl or heterocyclic groups and wherein each of the foregoing R¹ groups is optionally substituted by one or more groups selected from: -(C₁-C₄)alkyl, halogen, -OR⁶ or - CN; R² is OH; R³ is selected from H, -(C₂-C₆))alkyl, -(C₃-C₈)cycloalkyl, -(C₁-C₂)alkyl(C₃- C₈)cycloalkyl or heterocyclic groups and wherein each of latter four R³ groups is optionally substituted by one or more groups selected from: -OH, -(C₁-C₄)alkyl, -(CH₂)_n(C₃- C₅)cycloalkyl, halogen, -CN, -OR⁶ or -(CH₂)_nNR⁷R⁸ wherein n = 0, 1 or 2; R⁴ is selected from: H, F or Cl; R⁵ is selected from: F or Cl; R⁶, R⁷ and R⁸ are each independently selected from H, CH₃ or CH₂CH₃; wherein the heterocyclic group of R³ 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; and wherein the heterocyclic group of R¹ is selected from mono-cyclic 5- to 6-membered ring systems containing 1 N heteroatom. In some embodiments, compounds of Formula (XXI), preferably formula (XXI-IA), more preferably formula (XXI-IC), more preferably still formula (XXI-IE), and especially formula (XXI-IF), as defined hereinbefore wherein the heterocyclic group of R¹ where 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. Preferred R¹ groups for use herein are selected from -(C₁-C₄)alkyl, -(C₃- C₆)cycloalkyl, phenyl, pyridyl or pyrimidinyl wherein R¹ is optionally substituted by one or more groups selected from CH₃, CH₂CH₃, halogen, OCH₃, OCH₂CH₃, CN, CF₃ or OCF₃. More preferred R¹ groups 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 R¹ groups 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. Preferred R³ groups for use herein are selected from -H, -(C₂-C₆)alkyl, -(C₃- C₈)cycloalkyl, -(C₁-C₂)alkyl(C₃-C₈)cycloalkyl or heterocyclic and wherein each of the latter four R³ groups is optionally substituted by one or more groups selected from -OH, -(C₁- C₄)alkyl or -OR⁶ and wherein R⁶ is -H, CH₃ or CH₂CH₃ and wherein when R³ is a heterocyclic group said heterocyclic group is a monocyclic 6-membered ring system containing up to 2 N heteroatoms. More preferred R³ groups 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 R⁴ groups for use herein are selected from H, F or Cl and preferred R⁵ groups for use herein are selected from F or Cl. Preferred phenyl groups having R⁴ and R⁵ substituents for use herein are: a 2,4-substituted phenyl group wherein the R⁴ and R⁵ groups are each independently selected from F or Cl; or, a 4-mono-substituted phenyl group wherein R⁴ is H and R⁵ is F or Cl. More preferred phenyl groups for use herein to which R⁴ and R⁵ are attached are 4-chlorophenyl or 2,4-difluorophenyl groups. When R³ is H, in a preferred group of compounds herein of formula (XXI-IC), more preferably (XXI-IE) and especially (XXI-IF), R¹ is a phenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl or pyridin-2-yl group; R² is OH; and R⁴ is selected from: H or F and R⁵ is selected from: F or Cl. Preferred compounds herein wherein R³ is H are the compounds of examples 12, 16, 24 and 48 or pharmaceutically acceptable salts, solvates or hydrates thereof. When R³ is a heterocyclic group as defined herein after, in a preferred group of compounds of formula (XXI-IC), more preferably (XXI-IE) and especially (XXI-IF), herein, R¹ is a phenyl or pyridin-2-yl group; R² is -OH; R³ is 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 R⁴ and R⁵ are both F. Preferred compounds herein wherein R³ is 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 R³ is Et, i-Pr or t-Bu, in a preferred group of compounds herein of formula (XXI-IC), more preferably (XXI-IE) and especially (XXI-IF), R¹ is phenyl, 4-fluorophenyl, 4-chlorophenyl, 3-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, pyridin-2-yl; R² is OH; and R⁴ and R⁵ are F. Preferred compounds herein wherein R³ is 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. In some embodiments, compounds of Formula (XXI) include:

Preferred compounds of Formula (XXI) include: Compound 460, Compound 462, Compound 463, Compound 465, Compound 466, and Compound 478. More preferred compounds of Formula (XXI) include: Compound 460 and/or pharmaceutically acceptable acid salts thereof. In some embodiments, compound of Formula (XXI) can include the following groups: R¹ is selected from: (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₈)cycloalkyl, (C₅-C₈)cycloalkenyl, (C₁-C₂)alkyl(C₃-C₈)cycloalkyl, aryl, (C₁-C₂)alkylaryl, heterocyclic, or (C₁-C₂)alkylheterocyclic groups, wherein each of the foregoing R¹ groups is optionally substituted by one or more groups selected from: (C₁-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; R² is H, Oh or OMe; R³ is selected from: H, (C₁-C₆))alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₈)cycloalkyl, (C5- C₈)cycloalkenyl, (C₁-C₂)alkyl(C₃-C₈)cycloalkyl, aryl, (C₁-C₂)alkylaryl, heterocyclic, or (C₁- C₂)alkylheterocyclic groups, wherein each of latter ten R³ groups is optionally substituted by one or more groups selected from: OH, (C₁-C₄)alkyl, (CH₂)_n(C₃-C5)cycloalkyl, halogen, CN, (CH₂)_nOR⁶, (CH₂)_nN(R⁷)₂, SMe or SEt wherein n = 0, 1 or 2; R⁴ and R⁵ are each independently selected from: (C₁-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 R⁴ and R⁵ can together form a fused 5- to 7-membered saturated or unsaturated ring; R⁶, R⁷ and R⁸ are each independently selected from H, Me or Et; wherein the R¹ and R³ heterocyclic groups, where present, are optionally fused 4- to 10-membered ring systems containing up to 4 heteroatoms selected from O, N or S. In some embodiments, preferred substituents for Formula (XXI) include: R¹ is selected from: (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, (C₁-C₂)alkyl(C₃-C₈)cycloalkyl, aryl, (C₁- C₂)alkylaryl, heterocyclic, or (C₁-C₂)alkylheterocyclic groups and wherein R¹ is optionally substituted by one or more groups selected from (C₁-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; R² is H or OH; R³ is H, (C₁-C₆)alkyl, (C₃- C8)cycloalkyl, (C₁-C₂)alkyl(C₃-C₈)cycloalkyl, (C₁-C₂)alkylaryl, groups and wherein each of the latter four R³ groups is optionally substituted by one or more groups selected from OH, (C₁-C₄)alkyl, (CH₂)_n(C₃-C₅)cycloalkyl, halogen, CN, (CH₂)_nOR⁶, SMe or SEt wherein n = 0 or 1; R⁴ and R⁵ are independently selected from (C₁-C₄)alkyl, cyclopropyl, halogen, OR⁶, CN, CF₃, CH₂CF₃, OCF₃, OCH₂cF3, sMe, SEt or R⁴ and R⁵ together form a fused 5 to 6 membered saturated or unsaturated ring; and wherein R⁶ is as defined hereinbefore. In an embodiment, R¹ is a (C₁-C₄)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₂)alkyl(C₃-C₅)cycloalkyl, phenyl, pyridyl or pyrimidinyl group wherein R¹ is optionally substituted by one or more groups selected from Me, Et, halogen, OMe, OEt, CN, CF₃, OCF₃ and SMe; R² is OH; R³ is a (C₁ - C₆)alkyl group optionally substituted with one of the following groups OH, OR⁶, CF₃; R⁴ and R⁵ are each independently (C₁-C₄)alkyl, halogen, OR⁶, CN, CF₃, CH₂CF₃, OCF₃, OCH₂CF₃; R⁶ is H or Me. In an embodiment, R¹ is an n-butyl group, a cyclohexyl group, a phenyl group, or a 4-methyl phenyl group; R² is OH; R³ is an ethyl group or a t-butyl group; and R⁴ and R⁵ are each independently F. In some embodiments, the MC4R agonist is a compound described in EP 1716135B1, which is incorporated herein by reference in its entirety. In some embodiments, the MC4R agonist is a compound described in US 7,649,002, which is incorporated herein by reference in its entirety. In one aspect, the MC4R agonist is a compound of Formula (XXII): Y

( ), p armaceutically acceptable salt thereof, wherein R¹ is H, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, (C₃-C₆) cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, or R^1a , 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 R^B, wherein each R^B is halogen, -OH, -CN, C₁-C₄ alkyl, C₁- C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, (C₃-C₄) cycloalkyl, or R^B1, or two adjacent R^B together 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; R^1a is 5- or 6-membered heteroaryl optionally substituted with 1, 2, 3, or 4 independently selected R^A, wherein each R^A is halogen, -OH, -CN, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, (C₃-C₄) cycloalkyl, -N(C₁-C₄ alkyl)₂, R^A1, 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 R^A together 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, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, and C₁-C₄ haloalkoxy; R^A1 is 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, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, and C₁-C₄ haloalkoxy; R^B1 is 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; X¹ is C(R^X )₂, wherein each R^X is independently H or C₁-C₄ alkyl; each of R² and R³ is 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 R² and R³ together 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 Y⁵ is independently CR⁴ or N, provided that no more than 3 of Y¹, Y², Y³, Y⁴, and Y⁵ are N; and each R⁴ is independently H, halogen, -OH, -CN, C₁-C₄ alkyl, C₁- C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, -N(C₁-2 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. In some embodiments, compounds of Formula (XXII) include Formulas (XXIIa), (XXIIb) and (XXIIc):

( ), ein: R¹, R², R³, X¹, Y¹, Y², Y³, Y⁴, and Y⁵ are as defined above. In some embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (XXIIc) or a pharmaceutically acceptable salt thereof, and wherein the variables R¹, R², R³, Y¹, Y², Y³, Y⁴, and Y⁵ are as defined in Formula (XXII). In some embodiments, R¹ is 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 R^1a; R^1a is 5- or 6-membered heteroaryl optionally substituted with 1, 2, 3, or 4 independently selected R^A, wherein each R^A is 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 substituents each independently selected from halogen, -OH, - CN, (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, and (C₁-C₄) haloalkoxy; or two adjacent R^A together 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, (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, and (C₁-C₄) haloalkoxy. In an embodiment, R¹ is H, halogen, or a 4- to 7-membered heterocycloalkyl. In some embodiments, R¹ is H or halogen. In some embodiments, R¹ is H. In an embodiment, R¹ is halogen (e.g., Cl). In some embodiments, R¹ is 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, R¹ is R^1a. In some embodiments, R¹ is R^1a; and R^1a is a 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 independently selected R^A, wherein each R^A is 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 substituents each independently selected from halogen, -OH, -CN, (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, and (C₁-C₄) haloalkoxy; or two adjacent R^A together 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, R^1a is a 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 independently selected R^A, wherein each R^A is 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 substituents each independently selected from halogen, -OH, -CN, (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, and (C₁-C₄) haloalkoxy. In some embodiments, R^1a is a 5- membered heteroaryl optionally substituted with 1, 2, 3, or 4 independently selected R^A, wherein each R^A is 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 R^1a is a carbon or nitrogen atom. In some embodiments, R^1a is 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[1,5-a]pyrimidinyl, or [1,2,4]triazolo[1,5-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, R^1a is 1H- pyrazol-4-yl, 1H-1,2,4-triazol-3-yl, 2H-1,2,3-triazol-4-yl, 2H-tetrazol-5-yl, 1,2-thiazol-5-yl, 1,3,4- thiadiazol-2-yl, 1,2,4-thiadiazol-5-yl, 1,3,4- oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,3-thiazol-2-yl, 1,3-thiazol-4-yl, 1H-imidazol-4-yl, pyrazolo[1,5-a]pyrimidin-3-yl, or [1,2,4]triazolo[1,5-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, R¹ is R^1a; and R^1a is a 5-membered heteroaryl substituted with 2, 3, or 4 independently selected R^A, wherein each R^A is 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 substituents each independently selected from halogen, -OH, -CN, (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, and (C₁-C₄) haloalkoxy; or two adjacent R^A together 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 R^A are 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 R^A, 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 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 R^A are 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 R^A, 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 substituents each independently selected from halogen, -OH, -CN, (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, and (C₁- C₄) haloalkoxy. In an embodiment, R¹ is R^1a; and R^1a is 6-membered heteroaryl optionally substituted with 1, 2, 3, or 4 independently selected R^A, wherein each R^A is 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 substituents each independently selected from halogen, -OH, -CN, (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, and (C₁-C₄) haloalkoxy; or two adjacent R^A together 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, R^1a is 6- membered heteroaryl optionally substituted with 1, 2, 3, or 4 independently selected R^A, wherein each R^A is 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 substituents each independently selected from halogen, -OH, - CN, (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, and (C₁-C₄) haloalkoxy. In some embodiments, R^1a is 6- membered heteroaryl optionally substituted with 1, 2, 3, or 4 independently selected R^A, and wherein each R^A is 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 R^1a is a carbon or nitrogen atom. In some embodiments, 1, 2, or 3 of the ring-forming atoms of the 6- membered heteroaryl of R^1a are nitrogen atoms (and the rest of the ring-forming atoms are carbon atoms). In some embodiments, R^1a is pyridinyl, pyridazinyl, pyrazinyl, or pyrimidinyl, each of which is optionally substituted with 1, 2, or 3 independently selected R^A, wherein each R^A is halogen, -OH, -CN, (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, or (C₃-C₄) cycloalkyl. In an embodiment, R^1a is 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 R^A, wherein each R^A is halogen, -OH, -CN, (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁- C₄) haloalkoxy, or (C₃-C₄) cycloalkyl. In some embodiments, R^1a is pyrimidinyl optionally substituted with 1, 2, or 3 independently selected R^A, wherein each R^A is halogen, -OH, -CN, (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, or (C₃-C₄) cycloalkyl. In some embodiments, R^1a is pyrimidin-2-yl optionally substituted with 1 or 2 independently selected R^A, wherein each R^A is halogen, -OH, -CN, (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, or (C₃-C₄) cycloalkyl. In some embodiments, R^1a is pyrimidin-2- yl. In some embodiments, R¹ is phenyl, wherein the phenyl is substituted with 3 or 4 independently selected R^B, wherein two adjacent R^B together 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 R^B is independently halogen, -OH, -CN, (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, or (C₃-C₄) cycloalkyl; In some embodiments, R¹ is 1,2- benzoxazolyl (e.g., 2-benzoxazol-6-yl) or 1,3-benzothiazolyl (e.g., 1,3-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, R¹ is phenyl, wherein the phenyl is substituted with R^B1 and 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, R^B1 is 1,3,4-oxadiazolyl (e.g., 1,3,4-oxadiazol-2-yl), 1,2,4-oxadiazolyl (e.g., 1,2,4-oxadiazol-3-yl), or 1,3- oxazolyl (e.g., 1,3-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, X¹ is CH₂. In some embodiments, X¹ is CH(CH₃). In some embodiments, each of R² and R³ is independently H, F, or (C₁-C₄) alkyl. In some embodiments, each of R² and R³ is independently H, F, or (C₁-C₂)alkyl. In some embodiments, each of R² and R³ is independently H or (C₁-C₄) alkyl. In some embodiments, each of R² and R³ is independently H or (C₁-C₂)alkyl. In an embodiment, each of R² and R³ is independently H or methyl. In some embodiments, R² is (C₁-C₄) alkyl and R³ is H. In some embodiments, R² is (C₁-C₂)alkyl and R³ is H. In some embodiments, R² is methyl and R³ is H. In some embodiments, each of Y¹, Y², Y³, Y⁴, and Y⁵ is independently CR⁴. In some embodiments, one of Y¹, Y², Y³, Y⁴, and Y⁵ is N, and each of the rest is independently CR⁴. In some embodiments, Y³ is N, and each of Y¹, Y², Y⁴, and Y⁵ is independently CR⁴. In some embodiments, two of Y¹, Y², Y³, Y⁴, and Y⁵ are N, and each of the rest of Y¹, Y², Y³, Y⁴, and Y⁵ is independently CR⁴. In some embodiments, Y¹ is N, Y³ is N, and each of Y², Y⁴, and Y⁵ is independently CR⁴. In some embodiments, each R⁴ is independently H, halogen, (C₁-C₂)alkyl, (C₁-C₂)haloalkyl, - N((C₁-C₄) alkyl)2, (C₁-C₂)alkoxy, or (C₁-C₂)haloalkoxy. In some embodiments, each R⁴ is independently H, F, Cl, -CH₃, C₁ fluoroalkyl, -OCH₃, or C₁ fluoroalkoxy. In some embodiments, each R⁴ is independently H, halogen, or (C₁-C₂)alkoxy. In some embodiments, each R⁴ is independently H, F, Cl, or -OCH₃. In some embodiments, each R⁴ is independently H, F, or -OCH₃. In some embodiments, R¹ is R^1a; R^1a is 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[1,5- a]pyrimidinyl, or [1,2,4]triazolo[1,5-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; X¹ is CH₂ or CH(CH₃); R² is (C₁-C₂) alkyl and R³ is H; one of Y¹, Y², Y³, Y⁴, and Y⁵ is N, and each of the rest of Y¹, Y², Y³, Y⁴, and Y⁵ is independently CR⁴; and each R⁴ is independently H, F, Cl, - CH₃, C1 fluoroalkyl, -OCH₃, or C1 fluoroalkoxy. In some embodiments, R¹ is R^1a; R^1a is 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; X¹ is CH₂; R² is (C₁-C₂)alkyl and R³ is H; Y³ is N, and each of Y¹, Y², Y⁴, and Y⁵ is independently CR⁴; and each R⁴ is independently H, F, Cl, -CH₃, C1 fluoroalkyl, - OCH₃, or C1 fluoroalkoxy. In some embodiments, R¹ is R^1a; R^1a is tetrazolyl (e.g., 2H- tetrazol-5-yl) optionally substituted with 1, 2, or 3 independently selected R^A, wherein each R^A is halogen, -OH, -CN, (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, or (C₃-C₄) cycloalkyl (e.g., R^1a is 2H-tetrazol-5-yl substituted with (C₁-C₄) alkyl such as methyl); X¹ is CH₂; R² is methyl and R³ is H; Y³ is N, and each of Y¹, Y², Y⁴, and Y⁵ is independently CR⁴; and each R⁴ is independently H, F, Cl, or -OCH₃. In some embodiments, R¹ is R^1a; R^1a is pyrazolyl (e.g., 1H-pyrazol-4-yl) optionally substituted with 1, 2, or 3 independently selected R^A, wherein each R^A is halogen, -OH, -CN, (C₁-C₄) alkyl, (C₁- C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, or (C₃-C₄) cycloalkyl (e.g., R^1a is 1H- pyrazol-4-yl substituted with (C₁-C₄) alkyl such as methyl); X¹ is CH₂; R² is methyl and R³ is H; Y³ is N, and each of Y¹, Y², Y⁴, and Y⁵ is independently CR⁴; and each R⁴ is independently H, F, Cl, or -OCH₃ (e.g., each R⁴ is independently H, F, or - OCH₃). In some embodiments, R¹ is R^1a; R^1a is pyridinyl, pyridazinyl, pyrazinyl, or pyrimidinyl, each of which is optionally substituted with 1, 2, or 3 independently selected R^A, wherein each R^A is halogen, -OH, -CN, (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, or (C₃-C₄) cycloalkyl; X¹ is CH₂ or CH(CH₃); R² is (C₁-C₂)alkyl and R³ is H; one of Y¹, Y², Y³, Y⁴, and Y⁵ is N, and each of the rest of Y¹, Y², Y³, Y⁴, and Y⁵ is independently CR⁴; and each R⁴ is independently H, F, Cl, -CHF₂, or -OCH₃. In some embodiments, R¹ is R^1a; R^1a is pyridinyl, pyridazinyl, pyrazinyl, or pyrimidinyl, each of which is optionally substituted with 1, 2, or 3 independently selected R^A, wherein each R^A is halogen, -OH, -CN, (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, or (C₃-C₄) cycloalkyl; X¹ is CH₂; R² is (C₁-C₂) alkyl and R³ is H; Y³ is N, and each of Y¹, Y², Y⁴, and Y⁵ is independently CR⁴; and each R⁴ is independently H, F, or -OCH₃. In some embodiments, R¹ is R^1a; R^1a is pyrimidinyl (e.g., pyrimidin-2-yl) optionally substituted with 1, 2, or 3 independently selected R^A, wherein each R^A is halogen, -OH, -CN, (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, or (C₃-C₄) cycloalkyl (e.g., R^1a is unsubstituted pyrimidin-2-yl); X¹ is CH₂; R² is methyl and R³ is H; Y³ is N, and each of Y¹, Y², Y⁴, and Y⁵ is independently CR⁴; and each R⁴ is independently H, F, Cl, or -OCH₃ (e.g., each R⁴ is independently H, F, or - OCH₃). In some embodiments, R¹ is R^1a; R^1a is [1,2,4]triazolo[1,5-a]pyridin-2-yl optionally substituted with 1, 2, or 3 independently selected R^A, wherein each R^A is halogen, -OH, -CN, (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, or (C₃-C₄) cycloalkyl (e.g., R^1a is unsubstituted [1,2,4]triazolo[1,5-a]pyridin-2-yl); X¹ is CH₂; R² is methyl and R³ is H; Y³ is N, and each of Y¹, Y², Y⁴, and Y⁵ is independently CR⁴; and each R⁴ is independently H, F, Cl, or -OCH₃ (e.g., each R⁴ is independently H, F, or - OCH₃). In some embodiments, R¹ is R^1a; R^1a is pyridinyl, pyridazinyl, pyrazinyl, or pyrimidinyl, each of which is optionally substituted with 1, 2, or 3 independently selected R^A, wherein each R^A is halogen, -OH, -CN, (C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₁-C₄) alkoxy, (C₁-C₄) haloalkoxy, or (C₃-C₄) cycloalkyl; X¹ is CH₂ or CH(CH₃); R² is (C₁-C₂)alkyl and R³ is H; each of Y¹, Y², Y³, Y⁴, and Y⁵ is independently CR⁴; and each R⁴ is independently H, F, Cl,-CH₃, -CF₃, - CHF₂, or -OCH₃. In some embodiments, R¹ is H; X¹ is CH₂ or CH(CH₃); each of R² and R³ is independently H or (C₁-C₂)alkyl (e.g., each of R² and R³ is H); each of Y¹, Y², Y³, Y⁴, and Y⁵ is independently CR⁴; and each R⁴ is independently H, F, Cl, -CH₃, -CF₃, -CHF2, or - OCH₃ (e.g., each R⁴ is independently H or F, for example, one of R⁴ is F and each of the remaining R⁴ is H). In some embodiments, compounds of Formula (XXII) include:

or pharmaceutically acceptable salt thereof. In some embodiments, compounds of Formula (XXII) include:

or pharmaceutically acceptable salt thereof. In some embodiments, the MC4R agonist is a compound described in WO 2021/250541, which is incorporated herein by reference in its entirety. In one aspect, the MC4R agonist is a compound of Formula (XXIII):

r pharmaceutically acceptable salts, solvates (including hydrates), and prodrugs thereof, wherein n is 0 or 1; R¹ is -(C₁-C₄)alkyl, or Het¹; R² is phenyl or pyridyl, wherein said phenyl or pyridyl is optionally substituted by one to three substituents independently selected from halo, CN, -(C₁-C₄)alkyl and -(C₁-C₄)alkoxy wherein the -(C₁-C₄)alkyl and -(C₁-C₄)alkoxy groups are optionally substituted with 1 to 3 fluorine atoms; R³ is phenyl or pyridyl, wherein said phenyl or pyridyl is optionally substituted by one to three substituents independently selected from halo, CN, -(C₁-C₄)alkyl and -(C₁-C₄)alkoxy wherein the -(C₁-C₄)alkyl and -(C₁-C₄)alkoxy groups are optionally substituted with 1 to 3 fluorine atoms; either L is -CO- and R⁴ is -(C₁-C₄)alkyl, -(C₁- C₄)alkoxy, -(C₃-C₆)cycloalkyl, -(C₁-C₂)alkyl(C₃-C₆)cycloalkyl, -(C₁-C₂)alkyl(C₁-C₄)alkoxy, - NH₂, -NH(C-C₄)alkyl, -N[(C₁-C₄)alkyl]2 or Het², wherein the -(C₁-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 -(C₁-C₄)alkyl groups; or L is -SO2- and R⁴ is -(C₁-C₄)alkyl; -(C₃-C₆)cycloalkyl, -(C₁-C₂)alkyl(C₃-C₆)cycloalkyl, -(C₁-C₂)alkyl(C₁- C₄)alkoxy, -NH₂, -NH(C₁-C₄)alkyl, -N[(C₁-C₄)alkyl]₂, or Het²; Het¹ is (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 =O substituent, which ring is optionally substituted by one to three substituents independently selected from halo, CN, and -(C₁-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; Het² is (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. In some embodiments, R¹ is -(C₁-C₄)alkyl. In an embodiment, R¹ is t-butyl. In an embodiment, R¹ is Het¹ where Het¹ is (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 =O substituent, which ring is optionally substituted by a substituent selected from halo, CN, and -(C₁-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, R¹ is Het¹ where Het¹ is pyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, 6-oxo-1,6-dihydropyridazin-3-yl, 6-oxo-1,6- dihydropyridin-3-yl, 2-oxo-1,2-dihydropyrimidin-4-yl, 6-oxo-1,6-dihydropyrimidin-4-yl, 2- oxo-1,2-dihydropyridin-4-yl, [1,2,4]triazolo[4,3-b]pyridazin-6-yl or 6-oxo-1,6- dihydropyridin-2-yl, optionally substituted by one or two substituents independently selected from -(C₁-C₄)alkyl, halo and CN. In an embodiment, R¹ is Het¹ where Het¹ is 6-oxo-1,6- dihydropyridazin-3-yl, 1-methyl-6-oxo-1,6-dihydropyridazin-3-yl, or [1,2,4]thiazolo[4,3- b]pyridazin-6-yl. In an embodiment, R² is phenyl or pyridyl, wherein said phenyl or pyridyl is optionally substituted by one or two substituents independently selected from halo, CN, -(C₁- C₄)alkyl and -(C₁-C₄)alkoxy. In an embodiment, R² is 2,4-difluorophenyl, 2-fluoro-4- methoxyphenyl, 4-cyanophenyl or 5-chloropyrid-2-yl. In an embodiment, R³ is phenyl optionally substituted by one or two substituents independently selected from halo and (C₁- C₄)alkoxy. In an embodiment, R³ is 4-chlorophenyl. In an embodiment, L is -CO- and R⁴ is - (C₁-C₄)alkyl optionally substituted with 1 to 3 fluorine atoms, -(C₁-C₄)alkoxy, -(C₃- C₆)cycloalkyl optionally substituted with 1 or 2 fluorine atoms or -(C₁-C₄)alkyl groups, -(C₁- C₂)alkyl(C₃- C₆)cycloalkyl, -(C₁-C₂)alkyl(C₁-C₄)alkoxy_, -NH(C₁-C₄)alkyl, -N[(C₁- C₄)alkyl]2 or Het² wherein Het² is 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 R⁴ is -(C₁-C₄)alkyl or -(C₁-C₄)alkoxy wherein the -(C₁-C₄)alkyl group is optionally substituted with 1 to 3 fluorine atoms. In some embodiments, compounds of Formula (XXIII) include:

O ^Cl

N NH O ^Cl

or pharmaceutically acceptable salts, solvates (including hydrates), and prodrugs thereof. In some embodiments, the MC4R agonist is a compound described in WO 2010/015972, which is incorporated herein by reference in its entirety. In one aspect, the MC4R agonist is a compound of Formula (XXIV): XIV), wherein n is 1 or 2; R⁶ is selected from H, C₁-C₆ alkyl, C₃-

C₈cycloalkyl, aryl, heterocyclyl, heteroaryl, C(O)C₁-C₆alkyl, CO₂C₁-C₆alkyl, wherein each of said moieties is optionally substituted with one or more substituents independently selected from halo, CN, OH, =O, NH₂, NHCH₃, N(CH₃)₂, C₁-C₄alkyl and C₁-C₄alkoxy; R⁷ is 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, OC₁-C₄alkyl and C₁-C₄alkyl; R¹⁰ is a substituted piperidine group of formula (A):

( ); d R⁴ are each independently selected from H, C₁-C₄alkyl, OH, O(C₁-C₄alkyl), CH₂OCH₃ and NR⁸R⁹; R² is selected from H, OH, OC₁-C₄alkyl and NR⁸R⁹; R³ is selected from aryl or heteroaryl, wherein said moieties are optionally substituted with one or more substituents independently selected from halo, CN, CF₃, OCF₃, O(C₁-C₄alkyl), and C₁-C₄alkyl; R⁵ is selected from H and C₁-C₄alkyl; R⁸ is selected from H and C₁-C₄alkyl, wherein said C₁- C₄alkyl is optionally substituted with OH or OCH₃; R⁹ is selected from H, C₁-C₄alkyl, SO2C₁-C₄alkyl, C(O)C₁-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, R⁴ and R⁵ are not all simultaneously H; when R¹ is methyl and R⁴ is H, then R⁵ is not methyl; when R⁴ is methyl and R⁵ is H, then R¹ is not methyl; and when R⁵ is methyl and R⁴ is H, then R¹ is not methyl. In some embodiments, preferred compounds of Formula (XXIV) include: preferably n is 1. Preferably R¹ is selected from H, methyl, OH, OCH₃, OC₂H₅ and NR⁸R⁹. More preferably R¹ is selected from H, methyl, OH, OCH₃ and OC₂H₅. More preferably still R¹ is selected from H, methyl, OH and OCH₃. Most preferably R¹ is selected from H, methyl and OCH₃. Preferably R² is selected from H, OH, and OC₁-C₄alkyl. More preferably R² is selected from H, OH, OCH₃ and OC₂H₅. Most preferably R² is selected from OH, OCH₃ and OC₂H₅. Preferably R³ is 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 R³ is 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 R³ is 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 R³ is 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 R⁴ is selected from H, methyl, OH, OCH₃, OC₂H₅ and NR⁸R⁹. More preferably R⁴ is selected from H, methyl, OH, OCH₃ and OC₂H₅. More preferably still R⁴ is selected from H, methyl, OCH₃ and OC₂H₅. Most preferably R⁴ is selected from H, methyl and OCH₃. Preferably R⁵ is selected from H, methyl and ethyl. More preferably R⁵ is selected from H and methyl. Most preferably R⁵ is H. Preferably R⁶ is selected from C₁-C₈alkyl, C₃-C₈cycloalkyl, heterocyclyl, heteroaryl, C(O)C₁-C₆alkyl, CO₂C₁-C₆alkyl, wherein each of said moieties are optionally substituted with one or more substituents independently selected from halo, CN, OH, =O, C₁- C₄alkyl and C₁-C₄alkoxy. More preferably R⁶ is selected from C₁-C₆alkyl, heterocyclyl, heteroaryl, C(O)C₁-C₆alkyl, CO₂C₁-C₆alkyl, wherein each of said moieties are optionally substituted with one or more substituents independently selected from halo, CN, OH, =O, C₁- C₄alkyl and C₁-C₄alkoxy. More preferably still R⁶ is selected from C₁-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, =O, methyl and OCH₃. Most preferably R⁶ is 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, =O, OCH₃, and CN. Preferably R⁷ is 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 R⁷ is 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 R⁷ is 5-chloropyridin-2-yl or phenyl substituted by 1-2 groups independently selected from Cl, F, OCH₃ and CN. Most preferably R⁷ is 5-chloropyridin-2-yl, 2,4-difluorophenyl or 4-methoxyphenyl. Preferably R⁸ is selected from H, methyl, ethyl and propyl wherein said alkyl group is optionally substituted with OH or OCH₃. More preferably R⁸ is selected from H, methyl and ethyl. Most preferably R⁸ is selected from H and methyl. Preferably R⁹ is selected from H, C₁-C₄alkyl and SO2C₁-C₄alkyl. More preferably R⁹ is selected from H and C₁-C₄alkyl. Most preferably R⁹ is selected from H and methyl. In some embodiments, compounds of Formula (XXIV) include:

and their pharmaceutically acceptable salts, hydrates, solvates, polymorphs and prodrugs. In some embodiments, the MC4R agonist is a compound described in WO 2007/015162, which is incorporated herein by reference in its entirety. In one aspect, the MC4R agonist is a compound of Formula (XXI): R H₃

(XXI), or a pharmaceutically acceptable salt, hydrate, solvate, isomer or prodrug thereof, wherein: R¹ is selected from: -(C₁-C₆)alkyl, -(C₂-C₆)alkenyl, -(C₂- C₆)alkynyl, -(C₃-C₈)cycloalkyl, -(C₅-C₈)cycloalkenyl, -(C₁-C₂)alkyl(C₃-C₈)cycloalkyl, aryl, - (C₁-C₂)alkylaryl, heterocyclic, or -(C₁-C₂)alkylheterocyclic groups, wherein each of the foregoing R¹ groups is optionally substituted by one or more groups selected from: -(C₁- 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; R² is H, OH or OCH₃; R³ is selected from: H, -(C₁-C₆)alkyl, -(C₂-C₆)alkenyl, -(C₂-C₆)alkynyl, -(C₃- C₈)cycloalkyl, -(C₅-C₈)cycloalkenyl, -(C₁-C₂)alkyl(C₃-C₈)cycloalkyl, aryl, -(C₁-C₂)alkylaryl, heterocyclic, or -(C₁-C₂)alkylheterocyclic groups wherein each of the latter ten R³ groups is optionally substituted by one or more groups selected from: -OH, -(C₁-C₄)alkyl, -(CH₂)_n(C₃- C₅)cycloalkyl, halogen, -CN, -(CH₂)_nOR⁶ or -(CH₂)_nNR⁷R⁸ wherein n = 0, 1 or 2; R⁴ is selected from: -H, -(C₁-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)_PN R⁷SO₂R⁸, CF₃, CH₂CF₃, OCF₃ or OCH₂CF₃ groups wherein p = 0, 1 or 2; R⁵ is selected from: -(C₁-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; or R⁴ and R⁵ can together form a fused 5- to 7- membered saturated or unsaturated ring; R⁶, R⁷ and R⁸ are each independently selected from H, CH₃ or CH₂CH₃; and wherein the heterocyclic groups of R¹ and R³ are independently selected from 4- to 10- membered ring systems containing up to 4 heteroatoms independently selected from O, N or S. In some embodiments, suitable bicyclic heteroaryl groups for use herein include: 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 R¹ heterocyclic 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 R¹ heterocyclic rings are monocyclic 5- to 6-membered heteroaryl rings containing one or 2 N heteroatoms. Highly preferred R¹ heterocyclic rings herein are monocyclic 6-membered heteroaryl rings containing one or two N heteroatoms such as pyridinyl and pyrimidinyl. An especially preferred R¹ heteroaryl group herein is the pyridinyl group. Preferred R³ heterocyclic 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 R³ heterocyclic rings are monocyclic 5- to 6-membered heteroaryl rings containing one or two N heteroatoms. More preferred still as R³ heterocyclic 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 pyridin- 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 R⁴ and R⁵ together 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 R⁴ and R⁵ may form are: indane, 1,2,3,4-tetrahydronaphthalene, indolyl, indazolyl, naphthyl, quinolyl, benzothiazolyl, benzimidazolyl, benzo[1,3]dioxolane, 2,3- dihydrobenzo[1,4]dioxine, 2,3-dihydrobenzofuran, 2,3-dihydrobenzothiophene and 1,3- dihydroisobenzofuran. In some embodiments, preferred groups of compounds of Formula (XXI) include those in which: (a) R¹ is selected from: -(C₁-C₆)alkyl, -(C₃-C₈)cycloalkyl, -(C₁-C₂)alkyl(C₃- C₈)cycloalkyl, phenyl, -(C₁-C₂)alkylaryl, heterocyclic, or -(C₁-C₂)alkylheterocyclic groups wherein each of the foregoing R¹ groups is optionally substituted by one or more groups selected from: -(C₁-C₄)alkyl, halogen, -(CH₂)mOR⁶, CN, CF₃ or OCF₃, wherein m = 1 or 2; R² is OH; R³ is selected from: -H, -(C₁-C₆)alkyl, -(C₃-C₈)cycloalkyl, -(C₁-C₂)alkyl(C₃- C₈)cycloalkyl, aryl, -(C₁-C₂)alkylaryl, heterocyclic, or -(C₁-C₂)alkylheterocyclic groups wherein each of the latter seven R³ groups is optionally substituted by one or more groups selected from: -OH, -(C₁-C₄)alkyl, -(CH₂)_n(C₃-C5)cycloalkyl, halogen, CN, -(CH₂)_nOR⁶ or - (CH₂)_nNR⁷R⁸ wherein n = 0, 1 or 2; R⁴ is selected from: -H, -(C₁-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; R⁵ is selected from: -(C₁-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, R⁷ and R⁸ are each independently selected from H, CH₃ or CH₂CH₃; wherein the heterocyclic group of R³ 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, and wherein the heterocyclic group of R¹ is selected from mono-cyclic 5- to 6-membered ring systems containing up to 1 heteroatoms independently selected from O or N; (b) R¹ is 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) R³ is -H, -(C₂-C₆)alkyl, -(C₃-C₈)cycloalkyl, -(C₁- C₂)alkyl(C₃-C₈)cycloalkyl or heterocyclic wherein each of the latter four R³ groups is optionally substituted by one or more groups selected from -OH, -(C₁-C₄)alkyl or - OR⁶ wherein R⁶ is -H, CH₃ or CH₂CH₃ and wherein when R³ is a heterocyclic group said heterocyclic group is a monocyclic 6-membered ring system containing up to 2 N heteroatoms; (d) R³ is 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) R⁴ is selected from H, F or Cl and R⁵ is selected from F or Cl; and (f) the compound is of formula (XXIc): H

R (XXIc), wherein R¹ is a phenyl, 3-fluorophenyl, 4- fluorophenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl or pyridin-2-yl group; R² is OH; R³ is t-butyl; R⁴ is selected from: H or F and R⁵ is selected from: F or Cl. In one aspect, the MC4R agonist is a compound of Formula (XXIV): , or a pharmaceutically acceptable salt, wherein n is 1 or 2; R⁶ is

selected from H, C₁-C₆alkyl, C₃-C₈cycloalkyl, aryl, heterocyclyl, heteroaryl, C(O)C₁-C₆ 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; R⁷ is 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 C_1-C₄alkyl; R¹⁰ is a substituted piperidine group of formula (A-i):

(A i); wherein R¹ and R⁴ are each independently selected from H, C₁-C₄alkyl, OH, O(C₁-C₄alkyl), CH₂OCH₃ and NR⁸R⁹; R² is selected from H, OH, OC₁-C₄alkyl and NR⁸R⁹; R³ is selected from aryl or heteroaryl, wherein said moieties are optionally substituted with one or more substituents independently selected from halo, CN, CF₃, OCF₃, O(C₁-C₄alkyl), and C₁- C₄alkyl; R⁵ is selected from H and C₁-C₄alkyl; R⁸ is selected from H and C₁-C₄alkyl, wherein said C₁-C₄alkyl is optionally substituted with OH or OCH₃; R⁹ is selected from H, C₁- C₄alkyl, SO2C₁-C₄alkyl, C(O)C₁-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, R⁴ and R⁵ are not all simultaneously be H; when R¹ is methyl and R⁴ is H, then R⁵ is not methyl; when R⁴ is methyl and R⁵ is H, then R¹ is not methyl; and when R⁵ is methyl and R⁴ is H, then R¹ is not methyl. In one aspect, the MC4R agonist is a compound of Formula (XXIVa):

or a pharmaceutically acceptable salt thereof, wherein R¹ and R² are selected from the group consisting of: halogen, CF₃, CH₃, and OCH₃; R³ and R⁴ are independently selected from (C₁-C₄) alkyl, -CF₃, halogen, -O(C₁-C₄) alkyl, - OCF₃, -OCHF2, -S(O)p(C₁-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 R³ and R⁴ substituents 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(C₁-C₄) alkyl; R⁵ is 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 R⁵ is 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 R⁵ carbon atom are taken together with the carbon atom to form a 3- to 6- membered ring; each R⁶ is independently selected from the group consisting of: hydrogen, (C₁-C₈) 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 R⁶ substituents 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(C₁-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. In one aspect, the MC4R agonist is a compound of Formula (XXIVb):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is selected from the group consisting of: hydrogen, amidino, (C₁-C₄) alkyliminoyl, -(C₁-C₈) alkyl, -(CH₂)H-(C₃-C₇) 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 R³ and oxo; R² is 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 R³ is independently selected from the group consisting of: -(C₁-C₈) 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, trifluoromethyl, and (C₁-C₄) alkoxy, and wherein any alkyl, cycloalkyl, heterocycloalkyl, and methylene (CH₂) carbon atom in R³ is unsubstituted or substituted with one to two substituents independently selected from halogen, hydroxy, oxo, (C₁-C₄) alkyl, trifluoromethyl, and (C₁-C₄) alkoxy, or two R³ substituents on the same carbon atom are taken together with the carbon atom to form a cyclopropyl group; R⁴ is selected from the group consisting of: hydrogen, -(C₁-C₆) alkyl, -O(C₁-C₆) alkyl, and -(CH₂)πN(R⁸)C(O)R⁸; R⁵ is selected from the group consisting of: -CF₃, -(C₁-C₆) alkyl, -(C₂-C₈) alkenyl, - C_2.8 alkynyl, -O(C₁-C₈) alkyl, -CH₂)n(C₃-C₇) cycloalkyl, -(CH₂)_nheterocycloalkyl, -(CH₂)_n- phenyl, -(CH₂)_n-naphthyl, -(CH₂)_nheteroaryl, and -(CH₂)_n(C₃-C₇) 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 R³ and oxo, and wherein any methylene (CH₂) in R⁵ is unsubstituted or substituted with one to two substituents independently selected from halogen, hydroxy, oxo, and (C₁-C₄) alkyl; R⁶ is selected from the group consisting of: hydrogen, -(C₁-C₆) alkyl, and -O(C₁-C₆) alkyl; R⁷ is 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 R⁷ is 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 R⁷ together 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(C₁-C₄) alkyl; each R⁸ is independently selected from the group consisting of: hydrogen, -(C₁-C₈) alkyl, -(C₂-C₈) alkenyl, -(CH₂)_n(C₃-C₇) cycloalkyl, - (CH₂)_nheterocycloalkyl, -(CH₂)_n-phenyl, and -(CH₂)_n-heteroaryl; each R⁹ is independently selected from the group consisting of: -(C₁-C₈) alkyl, -(C₂-C₈) alkenyl, -(CH₂)_n-phenyl, - (CH₂)_n-naphthyl, -(CH₂)_n-heteroaryl, -(CH₂)_nheterocycloalkyl, -(CH₂)_n(C₃-C₇) cycloalkyl, halogen, -OR⁸, -(CH₂)_nC(O)R⁸, -(CH₂)_nOC(O)R⁸, -(CH₂)_nC(O)OR⁸, -(CH₂)_nC≡N, NO2, - (CH₂)_nN(R⁸)2, -(CH₂)_nC(O)N(R⁸)2, -(CH₂)_nNR⁸C(O)R⁸, -(CH₂)_nNR⁸C(O)OR⁸, - (CH₂)_nNR⁸C(O)-heteroaryl, -(CH₂)_nNR⁸C(O)N(R⁸)₂, -(CH₂)_nC(O)NR⁸N(R⁸)₂, - (CH₂)_nC(O)NR⁸NR⁸C(O)R⁸, -(CH₂)_nNR⁸S(O)pR⁸, -(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 R⁹ are unsubstituted or substituted with one or two substituents independently selected from halogen, hydroxy, oxo, (C₁-C₄) alkyl, trifluoromethyl, and (C₁-C₄) alkoxy, or two R⁹ substituents 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. In some embodiments, the MC4R agonist is a compound described in WO 2007/015157, which is incorporated herein by reference in its entirety. In one aspect, the MC4R agonist is a compound of Formula (XXV):

acemic or enantiomeric form or any combinations of these forms and wherein: A represents -CH₂-, -C(O)-, -C(O)-C(R^a)(R^b)-; X represents -CH- or -N-; R^a and R^b represent, independently, the hydrogen atom or a (C₁- C₆)alkyl radical; R¹ represents the hydrogen atom, a (C₁-C₈)alkyl radical optionally substituted by hydroxy or one or more identical or different halo radicals, (C₂-C₆)alkenyl, or a radical of formula -(CH₂)_n-X¹; R² represents a (C₁-C₈)alkyl radical optionally substituted by hydroxy or one or more identical or different halo radicals, (C₂-C₆)alkenyl, or a radical of formula -(CH₂)_n-X¹; each X¹ independently represents (C₁-C₆)alkoxy, (C₃-C₇)cycloalkyl, adamantyl, heterocycloalkyl, aryl or heteroaryl, the (C₃-C₇)cycloalkyl, heterocycloalkyl, aryl and heteroaryl radicals being optionally substituted by one or more identical or different substituents chosen from: -(CH₂)_n′-V¹-Y¹ halo, nitro, cyano and aryl; V¹ represents -O-, -S- or a covalent bond; Y¹ represents a (C₁-C₆)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 X¹ does not represent the alkoxy radical); or R¹ and R² form 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, (C₁-C₆)alkyl optionally substituted by hydroxy, (C₁-C₆)alkoxy-carbonyl, heterocycloalkyl and -C(O)NV^1′Y^1′ with V^1′ and Y^1′ independently representing the hydrogen atom or a (C₁-C₆)alkyl; or R¹ and R² together form a radical of one of the following formulas: ^{Z3 ′Z3}

C(R )(R )- Z³, -C(R^Z3)(R^′Z3)-(CH₂)p-Z³ or -C(O)-Z^′3; R^Z3 and R^′Z3 represent, independently, the hydrogen atom or a (C₁-C₆)alkyl radical; Z³ represents Z^3a, Z^3b, Z^3c, Z^3d, or Z^3e; Z^3a represents a (C₁- C₆)alkyl radical; Z^3b represents a (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, (C₁-C₆)alkylamino or di((C₁-C₆)alkyl)amino radical; Z^3c represents an aryl or heteroaryl radical; Z^3d represents a (C₁-C₆) alkoxy-carbonyl, amino-carbonyl, (C₁-C₆)alkylamino-carbonyl, di((C₁- C₆)alkyl)amino-carbonyl, (C₁-C₆)alkyl-C(O)-NH-, (C₃-C₇)cycloalkyl, heterocycloalkyl radical; the (C₃-C₇)cycloalkyl and heterocycloalkyl radicals being optionally substituted by one or more identical or different substituents chosen from: halo, nitro, (C₁-C₆)alkoxy optionally substituted by one or more identical or different halo radicals, (C₁-C₆)alkyl optionally substituted by one or more identical or different halo radicals, (C₁-C₆)alkyl- carbonyl, (C₁-C₆)alkoxy-carbonyl, amino-carbonyl, (C₁-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, (C₁-C₆)alkoxy-carbonyl-(C₁-C₆)alkenyl, (C₁-C₆)alkylamino-carbonyl-(C₁- C₆)alkenyl, -SO2-NR³¹R³², heterocycloalkyl, heteroaryl or -(CH₂)p′-V³-Y³; R³¹ and R³² form 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-, -NR^′3-SO₂-, -NR^′3, -NR^′3-C(O)-, - C(O)-NR^′3-, -NH-C(O)-NR^′3- or a covalent bond. Y³ represents the hydrogen atom, a (C₁- 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, (C₁-C₆)alkyl and (C₁-C₆)alkoxy, or an aryl-(C₁-C₆)alkyl radical optionally substituted by one or more identical or different substituents chosen from: halo, nitro, (C₁- C₆)alkyl and (C₁-C₆)alkoxy; Z^3e represents a radical of one of the following formulas:

, Z³ represents an aryl radical optionally substituted by one or more identical or different substituents chosen from: halo, nitro and -(CH₂)p″-V^′3-Y^′3; V^′3 represents -O-, -C(O)-, -C(O)-O-, -C(O)-NR^′3-, -NH-C(O)-NR^′3- or a covalent bond; Y^′3 represents the hydrogen atom or a (C₁-C₆)alkyl radical optionally substituted by one or more identical or different halo radicals; R^′3 represents the hydrogen atom, a (C₁-C₆)alkyl or (C₁-C₆)alkoxy radical; p represents an integer from 1 to 4; p′ and p″ represent, independently, an integer from 0 to 4; R⁴ represents a radical of formula -(CH₂)s-R^′4 where R^′4 represents the guanidine radical, a heterocycloalkyl containing at least one nitrogen atom and optionally substituted by (C₁-C₆)alkyl or aralkyl, a heteroaryl containing at least one nitrogen atom and optionally substituted by (C₁-C₆)alkyl, or a radical of formula -NW⁴W^′4 where W⁴ represents the hydrogen atom or (C₁-C₈)alkyl; W^′4 represents a radical of formula -(CH₂)s′-Z⁴; Z⁴ represents the hydrogen atom, (C₁-C₈)alkyl optionally substituted by one or more identical or different substituents chosen from: (C₁-C₆)alkoxy, (C₁-C₆)alkylthio and hydroxy; (C₂- C₆)alkenyl; (C₃-C₇)cycloalkyl optionally substituted by one or more identical or different (C₁-C₆)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; V⁴ represents -O-, -S-, -NH-C(O)-, -NV^4′- or a covalent bond; Y⁴ represents a hydrogen atom or a (C₁-C₆)alkyl radical optionally substituted by one or more identical or different halo radicals; V^4′ represents a hydrogen atom or a (C₁-C₆)alkyl; s″ represents an integer from 0 to 4; or Z⁴ represents a radical of formula:

; s and s′ represent, independently, an integer from 0 to 6; and i) when R³ represents -C(O)-Z^′3 and R⁴ represents a radical of formula -(CH₂)_s-NW⁴W^′4 and W⁴ and W^′4 represent, independently, the hydrogen atom or the (C₁-C₆)alkyl radical, then - (CH₂)s represents neither the ethylene radical nor the -(CH₂)-CH((C₁-C₄)alkyl)-radical and ii) when R³ represents -Z^3c and Z^3c represents a phenyl or naphthyl radical, then phenyl and naphthyl are not substituted by cyano; and it being understood that when R³ represents - Z^3d then Z^3d only represents one (C₃-C₇)cycloalkyl or heterocycloalkyl radical; or a pharmaceutically acceptable salt thereof. In some embodiments, preferred compounds of Formula (XXV) include: R¹ and R² represent, independently, a (C₁-C₈)alkyl radical; R³ represents -Z^3c, -(R^Z3)(R^′Z3)- Z^3c, -C(R^Z3)(R′^Z3)-Z^3d, -C(R^Z3)(R′^Z3)-(CH₂)_p-Z^3d; R⁴ represents a radical of formula -(CH₂)_s- R^′4; R^′4 represents a heterocycloalkyl containing at least one nitrogen atom and optionally substituted by (C₁-C₆)alkyl; or a radical of formula -NW⁴W^′4; W⁴ represents the hydrogen atom or (C₁-C₈)alkyl; W^′4 represents a radical of formula -(CH₂)_s′-Z⁴; Z⁴ represents 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 R^′4 is the piperidine ring; R^Z3 and R^′Z3 represent the hydrogen atom; Z³ represents 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; V³ represents -O-, -C(O)-, -C(O)-O-, -C(O)-NR^′3- or a covalent bond; R^′3 represents the hydrogen atom or a (C₁-C₆)alkyl radical; Y³ represents the hydrogen atom; a (C₁-C₆)alkyl radical optionally substituted by one or more identical or different halo radicals; Z^3d represents the (C₁-C₆)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 (XXV) as defined above, characterized in that X represents -CH- and A represents -C(O)-C(R^a)(R^b)- with R^a and R^b representing the methyl radical; and more particularly R¹ and R² represent, independently, a (C₁-C₈)alkyl radical; R³ represents -Z^3c, -C(R^Z3)(R^′Z3)-Z^3c, -C(R^Z3)(R′^Z3)- Z^3d or -C(R^Z3)(R^′Z3)-(CH₂)_p-Z^3d; R⁴ represents a radical of formula -(CH₂)_s-R^′4; R^′4 represents a heterocycloalkyl containing at least one nitrogen atom and optionally substituted by (C₁- C₆)alkyl; or a radical of formula -NW⁴W^′4; W⁴ represents the hydrogen atom or (C₁-C₈)alkyl; W^′4 represents a radical of formula -(CH₂)_s′-Z⁴; Z⁴ represents 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 R^Z3 and R^′Z3 represent, independently, the hydrogen atom; Z^3c represents a thienyl radical optionally substituted by (C₁-C₆)alkoxy-carbonyl; or phenyl substituted by one or more identical or different substituents chosen from: halo, nitro or -(CH₂)_p′-V³-Y³; V³ represents -O-, -C(O)-, -C(O)-O-, -C(O)-NR^′3- or a covalent bond; Y³ represents the hydrogen atom; a (C₁-C₆)alkyl radical optionally substituted by one or more identical or different halo radicals; R^′3 represents the hydrogen atom; Z^3d represents a (C₁-C₆)alkoxy- carbonyl radical; the heterocycloalkyl represented by R^′4 is piperidine; the heteroaryl represented by Z⁴ is pyridine; or a pharmaceutically acceptable salt thereof. Preferably, the invention also relates to compounds of Formula (XXV) as defined above, characterized in that X represents -CH- and A represents -C(O)-, and more particularly R³ represents -C(O)-Z^′3; R¹ and R² represent, independently, a (C₁-C₈)alkyl radical; Z^′3 represents 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^′3 represents -O-, -C(O)-O- or a covalent bond; Y^′3 represents the hydrogen atom or a (C₁-C₆)alkyl radical; p″ represents the integer 0; R⁴ represents a radical of formula -(CH₂)s-R^′4 where R^′4 represents a radical of formula -NW⁴W^′4 where W⁴ represents the hydrogen atom or (C₁-C₈)alkyl; W^′4 represents a radical of formula -(CH₂)_s′-Z⁴ and Z⁴ represents 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. Preferably, the invention also relates to compounds of Formula (XXV) as defined above, characterized in that X represents -CH- and A represents -C(O)-, and R¹ represents a hydrogen atom, a (C₁-C₈)alkyl radical optionally substituted by hydroxy, (C₂-C₆)alkenyl or a radical of formula -(CH₂)_n-X¹; R² represents a (C₁-C₈)alkyl radical optionally substituted by hydroxy, (C₂-C₆)alkenyl or a radical of formula -(CH₂)_n-X¹; each X¹ represents, independently, (C₁-C₆)alkoxy, (C₃-C₇)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; V¹ represents -O- or a covalent bond; Y¹ represents a (C₁-C₆)alkyl radical optionally substituted by one or more identical or different halo radicals; or aryl; or R¹ and R² form 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, (C₁-C₆)alkyl optionally substituted by hydroxy, (C₁-C₆)alkoxy- carbonyl, heterocycloalkyl and -C(O)NV^1′Y^1′ with V^1′ and Y^1′ independently representing the hydrogen atom or a (C₁-C₆)alkyl, or R¹ and R² together form a radical of formula: nts -Z³, -C(R^Z3)(R^′Z3) ^{3 Z3 ′Z3 3}

-Z or -C(R )(R )-(CH₂)_p-Z ; R⁴ represents a radical of formula -(CH₂)_s-R^′4, where R^′4 represents a heterocycloalkyl containing at least one nitrogen atom and optionally substituted by (C₁-C₆)alkyl or aralkyl; a heteroaryl containing at least one nitrogen atom and optionally substituted by (C₁-C₆)alkyl; or a radical of formula -NW⁴W^′4, where W⁴ represents the hydrogen atom or (C₁-C₈)alkyl; W^′4 represents a radical of formula -(CH₂)s′-Z⁴; Z⁴ represents 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 X¹ is cyclopropyl; the aryl radical represented by X¹ the phenyl radical; the heteroaryl radical represented by X¹ is pyridine; the heterocycloalkyl that R¹ and R² form 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 R^′4, optionally substituted by (C₁-C₆)alkyl or benzyl, is chosen from: pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl; the heteroaryl radical represented by R^′4 is the imidazolyl radical; the cycloalkyl represented by Z⁴ is chosen from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; the aryl represented by Z⁴ is phenyl; or a pharmaceutically acceptable salt thereof. Very preferably, the invention relates to compounds of Formula (XXV) as defined above, characterized in that R⁴ represents a radical of formula -(CH₂)_s-R^′4 with R^′4 representing the pyrrolidinyl or piperidinyl radical; or a radical of formula -NW⁴W^′4, where W⁴ represents the hydrogen atom or (C₁-C₈)alkyl; W^′4 represents a radical of formula - (CH₂)s′-Z⁴ with Z⁴ representing 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. Very preferably also, the invention relates to compounds of Formula (XXV) as defined above, characterized in that R¹ and R² represent, independently, a (C₁-C₈)alkyl radical; or a pharmaceutically acceptable salt thereof. Preferably, the invention also relates to compounds of Formula (XXV) as defined above, characterized in that X represents -CH-, A represents -C(O)-, and R³ represents -Z³ and Z³ represents Z^3c, Z^3d or Z^3e; Z^3d represents a (C₃- C₇)cycloalkyl or heterocycloalkyl radical; and more particularly Z^3c represents 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: (C₁-C₆)alkyl-carbonyl and (C₁-C₆)alkoxy-carbonyl; the aryl radical being optionally substituted by one or more identical or different substituents chosen from: halo, cyano, nitro, azido, (C₁-C₆)alkoxy-carbonyl-(C₁-C₆)alkenyl, oxy, -SO2-NR³¹R³², heterocycloalkyl, heteroaryl, or -(CH₂)_p′-V³-Y³; R³¹ and R³² form together with the nitrogen atom to which they are attached, the piperidine ring; V³ represents -O-, -S-, -C(O)-, -C(O)-O-, -SO2-, -SO2NH-, - NR′3-, -NR′3-C(O)-, -C(O)-NR^′3-, -NH-C(O)-NR^′3- or a covalent bond; Y³ represents the hydrogen atom; a (C₁-C₆)alkyl radical optionally substituted by one or more identical or different halo radicals; phenyl; or benzyl; R^′3 represents the hydrogen atom, a (C₁-C₆)alkyl or (C₁-C₆)alkoxy radical; Z^3d represents the cyclopropyl, cyclohexyl or piperidinyl radical, each being able to be substituted by a (C₁-C₆)alkoxy-carbonyl radical; or a pharmaceutically acceptable salt thereof. Preferably, the invention also relates to compounds of Formula (XXV) as defined above, characterized in that X represents -CH-, A represents -C(O)-, and R³ represents - Z³ and Z³ represents Z^3c, Z^3d or Z^3e; Z^3d represents a (C₃-C₇)cycloalkyl or heterocycloalkyl radical; and more particularly Z^3c represents 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; V³ represents -O-, -S-, -C(O)-, -C(O)-O-, -SO₂-, -SO₂NH-, - NR^′3-C(O)-, -C(O)-NR^′3-, -NH-C(O)-NR^′3- or a covalent bond; Y³ represents the hydrogen atom; a (C₁-C₆)alkyl radical optionally substituted by one or more identical or different halo radicals; a phenyl radical; or a benzyl radical; R^′3 represents the hydrogen atom, a (C₁- C₆)alkyl or (C₁-C₆)alkoxy radical; Z^3d represents the cyclopropyl or piperidinyl radical, each optionally substituted by (C₁-C₆)alkoxy-carbonyl; and preferably Z³ represents Z^3c or Z^3e; Z^3c represents a phenyl being optionally substituted by one or more identical or different substituents chosen from nitro and -(CH₂)_p′-V³-Y³; V³ represents -O-, -S-, -C(O)-, -C(O)-O-, - SO2-, -SO2NH-, -NR^′3-C(O)-, -C(O)-NR^′3- or a covalent bond; Y³ represents the hydrogen atom; a (C₁-C₆)alkyl radical; a phenyl radical; or a benzyl radical; R^′3 represents the hydrogen atom; Z^3e represents

; or a pharmaceutically acceptable salt thereof. Preferably, the invention also relates to compounds of Formula (XXV) as defined above, characterized in that X represents -CH-, A represents -C(O)-; R³ represents - C(R^Z3)(R′^Z3)-Z³ and Z³ represents Z^3b, Z^3c, Z^3d or Z^3e; or a pharmaceutically acceptable salt thereof. Very preferably, the invention also relates to compounds of Formula (XXV) as defined above, characterized in that X represents -CH-, A represents -C(O)-, and R³ represents -C(R^Z3)(R^′Z3)-Z³ and Z³ represents Z^3b or Z^3c; R^Z3 and R^′Z3 represent the hydrogen atom; and more particularly Z^3b represents a (C₁-C₆)alkoxy radical; Z^3c represents 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; V³ represents -O-, -S-, -C(O)-, -C(O)-O-, -SO2-, -SO2NH-, -NR^′3-C(O)-, -C(O)-NR^′3-; Y³ represents the hydrogen atom, a (C₁-C₆)alkyl radical optionally substituted by one or more identical or different halo radicals; R^′3 represents the hydrogen atom; or a pharmaceutically acceptable salt thereof. Very preferably, the invention relates to compounds of Formula (XXV) as defined above, characterized in that X represents -CH-, A represents -C(O)-, and R³ represents -C(R^Z3)(R^′Z3)-Z³ and Z³ represents Z^3b or Z^3c; R^Z3 and R^′Z3 represent the hydrogen atom; and more particularly Z^3b represents a (C₁-C₆)alkoxy radical Z^3c represents 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; V³ represents -O-, -S-, -C(O)-, -C(O)-O-, -SO2-, - SO2NH-, -C(O)-NR^′3-; Y³ represents the hydrogen atom, or a (C₁-C₆)alkyl radical optionally substituted by one or more identical or different halo radicals; R^′3 represents the hydrogen atom; and preferably Z³ represents Z^3c; Z^3c represents 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; V³ represents -O-, -S-, -C(O)-, -C(O)-O-, -SO₂-, -SO₂NH-, -C(O)- NR^′3-; Y³ represents the hydrogen atom; or a (C₁-C₆)alkyl radical optionally substituted by one or more identical or different halo radicals; R^′3 represents the hydrogen atom; or a pharmaceutically acceptable salt thereof. Very preferably, the invention also relates to compounds of Formula (XXV) as defined above, characterized in that X represents -CH-, A represents -C(O)-, and R³ represents -C(R^Z3)(R^′Z3)-Z³ and Z³ represents Z^3d or Z^3e; R^Z3 and R^′Z3 represent the hydrogen atom or (C₁-C₆)alkyl; Z^3d represents a (C₁-C₆)alkoxy-carbonyl, (C₃-C₇)cycloalkyl or heterocycloalkyl radical; Z^3e represents and m

ore particularly Z^3d represents a (C₁-C₆)alkoxy-carbonyl, cyclohexyl or a tetrahydrofuranyl radical; or a pharmaceutically acceptable salt thereof. Very preferably, the invention also relates to compounds of Formula (XXV) as defined above, characterized in that X represents -CH-; A represents -C(O)-, and R³ represents -C(R^Z3)(R^′Z3)-Z³ and Z³ represents Z^3d or Z^3e; Z^3d represents a (C₁-C₆)alkoxy-carbonyl radical; Z^3e represents ; and pr

Z³ represents Z^3e aceutically acceptable salt thereof.

Preferably, the invention also relates to compounds of Formula (XXV) as defined above, characterized in that X represents -CH-; A represents -C(O)-; R³ represents - C(R^Z3)(R^′Z3)-(CH₂)p-Z³ and Z³ represents Z^3b, Z^3c or Z^3d; or a pharmaceutically acceptable salt thereof. Very preferably, the invention relates to compounds of Formula (XXV) as defined above, characterized in that X represents -CH-; A represents -C(O)-; and R³ represents - C(R^Z3)(R′^Z3)-(CH₂)p-Z³ and Z³ represents Z^3b; and more particularly R^Z3 and R^′Z3 represent, independently, the hydrogen atom or a (C₁-C₆)alkyl radical; Z^3b represents a (C₁-C₆)alkoxy, (C₁-C₆)alkylthio or di((C₁-C₆)alkyl)amino radical; or a pharmaceutically acceptable salt thereof. Very preferably, the invention also relates to compounds of Formula (XXV) as defined above, characterized in that X represents -CH-; A represents -C(O)-; and R³ represents -C(R^Z3)(R^′Z3)-(CH₂)_p-Z³ and Z³ represents Z^3b; and more particularly R^Z3 and R^′Z3 represent, independently, the hydrogen atom or a (C₁-C₆)alkyl radical; Z^3b represents a (C₁-C₆)alkoxy or (C₁-C₆)alkylthio radical; or a pharmaceutically acceptable salt thereof. Very preferably, the invention also relates to compounds of Formula (XXV) as defined above, characterized in that X represents -CH-; A represents -C(O)-; and R³ represents - C(R^Z3)(R^′Z3)-(CH₂)p-Z³ and Z³ represents Z^3c or Z^3d; and more particularly R^Z3 and R^′Z3 represent, independently, the hydrogen atom or a (C₁-C₆)alkyl radical; Z^3c represents 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; V³ represents - SO2NH-; Y³ represents the hydrogen atom, or a (C₁-C₆)alkyl radical; Z^3d represents a (C₁- C₆)alkoxy-carbonyl, amino-carbonyl, (C₁-C₆)alkyl-amino-carbonyl, (C₁-C₆)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 (XXV) as defined above, characterized in that X represents -CH-; A represents -C(O)-; and R³ represents - C(R^Z3)(R^′Z3)-(CH₂)p-Z³ and Z³ represents Z^3c or Z^3d; and more particularly Z³ represents Z^3d; R^Z3 and R^′Z3 represent, independently, the hydrogen atom or a (C₁-C₆)alkyl radical; Z^3d represents a (C₁-C₆)alkoxy-carbonyl, amino-carbonyl, (C₁-C₆)alkylamino-carbonyl, (C₁- C₆)alkyl-C(O)-NH- or heterocycloalkyl radical, and preferably pyrrolidine or imidazolidine, optionally substituted by oxy; or a pharmaceutically acceptable salt thereof. 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. In one aspect, the MC4R agonist is a compound consisting of:

In some embodiments, the MC4R agonist is a compound described in US 8,129,413, which is incorporated herein by reference in its entirety. In one aspect, the MC4R agonist is a compound of Formula (XXVI):

( ), His is L-histidyl; 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 (XXVI), 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(O)- 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- phenylalanyl. 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. In some embodiments, compounds of Formula (XXVI) have the following combinations of Z, Y, X, W, m, and n:

The MC4R agonists in the provided in the table above refer to SEQ ID NOs: 893-901, respectively. In some embodiments, the MC4R agonist is a compound described in US WO 2005/060985, which is incorporated herein by reference in its entirety. In one aspect, the MC4R agonist is a compound from the group consisting of:

and pharmaceutically acceptable salts thereof. In some embodiments, the MC4R agonist is a compound described in EP 1534074, which is incorporated herein by reference in its entirety. In one aspect, the MC4R agonist is a compound of Formula (XXVII):

(XXVII), or a pharmaceutically acceptable salt thereof, wherein: Q is

o ; s O, S, o NR^4b ; each p is independently 1 or 2; each n is independently 0, 1, or 2; R^l is selected from the group consisting of hydrogen, (C₁-C₈) 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 R⁶ and oxo; R² is selected from the group consisting of hydrogen, (C₁-C₈) alkyl, (CH₂)_n(C₃-C₆) cycloalkyl, and (CH₂)_naryl; each R³ is independently selected from the group consisting of hydrogen, (C₁-C₈) 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 R⁶ and oxo; or R³ and R^5a and 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; R^4a and R^4b are each independently selected from the group consisting of hydrogen, (C₁-C₈) alkyl, (CH₂)_n- aryl, (CH₂)_n(C₃-C₆)-cycloalkyl, (CH₂)_n-heteroaryl, (CH₂)_n-heterocyclyl, COC(R₇)₂NH₂, COR⁷, (CH₂)_nOR⁷, (CH₂)_nCO₂R⁷, CH₂C≡CH, 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 R⁶ and oxo; or R^4a and R² and 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 R^4a and R^4b and the atoms to which they are attached form a 5- to 7-membered ring; R^5a and R^5b are each independently selected from the group consisting of hydrogen, (C₁-C₈) alkyl, (CH₂)_n-aryl, and (C₃-C₈)-cycloalkyl; wherein alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R₆ and oxo; aryl is unsubstituted or substituted with one to three groups independently selected from R⁶; or R⁵ and R^5b together with the carbons to which they are attached form a 5- to 7- membered ring; R⁶ is selected from the group consisting of hydrogen, (C₁-C₈) alkyl, (CH₂)_n-aryl, (CH₂)_n(C₃-C₇)-cycloalkyl, (CH₂)_n-heteroaryl, halogen, OR⁷, NHSO₂R⁷, N(R⁷)₂, C≡N, CO₂R⁷, C(R⁷)(R⁷)N(R⁷)₂, NO₂, SO2N(R⁷)2, S(O)0-2R⁷, CF₃, and OCF₃; or two R⁶ substituents, 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 R⁷ is independently selected from the group consisting of hydrogen, (C₁-C₈) alkyl, (CH₂)n-aryl, and (CH₂)_n(C₃-C₇)-cycloalkyl; each R⁸ is independently selected from the group consisting of: hydrogen, (C₁-C₈)-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 R⁶ and oxo; or two R⁸ groups 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 R⁹ is independently selected from the group consisting of hydrogen, (C₁-C₈) alkyl, (CH₂)_n-aryl, (CH₂)_n(C₃-C₆) cycloalkyl, (CH₂)_n-heteroaryl, halogen, OR⁷, NHSO2R⁷, N(R⁷)2, C≡N, CO2R⁷, C(R⁷)(R⁷)N(R⁷)₂, NO₂, SO₂N(R⁷)₂, S(O)_0-2R⁷, CF₃, and OCF₃; X is selected from the group consisting of (C₁-C₈) alkyl, (CH₂)_n(C₃-C₈) cycloalkyl, (CH₂)_naryl, (CH₂)_nheteroaryl, (CH₂)_nheterocyclyl, (CH₂)_nC≡N, (CH₂)_nCONR⁸R⁸, (CH₂)_nCO2R⁸, (CH₂)_nCOR⁸, (CH₂)_nNR⁸C(O)R⁸, (CH₂)_nNR⁸CO₂R⁸, (CH₂)_nNR⁸C(O)N(R⁸)₂, (CH₂)_nNR⁸SO₂R⁸, (CH₂)_nS(O)_0-2R⁸, (CH₂)_nSO₂N(R⁸)(R⁸), (CH₂)_nOR⁸, (CH₂)_nOC(O)R⁸, (CH₂)_nOC(O)OR⁸, (CH₂)_nOC(O)N(R⁸)2, (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 R⁶ and oxo; Y is selected from the group consisting of hydrogen, (C₁-C₈)-alkyl, (CH₂)_n(C₃-C₈)-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 R⁶ and oxo. In some embodiments, compounds of Formula (XXVII) include: Q is , is O or NR^4b an ^{2 3 4a 4b 5a 5b}

_; d R , R , R , R , R , R and R⁹ are as defined herein. In some embodiments, compounds of Formula (XXVII) include: Q is

, wherein R², R³, R^4a, R^4b, R^5a, R^5b are as defined herein. In some embodiments, compounds of Formula (XXVII) include: R^4a and R^4b are each independently selected from the group consisting of hydrogen, (C₁-C₈)-alkyl, (CH₂)_n-aryl, (CH₂)_n- heteroaryl, (CH₂)_n-heterocyclyl, (CH₂)_n(C₃-C₆) -cycloalkyl, (CH₂)_nCO2R⁷, (CH₂)_nOR⁷, COC(R⁷)NH₂, CH₂C≡CH, and CH₂CHF2; or R^4a and R^4b and the atoms to which they are attached form a 6-membered ring; R³, R^5a, and R^5b are each independently hydrogen, (C₁-C₄)-alkyl, (C₃-C₆) cycloalkyl, or aryl; wherein aryl is unsubstituted or substituted with one to three groups independently selected from R⁶; or R³ and R⁵ and the carbons to which they are attached form a 6-membered ring optionally containing an additional heteroatom selected from O, S, and NR⁷. In some embodiments, R^4a and R^4b are each independently selected from the group consisting of hydrogen, (C₁-C₄) alkyl, CH₂-aryl, CH₂-heteroaryl, CH₂-heterocyclyl, (CH₂)_{0- 1}(C₃-C₆) cycloalkyl, CH₂CO₂R⁷, (CH₂)₂OR⁷, COC(R⁷)NH₂, CH₂C≡CH, and CH₂CHF₂; or R^4a and R^4b and the atoms to which they are attached form a 6-membered ring; R³, R^5a, and R^5b are each independently hydrogen, (C₁-C₄) alkyl, (C₃-C₆) cycloalkyl, or phenyl; wherein phenyl is unsubstituted or substituted with one to three groups independently selected from R⁶; or R³ and R^5a and the carbons to which they are attached form a 6-membered ring optionally containing an additional heteroatom selected from O, S, and NR⁷. In some embodiments, compounds of Formula (XXVII) include: R^l is CHR⁷-aryl, CHR⁷OCHR⁷-aryl, or CHR⁷-heteroaryl wherein aryl and heteroaryl are optionally substituted with one or two R⁶ groups. In some embodiments, R^l is benzyl optionally substituted with one or two groups selected from halogen, (C₁-C₄) alkyl, (C₁-C₄) alkoxy, CN, CF₃, and OCF₃. In some embodiments, R^l is 4-chlorobenzyl; 4-fluorobenzyl; 3,4-difluorobenzyl; 3,5- difluorobenzyl; 2-cyano-4-fluorobenzyl; or 4-methoxybenzyl. In some embodiments, compounds of Formula (XXVII) include R² is H or CH₃. In some embodiments, compounds of Formula (XXVII) include: X is (C₁-C₆) alkyl, (CH₂)_n-aryl, (CH₂)_n-heteroaryl, (CH₂)_n-heterocyclyl, (CH₂)_nC(O)N(R⁸)(R⁸), (CH₂)_nCO2R⁸, (CH₂)_nOR⁸, (CH₂)_nS(O)_0-2R⁸, (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 R⁶ and oxo; the (CH₂)_n group is optionally substituted with one to three groups selected from R⁷, halogen, S(O)_0-2R⁷, N(R⁷)₂, and OR⁷; and R⁸ is each independently selected from H, (C₁-C₈) alkyl, and (C₃-C₆) cycloalkyl optionally substituted with one to three groups selected from R⁶ and oxo; or two R⁸ groups 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 (C₁-C₆) alkyl, (CH₂)₀- _l heteroaryl, CH₂-heterocyclyl, CO₂R⁸, CH₂OR⁸, CH₂S(O)_0-2R⁸, NΗC(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 R⁶ and oxo; and R⁸ is each independently selected from H, (C₁-C₈) alkyl, and (C₃-C₆) cycloalkyl optionally substituted with one to three groups selected from R⁶ and oxo; or two R⁸ groups 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, compounds of Formula (XXVII) include: Y is (C₁-C₈) alkyl, (CH₂)_n(C₃-C₇) 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 R⁶ and oxo. In a class of this embodiment, Y is cyclohexyl, cycloheptyl, cyclopentyl, or (C₁-C₆) alkyl, unsubstituted or substituted with one to three groups selected from R⁶ and oxo. In some embodiments, Y is cyclohexyl or (C₁-C₆) alkyl, wherein the cyclohexyl and alkyl groups are unsubstituted or substituted with one to three groups selected from R⁶ and oxo. In some embodiments, the carbon atom marked with * has the R configuration. In some embodiments, compounds of Formula (XXVII) include: X is selected from the group consisting of:

-NH-C(O)CH₃ -C(O)N(CH₃)₂ -C(O)NH-t-Bu; ,

C(O)NHCH(Et)₂; -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;

In some embodiments, compounds of Formula (XXVII) include compounds of Formula (XXVIIa) with the indicated stereochemistry at the stereogenic center marked with ** are:

In some embodiments, compounds of Formula (XXVII) include compounds of Formula (XXVIIb) with the indicated stereochemistry at the stereogenic center marked with ** are: (XXVIIb)

In some embodiments, compounds of Formula (XXVII) include compounds of Formula (XXVIIc) with the indicated stereochemistry at the stereogenic center marked with ** are:

In some embodiments, the MC4R agonist is a compound described in WO 2001/070708, which is incorporated herein by reference in its entirety. In one aspect, the MC4R agonist is a compound of Formula (XXVIII):

O (XXVIII), or a 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; R^l is selected from the group consisting of hydrogen, amidino, (C₁-C₄) alkyliminoyl, (C₁-C₁₀)alkyl, (CH₂)_n-(C₃-C₇) 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 R³ and oxo; R² is 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 R³ is independently selected from the group consisting of (C₁-C₆) -alkyl, (CH₂)_n-phenyl, (CH₂)_n- naphthyl, (CH₂)_n-heteroaryl, (CH₂)_n-heterocyclyl, (CH₂)_n(C₃-C₇)-cycloalkyl, halogen, OR⁴, (CH₂)_nN(R⁴)₂, (CH₂)_nC≡N, (CH₂)_nCO2R⁴, 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, (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) carbon atom in R³ is 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 R⁴ is independently selected from the group consisting of hydrogen, (C₁-C₆) alkyl, (CH₂)_n-phenyl, (CH₂)_n- heteroaryl, (CH₂)_n-naphthyl, (CH₂)_n-heterocyclyl, (CH₂)_n(C₃-C₇) cycloalkyl, and (CH₂)_n(C₃- C₇) 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 R⁴ 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(C₁-C₄)alkyl; each R⁵ is independently selected from the group consisting of hydrogen, (C₁-C₈) alkyl, (CH₂)_n-phenyl, (CH₂)_n-naphthyl, (CH₂)_n-heteroaryl, and (CH₂)_n(C₃-C₇) 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 R³ and oxo; and wherein any methylene (CH₂) in R³ is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and (C₁-C₄) alkyl; or two R⁵ 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(C₁-C₄) alkyl; X is selected from the group consisting of (C₁-C₈) alkyl, (CH₂)_n(C₃-C₈) cycloalkyl, (CH₂)_n-phenyl, (CH₂)_n-naphthyl, (CH₂)_n-heteroaryl, (CH₂)_nheterocyclyl, (CH₂)_nC≡N, (CH₂)_nCON(R⁵R⁵), (CH₂)_nCO2R⁵, CH₂)nCOR⁵, (CH₂)_nNR⁵C(O)R⁵, (CH₂)_nNR⁵CO2R⁵, (CH₂)_nNR⁵C(O)N(R⁵)₂, (CH₂)_nNR⁵SO₂R⁵, (CH₂)_nS(O)_pR⁵, (CH₂)_nSO₂N(R⁵)₂, (CH₂)_nOR⁵, (CH₂)_nOC(O)R⁵, (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 R³ and 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, (C₁-C₈) alkyl, (C₂-C₆)alkenyl, (CH₂)_n(C₃-C₈) 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 R³ and 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. In some embodiments, compounds of Formula (XXVIII) include: R¹ is selected from the group consisting of hydrogen, (C₁-C₆) alkyl, (CH₂)_0-l(C₃-C₆) cycloalkyl, and (CH₂)_0-l- 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 R³ and oxo. In some embodiments, R² is phenyl or thienyl optionally substituted with one to three groups independently selected from R³. In some embodiments, R² is 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-C₈) 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 R³ and 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)_0-l-phenyl, (CH₂)_0-l-heteroaryl, (CH₂)₀-1-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 R³ and oxo; and CH₂ is 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. In one aspect, the MC4R agonist is a compound of Formula (XXVIIIa) or (XXVIIIb) having the trans orientation of the R2 and piperidinecarbonyl substituents: X

(XXVIIIa) (XXVIIIb) or a pharmaceutically acceptable salt thereof; wherein r is 1 or 2; n is 0, 1, or 2; p is 0, 1, or 2; R¹ is hydrogen, amidino, (C₁-C₄) alkyliminoyl, (C₁-C₆) alkyl, (C5-C₆) cycloalkyl, (CH₂)_0-l phenyl, (CH₂)_0-l 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 R³ and oxo; R² is phenyl or thienyl optionally substituted with one to three groups independently selected from R³;each R³ is independently selected from the group consisting of (C₁-C₆) 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 R³ is 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 R⁴ is independently selected from the group consisting of hydrogen, (C₁-C₈) alkyl, phenyl, heteroaryl, (CH₂)_0-l heterocyclyl, and (C₃-C₆) 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(C₁-C₄)alkyl; and X is phenyl or heteroaryl each of which is optionally substituted with one to three groups independently selected from R³. In one aspect, the MC4R agonist is a compound of Formula (XXVIIIc) or (XXVIIId) having the trans orientation of the phenyl and piperidinecarbonyl substituents:

(XXVIIIc) (XXVIIId) or a pharmaceutically acceptable salt thereof; wherein r is 1 or 2; R¹ is hydrogen, (C₁-C₄) alkyl, or (CH₂)_0-1 phenyl; each R³ is independently selected from the group consisting of (C₁- C₆) alkyl, (CH₂)_0-l-heteroaryl, (CH₂)_0-1-heterocyclyl, halogen, OR⁴, (CH₂)_0-1N(R⁴)₂, (CH₂)_0- lC≡N, (CH₂)₀-1CO2R⁴, (CH₂)₀-₁NR⁴SO2R⁴, (CH₂)₀-1SO2N(R⁴)₂, (CH₂)₀-1S(O)pR⁴, (CH₂)₀- ₁NR⁴C(O)N(R⁴)₂, (CH₂)₀-1C(O)N(R⁴)₂, (CH₂)₀-₁NR⁴C(O)R⁴, (CH₂)₀-₁NR⁴CO2R⁴, (CH₂)₀- ₁NR⁴C(O)-heteroaryl, (CH₂)_0-1C(O)NR⁴N(R⁴)₂, (CH₂)_0-1C(O)NR⁴NR⁴C(O)R⁴, O(CH₂)_0- 1C(O)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 R³ is 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 R⁴ is independently selected from the group consisting of hydrogen, (C₁-C₈) alkyl, phenyl, heteroaryl, (CH₂)_0-l heterocyclyl, and (C₃-C₆) 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 R⁴ 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(C₁-C₄)alkyl. In some embodiments, compounds of any of Formulas (XXVIII), (XXVIIIa), (XXVIIIb), (XXVIIIc), and (XXVIIId) include:

o a p a aceut ca y acceptabe sat t e eo . In some embodiments, the MC4R agonist is a compound described in WO 2002/068388, which is incorporated herein by reference in its entirety. In one aspect, the MC4R agonist is a compound of Formula (XXVIII):

_O ^R (XXVIII), or a 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; R¹ is NR⁶R⁷ wherein R⁶ and R⁷ are independently selected from the group consisting of: hydrogen, amidino, (C₁-C₄) alkyliminoyl, (C₁-C₄) alkyl, (CH₂)_n-(C₃-C₇) 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 R³ and oxo; or R⁶ and R⁷ together 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(C₁-C₄)alkyl; R² is 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; R³ is selected from the group consisting of: (C₁-C₆) 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)_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 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)_n is unsubstituted or substituted with one to two groups independently selected from halogen and (C₁-C₄) alkyl; each R⁴ is independently selected from the group consisting of: hydrogen, (C₁-C₆) alkyl, (CH₂)_n-phenyl, (CH₂)_n- naphthyl, and (CH₂)_n(C₃-C₇) cycloalkyl; or two R⁴ 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(C₁-C₄)alkyl; each R⁵ is independently selected from the group consisting of: hydrogen, (C₁-C₈) alkyl, (CH₂)_n-phenyl, (CH₂)_n-naphthyl, (CH₂)_n-heteroaryl, and (CH₂)_n(C₃-C₇) 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)_n are unsubstituted or substituted with one to three groups independently selected from R³ and oxo; or two R⁵ 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(C₁-C₄) alkyl; X is selected from the group consisting of: (C₁-C₈) alkyl, (CH₂)_n(C₃-C₈) cycloalkyl, (CH₂)_n-phenyl, (CH₂)_n-naphthyl, (CH₂)_n-heteroaryl, (CH₂)_nheterocyclyl, (CH₂)_nC≡N, (CH₂)_nCON(R⁵R⁵), (CH₂)_nCO2R⁵, (CH₂)_nCOR⁵, (CH₂)_nNR⁵C(O)R⁵, (CH₂)_nNR⁵CO2R⁵, (CH₂)_nNR⁵C(O)N(R5)2, (CH₂)_nNR⁵SO2R⁵, (CH₂)_nS(O)_pR⁵, (CH₂)_nSO₂NR⁵)(R⁵), (CH₂)_nOR⁵, (CH₂)_nOC(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 R³ and oxo; Y is selected from the group consisting of: hydrogen, (C₁-C₈) alkyl, (C₂- C₆)alkenyl, (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 R³ and oxo. In some embodiments, compounds of Formula (XXVIII) include: R¹ is selected from the group consisting of hydrogen, (C₁-C₆) alkyl, (CH₂)_0-1(C₃-C₇) cycloalkyl, and (CH₂)_0-1- 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 R³ and oxo; R² is phenyl or thienyl optionally substituted with one to three groups independently selected from R³ or R² is phenyl optionally substituted with one to three groups independently selected from R³; X is selected from the group consisting of (C₁-C₆) 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 R³ and oxo; and the (CH₂)_n group is optionally substituted with one to three groups independently selected from R⁴, halogen, S(O)_pR⁴, N(R⁴)₂, and OR⁴ or X is selected from the group consisting of (C₁-C₆) alkyl, (CH₂)_0-1-phenyl, (CH₂)₀-1-heteroaryl, (CH₂)₀-1-heterocyclyl, (CH₂)₀-1NHC(O)R⁵, (CH₂)₀-1CO2R⁵, and (CH₂)₀- ₁C(O)N(R⁵)(R⁵); 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 R³ and 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, (C₁-C₈) alkyl, (C₂-C₆)alkenyl, (CH₂)_n(C₅-C₇) 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 R³ and oxo, Y is selected from the group consisting of hydrogen, (C₁-C₈) 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 R³ and oxo. Y is cyclohexyl or (C₁-C₆) alkyl; wherein the cyclohexyl and alkyl groups are unsubstituted or substituted with one to three groups independently selected from R³ and oxo, or Y is hydrogen; r is 1 or 2 and s is 1. In one aspect, the MC4R agonist is a compound of Formula (XXVIIIa) or (XXVIIIb) having the trans orientation of the R² and piperidinecarbonyl substituents:

( IIb), or a pharmaceutically acceptable salt thereof; wherein: r is 1 or 2; n is 0, 1, or 2; p is 0, 1, or 2; R¹ is NR⁶R⁷ wherein R⁶ and R⁷ are each independently selected from the group consisting of hydrogen, (C₁-C₆) alkyl, (C₃-C₆) cycloalkyl, (CH₂)₀-1 phenyl, (CH₂)₀-1 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 R³ and oxo; R² is phenyl or thienyl optionally substituted with one to three groups independently selected from R³; R³ is selected from the group consisting of: (C₁-C₆) 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)_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 two substituents independently selected from halogen, (C₁-C₄) alkyl, trifluoromethyl, and (C₁-C₄) alkoxy; and (CH₂)_n is unsubstituted or substituted with one to two groups independently selected from halogen and (C₁-C₄) alkyl; each R⁴ is independently selected from the group consisting of: hydrogen, (C₁-C₈) alkyl, and (C₃-C₆) cycloalkyl; or two R⁴ 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(C₁-C₄)alkyl; each R⁵ is independently selected from the group consisting of: hydrogen, C_1-5 alkyl, phenyl, naphthyl, heteroaryl, and (C₅-C₆) 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 R³ and oxo; or two R⁵ groups 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, (C₁-C₈) alkyl, (C₂-C₆) alkenyl, (CH₂)₀-1(C₅-C₇) cycloalkyl, (CH₂)₀-1-phenyl, (CH₂)_0-1-naphthyl, and (CH₂)_0-1-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 R³ and oxo; and X is selected from the group consisting of:

In one aspect, the MC4R agonist is a compound of Formula (XXVIIIc) or (XXVIIId) having the trans orientation of the phenyl and piperidinecarbonyl substituents:

Id), or a pharmaceutically acceptable salt thereof; wherein: r is 1 or 2; R¹ is NR⁶R⁷ wherein R⁶ and R⁷ are each independently hydrogen, (C₁-C₄) alkyl, (CH₂)_0-1(C₃-C₆) cycloalkyl, or (CH₂)_{0- 1} 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 R³ and oxo; each R³ is 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:

In one aspect, the MC4R agonist is a compound of Formula (XXVIIIe) or (XXVIIIf) having the trans orientation of the phenyl and piperidinecarbonyl substituents:

), or a pharmaceutically acceptable salt thereof; wherein: r is 1 or 2; R¹ is NR⁶R⁷ wherein R⁶ and R⁷ are each independently hydrogen or (C₁-C₄) alkyl; and R³ is selected from the group consisting of: (C₁-C₆) 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)_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, trifluoromethyl, and (C₁-C₄) alkoxy; and (CH₂)_n is unsubstituted or substituted with one to two groups independently selected from halogen and (C₁-C₄) alkyl; and each R⁴ is independently selected from the group consisting of: hydrogen, (C₁-C₆) alkyl, (CH₂)_n-phenyl, (CH₂)_n-naphthyl, and (CH₂)_n(C₃-C₇) cycloalkyl; or two R⁴ 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(C₁- C₄)alkyl. In some embodiments, compounds of Formulas (XXVIII), (XXVIIIa), (XXVIIIb), (XXVIIIc), (XXVIIId), (XXVIIIe), and (XXVIIIf) include following:

or a pharmaceutically acceptable salt thereof. In some embodiments, the MC4R agonist is a compound described in US 7,012,084, which is incorporated herein by reference in its entirety. In one aspect, the MC4R agonist is a compound of Formula (XXIX) or Formula (XXIXa): 4 4

O (XXIX) O (XXIXa), 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)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; R¹ is selected from the group consisting of: hydrogen, -(CH₂)_n-NR⁷R⁸, amidino, (C₁-C₄) alkyliminoyl, (C₁-C₁₀)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 R³ and oxo; R² is 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 R³ is independently selected from the group consisting of: (C₁-C₆) 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)_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 R⁴ is independently selected from the group consisting of: hydrogen, (C₁-C₈) 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)_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 R⁵ is independently selected from the group consisting of: hydrogen, (C₁-C₈) 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 R⁵ 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(C₁-C₄)alkyl; each R⁶ is independently selected from the group consisting of: hydrogen, (C₁-C₆) alkyl, - (CH₂)_nC_3- 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)_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)- (C₁-C₈) 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 R³ and oxo, and wherein any methylene (CH₂) in R⁶ is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and (C₁-C₄) alkyl; or wherein two R⁶ groups 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 R³ and oxo; each R⁷ and R⁸ is independently selected from the group consisting of: hydrogen, amidino, (C₁-C₄) alkyliminoyl, (C₁-C₁₀)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 R³ and oxo; each R⁹ is independently selected from the group consisting of: hydrogen, C₁ 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)_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)- (C₁-C₈) alkyl, -(CH₂)mN(R⁵)-S(O)2- (C₁-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 R³ and oxo, and wherein any methylene (CH₂) in R⁹ is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and (C₁-C₄) alkyl; or wherein two R⁹ groups 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 R³ and 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. In some embodiments, compounds of Formula (XXIX) and Formula (XXIXa) include: R¹ is selected from the group consisting of hydrogen, (C₁-C₆) alkyl, -(CH₂)_0-1-(C₃- C₆) cycloalkyl, -(CH₂)₀-1-phenyl, and -(CH₂)₀-1-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 R³ and oxo. In a class of this embodiment, R¹ is selected from the group consisting of hydrogen, and (C₁-C₆) alkyl, and alkyl is optionally substituted with one to three groups independently selected from R³ and oxo. In another class of this embodiment, R¹ is -(CH₂)_0-1- NR⁷R⁸; R² is phenyl or thienyl optionally substituted with one to three groups independently selected from R³. In a class of this embodiment, R² is phenyl optionally substituted with one to three groups independently selected from R³; R³ is selected from the group consisting of (C₁-C₆) alkyl, -(CH₂)_n-phenyl, -(CH₂)_n-heteroaryl, -(CH₂)_n(C₂-C₇) 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) 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, R³ is selected from the group consisting of (C₁-C₆) 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; R⁴ is selected from the group consisting of hydrogen, (C₁-C₆) alkyl, halogen, OR⁵, -(CH₂)_nN(R⁵)₂, - (CH₂)_nC≡N, -(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; R⁶ is independently selected from the group consisting of: hydrogen, (C₁-C₆) alkyl, -(CH₂)_n(C₃-C₇) cycloalkyl, - (CH₂)_n-phenyl, -(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)_nOC(O)R⁵, - (CH₂)_nO-(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(R⁵)C(O)(CH₂)_nN(R⁵)₂, -(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 and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R³ and oxo, and wherein any methylene (CH₂) in R⁶ is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and (C₁-C₄) alkyl, or wherein two R⁶ groups 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 R³ and 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 (XXIX) and Formula (XXIXa), Z is N. In a class of this embodiment, Z is N and R¹ is selected from the group consisting of hydrogen, amidino, (C₁- C₄) alkyliminoyl, (C₁-C₁₀)alkyl, -(CH₂)_n-(C₃-C₇) cycloalkyl, -(CH₂)_n-phenyl, -(CH₂)_n- naphthyl, and -(CH₂)_n-heteroaryl. In some embodiments of Formula (XXIX) and Formula (XXIXa), Z is CH. In a class of this embodiment, Z is CH and R¹ is -(CH₂)_n-NR⁷R⁸. In one aspect, the MC4R agonist is a compound of Formula (XXIXb) or Formula (XXIXc) having the trans orientation of the R² and piperidinecarbonyl substituents:

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)₂ and the other is selected from the group consisting of C(R⁶)₂, N(R⁶), C(O), ═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; R¹ is selected from the group consisting of hydrogen, amidino, (C₁-C₄) alkyliminoyl, (C₁- C₆) alkyl, (C₅-C₆)cycloalkyl, -(CH₂)_0-1 phenyl, -(CH₂)_0-1 heteroaryl, and -(CH₂)_0-1-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 R³ and oxo; R² is phenyl or thienyl optionally substituted with one to three groups independently selected from R³; each R³ is independently selected from the group consisting of: (C₁-C₆) 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)_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 R⁴ is independently selected from the group consisting of: hydrogen, (C₁-C₈) 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)_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 R⁵ is independently selected from the group consisting of: hydrogen, (C₁-C₈) 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 R⁵ 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(C₁-C₄)alkyl; each R⁶ is independently selected from the group consisting of: hydrogen, (C₁-C₆) 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)_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)-(C₁-C₈) 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 R³ and oxo, and wherein any methylene (CH₂) in R⁶ is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and (C₁-C₄) alkyl, or wherein two R⁶ groups 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 R³ and oxo; each R⁷ and R⁸ is independently selected from the group consisting of: hydrogen, amidino, (C₁-C₄) alkyliminoyl, C_1-10 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 R³ and oxo; each R⁹ is independently selected from the group consisting of: hydrogen, (C₁-C₆) 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)_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)-(C₁-C₈) alkyl, -(CH₂)_mN(R⁵)-S(O)₂-(C₁-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 R³ and oxo, and wherein any methylene (CH₂) in R⁹ is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and (C₁-C₄) alkyl; or wherein two R⁹ groups 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 R³ and 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. In one aspect, the MC4R agonist is a compound of Formula (XXIXd) or Formula (XXIXe) having the trans orientation of the phenyl and piperidinecarbonyl substituents:

( , e), 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)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; R¹ is selected from the group consisting of hydrogen, (C₁-C₄) alkyl, -(CH₂)_0-1- phenyl, and -(CH₂)₀-1-NR⁷R⁸; each R³ is independently selected from the group consisting of: (C₁-C₆) alkyl, -(CH₂)₀-1-phenyl, -(CH₂)₀-1-naphthyl, -(CH₂)₀-1-heteroaryl, -(CH₂)₀-1-(C₂- C₇)heterocycloalkyl, -(CH₂)_0-1-(C₃-C₇) cycloalkyl, halogen, OR⁵, -(CH₂)_0-1-N(R⁵)₂, -(CH₂)_0-1- C≡N, -(CH₂)₀-1-CO2R⁵, NO2, -(CH₂)O-, -NR⁵S(O)1-2R⁵, -(CH₂)₀-1-S(O)1-2N(R⁵)₂, -(CH₂)₀-1- S(O)0-2R⁵, -(CH₂)₀-1-NR⁵C(O)N(R⁵)₂, -(CH₂)₀-1-C(O)N(R⁵)₂, -(CH₂)₀-1-NR⁵C(O)R⁵, -(CH₂)₀- 1-NR⁵CO₂R⁵, -(CH₂)_0-1-NR⁵C(O)-heteroaryl, -(CH₂)_0-1-C(O)NR⁵N(R⁵)₂, -(CH₂)_0-1- C(O)NR⁵NR⁵C(O)R⁵, O(CH₂)_0-1-C(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 R⁴ is independently selected from the group consisting of: hydrogen, (C₁-C₈) alkyl, -(CH₂)₀-1-phenyl, -(CH₂)₀-1- naphthyl, -(CH₂)₀-1-heteroaryl, -(CH₂)₀-1-(C₂-C₇) heterocycloalkyl, -(CH₂)₀-1-(C₃-C₇) cycloalkyl, halogen, OR⁵, -(CH₂)_0-1-N(R⁵)₂, -(CH₂)_0-1-C≡N, -(CH₂)_0-1-C(O)OR⁵, -(CH₂)_0-1- OC(O)R⁵, NO2, -(CH₂)₀-1-NR⁵S(O)1-2-R⁵, -(CH₂)₀-1-N(S(O)1-2-R⁵)₂, -(CH₂)₀-1-S(O)1-2-N(R⁵)₂, -(CH₂)₀-1-S(O)0-2-R⁵, -(CH₂)₀-1-NR⁵C(O)N(R⁵)₂, -(CH₂)₀-1-C(O)N(R⁵)₂, -(CH₂)₀-1- NR⁵C(O)R⁵, -(CH₂)_0-1-NR⁵CO₂R⁵, -(CH₂)_0-1-NR⁵C(O)-heteroaryl, -(CH₂)_0-1-C(O)NR⁵N(R⁵)₂, -(CH₂)_0-1-C(O)NR⁵NR⁵C(O)R⁵, O(CH₂)_0-1-C(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 R⁵ is independently selected from the group consisting of: hydrogen, (C₁-C₈) alkyl, -(CH₂)₀-1-(C₃-C₇) cycloalkyl, -(CH₂)_0-1-(C₂-C₇) heterocycloalkyl, -(CH₂)_0-1-phenyl, -(CH₂)_0-1-naphthyl, -(CH₂)_0-1- heteroaryl, and -(CH₂)_0-1-(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 R⁵ 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(C₁-C₄)alkyl; each R⁶ is independently selected from the group consisting of: hydrogen, (C₁-C₆) alkyl, -(CH₂)_0-1-(C₃-C₇) cycloalkyl, -(CH₂)₀-1-(C₂-C₇) heterocycloalkyl, -(CH₂)₀-1-phenyl, -(CH₂)₀-1-naphthyl, -(CH₂)₀-1- heteroaryl, -(CH₂)₀-1-C(O)R⁵, -(CH₂)₀-1-C(O)OR⁵, -(CH₂)₀-1-C(OH)R⁵, -(CH₂)₀-1-(O)(CH₂)₀-1- N(R⁵)₂, -(CH₂)_0-1C(O)(CH₂)_0-1-NR⁷R⁸, -(CH₂)_0-1-OR⁵, -(CH₂)_0-1-OC(O)R⁵, -(CH₂)_0-1-O- (CH₂)1-2-N(R⁵)₂, -(CH₂)₀-1-CN, -(CH₂)₀-3-N(R⁵)₂, -(CH₂)₀-3-N(R⁵)C(O)R⁵, -(CH₂)₀-3- N(C(O)R⁵)₂, -(CH₂)₀-3-N(R⁵)C(O)OR⁵, -(CH₂)₀-1-N(C(O)OR⁵)₂, -(CH₂)₀-1-N(R⁵)C(O)(CH₂)₀- ₁N(R⁵)₂, -(CH₂)_0-3-N(R⁵)-S(O)- (C₁-C₈) alkyl, -(CH₂)_0-3-N(R⁵)-S(O)₂-(C₁-C₈) alkyl, -(CH₂)_0-1- S-R⁵, -(CH₂)_0-1-S(O)-R⁵, and -(CH₂)_0-1-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 R³ and oxo, and wherein any methylene (CH₂) in R⁶ is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and (C₁-C₄) alkyl, or wherein two R⁶ groups 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 R³ and oxo; each R⁷ and R⁸ is independently selected from the group consisting of: hydrogen, amidino, (C₁-C₄) alkyliminoyl, C_1-10alkyl, -(CH₂)_0-1-(C₃-C₇) cycloalkyl, - (CH₂)_0-1-phenyl, -(CH₂)_0-1-naphthyl, and -(CH₂)_0-1-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 R³ and oxo; each R⁹ is independently selected from the group consisting of: hydrogen, (C₁-C₆) alkyl, -(CH₂)₀-1-(C₃-C₇) cycloalkyl, -(CH₂)₀-1-(C₂-C₇) heterocycloalkyl, -(CH₂)₀-1-phenyl, -(CH₂)₀-1-naphthyl, -(CH₂)₀-1-heteroaryl, -(CH₂)₀-1- C(O)R⁵, -(CH₂)_0-1-C(O)OR⁵, -(CH₂)_0-1-C(OH)R⁵, -(CH₂)_0-1-C(O)(CH₂)_0-1-N(R⁵)₂, -(CH₂)_0-1- C(O)(CH₂)_0-1-NR⁷R⁸, -(CH₂)_1-3-OR⁵, -(CH₂)_1-3-OC(O)R⁵, -(CH₂)_1-3-O-(CH₂)_1-2-N(R⁵)₂, - (CH₂)1-3-CN, -(CH₂)1-3-N(R⁵)₂, -(CH₂)1-3-N(R⁵)C(O)R⁵, -(CH₂)1-3-N(C(O)R⁵)₂, -(CH₂)1-3- N(R⁵)C(O)OR⁵, -(CH₂)_1-3-N(C(O)OR⁵)₂, -(CH₂)_1-3-N(R⁵)C(O)(CH₂)_0-1N(R⁵)₂, -(CH₂)_1-3- N(R⁵)-S(O)-(C₁-C₈) alkyl, -(CH₂)_1-3-N(R⁵)-S(O)₂-(C₁-C₈) alkyl, -(CH₂)_1-3-S-R⁵, -(CH₂)_0-1- S(O)-R⁵, and -(CH₂)₀-1-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 R³ and oxo, and wherein any methylene (CH₂) in R⁹ is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and (C₁-C₄) alkyl; or wherein two R⁹ groups 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 R³ and oxo; r is 1 or 2; and s is 1 or 2. In one aspect, the MC4R agonist is a compound of Formula (XXIXf):

( ), wherein R¹, R², R⁴, X, Y, r, and s are defined as above. In some embodiments, compounds of Formula (XXIX), (XXIXa), (XXIXb), (XXIXc), (XXIXd), (XXIXe), and (XXIXf) include:

or a pharmaceutically acceptable salt thereof. In one aspect, the MC4R agonist is a compound of Formula (XXX):

(XXX), o a 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; R¹ is selected from the group consisting of: hydrogen, -(CH₂)_n-NR⁷R⁸, amidino, (C₁-C₄) alkyliminoyl, (C₁-C₁₀)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 R³ and oxo; R² is 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 R³ is independently selected from the group consisting of: (C₁-C₆) 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)_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 R⁴ is independently selected from the group consisting of: hydrogen, (C₁-C₈) 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)_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 R⁵ is independently selected from the group consisting of: hydrogen, (C₁-C₈) 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 R⁵ 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(C₁-C₄)alkyl; each R⁶ is independently selected from the group consisting of: hydrogen, (C₁-C₆) 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)_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)- (C₁-C₈) 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 R³ and oxo, and wherein any methylene (CH₂) in R⁶ is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and (C₁-C₄) alkyl; or wherein two R⁶ groups 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 R³ and oxo; each R⁷ and R⁸ is independently selected from the group consisting of: hydrogen, amidino, (C₁-C₄) alkyliminoyl, (C₁-C₁₀)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 R³ and oxo; each R⁹ is independently selected from the group consisting of: hydrogen, (C₁-C₆) 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)_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)- (C₁-C₈) alkyl, -(CH₂)mN(R⁵)-S(O)2-(C₁-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 R³ and oxo, and wherein any methylene (CH₂) in R⁹ is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and (C₁-C₄) alkyl; or wherein two R⁹ groups 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 R³ and oxo; each R¹⁰ is independently selected from the group consisting of hydrogen, -(C₁-C₆) alkyl, -C(O)- (C₁-C₆) alkyl, and -S(O)₂-(C₁-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. In some embodiments, compounds of Formula (XXX) include:

In some embodiments, the MC4R agonist is a compound described in US 7,329,673, which is incorporated herein by reference in its entirety. In one aspect, the MC4R agonist is a compound of Formula (XXXI):

(XXXI), or a pharmaceutically acceptable salt thereof; wherein is selected from the group consisting of: hydrogen, amidino, (C₁-C₄) alkyliminoyl; (C₁-C₁₀)alkyl; -(CH₂)_n-NR⁷R⁸, -(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 R³ and oxo; R² is 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 R³ is independently selected from the group consisting of: hydrogen, (C₁-C₆) 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)-heteroaryl, -(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 R³ is 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; R⁴ is selected from the group consisting of: -(CH₂)_n-N(R⁵)-NR⁵R⁶ ; -(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)_n-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; R⁵ is selected from the group consisting of: hydrogen, (C₁-C₆) alkyl and C(O) (C₁-C₆) alkyl wherein alkyl is unsubstituted or substituted with one to three groups independently selected from halogen, (C₁-C₄) alkyl hydroxy, oxo, and (C₁-C₄) alkoxy; R⁶ is selected from the group consisting of: hydrogen, (C₁-C₆) alkyl C(O)C_l-6 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)_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 R⁶ 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(C₁-C₄)alkyl; each R⁷ and R⁸ is independently selected from the group consisting of: hydrogen, amidino, (C₁-C₄) alkyliminoyl (C₁-C₁₀)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 R³ and oxo; R⁹ is 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, phenylstatine, 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^l), 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. In an embodiment of Formula (XXXI), R^l is selected from the group consisting of: hydrogen, (C₁-C₄) alkyl-(CH₂)_0-l(C₃-C₆) cycloalkyl and -(CH₂)_0-l-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 R³ and oxo. In an embodiment, R^l is selected from the group consisting of: hydrogen, and (C₁-C₄) alkyl, and alkyl is optionally substituted with one to three groups independently selected from R³ and oxo. In another class of this embodiment, R¹ is -(CH₂)_0-1NR⁷R⁸. In some embodiments of Formula (XXXI), R² is phenyl or thienyl optionally substituted with one to three groups independently selected from R³. In a class of this embodiment, R² is phenyl optionally substituted with one to three groups independently selected from R³. In some embodiments of Formula (XXXI), R³ is selected from the group consisting of: (C₁-C₄) alkyl -(CH₂)_n-phenyl-(CH₂)_n-heteroaryl, -(CH₂)_n(C₂-C₇) 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, R³ is 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. In some embodiments of Formula (XXXI), R³ is 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(C₁-C₆) alkyl, -(CH₂)_n-N(R⁵)-(CH₂)_n-N((C₁-C₆) alkyl)2, -(CH₂)_n-N(R⁵)- (CH₂)_n-NHC(O) (C₁-C₆) alkyl, -(CH₂)_n-N(R⁵)-(CH₂)_n-N(R⁵)C(O) (C₁-C₆) alkyl -(CH₂)_n- N(R⁵)-(CH₂)_n-N(C(O) (C₁-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)_n- C(R⁵)(NH₂)(CH₂)_q-O(C₁-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)_n-R⁶, - (CH₂)_n-N(R⁵)-(CH₂)_n-C(R⁵)(NH₂)(CH₂)q-SH, -(CH₂)_n-N(R⁵)-(CH₂)_n-C(R⁵)(NH₂)(CH₂)q-S- (C₁-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-(C₁-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)_n are 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. In some embodiments of Formula (XXXI), R⁴ is 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(C₁-C₆) alkyl -(CH₂)_n-N(R⁵)-(CH₂)_q-N((C₁-C₆) alkyl)₂, -(CH₂)_n-N(R⁵)-(CH₂)_q-NHC(O)(C₁-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-N(R⁵)-(CH₂)_n-C(R⁵)(NH₂)(CH₂)q-O(C₁-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-(C₁-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)_n are 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. In some embodiments of the compounds of Formula (XXXI), R⁶ is selected from the group consisting of: hydrogen, (C₁-C₆) alkyl, C(O) (C₁-C₆) 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 R⁶ 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(C₁-C₄)alkyl. In an embodiment, Z is N. In some embodiments, Z is N and R^l is selected from the group consisting of: hydrogen, amidino, (C₁-C₄) alkyliminoyl, Cl-10 alkyl- (CH₂)_n-(C₃-C₇) cycloalkyl-(CH₂)_nphenyl-(CH₂)_n-naphthyl and -(CH₂)_n-heteroaryl. In an embodiment, Z is N and R¹ is (C₁-C₁₀)alkyl. In an embodiment, Z is CH. In an embodiment, Z is CH and R¹ is -(CH₂)_n-NR⁷R⁸. In an embodiment, r is 1 or 2 and s is 1. In one aspect, the MC4R agonist is a compound of Formula (XXXIa) or (XXXIb) having the trans orientation of the phenyl and piperidinecarbonyl substituents:

a pharmaceutically acceptable salt thereof; wherein R¹ is selected from the group consisting of: hydrogen, amidino, (C₁-C₄) alkyliminoyl, (C₁-C₆) alkyl, (C₅-C₆) cycloalkyl, -(CH₂)_0-l phenyl, and -(CH₂)_0-l heteroaryl, 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 R³ and oxo; each R³ is independently selected from the group consisting of: hydrogen, (C₁-C₆) 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)0-lR⁶, - (CH₂)_nNR⁶C(O)N(R⁶)₂, -(CH₂)_nC(O)N(R⁶)₂, -(CH₂)_nNR⁶C(O)R⁶, -(CH₂)_nNR⁶CO2R⁶, - (CH₂)_nNR⁶C(O)-heteroaryl -(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 R³ is 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; R⁴ is selected from the group consisting of: -(CH₂)-N(R⁵)-NR⁵R⁶, -(CH₂)- N(R⁵)-(CH₂)_1-3-NR⁵R⁶, -(CH₂)-N(R⁵)-C(=NR⁵)-NR⁵R⁶, -(CH₂)-N(R⁵)-(CH₂)_l-3-N(R⁵)- (C=NR⁵)-NR⁵R⁶, -(CH₂)-N(R⁵)-(CH₂)_0-2-C(R⁵)(N(R⁵)₂)-(CH₂)_1-2-OR⁶, -(CH₂)-N(R⁵)-(CH₂)_0- 2-C(R⁵)(N(R⁵)₂)(CH₂)1-2-R⁶, -(CH₂)-N(R⁵)-(CH₂)₀-2-C(R⁵)(N(R⁵)₂)(CH₂)1-2-S-R⁶, -(CH₂)- N(R⁵)-(CH₂)₀-2-C(R⁵)(N(R⁵)₂)(CH₂)1-4-NR⁵R⁶, -(CH₂)-N(R⁵)-C(O)(CH₂)₀-2- C(R⁵)(N(R⁵)₂)(CH₂)_1-2-R⁶, -(CH₂)-N(R⁵)-C(O)(CH₂)_0-2-C(R⁵)(N(R⁵)₂)(CH₂)_1-2-S-R⁶, -(CH₂)- N(R⁵)-C(O)(CH₂)₀-2-C(R⁵)(N(R⁵)₂)(CH₂)1-4-NR⁵R⁶, and -(CH₂)-N(R⁵)-R⁹, wherein (CH₂) is unsubstituted or substituted with one to three groups independently selected from halogen, (C₁-C₄) alkyl, hydroxy, oxo, and (C₁-C₄) alkoxy; R⁵ is selected from the group consisting of: hydrogen, (C₁-C₆) alkyl, and C(O) (C₁-C₆) alkyl wherein alkyl is unsubstituted or substituted with one to three groups independently selected from halogen, (C₁-C₄) alkyl, hydroxy, oxo, and (C₁-C₄) alkoxy; R⁶ is selected from the group consisting of: hydrogen, (C₁-C₆) alkyl, C(O) (C₁-C₆) alkyl, -(CH₂)_n(C₃-C₇) cycloalkyl -(CH )_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)_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 R⁶ 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(C₁-C₄)alkyl; each R⁷ and R⁸ is independently selected from the group consisting of: hydrogen, amidino, (C₁-C₄) alkyliminoyl (C₁-C₁₀)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 R³ and oxo; R9 is 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, phenylstatine, 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(R¹), and N; r is l or 2; s is 0, 1, or 2; and n is 0, 1, 2, 3 or 4. In one aspect, the MC4R agonist is a compound of Formula (XXXIc) or (XXXId) having the trans orientation of the difluorophenyl and piperidinecarbonyl substituents: a

pharmaceutically acceptable salt thereof; wherein: R¹ is selected from the group consisting of: hydrogen, (C₁-C₄) alkyl and -(CH₂)₀-1 phenyl; each R³ is independently selected from the group consisting of: hydrogen, (C₁-C₆) 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)0-lR⁶, - (CH₂)_nNR⁶C(O)N(R⁶)₂, -(CH₂)_nC(O)N(R⁶)₂, -(CH₂)_nNR⁶C(O)R⁶, -(CH₂)_nNR⁶CO2R⁶, - (CH₂)_nNR⁶C(O)-heteroaryl -(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 R³ is 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; R⁴ is selected from the group consisting of: -(CH₂)-N(R⁵)-NR⁵R⁶, -(CH₂)- N(R⁵)-(CH₂)1-3-NR⁵R⁶, -(CH₂)-N(R⁵)-C(=NR⁵)-NR⁵R⁶ -(CH₂)-N(R⁵)-(CH₂)1-3-N(R⁵)- (C=NR⁵)-NR⁵R⁶, -(CH₂)-N(R⁵)-(CH₂)_0-2-C(R⁵)(N(R⁵)₂)-(CH₂)_1-2-OR⁶, -(CH₂)-N(R⁵)-(CH₂)_0- 2-C(R⁵)(N(R⁵)₂)(CH₂)1-2-R⁶, -(CH₂)-N(R⁵)-(CH₂)₀-2-C(R⁵)(N(R⁵)₂)(CH₂)1-2-S-R⁶, -(CH₂)- N(R⁵)-(CH₂)₀-2-C(R⁵)(N(R⁵)₂)(CH₂)1-4-NR⁵R⁶, -(CH₂)-N(R⁵)-C(O)(CH₂)₀-2- C(R⁵)(N(R⁵)₂)(CH₂)_1-2-R⁶, -(CH₂)-N(R⁵)-C(O)(CH₂)_0-2-C(R⁵)(N(R⁵)₂)(CH₂)_1-2-S-R⁶, -(CH₂)- N(R⁵)-C(O)(CH₂)_0-2-C(R⁵)(N(R⁵)₂)(CH₂)_1-4-NR⁵R⁶, and -(CH₂)-N(R⁵)-R⁹, wherein (CH₂) is unsubstituted or substituted with one to three groups independently selected from halogen, (C₁-C₄) alkyl, hydroxy, oxo, and (C₁-C₄) alkoxy; R⁵ is selected from the group consisting of: hydrogen, (C₁-C₆) alkyl and C(O) (C₁-C₆) alkyl wherein alkyl is unsubstituted or substituted with one to three groups independently selected from halogen, (C₁-C₄) alkyl hydroxy, oxo, and (C₁-C₄) alkoxy; R⁶ is selected from the group consisting of: hydrogen, (C₁-C₆) alkyl C(O) (C₁-C₆) 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)_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 R⁶ 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(C₁-C₄)alkyl; each R⁷ and R is independently selected from the group consisting of: hydrogen, amidino, (C₁-C₄) alkyliminoyl (C₁-C₁₀)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 R³ and oxo; R⁹ is 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, phenylstatine, 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^l), and N; r is 1 or 2; s is 0, 1, or 2; and n is 0, 1, 2, 3, or 4. In some embodiments, compounds disclosed herein include compounds of Formula (XXXIe) and (XXXIf):

XXXIf), wherein R¹, R², R³, R⁴, r, s, n, p, and q are as defined in WO 2005/009950; and pharmaceutically acceptable salts thereof. In some embodiments, compounds disclosed herein include compounds of Formula (XXXIg) or (XXXIh):

XXXIh), wherein R¹, R², R³, R⁴, r, s, n, p, and q are as defined in WO 2005/009950; and pharmaceutically acceptable salts thereof. In some embodiments, compounds disclosed herein include compounds of Formula (XXXIj) or (XXXIk):

( j, ), wherein R¹, R², R³, R⁴ , r, s, n, p, and q are as defined in WO 2005/009950; and pharmaceutically acceptable salts thereof. In some embodiments, compounds disclosed in WO 2005/009950 include:

In some embodiments, the MC4R agonist is a compound described in WO 2005/009950, which is incorporated herein by reference in its entirety. In one aspect, the MC4R agonist is a compound of Formula (XXXII):

( ), r a pharmaceutically acceptable salt thereof; wherein: X and Y are independently selected from the group consisting of: hydrogen, (C₁-C₈) alkyl, (C₂-C₆)alkenyl, -(CH₂)_n(C₃-C₈) cycloalkyl, -(CH₂)_n-phenyl, -(CH₂)_n-naphthyl, -(CH₂)_n- heteroaryl, -(CH₂)_n(C₂-C₈) heterocycloalkyl, -(CH₂)_nC≡N, -(CH₂)_nCON(R⁵)₂, -(CH₂)_nCO2R⁵, -(CH₂)_nCOR⁵, -(CH₂)_nNR⁵C(O)R⁵, -(CH₂)_nNR⁵CO₂R⁵, -(CH₂)_nNR⁵C(O)N(R⁵)₂, - (CH₂)_nNR⁵SO2R⁵, -(CH₂)_nS(O)pR⁵, -(CH₂)_nSO2N(R⁵)₂, -(CH₂)_nOR⁵, -(CH₂)_nOC(O)R⁵, - (CH₂)_nOC(O)OR⁵, -(CH₂)_nOC(O)N(R⁵)₂, -(CH₂)_nN(R⁵)₂, and -(CH₂)_nNR⁵SO2N(R⁵)₂, wherein alkenyl, phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R³, and wherein alkyl, cycloalkyl, heterocycloalkyl, and (CH₂) are unsubstituted or substituted with one to three groups independently selected from R³ and oxo; R¹ is selected from the group consisting of: hydrogen, amidino, (C₁-C₄) alkyliminoyl, (C₁-C₁₀)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 R³ and oxo; R² is selected from the group consisting of: (C₁-C₆) alkyl, phenyl, naphthyl, and heteroaryl, wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R³, and wherein alkyl is unsubstituted or substituted with one to three groups independently selected from R³ and oxo; each R³ is independently selected from the group consisting of: (C₁-C₈) alkyl, -(CH₂)_n-phenyl, -(CH₂)_n-naphthyl, -(CH₂)_n-heteroaryl, -(CH₂)_n(C₂-C₈) heterocycloalkyl, -(CH₂)_n(C₃-C₇) cycloalkyl, halogen, OR⁴ -(CH₂)_nN(R⁴)₂, -(CH₂)_nC≡N, - (CH₂)_nCO2R⁴, 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, - (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, 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 R³ substituents on the same carbon atom are taken together with the carbon atom to form a cyclopropyl group; each R⁴ is independently selected from the group consisting of: hydrogen, (C₁-C₆) alkyl, -(CH₂)_n- phenyl, -(CH₂)_n-heteroaryl, -(CH₂)_n-naphthyl, -(CH₂)_n(C₂-C₈) heterocycloalkyl, -(CH₂)_n(C₃-C₇) cycloalkyl, and -(CH₂)_n(C₃-C₇) bicycloalkyl; wherein alkyl, phenyl, heteroaryl, heterocycloalkyl, 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 two R⁴ 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(C₁-C₄)alkyl; each R⁵ is independently selected from the group consisting of: hydrogen, (C₁-C₈) alkyl, -(CH₂)_n-phenyl, -(CH₂)_n-naphthyl, -(CH₂)_n-heteroaryl, and -(CH₂)_n(C₃-C₇) cycloalkyl; wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R³, and wherein alkyl, (CH₂) and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R³ and oxo, or wherein two R⁵ 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(C₁-C₄)alkyl; R⁶ and R⁷ are each independently selected from the group consisting of: hydrogen, (C₁-C₈) alkyl, -(CH₂)_n(C₃-C₆) cycloalkyl, -(CH₂)_n-aryl, hydroxy, halogen, and amino; r is 1 or 2; s is 0, 1, or 2; t is 1, 2, or 3; n is 0, 1 or 2; and p is 0, 1, or 2. In some embodiments of the compounds of Formula (XXXII), R¹ is selected from the group consisting of hydrogen, (C₁-C₆) alkyl, -(CH₂)_0-l(C₃-C₆) cycloalkyl, and -(CH₂)_0-l- phenyl, wherein phenyl is unsubstituted or substituted with one to three groups independently selected from R³, and wherein alkyl, cycloalkyl, and (CH₂) are optionally substituted with one to three groups independently selected from R³ and oxo. In some embodiments of the compounds of Formula (XXXII), R² is phenyl or thienyl optionally substituted with one to three groups independently selected from R³. In some embodiments, R² is phenyl optionally substituted with one to three groups independently selected from R³. In some embodiments of the compounds of Formula (XXXII), R³ is independently selected from the group consisting of: (C₁-C₈) alkyl, -(CH₂)_n-phenyl, -(CH₂)_n-naphthyl, -(CH₂)_n-heteroaryl, - (CH₂)_n(C₂-C₈) heterocycloalkyl, -(CH₂)_n(C₃-C₇) cycloalkyl, halogen, 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 R³ substituents on the same carbon atom are taken together with the carbon atom to form a cyclopropyl group. In some embodiments of the compounds of Formula (XXXII), X is selected from the group consisting of: hydrogen, -(CH₂)_n-phenyl, -(CH₂)_n-naphthyl, -(CH₂)_n-heteroaryl, - (CH₂)_n(C₃-C₈) cycloalkyl, and -(CH₂)_n(C₂-C₈) heterocycloalkyl, wherein phenyl, naphthyl, and heteroaryl are optionally substituted with one to three groups independently selected from R³, and wherein cycloalkyl, heterocycloalkyl, and (CH₂) are optionally substituted with one to three groups independently selected from R³ and oxo. In some embodiments, X is selected from the group consisting of hydrogen, -(CH₂)_0-l-phenyl, -(CH₂)_0-l-heteroaryl, - (CH₂)_0-l(C₂-C₈) heterocycloalkyl, and -(CH₂)_0-l(C₃-C₈) cycloalkyl, wherein phenyl and heteroaryl are optionally substituted with one to three groups independently selected from R³, and wherein cycloalkyl, heterocycloalkyl, and CH₂ are optionally substituted with one to three groups independently selected from R³ and oxo. In some embodiments, X is selected from the group consisting of hydrogen and -(CH₂)_0-l-(C₃-C₈) cycloalkyl, wherein cycloalkyl and (CH₂) are optionally substituted with one to three groups independently selected from R³ and oxo. In some embodiments, X is selected from the group consisting of hydrogen and cyclohexyl, wherein cyclohexyl is optionally substituted with one to three groups independently selected from R³ and oxo. In some embodiments of the compounds of Formula (XXXII), Y is selected from the group consisting of (C₁-C₆)-alkyl, -(CH₂)_n-phenyl, -(CH₂)_n-naphthyl, -(CH₂)_n-heteroaryl, - (CH₂)_n-(C₃-C₈) cycloalkyl, -(CH₂)_n(C₂-C₈) heterocycloalkyl, -(CH₂)_nC(O)N(R⁵)₂, - (CH₂)_nCO2R⁵, -(CH₂)_nS(O)pR⁵, -(CH₂)_nOR⁵, -(CH₂)_nNR⁵C(O)R⁵, and -(CH₂)_nNR⁵SO2R⁵, wherein phenyl, naphthyl, and heteroaryl are optionally substituted with one to three groups independently selected from R³, and wherein alkyl, cycloalkyl, heterocycloalkyl and (CH₂) are optionally substituted with one to three groups independently selected from R³ and oxo. In some embodiments, Y is selected from the group consisting of (C₁-C₆) alkyl, -(CH₂)_0-l- phenyl, -(CH₂)_0-l-heteroaryl, -(CH₂)_n-(C₃-C₈) cycloalkyl, -(CH₂)_0-l(C₂-C₈)-heterocycloalkyl, - (CH₂)_0-lNHC(O)R⁵, -(CH₂)_0-lCO₂R⁵, -(CH₂)_0-1C(O)N(R⁵)₂, and -(CH₂)_0-lS(O)_pR⁵, wherein phenyl and heteroaryl are optionally substituted with one to three groups independently selected from R³, and wherein alkyl, cycloalkyl, heterocycloalkyl, and (CH₂) are optionally substituted with one to three groups independently selected from R₃ and oxo. In some embodiments, Y is selected from the group consisting of -(CH₂)_0-l-phenyl, -(CH₂)₀- 1NHC(O)R⁵, -(CH₂)₀-1C(O)N(R⁵)₂, and -(CH₂)_0-lS(O)pR⁵, wherein (CH₂) is optionally substituted with one to three groups independently selected from R³ and oxo. In some embodiments, r is 1. In some embodiments, r is 1 and s is 1. In some embodiment, r is 2. In some embodiments, r is 2 and s is 1. In some embodiments, t is 2. In one aspect, the MC4R agonist is a compound of Formula (XXXIIa) or (XXXIIb):

Ib), or a pharmaceutically acceptable salt thereof; wherein X is selected from the group consisting of: hydrogen, -(CH₂)_n-phenyl, -(CH₂)_n -naphthyl, -(CH₂)_n-heteroaryl, -(CH₂)_n(C₂-C₈) cycloalkyl, and -(CH₂)_n(C₂-C₈) heterocycloalkyl, wherein phenyl, naphthyl, and heteroaryl are optionally substituted with one to three groups independently selected from R³, and wherein cycloalkyl, heterocycloalkyl, and (CH₂) are optionally substituted with one to three groups independently selected from R³ and oxo; Y is selected from the group consisting of:

-C(O)N-t-Bu, -NCH₂(O)CH₃, -C(O)N(CH₃)₂, -CH₂SCH(CH₃)₂, -CH₂CH₂NEt₂, CH₂CONEt_2, -CH₂S(OH)CH₂(CH₃)₂, -CH₂S(O)2CH(CH₃)₂, -C(O)NHCH₂CH₂N(CH₃)₂, C(O)CH(CH₃)₂, -CH₂NHCOtBu, -CH₂SCH₃, -CH₂S(O)CH₃, -CH₂S(O)2CH₃, -CH₂N(CH₃)C(O)t-Bu, -CH₂N(iPr)COMe, -CH₂N(iPr)SO₂Me, -CH(Et)NHC(O)Me, -CH(Me)NHC(O)Me, -CH₂NHC(O)Me, -C(O)NHC(Me)₂CH₂OMe, -C(O)NHC(Me)₂CH₂OH, -CH₂CH₂C(Me)₂OH,

, wherein phenyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R³, and wherein alkyl, cycloalkyl, heterocycloalkyl, and (CH₂) are unsubstituted or substituted with one to three groups independently selected from R³ and oxo; R¹ is hydrogen, amidino, (C₁-C₄) alkyliminoyl, (C₁-C₆) alkyl, (C₅-C₆)cycloalkyl, - (CH₂)_0-l phenyl, -(CH₂)_0-l heteroaryl, wherein phenyl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R³, and wherein alkyl, cycloalkyl, and (CH₂) are unsubstituted or substituted with one to three groups independently selected from R³ and oxo; R² is phenyl or thienyl optionally substituted with one to three groups independently selected from R³; each R³ is independently selected from the group consisting of: (C₁-C₈) alkyl, -(CH₂)_n-heteroaryl, -(CH₂)_n(C₂-C₈) heterocycloalkyl, 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; 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 R³ substituents on the same carbon atom are taken together with the carbon atom to form a cyclopropyl group; each R⁴ is independently selected from the group consisting of: hydrogen, (C₁-C₈) alkyl, phenyl, heteroaryl, -(CH₂)_n(C₂-C₈) heterocycloalkyl, and (C₃-C₆) cycloalkyl; wherein alkyl, phenyl, heteroaryl, heterocycloalkyl, 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 two R⁴ 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(C₁-C₄) alkyl; each R5 is independently selected from the group consisting of: hydrogen, (C₁-C₈) alkyl, -(CH₂)_n- phenyl, -(CH₂)_n-naphthyl, -(CH₂)_n-heteroaryl, and -(CH₂)_n(C₃-C₇) cycloalkyl; wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R³, and wherein alkyl, (CH₂) and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R³ and oxo, or wherein two R⁵ 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(C₁-C₄)alkyl; R⁶ and R⁷ are each independently selected from the group consisting of: hydrogen, (C₁-C₈) alkyl, -(CH₂)_n(C₃-C₆) cycloalkyl, -(CH₂)_n-aryl, hydroxy, halogen, and amino; r is 1 or 2; s is 0, 1 or 2; t is 1, 2, or 3; n is 0, 1, or 2; and is 0, l, or 2. In some embodiments, Y is selected from the group consisting of: -CH₂SCH₃, - CH₂S(O)CH₃, -CH₂S(O)₂CH₃, -CH(Et)NHC(O)Me, -CH₂CH₂NEt₂, -CH₂CONEt₂,

, wherein phenyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R³, and wherein alkyl, cycloalkyl, heterocycloalkyl, and (CH₂) are unsubstituted or substituted with one to three groups independently selected from R and oxo. In one aspect, the MC4R agonist is a compound of Formula (XXXIIc) or (XXXIId) having the trans orientation of the phenyl and piperidine carbonyl substituents:

( c, d), or a pharmaceutically acceptable salt thereof; wherein X is selected from the group consisting of hydrogen, -(CH₂)_0-l-phenyl, -(CH₂)_0-l-naphthyl, -(CH₂)_0-l-heteroaryl, -(CH₂)_0-l-(C₃-C₈) cycloalkyl, and -(CH₂)_0-l(C₂-C₈) heterocycloalkyl, wherein phenyl, naphthyl, and heteroaryl are optionally substituted with one to three groups independently selected from R³, and wherein cycloalkyl, heterocycloalkyl, and (CH₂) are optionally substituted with one to three groups independently selected from R³ and oxo; Y is selected from the group consisting of - CH₂SCH₃, -CH₂S(O)CH₃, -CH₂S(O)₂CH₃, -CH(Et)NHC(O)Me, -CH₂CH₂NEt₂, - CH₂CONEt₂,

l, and heteroaryl are

unsubstituted or substituted with one to three groups independently selected from R , and wherein alkyl, cycloalkyl, heterocycloalkyl, and (CH₂) are unsubstituted or substituted with one to three groups independently selected from R³ and oxo; R¹ is hydrogen, (C₁-C₄) alkyl, or -(CH₂)_0-l phenyl; each R³ is independently selected from the group consisting of: (C₁-C₈) alkyl, -(CH₂)_0-l-heteroaryl, -(CH₂)_0-l(C₂-C₈) heterocycloalkyl, halogen, OR⁴, -(CH₂)₀-1N(R⁴)₂, -(CH₂)_0-1C≡N, -(CH₂)_0-1CO₂R⁴, -(CH₂)_0-1NR⁴SO₂R⁴, -(CH₂)_0-lSO₂N(R⁴)₂, -(CH₂)_0-lS(O)_0-3R⁴, -(CH₂)₀-₁NR⁴C(O)N(R⁴)₂, -(CH₂)₀-1C(O)N(R⁴)₂, -(CH₂)₀-₁NR⁴C(O)R⁴, -(CH₂)₀-₁NR⁴CO2R⁴, - (CH₂)_0-lNR⁴C(O)-heteroaryl, -(CH₂)₀-1C(O)NR⁴N(R⁴)₂, -(CH₂)₀-1C(O)NR⁴NR⁴C(O)R⁴, O(CH₂)_0-lC(O)N(R⁴)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 R³ substituents on the same carbon atom are taken together with the carbon atom to form a cyclopropyl group; each R⁴ is independently selected from the group consisting of: hydrogen, (C₁-C₈) alkyl, phenyl, heteroaryl, -(CH₂)_0-l(C₂-C₈) heterocycloalkyl, and (C₃-C₆) cycloalkyl; wherein alkyl, phenyl, heteroaryl, heterocycloalkyl, 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 two R⁴ 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(C₁-C₄) alkyl; each R⁵ is independently selected from the group consisting of: hydrogen, (C₁-C₈) alkyl, -(CH₂)_0-l-phenyl, -(CH₂)_0-l- naphthyl, -(CH₂)_0-l-heteroaryl, and -(CH₂)₀-1(C₃-C₇) cycloalkyl; wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R³, and wherein alkyl, (CH₂) and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R³ and oxo, or wherein two R⁵ 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(C₁- C₄) alkyl; R⁶ and R⁷ are each independently selected from the group consisting of: hydrogen, (C₁-C₈) alkyl, -(CH₂)₀-1-(C₃-C₆) cycloalkyl, -(CH₂)_0-l-aryl, hydroxy, halogen, and amino; t is 1, 2, or 3; r is 1 or 2; and s is 0, 1 or 2. In some embodiments, compounds disclosed in WO 2004/087159 include:

or a pharmaceutically acceptable salt thereof. In some embodiments, the MC4R agonist is a compound described in WO 2004/087159, which is incorporated herein by reference in its entirety. In some embodiments, the MC4R agonist is a peptide, e.g., a peptide shown in Table 2 below. Table 2: Exemplary MC4R agonists

In one aspect, the present disclosure features a compound of Formula (XXXIV):

R (XXXIV), or a pharmaceutically acceptable salt thereof, wherein Z is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R¹; L¹ is absent, C_1-6 alkylene, C_2-6 alkenylene, C_2-6 alkynylene, or C_1-6 heteroalkylene, wherein each alkylene, alkenylene, alkynylene, and heteroalkylene is optionally substituted with one or more R³; each R¹ is independently C₁-C₆-alkyl, C₂-C₆- alkenyl, C₂-C₆-alkynyl, C₁-C₆-heteroalkyl, cycloalkyl, heterocyclyl, aryl, C₁-C₆ alkylene- aryl, C₁-C₆ alkenylene-aryl, C₁-C₆ alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, –OR^A, – NR^BR^C, –NR^BC(O)R^D, –NO₂, –C(O)NR^BR^C, –C(O)R^D, –C(O)OR^D, –SR^E, or –S(O)_xR^D, wherein each alkyl, alkylene, alkenyl, alkenylene, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R⁴; or two R¹ groups, together with the atoms to which they are attached, form a 3-7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R⁴; each R^2a and R^2b is independently hydrogen, C_1-6 alkyl, C_1-6 heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R⁷; or R^2a and R^2b, together with the atoms to which they are attached, form a 3-7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R⁷; each R⁵ is independently hydrogen, halo, cyano, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, or –OR^A; each R^6a and R^6b is independently hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, –C(O)NR^BR^C, –C(O)R^D, –C(O)OR^D, or –S(O)_xR^D, wherein each of alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R⁸; each R³, R⁴, R⁷, and R⁸ is independently C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, –OR^A, –NR^BR^C, –NR^BC(O)R^D, –NO₂, – C(O)NR^BR^C, –C(O)R^D, –C(O)OR^D, –SR^E, or –S(O)xR^D; each R^A is independently hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, aryl, heteroaryl, C₁-C₆ alkylene-aryl, C₁-C₆ alkylene-heteroaryl, –C(O)R^D, or –S(O)_xR^D; each of R^B and R^C is independently hydrogen, C₁-C₆ alkyl, C₁-C₆- heteroalkyl, cycloalkyl, heterocyclyl, –OR^A; or R^B and R^C together with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with one or more R⁹; each R^D and R^E is independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C₁-C₆ alkylene-aryl, or C₁-C₆ alkylene-heteroaryl; each R⁹ is independently hydrogen, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and m is 0, 1, 2, 3, 4, 5 or 6. In an embodiment, Z is aryl or heteroaryl optionally substituted with one or more R¹. In an embodiment, Z is aryl or heterocyclyl optionally substituted with one or more R¹. In an embodiment, Z is aryl optionally substituted with one or more R¹. In an embodiment, Z is heterocyclyl optionally substituted with one or more R¹. In an embodiment, Z is a 5- membered nitrogen-containing heterocyclyl, optionally substituted with one or more R¹, and L¹ is absent. In an embodiment, R¹ is C_1-6 alkyl (e.g., C₄alkyl) or aryl, optionally substituted with one or more R⁴ (e.g., halo). In an embodiment, Z is a 6-membered aryl (e.g., phenyl), optionally substituted with one or more R¹, and L¹ is absent, C_1-6 alkylene, or C_1-6 heteroalkylene. In an embodiment, R¹ is heteroaryl (e.g., -CH₂-tetrazole). In an embodiment, R¹ is optionally substituted C_1-6 heteroalkyl (e.g., -CH(CH₃)-C(O)NH₂). In an embodiment, L¹ is -CH₂CHNH(CH₂)-. In an embodiment, each of R^2a and R^2b is independently hydrogen, C_1-6 alkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl, optionally substituted with one or more R⁷. In an embodiment, R⁷ is cycloalkyl, heterocyclyl, aryl, or heteroaryl. In an embodiment, R⁷ is nitrogen-containing heteroaryl (e.g., tetrazolyl). In an embodiment, R^2a and R^2b, together with the atoms to which they are attached, form a 3-7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R⁷. In an embodiment, R^2a and R^2b, together with the atoms to which they are attached, form a 3-7-membered nitrogen-containing heterocyclyl, optionally substituted with one or more R⁷. In an embodiment, R⁵ is independently halo, cyano, C₁-C₆- alkyl, or –OR^A. In an embodiment, m is 0, 1, or 2. In an embodiment, m is 0. In an embodiment, each R^6a and R^6b is independently hydrogen, C₁-C₆-alkyl, C₁-C₆- heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, –C(O)NR^BR^C, –C(O)R^D, –C(O)OR^D, or –S(O)_xR^D, wherein each of alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R⁸. In an embodiment, one of R^6a and R^6b is independently hydrogen or C₁-C₆-alkyl, and the other of R^6a and R^6b is independently C₁-C₆-alkyl, C₁-C₆-heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, –C(O)NR^BR^C, –C(O)R^D, –C(O)OR^D, or –S(O)_xR^D, wherein each of alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R⁸. In an embodiment, one of R^6a and R^6b is independently hydrogen, and the other of R^6a and R^6b is independently C₁-C₆-alkyl, C₁-C₆-heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, –C(O)NR^BR^C, –C(O)R^D, –C(O)OR^D, or –S(O)_xR^D, wherein each of alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R⁸. In an embodiment, one of R^6a and R^6b is independently hydrogen, and the other of R^6a and R^6b is independently C₁-C₆-heteroalkyl optionally substituted with one or more R⁸ (e.g., oxo). In an embodiment, one of R^6a and R^6b is independently C₁-C₆-alkyl, C₁-C₆-heteroalkyl, and the other of R^6a and R^6b is independently aryl optionally substituted with one or more R⁸ (e.g., halo). In some embodiments, the present disclosure features a compound of Formula (XXXV):

(XXXV), or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from optionally substituted C_1-6 alkyl, C_1-4 alkylene-carbamoyl, and C_1-4 alkylene-heteroaryl; R² is selected from optionally substituted C_1-6 alkyl, C_1-6 heteroalkyl, and C_1-4 alkylene-heteroaryl; R^3a and R^3b are each independently selected from H and C_1-4 alkyl; R⁴ is halo; and m is selected from 0, 1, 2, 3, 4, or 5. In an embodiment, R¹ is C_1-6 alkyl (e.g., C₄ alkyl). In an embodiment, R¹ is heteroaryl (e.g., -CH₂-tetrazole). In an embodiment, R¹ is optionally substituted C_1-6 heteroalkyl (e.g., - CH(CH₃)-C(O)NH₂). In some embodiments, the compound is a compound of Formula (XXXV-i):

(XXXV i) or a pharmaceutically acceptable salt, wherein R¹ is selected from optionally substituted C_1-6 alkyl, C_1-4 alkylene-carbamoyl, and C_1-4 alkylene-heteroaryl; R² is selected from optionally substituted C_1-6 alkyl, C_1-6 heteroalkyl, and C_1-4 alkylene-heteroaryl; R^3a and R^3b are each independently selected from H and C_1-4 alkyl; R⁴ is halo; and m is selected from 0, 1, 2, 3, 4, or 5. In another aspect, the present disclosure features a compound of Formula (XXXVI):

or a pharmaceutically acceptable salt thereof, wherein A is cycloalkyl, heterocyclyl, aryl, or heteroaryl; L² is absent, -N(R⁶)-, C_1-6 alkylene, C_2-6 alkenylene, C_2-6 alkynylene, or C_1-6 heteroalkylene, wherein each alkylene, alkenylene, alkynylene, and heteroalkylene is optionally substituted with one or more R⁶; each R¹ is independently C₁-C₆-alkyl, C₁-C₆-heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C₁- C₆ alkylene-aryl, C₁-C₆ alkylene-heteroaryl, C₁-C₆ alkylene-heterocyclyl, C₁-C₆ alkylene- cycloalkyl, –C(O)NR^BR^C, –C(O)R^D, or –S(O)_xR^D, wherein each alkyl, alkylene, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R⁷; each R² or R³ is independently halo, cyano, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, or – OR^A; each R^4a and R^4b is independently hydrogen, C_1-6 alkyl, C_1-6 heteroalkyl, –C(O)NR^BR^C, –C(O)R^D, or –S(O)xR^D, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R⁸; or R^4a and R^4b, together with the atoms to which they are attached, form a 3-7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R⁸; each R⁵ is independently hydrogen, halo, cyano, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, or –OR^A; each R⁶, R⁷, and R⁸ is independently C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, –OR^A, –NR^BR^C, –NR^BC(O)R^D, –NO2, – C(O)NR^BR^C, –C(O)R^D, –C(O)OR^D, –SR^E, or –S(O)_xR^D; each R^A is independently hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, aryl, heteroaryl, C₁-C₆ alkylene-aryl, C₁-C₆ alkylene-heteroaryl, –C(O)R^D, or –S(O)xR^D; each of R^B and R^C is independently hydrogen, C₁-C₆ alkyl, C₁-C₆- heteroalkyl, cycloalkyl, heterocyclyl, –OR^A; or R^B and R^C together with the atom to which they are attached form a 3-7-membered heterocyclyl ring optionally substituted with one or more R⁹; each R^D and R^E is independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C₁-C₆ alkylene-aryl, or C₁-C₆ alkylene-heteroaryl; each R⁹ is independently hydrogen, C₁-C₆ alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; y is 0 or 1; and each of m, n, and p is independently 0, 1, 2, 3, 4, 5 or 6. In an embodiment, A is aryl or heteroaryl optionally substituted with one or more R⁵. In an embodiment, A is aryl or heterocyclyl optionally substituted with one or more R⁵. In an embodiment, A is aryl optionally substituted with one or more R⁵. In an embodiment, A is heterocyclyl optionally substituted with one or more R⁵. In an embodiment, A is a 5- membered nitrogen-containing heterocyclyl, optionally substituted with one or more R⁵. In an embodiment, R⁵ is C_1-6 alkyl (e.g., C₄alkyl) or aryl. In an embodiment, A is a 6- membered aryl (e.g., phenyl), optionally substituted with one or more R⁵. In an embodiment, L² is absent or N(R₆) (e.g., NH). In an embodiment, L² is absent. In an embodiment, L² is N(R6) (e.g., NH). In an embodiment, m is 0. In an embodiment, R³ is C_1-6 alkyl (e.g., C4 alkyl) or halo (e.g,. chloro or fluoro). In an embodiment, R³ is halo (e.g,. chloro or fluoro). In an embodiment, R³ is chloro. In an embodiment, n is 0, 1, or 2. In an embodiment, n is 0. In an embodiment, n is 1. In an embodiment, n is 1 and R³ is chloro. In an embodiment, p is 1. In an embodiment, each of R^4a and R^4b is independently hydrogen, C_1-6 alkyl, C_1-6 heteroalkyl, –C(O)NR^BR^C, –C(O)R^D, or –S(O)_xR^D, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R⁸. In an embodiment, R⁸ is cycloalkyl, heterocyclyl, aryl, or heteroaryl. In an embodiment, R⁸ is nitrogen-containing heteroaryl (e.g., tetrazolyl). In an embodiment, R^4a and R^4b, together with the atoms to which they are attached, form a 3-7- membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R⁸. In an embodiment, R^4a and R^4b, together with the atoms to which they are attached, form a 3-7- membered nitrogen-containing heterocyclyl, optionally substituted with one or more R⁸. In an embodiment, y is 0. In an embodiment, y is 1. In some embodiments, the compound of Formula (XXXVI) is a compound of Formula (XXXVI-a):

or a pharmaceutically acceptable salt thereof, wherein each of R¹, L², R^4a, R^4b, R⁵, y, and p are as defined for Formula (XXXVI). In some embodiments, the compound of Formula (XXXVI) is a compound of Formula (XXXVI-b):

or a pharmaceutically acceptable salt thereof, wherein each of R^8-i, R^8-iii, and R^8-iii, is independently hydrogen, C₁-C₆-alkyl, C₂-C₆- alkenyl, C₂-C₆-alkynyl, C₁-C₆-heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, –OR^A, – NR^BR^C, –NR^BC(O)R^D, –C(O)NR^BR^C, –C(O)R^D, –C(O)OR^D, wherein each of R^B, R^C, R^D is defined as for Formula (XXXVI). In an embodiment, R^8-i is C_1-4 alkyl or aryl. In an embodiment, R^8-i is C₃ alkyl. In an embodiment, R^8-i is aryl (e.g., phenyl). In an embodiment, each of R^8-ii and R^8-iii is independently selected from H and C1 alkyl. In an embodiment, at least one of R^8-ii and R^8-iii is H. In an embodiment, one of R^8-ii and R^8-iii is CH₃. In some embodiments, the compound of Formula (XXXVI) is a compound of Formula (XXXVI-c):

(xxii), or a pharmaceutically acceptable salt thereof, wherein each of R^8-i, R^8-iii, and R^8-iii, is independently hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, –OR^A, –NR^BR^C, –NR^BC(O)R^D, –C(O)NR^BR^C, –C(O)R^D, –C(O)OR^D, wherein each of Ring A, R^B, R^C, R^D is defined as for Formula (XXXVI). In some embodiments, the compound of Formula (XXXVI) is a compound of Formula (XXXVI-d):

( V d), or a pharmaceutically acceptable salt thereof, wherein each of R^8-i, R^8-iii, and R^8-iii, is independently hydrogen, C₁-C₆-alkyl, C₂-C₆- alkenyl, C₂-C₆-alkynyl, C₁-C₆-heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, –OR^A, – NR^BR^C, –NR^BC(O)R^D, –C(O)NR^BR^C, –C(O)R^D, –C(O)OR^D, wherein each of R^B, R^C, R^D is defined as for Formula (XXXVI). In some embodiments, the MC4R agonist is a small molecule, e.g., a small molecule described in Table 3 below. Table 3: Exemplary MC4R agonists

Examples of administration of a compound or composition comprising a compound or pharmaceutical salt of a compound of the disclosure include peripheral administration. Examples of peripheral administration include oral, subcutaneous, intraperitoneal, intramuscular, intravenous, rectal, transdermal or intranasal forms of administration. As used herein, peripheral administration can include all forms of administration of a compound or a composition comprising a compound of the instant disclosure which excludes intracranial administration. Examples of peripheral administration include, but are not limited to, oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, extended release, slow release implant, depot and the like), nasal, vaginal, rectal, sublingual or topical routes of administration, including transdermal patch applications and the like. 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. The compounds of the disclosure 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. The compounds described herein may exist in one or more tautomeric forms. All tautomers and mixtures thereof are included in the scope of the present disclosure. For example, a claim to 2-hydroxypyridinyl would also cover its tautomeric form, α-pyridonyl. The present disclosure further features providing an MC4R agonist in combination with an additional agent. Exemplary agents include a second MC4R agonist (e.g., an agent described herein or elsewhere), or an agent aimed to treat a symptom of obesity or a co- morbidity. For example, the additional agent may be an anti-hypertensive drug, a pain medication, an anti-inflammatory, a lipid-lowering agent, a cardiovascular drug, or a diuretic. The combination therapy may be administered as a single formulation or as separate formulations. In an embodiment, the MC4R agonist and the additional agent are administered as a single pharmaceutical composition. In an embodiment, the MC4R agonist and the additional agent are administered as separate pharmaceutical compositions. In the case of separate formulations, the MC4R agonist and the additional agent may be administered concomitantly or sequentially. In an embodiment, the MC4R agonist and the additional agent are administered concomitantly. In an embodiment, the MC4R agonist and the additional agent are administered sequentially. For example, the MC4R agonist may be administered prior to the additional agent or subsequent to the additional agent. In some embodiments, the administration of the MC4R agonist and the additional agent has a synergistic or additive effect. For example, the administration of the MC4R agonist and the additional agent may have an additive effect, in which the therapeutic effect of the MC4R agonist and the additional agent is the total sum of the effects of each of the components individually. In contrast, the administration of the MC4R agonist and the additional agent may have a synergistic effect, in which the therapeutic effect of the MC4R agonist and the additional agent is greater than the sum of the individual components. The synergistic effect of the combination of the MC4R agonist and the additional agent may be 0.1%, 0.25%.0.5%.0.75%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%.90%.95%, or more than the total sum of the effects of the MC4R agonist and the additional agent administered individually. In an embodiment, the synergistic effect of the combination of the MC4R agonist and the additional agent is greater than between 5% and 75% of the total sum of the effects of the MC4R agonist and the additional agent administered individually. 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 this disclosure belongs. Also, all publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. Pharmaceutical Compositions/Administration In accordance with any method or composition described herein, in embodiments, provided herein is a unit dosage of a MC4R agonist described herein, e.g., setmelanotide. In embodiments, the unit dosage contains 0.1-10 mg, e.g., 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 mg of the MC4R agonist. In embodiments, the unit dosage contains about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2 mg of the agonist. In embodiments, the unit dosage is suitable for injection, e.g., subcutaneous injection. In embodiments, the unit dosage is disposed in a delivery device suitable for injection, e.g., subcutaneous injection. In embodiments, the unit dosage is disposed in a syringe suitable for injection, e.g., subcutaneous injection, or a pen-type injector. Exemplary pen-type injectors are described, e.g., in US 8512297B2, US5688251A, US5820602A, US2014/0163526A1, and US5226895A, incorporated herein by reference. In embodiments, also provided herein is a pharmaceutical composition comprising a MC4R agonist described herein, e.g., setmelanotide. In embodiments, the pharmaceutical composition includes a therapeutically effective amount of a MC4R agonist described herein, e.g., setmelanotide. A therapeutically effective amount of the agonist can vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the agonist to elicit a desired response in the individual, e.g., amelioration of at least one disorder parameter, e.g., a parameter of obesity or hyperphagia, or amelioration of at least one symptom of the disorder, e.g., obesity, hyperphagia, a disease or disorder associated with a gene in Table 1, or other obesity-associated genetic disorder. In embodiments, a therapeutically effective amount is also one in which any toxic or a detrimental effect of the composition is outweighed by the therapeutically beneficial effects. In certain embodiments, the agonist may be prepared with a carrier that will protect it against rapid release, such as a controlled release formulation, including implants, and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are patented or generally known. See, e.g., Sustained and Controlled Release Drug Delivery Systems, J. R. Robinson, ed., Marcel Dekker, Inc., New York, 1978. In other embodiments, the MC4R agonist can be prepared as described in WO2014/144842, incorporated herein by reference. In embodiments, the MC4R agonist is prepared in a formulation comprising an anionic excipient, e.g., PEG-carboxylic acid, fatty acid having 10 or more carbon atoms, and/or anionic phospholipid. In embodiments, the anionic phospholipid is described in WO2014/144842 (e.g., at pages 7-9). In some embodiments, the anionic phospholipid is 1,2-distearoyl-sn-Glycero-3-Phosphoethanolamine (DSPE), optionally conjugated to polyethylene glycol (PEG), the structure of which is:

, with the value of “n” varying with molecular weight. In embodiments, the fatty acid is described in WO2014/144842 (e.g., at page 9). In embodiments, the PEG-carboxylic acid is described in WO2014/144842 (e.g., at pages 9-11). In embodiments, the molar ratio of the agonist to the anionic excipient ranges from about 1:1 to about 1:10. In embodiments, the MC4R agonist forms an ionic complex with the other components of the formulation, and e.g., provides a desirable pharmacokinetic profile for the agonist (e.g., extend duration of drug action and/or minimize adverse effects). In embodiments, the formulation is a sustained release formulation. In embodiments, the formulation provides reduced fluctuations in concentration of the agonist after administration. In other embodiments, the MC4R agonist can be prepared as described in WO 2019/099735, incorporated herein by reference. In embodiments, the MC4R agonist is prepared in a formulation comprising a neutral diacyl lipid and/or a tocopherol; a phospholipid: an alcohol; and optionally, a polar solvent, e.g., a buffer, optionally comprising an antioxidant. In an embodiment, the neutral diacyl lipid comprises glycerol dioleate (GDO). In an embodiment, the amount of the neutral diacyl lipid (e.g., GDO) is between 20-80%, 30-70%, 33-60%, or 38-43% by weight, e.g., of the total formulation. In an embodiment, the phospholipid comprises phosphatidylcholine (e.g., soybean phosphatidylcholine). In an embodiment, the amount of the phospholipid (e.g., phosphatidylcholine (e.g., soybean phosphatidylcholine)) is between 20-80%, 30-70%, 33-60%, or 38-43% by weight, e.g., of the total formulation. In an embodiment, the alcohol comprises ethanol. In an embodiment, the amount by weight % of ethanol is greater than 1% by weight, e.g., between 1-20% by weight, e.g., of the total formulation. In an embodiment, the polar solvent, e.g., buffer, comprises citrate buffer, optionally wherein the pH of the buffer is 6.4. In an embodiment, the polar solvent, e.g., buffer, comprises citrate acid monohydrate. In an embodiment, the polar solvent, e.g., buffer, comprises an additional component, e.g., an antioxidant, or a chemical or physical stabilizing agent. In an embodiment, the antioxidant is EDTA. A MC4R agonist described herein, e.g., setmelanotide, can be administered to a subject, e.g., human subject, by various methods. In some embodiments, pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and/or to other mucosal surfaces. In embodiments, the route of administration is one of: intravenous injection or infusion, subcutaneous injection, or intramuscular injection. In embodiments, the route of administration is subcutaneous injection. In embodiments, pharmaceutical compositions, e.g., comprising a MC4R agonist described herein, can be administered with medical devices. For example, compositions comprising the agonist can be administered with a needleless hypodermic injection device, such as the devices disclosed in U.S. Pat. No.5,399,163, 5,383,851, 5,312,335, 5,064,413, 4,941,880, 4,790,824, or 4,596,556. Examples of implants and modules include: U.S. Pat. No.4,487,603, which discloses an implantable micro-infusion pump for dispensing medication at a controlled rate; U.S. Pat. No.4,486,194, which discloses a therapeutic device for administering medicaments through the skin; U.S. Pat. No.4,447,233, which discloses a medication infusion pump for delivering medication at a precise infusion rate; U.S. Pat. No.4,447,224, which discloses a variable flow implantable infusion apparatus for continuous drug delivery; U.S. Pat. No.4,439,196, which discloses an osmotic drug delivery system having multi-chamber compartments; and U.S. Pat. No.4,475,196, which discloses an osmotic drug delivery system. Other such implants, delivery systems, and modules can also be used. In embodiments, continuous administration can be indicated, e.g., via subcutaneous pump. In embodiments, the agonist is administered via a syringe (e.g., prefilled syringe), an implantable device, a needleless hypodermic injection device, an infusion pump (e.g., implantable infusion pump), or an osmotic delivery system. In embodiments, the agonist is administered at a unit dosage, e.g., comprising 0.1-10 mg, e.g., 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 mg of the agonist, e.g., subcutaneously. In embodiments, the MC4R agonist is administered in a bolus at a dose of between 0.1-10 mg, e.g., 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 mg of the MC4R agonist, e.g., subcutaneously. In embodiments, the MC4R agonist is administered continuously, e.g., via a pump, e.g., subcutaneous pump. In embodiments, the MC4R agonist, e.g., a unit dosage of the MC4R agonist, is disposed within a delivery device, e.g., a syringe (e.g., prefilled syringe), an implantable device, a needleless hypodermic injection device, an infusion pump (e.g., implantable infusion pump), or an osmotic delivery system. In embodiments, a daily dosage of the MC4R agonist is administered, e.g., subcutaneously, to a subject. In embodiments, the daily dosage of the MC4R agonist is about 0.1 mg to about 10 mg, e.g., 0.1-0.2, 0.2-0.4, 0.4-0.6, 0.6-0.8, 0.8-1, 1-1.2, 1.2-1.5, 1.5-2, 2- 2.5, 2.5-3, 3-3.5, 3.5-4, 4-4.5, 4.5-5, 5-5.5, 5.5-6, 6-6.5, 6.5-7, 7-7.5, 7.5-8, 8-8.5, 8.5- 9, 9-9.5, 9.5-10 mg, e.g., administered subcutaneously. In embodiments, the MC4R agonist, e.g., setmelanotide, is administered, e.g., via one or multiple administrations, over a period of at least 3 weeks, e.g., at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 weeks or more, or at least 1, 2, 3, 4, 5, 6, 7, 8, 8, 9, 10, 11, or 12 months or more, or at least 1, 2, 3, 4 years or more. In embodiments, where multiple administrations are provided of the MC4R agonist, the time interval in between any two of the administrations is at least 6 hours, e.g., 6 h, 12 h, 24 h, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 1 week, 2 weeks, 3 weeks, 4 weeks, or more. In embodiments, the interval in between any two of the administrations is 1 day. Kits A MC4R agonist described herein, e.g., setmelanotide, can be provided in a kit. The kit may include a MC4R agonist described herein and, optionally, a container, a pharmaceutically acceptable carrier and/or informational material. The informational material can be descriptive, instructional, marketing or other material that relates to the methods described herein and/or the use of the MC4R agonist for the methods described herein. The informational material of the kits is not limited in its form. In one embodiment, the informational material can include information about production of the MC4R agonist, physical properties of the MC4R agonist, concentration, date of expiration, batch or production site information, and so forth. In one embodiment, the informational material relates to methods for administering the MC4R agonist, e.g., by a route of administration described herein and/or at a dose and/or dosing schedule described herein. In one embodiment, the informational material can include instructions to administer an MC4R agonist described herein in a suitable manner to perform the methods described herein, e.g., in a suitable dose, dosage form, or mode of administration (e.g., a dose, dosage form, or mode of administration described herein). In another embodiment, the informational material can include instructions to administer an MC4R agonist to a suitable subject, e.g., a human, e.g., an obese human, e.g., severely obese human, e.g., having a disease or disorder associated with a gene in Table 1. The informational material of the kits is not limited in its form. In many cases, the informational material, e.g., instructions, is provided in printed matter, e.g., a printed text, drawing, and/or photograph, e.g., a label or printed sheet. However, the informational material can also be provided in other formats, such as Braille, computer readable material, video recording, or audio recording. In another embodiment, the informational material of the kit is contact information, e.g., a physical address, email address, website, or telephone number, where a user of the kit can obtain substantive information about an MC4R agonist described herein and/or its use in the methods described herein. The informational material can also be provided in any combination of formats. In addition to an MC4R agonist, the composition of the kit can include other ingredients, such as a surfactant, a lyo-protectant or stabilizer, an antioxidant, an antibacterial agent, a bulking agent, a chelating agent, an inert gas, a tonicity agent and/or a viscosity agent, a solvent or buffer, a stabilizer, a preservative, a pharmaceutically acceptable carrier and/or a second agent for treating a condition or disorder described herein. Alternatively, the other ingredients can be included in the kit, but in different compositions or containers than an MC4R agonist described herein. In some embodiments, a component of the kit is stored in a sealed vial, e.g., with a rubber or silicone closure (e.g., a polybutadiene or polyisoprene closure). In some embodiments, a component of the kit is stored under inert conditions (e.g., under Nitrogen or another inert gas such as Argon). In some embodiments, a component of the kit is stored under anhydrous conditions (e.g., with a desiccant). In some embodiments, a component of the kit is stored in a light blocking container such as an amber vial. An MC4R agonist described herein can be provided in any form, e.g., liquid, frozen, dried or lyophilized form. It is preferred that a composition including the MC4R agonist described herein be substantially pure and/or sterile. When an MC4R agonist described herein such as setmelanotide is provided in a liquid solution, the liquid solution preferably is an aqueous solution, with a sterile aqueous solution being preferred. In one embodiment, the MC4R agonist is supplied with a diluents or instructions for dilution. The diluent can include for example, a salt or saline solution, e.g., a sodium chloride solution having a pH between 6 and 9, lactated Ringer’s injection solution, D5W, or PLASMA-LYTE A Injection pH 7.4^® (Baxter, Deerfield, IL). The kit can include one or more containers for the composition containing an MC4R agonist described herein. In some embodiments, the kit contains separate containers, dividers or compartments for the composition and informational material. For example, the composition can be contained in a bottle, vial, IV admixture bag, IV infusion set, piggyback set or syringe (e.g., prefilled syringe), and the informational material can be contained in a plastic sleeve or packet. In other embodiments, the separate elements of the kit are contained within a single, undivided container. For example, the composition is contained in a bottle, vial or syringe that has attached thereto the informational material in the form of a label. In embodiments, the composition is contained in an injector device, e.g., a pen-type injector. The containers of the kits can be airtight or waterproof (e.g., impermeable to changes in moisture or evaporation). ENUMERATED EMBODIMENTS 1. A method of treating a disease, disorder, or condition in a subject, comprising administering to the subject a melanocortin-4 receptor (MC4R) agonist, wherein the subject: (i) has or is identified as having a non-genetic obesity; (ii) has or is identifying as having damage to the brain tissue; and/or (iii) has or is identified as having a proliferative brain disease. 2. The method of embodiment 1, comprising (i). 3. The method of any one of the preceding embodiments, comprising (ii). 4. The method of any one of the preceding embodiments, comprising (iii). 5. The method of any one of the preceding embodiments, wherein the non-genetic obesity comprises obesity is caused by a neurodevelopmental abnormality or a brain malformation. 6. The method of any one of the preceding embodiments, wherein the damage to the brain tissue is present in the hypothalamus. 7. The method of embodiment 6, wherein the damage to the brain tissue is present in the paraventricular hypothalamic nucleus, ventromedial hypothalamic nucleus, or arcuate hypothalamic nucleus. 8. The method of embodiment 7, wherein the damage or trauma in the brain occurs in the ventromedial nucleus. 9. The method of any one of the preceding embodiments, wherein the disease, disorder, or condition comprises hypothalamic obesity. 10. The method of any one of the preceding embodiments, wherein the proliferative brain disease comprises a benign tumor, a benign lesion, or a malignant tumor (e.g., cancer). 11. The method of embodiment 10, wherein the proliferative brain disease is present in the hypothalamus. 12. The method of any one of embodiments 10 or 11, wherein the proliferative brain disease is present in the paraventricular hypothalamic nucleus, ventromedial hypothalamic nucleus, or arcuate hypothalamic nucleus. 13. The method of any one of embodiments 10-12, wherein the proliferative brain disease comprises craniopharyngioma or astrocytoma. 14. The method of any one of the preceding embodiments, wherein the subject has undergone a surgery (e.g., tumor removal or bariatric surgery) or received radiation. 15. The method of any one of the preceding embodiments, wherein the subject is obese, e.g., severely obese. 16. The method of any one of the preceding embodiments, wherein the subject is hyperphagic. 17. The method of any one of the preceding embodiments, wherein the subject has a body mass index (BMI) greater than 35 kg/m² (e.g., ≥36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg/m² or greater) prior to administration of the MC4R agonist, e.g., at the time the MC4R agonist is prescribed, or at the time of the first administration. 18. The method of any one of the preceding embodiments, wherein the subject has a body mass index (BMI) greater than 40 kg/m² (e.g., ≥41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 kg/m² or greater) prior to administration of the MC4R agonist, e.g., at the time the MC4R agonist is prescribed, or at the time of the first administration. 19. The method of any one of the preceding embodiments, wherein the subject has failed one or more previous therapies, e.g., exercise, diet, or behavioral therapies, prior to administration of the MC4R agonist, e.g., at the time the MC4R agonist is prescribed, or at the time of the first administration. 20. The method of any one of the preceding embodiments, wherein the subject has a lower body weight after administration of the MC4R agonist than before administration of the MC4R agonist. 21. The method of any one of the preceding embodiments, 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), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI) (e.g., as described herein). 22. The method of any one of the preceding embodiments, wherein the MC4R agonist is a peptide or a small molecule, or a pharmaceutically acceptable salt thereof. 23. The method of any one of the preceding embodiments, wherein the MC4R agonist is a peptide, e.g., selected from any one of SEQ ID NOs: 1-915. 24. The method of any one of the preceding embodiments, wherein the MC4R agonist is not Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH₂ (SEQ ID NO: 140). 25. The method of any one of embodiments 1-22, wherein the MC4R agonist is a small molecule, or a pharmaceutically acceptable salt thereof. 26. The method of embodiment 25, wherein the MC4R agonist is selected from any one of Compound Nos.100-825, or a pharmaceutically acceptable salt thereof. 27. The method of any one of embodiments 25-26, wherein the MC4R agonist is a compound of any one of Formulas (XIV)-(XXXVI), or a pharmaceutically acceptable salt thereof. 28. The method of any one of embodiments 25-27, wherein the MC4R agonist is a compound of Formula (XIV), or a pharmaceutically acceptable salt thereof. 29. The method of embodiment 28, wherein the MC4R agonist is selected from any one of Compounds 100-221, or a pharmaceutically acceptable salt thereof. 30. The method of any one of embodiments 25-27, wherein the MC4R agonist is a compound of Formula (XV), or a pharmaceutically acceptable salt thereof. 31. The method of embodiment 30, wherein the MC4R agonist is selected from any one of Compounds 300-383, or a pharmaceutically acceptable salt thereof 32. The method of any one of embodiments 25-27, wherein the MC4R agonist is a compound of Formula (XVI), or a pharmaceutically acceptable salt thereof. 33. The method of embodiment 32, wherein the MC4R agonist is selected from any one of Compounds 390-394, or a pharmaceutically acceptable salt thereof 34. The method of any one of embodiments 25-27, wherein the MC4R agonist is a compound of Formula (XVII), or a pharmaceutically acceptable salt thereof. 35. The method of embodiment 34, wherein the MC4R agonist is selected from any one of Compounds 400-403, or a pharmaceutically acceptable salt thereof. 36. The method of any one of embodiments 25-27, wherein the MC4R agonist is a compound of Formula (XX), or a pharmaceutically acceptable salt thereof. 37. The method of embodiment 36, wherein the MC4R agonist is selected from any one of Compounds 410-449, or a pharmaceutically acceptable salt thereof. 38. The method of any one of embodiments 25-27, wherein the MC4R agonist is a compound of Formula (XXI), or a pharmaceutically acceptable salt thereof. 39. The method of embodiment 38, wherein the MC4R agonist is selected from any one of Compounds 460-481, or a pharmaceutically acceptable salt thereof. 40. The method of any one of embodiments 25-27, wherein the MC4R agonist is a compound of Formula (XXIV), or a pharmaceutically acceptable salt thereof. 41. The method of embodiment 40, wherein the MC4R agonist is selected from any one of Compounds 550-576, or a pharmaceutically acceptable salt thereof. 42. The method of any one of the preceding embodiments, wherein the MC4R agonist is Compound 580, or a pharmaceutically acceptable salt thereof. 43. The method of any one of the preceding embodiments, wherein the MC4R agonist is selected from any one of Compounds 600-626, or a pharmaceutically acceptable salt thereof. 44. The method of any one of embodiments 25-27, wherein the MC4R agonist is a compound of any of Formulas (XXVIII), (XXVIIIa), (XXVIIIb), (XXVIIIc), and (XXVIIId) or a pharmaceutically acceptable salt thereof. 45. The method of embodiment 44, wherein the MC4R agonist is selected from any one of Compounds 650-682, or a pharmaceutically acceptable salt thereof. 46. The method of any one of embodiments 25-27, wherein the MC4R agonist is a compound of any of Formulas (XXVIII), (XXVIIIa), (XXVIIIb), (XXVIIIc), (XXVIIId), (XXVIIIe), and (XXVIIIf) or a pharmaceutically acceptable salt thereof. 47. The method of embodiment 46, wherein the MC4R agonist is selected from any one of Compounds 690-693, or a pharmaceutically acceptable salt thereof. 48. The method of any one of embodiments 25-27, wherein the MC4R agonist is a compound of any of Formulas (XXIX), (XXIXa), (XXIXb), (XXIXc), (XXIXd), (XXIXe), and (XXIXf) or a pharmaceutically acceptable salt thereof. 49. The method of embodiment 46, wherein the MC4R agonist is selected from any one of Compounds 700-737, or a pharmaceutically acceptable salt thereof. 50. The method of any one of embodiments 25-27, wherein the MC4R agonist is a compound of Formula (XXX) or a pharmaceutically acceptable salt thereof. 51. The method of embodiment 50, wherein the MC4R agonist is selected from any one of Compounds 740-741, or a pharmaceutically acceptable salt thereof. 52. The method of any one of embodiments 25-27, wherein the MC4R agonist is selected from any one of Compounds 742-751, or a pharmaceutically acceptable salt thereof. 53. The method of any one of embodiments 25-27, wherein the MC4R agonist is selected from any one of Compounds 760-762, or a pharmaceutically acceptable salt thereof. 54. The method of any one of embodiments 25-27, wherein the MC4R agonist is a compound of any one of Formulas (XXXIV)-(XXXVI) or a pharmaceutically acceptable salt thereof. 55. The method of any one of embodiments 25-27, wherein the MC4R agonist is selected from any one of Compounds 1000-1013, or a pharmaceutically acceptable salt thereof. 56. The method of any one of embodiments 25-27, wherein the MC4R agonist is selected from any one of Compounds 800-825, or a pharmaceutically acceptable salt thereof. 57. The method of any one of the preceding embodiments, wherein the MC4R agonist is formulated as a pharmaceutical composition. 58. The method of embodiment 57, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable excipient. 59. The method of embodiment 58, wherein the pharmaceutical composition comprises a polyethylene glycol (e.g., a modified polyethylene glycol, e.g., mPEG-DSPE, e.g., mPEG- 2,000-DSPE). 60. The method of any one of the preceding embodiments, comprising administering the MC4R agonist in a unit dosage suitable for injection, e.g., subcutaneous injection, to the subject. 61. The method of embodiment 60, wherein the unit dosage form is disposed within a delivery device, e.g., a syringe (e.g., prefilled syringe), an implantable device, a needleless hypodermic injection device, an infusion pump (e.g., implantable infusion pump), or an osmotic delivery system. 62. The method of embodiment 61, wherein the MC4R agonist is administered subcutaneously, e.g., by subcutaneous injection. 63. The method of any one of the preceding embodiments, comprising administering the MC4R agonist in a unit dosage suitable for oral delivery to the subject. 64. The method of any one of the preceding embodiments, comprising administering the MC4R agonist in a unit dosage suitable for bucchal delivery to the subject. 65. The method of any one of the preceding embodiments, wherein the subject is a human. 66. The method of any one of the preceding embodiments, wherein the subject is an adult (e.g., over the age of 18 years old). 67. The method of any one of the preceding embodiments, wherein the subject is a pediatric subject, e.g., a child (e.g., under the age of 18, 16, 14, 12, 10, 8, 6, or 4 years). 68. The method of any one of the preceding embodiments, wherein prior to administration of the MC4R agonist, the subject has previously received treatment for obesity, e.g., a non-genetic obesity, e.g., hypothalamic obesity. 69. The method of any one of the preceding embodiments, wherein after a first administration of the MC4R agonist (e.g., at least 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 4 months, 5 months, 6 months, 8 months, 10 months, 1 year, or longer), the subject exhibits a reduction in BMI. 70. The method of claim 69, wherein the reduction of BMI in the subject is greater than 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14% 16%, 18%, 20%, or more, e.g., relative to a reference standard (e.g., BMI prior to administration of the MC4R agonist). 71. The method of any one of embodiments 69-70, wherein the reduction of BMI in the subject is greater than 0.5%, e.g., relative to a reference standard (e.g., BMI prior to administration of the MC4R agonist). 72. The method of any one of embodiments 69-71, wherein the reduction of BMI in the subject is greater than 5%, e.g., relative to a reference standard (e.g., BMI prior to administration of the MC4R agonist). 73. The method of any one of embodiments 69-72, wherein the reduction of BMI in the subject is greater than 10%, e.g., relative to a reference standard (e.g., BMI prior to administration of the MC4R agonist). 74. The method of any one of embodiments 69-73, wherein the reduction of BMI in the subject is between 1%-10% (e.g., 1-5%, or 5-10%), e.g., relative to a reference standard (e.g., BMI prior to administration of the MC4R agonist). 75. The method of any one of embodiments 69-74, wherein the reduction of BMI in the subject occurs between 8 weeks and 6 months after administration of the MC4R agonist. 76. The method of any one of the preceding embodiments, wherein the subject is administered an additional agent (e.g., an additional therapeutic agent). EXAMPLES In order that the invention described herein may be more fully understood, the following examples are set forth. The examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope. The compounds provided herein can be prepared from readily available starting materials using modifications to the specific synthesis protocols set forth below that would be well known to those of skill in the art. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by those skilled in the art by routine optimization procedures. Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in Greene et al., Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein. Reactions can be purified or analyzed according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance (NMR) spectroscopy (e.g., ¹H or ¹³C), infrared (IR) spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry (MS), or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC). In some embodiments, absolute stereochemistry of chiral compounds provided herein is arbitrarily assigned. ¹H NMR: ¹H NMR spectra were recorded on a Bruker Ultrashield (400 MHz or 500 MHz). Chemical shifts were reported in ppm. The multiplicity of a signal is designated by the following abbreviations: br s, broad singlet; s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; m, multiplet. All observed coupling constants, J, are reported in Hertz (Hz). Exchangeable protons are not always observed. LC/MS analysis: LC/MS data was generated using a Waters Acquity UPLC. Waters PDA 2998 detector, Waters QDa MS detector. LC/MS method: reverse phase UPLC analysis. LC/MS Methods, as referenced in the examples, were performed using one of the following conditions: LC/MS Method 1: Column: BEH-C18, Length: 100 mm, Internal diameter: 2.1 mm, Particle size: 1.7 µm; Mobile Phase A: (0.5 g/L AcNH4 in a mixture of 95% H₂O and 5% CH₃CN); Mobile Phase B: CH₃CN; UV detection: 220 nm; Flow Rate: 0.343 mL/min; Gradient table:

LC/MS Method 2: Column: BEH-C18, length: 50 mm, Internal diameter: 2.1 mm, particle size: 1.7 µm; Mobile Phase A: (0.5 g/L AcNH4 in a mixture of 95% H₂O and 5% CH₃CN); Mobile Phase B: CH₃CN. LC/MS Method 3: Column: HSS-T3, length: 100 mm, Internal diameter: 2.1 mm, particle size: 1.8 µm; Mobile Phase A: CH₃CN; Mobile Phase B: (0.5 g/L AcNH4 in a mixture of 95% H₂O and 5% CH₃CN); UV detection: 220 nm; Flow Rate: 0.35 mL/min; Gradient table:

Preparative HPLC purification: prep-HPLC purification was performed on a Waters-2545 or Shimadzu, using one of the following conditions: Condition 1: Column: YMC–Actus Triart Prep C18-S 150*30 mm, 5 µm; Mobile Phase A: water (0.1% HCOOH, pH=2.5), Mobile Phase B: acetonitrile; Flow rate 40 ml/min; Gradient a: 5% B to 90% B; Gradient b: 5% B to 75% B; Chiral SFC SFC Purity Analysis method: Column: ChiralPak AD-3 (4.6x100 mm); Column Temperature: 35 °C; Flow Rate: 3.50 mL/min; Detector Wavelength: 220-410nm; Injection Volume: 2 µL; BPR: 1500 PSI; Mobile Phase (Isocratic Conditions): see specified conditions for each compound. SFC Purification method: Column: ChiralPak AD-H (30x250 mm); Column Temperature: 35 °C; Flow Rate: 150 mL/min; Detector Wavelength: 220 nm; Injection Volume: 1 mL; BPR: 100 bar; Mobile Phase (Isocratic Conditions): see specified conditions for each compound. Synthesis of Peptides General method for peptide synthesis Method 0 for preparation of the resin At room temperature, RINK amide MBHA (1 eq., 500 mg 0.41 mmol) was immersed in DMF (5 mL) for 18 hours. The resin was treated with a solution of piperidine 20% in DMF (25 eq., 5 mL, 10 mmol) with agitation 30 minutes. The resin was alternately washed with DMF (5 mL) and isopropanol (5 mL) until neutral pH (7 washes in total). Method A for coupling At room temperature, the protected amino acid was dissolved in DMF (3 mL), then were added HBTU 20% in DMF (2 eq.), HOBt (2 eq.) and DIPEA (4 eq.) the solution was stirred for 30 minutes. Then, the solution was added to the resin and was agitated 1 hour. The resin was then washed alternately with DMF (5 mL) and i-PrOH (5 mL) 3 washes in total, neutral pH of the last filtrate. Method B for Fmoc deprotection At room temperature, the resin was treated with a solution of piperidine 20% in DMF (25 eq., 5 mL, 10 mmol) agitation 30 minutes. The resin was washed alternately with DMF (5 mL) and i-PrOH (5 mL) until neutral pH. The last wash was done with DMF (5 mL) (7 washes in total). Method A and B were alternately applied on subsequent amino acids until the end of the sequence. Method C for capping At room temperature, the resin was treated with a solution of acetic anhydride (50 eq.) and DIPEA (50 eq.) in DMF (3 mL), the solution was agitated for 30 minutes at room temperature. The solution was filtered, resin was alternately washed with DMF (5 mL) and isopropanol (5 mL) until neutral pH (5 washes in total). Method D for resin cleavage Resin beads were added to an Erlenmeyer. The flask was cooled with an ice-bath, then a solution of TFA (157 eq., 4.8 mL, 64.6 mmol), triisopropylsilane (1.55 eq., 0.13 mL, 0.63 mmol) and H₂O (17 eq., 0.13 mL, 7.22 mmol) was added. At the end of the addition, the ice-bath was removed, and the solution was stirred at room temperature for 3 hours. Resin beads were filtered and washed with TFA. The filtrate was concentrated to afford the crude peptide. Method E for cyclisation To the crude peptide was added a solution of NH₄HCO₃ aqueous, until pH 7-8. The solution was stirred at room temperature for 72 hours. Amino-acids used for synthesis: The following amino acids were used as commercially available compounds: Fmoc-S-trityl-L-cysteine, (2S)-2-({[(9H-fluoren-9- yl)methoxy]carbonyl}amino)-5-{N'-[(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5- yl)sulfonyl]carbamimidamido}pentanoic acid, Fmoc-O-tert-butyl-L-threonine, (2R)-2- ({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)-3-phenylpropanoic acid, (2S)-2-({[(9H- fluoren-9-yl)methoxy]carbonyl}amino)-3-phenylpropanoic acid, N-Fmoc-N'-trityl-L- histidine, (2R)-2-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)propanoic acid, (3R)-3-(4- chlorophenyl)-3-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)propanoic acid, (3S)-3-(4- chlorophenyl)-3-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)propanoic acid, Fmoc-L- proline, (2S)-3-{1-[(tert-butoxy)carbonyl]-1H-indol-3-yl}-2-({[(9H-fluoren-9- yl)methoxy]carbonyl}amino)propanoic acid, (4S)-3-[(2S)-2-({[(9H-fluoren-9- yl)methoxy]carbonyl}amino)-3-phenylpropanoyl]-2,2-dimethyl-1,3-oxazolidine-4-carboxylic acid, and (4S,5R)-3-[(2S)-2-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)-3- phenylpropanoyl]-2,2,5-trimethyl-1,3-oxazolidine-4-carboxylic acid. Example 1: Preparation of tri peptides Synthesis of Peptide 1 N

Prepared following general method for peptides, the resin was prepared following Method 0 then the protected amino-acid (2S)-2-({[(9H-fluoren-9- yl)methoxy]carbonyl}amino)-5-{N'-[(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5- yl)sulfonyl]carbamimidamido}pentanoic acid (2 eq., 476 mg, 0.72 mmol) was coupled to the resin following method A. Then, method B was applied. Method A and B were alternately applied on Fmoc-L-proline (1.99 eq., 247 mg, 0.72 mmol). Method A was applied on (2S)-2- (dimethylamino)-3-phenylpropanoic acid (2 eq., 146 mg, 0.72 mmol). Method D was applied, the crude was purified by Reversed Phase Preparative HPLC (Condition 1, Gradient a) and freeze dried to give the desired compound Peptide 1 (85 mg, 27%) as a powder. The compounds reported in the following table were prepared via an analogous procedure.

Example 2: Representative procedure for the preparation of tetra peptides Synthesis of Peptide 3 HN N A

This peptide was prepared following general method, the resin was prepared following Method 0 then the protected (2S)-2-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)-5-{N'- [(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5- yl)sulfonyl]carbamimidamido}pentanoic acid (2 eq., 428 mg, 0.66 mmol) was coupled to the resin following method A. Method B was applied. Then, method A and B were alternately applied on: Fmoc-L-proline (1.96 eq., 223 mg, 0.65 mmol), (2S)-2-({[(9H-fluoren-9- yl)methoxy]carbonyl}amino)-3-phenylpropanoic acid (2 eq., 256 mg, 0.66 mmol), N-Fmoc- N'-trityl-L-histidine (2 eq., 409 mg, 0.66 mmol). Then, methods C and D were consecutively applied, the crude was purified by Reversed Phase Preparative HPLC (Condition 1, Gradient a) and freeze dried to give the desired compound Peptide 3 as a solid (32 mg, 12%). The compounds reported in the following table were prepared via an analogous procedure.

– 3.97 (m, 1H), 3.13 – 2.95 (m, 4H), 2.86 – 2.77 (m, 2H), 2.72 – 2.64 (m, 1H), 1.77 (s, 4H), 1.53 (s, 3H), 1.22 (d, J = 5.2 Hz, 1H), 1.08 – 1.00 (m, 3H), 0.98 (dd, J = 6.5, 3.8 Hz, 0.5H). Example 3: Preparation of cyclic peptides Synthesis of Peptide 7 HO O O HN N

Prepared following general method, the resin was prepared following Method 0 then the protected amino-acid Fmoc-S-trityl-L-cysteine (2 eq., 480 mg, 0.82 mmol) was coupled to the resin following method A, then method B was applied. Then methods A and B were alternately applied on: (2S)-2-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)-5-{N'- [(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5- yl)sulfonyl]carbamimidamido}pentanoic acid (1.96 eq., 532 mg, 0.8 mmol), Fmoc-O-tert- butyl-L-threonine (2 eq., 326 mg, 0.82 mmol), (2R)-2-({[(9H-fluoren-9- yl)methoxy]carbonyl}amino)-3-phenylpropanoic acid (2 eq., 324 mg, 0.82 mmol), N-Fmoc- N'-trityl-L-histidine (2 eq., 530 mg, 0.82 mmol), (2R)-2-({[(9H-fluoren-9- yl)methoxy]carbonyl} amino)propanoic acid (2 eq., 264 mg, 0.82 mmol), Fmoc-S-trityl-L- cysteine (2 eq., 481 mg, 0.82 mmol), (2S)-2-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)- 5-{N'-[(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5- yl)sulfonyl]carbamimidamido}pentanoic acid (1.96 eq., 532 mg, 0.8 mmol). Then, methods C, D and E were consecutively applied, the crude was purified by Reversed Phase Preparative HPLC (Condition 1, Gradient b) and freeze dried to give the desired compound Peptide 7 (93 mg, 0.09 mmol, 11%). The compounds in the following table were prepared via an analogous procedure.

Preparation of small molecules series Example 4: Synthesis of Int-C4 and Int-C5 Preparation of Int-C1 C

In a three necked round bottom flask with an internal thermal sensor, to a solution of methyl (2E)-3-(4-chlorophenyl)prop-2-enoate (1 eq., 20 g, 102 mmol) in DCM (200 mL) at 0 °C was added N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (1.3 eq., 33.8 mL, 132 mmol) before dropwise addition of a solution of TFA (0.1 eq., 0.76 mL, 10.2 mmol) in DCM (40 mL) maintaining the internal temperature below 5 °C. The reaction mixture was stirred from 0 °C to room temperature for 20 hours. The reaction mixture was diluted with a saturated NaHCO3 aqueous solution and DCM. The layers were separated, and the organic layer was washed with water, dried over MgSO4, filtered, and concentrated to give a crude which was purified by normal phase LC (0-10% EtOAc in Heptane) to give methyl (3S,4R)- 1-benzyl-4-(4-chlorophenyl)pyrrolidine-3-carboxylate as a liquid (Int-C1, 27 g, 81%). LC/MS (ESI+): m/z 330.3 [M+H]⁺.¹H NMR (500 MHz, CDCl3) δ 7.38 – 7.29 (m, 4H), 7.29 – 7.22 (m, 5H), 3.72 – 3.60 (m, 6H), 3.12 – 3.01 (m, 2H), 2.96 (t, J = 8.8 Hz, 1H), 2.82 (dd, J = 8.8, 6.7 Hz, 1H), 2.74 (dd, J = 9.4, 5.8 Hz, 1H). Preparation of Int-C2 BnN

In a three necked round bottom flask equipped with an internal thermal sensor to a solution of Int-C1 (1 eq., 4.16 g, 12.6 mmol) in toluene (250 mL) at room temperature was added dropwise 1-chloroethyl chloroformate (2.5 eq., 3.41 mL, 31.5 mmol) maintaining the internal temperature below 30 °C, and the resulting reaction mixture was stirred at room temperature for 10 minutes and then, at 110 °C for 18 hours. The reaction mixture was cooled down to room temperature and concentrated and diluted with MeOH (250 mL) and stirred at 70 °C for 4 hours. The reaction mixture was cooled down to room temperature and concentrated to give rac-methyl (3R,4S)-4-(4-chlorophenyl)pyrrolidine-3-carboxylate hydrochloride as a powder (Int-C2, 3.5 g, 100%). LC/MS (ESI+): m/z 240.2 [M+H]⁺. ¹H NMR (400 MHz, MeOD) δ 7.42 – 7.34 (m, 4H), 3.82 – 3.64 (m, 7H), 3.49 – 3.41 (m, 1H), 3.39 – 3.32 (m, 1H). Preparation of Int-C3

In a three necked round bottom flask equipped with an internal temperature sensor, to a solution of Int-C2 (1 eq., 23.5 g, 85.1 mmol) in MeOH (250 mL) at room temperature were added formaldehyde (20 eq., 128 mL, 1.7 mol) and AcOH (2 eq., 9.75 mL, 170 mmol) and the resulting mixture was stirred at room temperature for 1 hour before addition of sodium triacetoxyborohydride (2.5 eq., 45.1 g, 213 mmol) at room temperature and the resulting reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with an a saturated NaHCO₃ aqueous solution and EtOAc. The layers were separated, and the aqueous solution was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over MgSO₄, filtered, and concentrated to give rac-methyl (3R,4S)-4-(4- chlorophenyl)-1-methylpyrrolidine-3-carboxylate as an oil (Int-C3, 16.6 g, 77%). LC/MS (ESI+): m/z 254.2 [M+H]⁺.¹H NMR (500 MHz, CDCl3) δ 7.30 – 7.22 (m, 4H), 3.71 – 3.61 (m, 4H), 3.08 – 2.95 (m, 3H), 2.88 (dd, J = 9.2, 6.6 Hz, 1H), 2.65 (dd, J = 9.3, 6.6 Hz, 1H), 2.39 (s, 3H). Preparation of Int-C4 and Int-C5

In a three necked round bottom flask equipped with an internal temperature sensor, to a mixture of Int-C3 (1 eq., 16.6 g, 65.4 mmol) in MeOH (166 mL) at room temperature was added a solution of LiOH (2.5 eq., 7.0 g, 164 mmol) in H₂O (83 mL) maintaining the internal temperature below 25 °C and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated. The resulting solid was dissolved in MeOH and stirred for 30 minutes. The suspension was filtered, and the filtrate was concentrated. The resulting mixture was purified by chiral SFC (Mobile Phase (Isocratic Conditions): 20:80 EtOH:CO₂ (0.6% v/v i-PrNH₂)) to afford (3S,4R)-4-(4-chlorophenyl)-1-methylpyrrolidine-3-carboxylic acid (Int-C4, 6.88 g, 31%) and (3R,4S)-4-(4-chlorophenyl)-1-methylpyrrolidine-3-carboxylic acid (Int-C5, 9.5 g, 43%). Int-C4: LC/MS (ESI+): m/z 240.3 [M+H]⁺, (ESI-): m/z 238.1 [M-H]-.¹H NMR (400 MHz, CDCl3) δ 7.33 – 7.25 (m, 4H), 4.33 – 4.23 (m, 1H), 4.16 – 4.07 (m, 1H), 3.92 (t, J = 9.5 Hz, 1H), 3.10 – 2.98 (m, 3H), 2.80 – 2.71 (m, 4H). OH missing. [α]D²⁰ = -40.0 ° (589 nm, c = 0.08 w/v%, MeOH). (3S, 4R), SFC Separation Method: 20:80 EtOH:CO2 (0.6% v/v i-PrNH₂); SFC Analysis: 20:80 EtOH:CO₂ (0.3% v/v i-PrNH₂); Rt (min): 1.10; SFC purity: 100%. Int-C5: LC/MS (ESI+): m/z 240.3 [M+H]⁺, (ESI-): m/z 238.1 [M-H]-.¹H NMR (400 MHz, MeOD) δ 7.41 – 7.31 (m, 2H), 7.31 – 7.18 (m, 2H), 3.83 – 3.71 (m, 1H), 3.14 (t, J = 8.6 Hz, 1H), 3.04 – 2.93 (m, 2H), 2.89 – 2.74 (m, 2H), 2.41 (s, 3H), OH missing. [α]D²⁰ = + 50.8 ° (589 nm, c = 0.08 w/v%, MeOH). (3R, 4S), SFC Separation Method: 20:80 EtOH:CO₂ (0.6% v/v i-PrNH₂); SFC Analysis: 20:80 EtOH:CO2 (0.3% v/v i-PrNH₂); Rt (min): 2.05; SFC purity: 100%. Example 5: Synthesis of Proline derivative Preparation of Int-A1

In a three necked round bottom flask equipped with an internal thermal sensor, to a solution of 1-tert-butyl 2-methyl (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate hydrochloride (1 eq., 9.0 g, 32.1 mmol) in a mixture of H₂O (30 mL) and Dioxane (60 mL) at 0 °C was added and Na2CO3 (3 eq., 10.2 g, 96.2 mmol) before dropwise addition of benzyl chloroformate (1.1 eq., 6.02 g, 5.01 mL, 35.3 mmol) maintaining the internal temperature below 5 °C and the resulting reaction mixture was stirred from 0 °C to room temperature for 16 hours. The reaction mixture was diluted with a mixture of water and EtOAc. The layers were separated and the organic layer was washed with brine, dried over MgSO₄, filtered and concentrated to give a crude which was purified by normal phase LC (Stationary phase: irregular SiOH, 15µm, 180 g, dry loading on celite, 0-50% EtOAc in Heptane) to give 1-tert-butyl 2-methyl (2S,4S)-4- {[(benzyloxy)carbonyl]-amino}pyrrolidine-1,2-dicarboxylate (Int-A1, 8 g, 66%) as an oil. LC/MS (ESI-): m/z 377.3 [M-H]-.¹H NMR (500 MHz, CDCl₃) δ 7.41 – 7.28 (m, 5H), 5.95 – 5.59 (m, 1H), 5.11 (d, J = 22.7 Hz, 2H), 4.45 – 4.18 (m, 2H), 3.74 (d, J = 7.3 Hz, 3H), 3.69 – 3.60 (m, 1H), 3.50 (dd, J = 45.4, 11.4 Hz, 1H), 2.53 – 2.38 (m, 1H), 1.96 (t, J = 14.7 Hz, 1H), 1.47 – 1.38 (m, 9H). Preparation of Int-A2

To a solution of 1-tert-butyl 2-methyl (2S,4S)-4-{[(benzyloxy)carbonyl]amino} pyrrolidine-1,2-dicarboxylate (Int-A1, 1 eq., 6 g, 15.9 mmol) in DCM (60 mL) at room temperature was added TFA (5 eq., 5.9 mL, 79.3 mmol) and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated to give methyl (2S,4RS)-4-{[(benzyloxy)carbonyl] amino}pyrrolidine-2-carboxylate trifluoroacetic acid (Int-A2, 6.22 g, 100%) as an oil. LC/MS (ESI+): m/z 279.2 [M+H]⁺.¹H NMR (500 MHz, CDCl3) δ 7.39 – 7.27 (m, 5H), 5.11 (d, J = 12.4 Hz, 1H), 5.08 (d, J = 12.7 Hz, 1H), 4.51 (t, J = 8.6 Hz, 1H), 4.30 (dt, J = 12.6, 6.2 Hz, 1H), 3.84 (s, 3H), 3.56 (dd, J = 12.0, 7.0 Hz, 1H), 3.37 (dd, J = 12.3, 5.5 Hz, 1H), 2.72 (ddd, J = 13.8, 9.0, 7.3 Hz, 1H), 2.19 (dt, J = 14.4, 7.4 Hz, 1H).¹⁹F NMR (471 MHz, MeOD) δ -77.20. Example 6: Preparation of Int-A8 Preparation of Int-A3

To a suspension of (3R)-3-amino-3-(4-chlorophenyl)propanoic acid (1 eq., 4 g, 20 mmol) in Dioxane (40 mL) and water (40 mL) at room temperature were added NaHCO3 (1.1 eq., 1.85 g, 22 mmol) and Boc2O (1.5 eq., 6.56 g, 6.43 mL, 30 mmol) and the resulting reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered and the dioxane was removed by evaporation. The aqueous layer was washed with Et2O, and the aqueous layer was neutralized until pH = 5 with 3N HCl solution to give a cloudy solution which was extracted with EtOAc (3x). the combined organic layers were dried over Na₂SO₄, filtered, and concentrated to give a solid which was taken up in THF and Heptane and concentrated to give (3R)-3-{[(tert-butoxy)carbonyl]amino}-3-(4-chlorophenyl)propanoic acid (Int-A3) as a solid. LC/MS (ESI-): m/z 298.1 [M-H]-. ¹H NMR (400 MHz, DMSO) δ 12.41 (s, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.44 – 7.34 (m, 2H), 7.34 – 7.25 (m, 2H), 4.85 (q, J = 7.8 Hz, 1H), 2.69 – 2.53 (m, 2H), 1.35 (s, 9H). Preparation of Int-A4

To a solution of (3R)-3-{[(tert-butoxy)carbonyl]amino}-3-(4-chlorophenyl)propanoic acid (Int-A3, 1 eq., 1.48 g, 4.94 mmol) in THF (15 mL) at 0 °C was added NaH (2.2 eq., 0.44 g, 11.0 mmol) portion-wise. The resulting reaction mixture was stirred 5 minutes at 0 °C before addition of MeI (3 eq., 2.13 g, 0.94 mL, 15.0 mmol) and the resulting reaction mixture was stirred from 0 °C to room temperature for 16 hours. The reaction mixture was cooled down to 0 °C and extra NaH (1.1 eq., 0.13 g, 5.51 mmol) was added followed by extra MeI (1.5 eq., 1.07 g, 0.47 mL, 7.51 mmol) and the reaction mixture was stirred from 0 °C to room temperature for 16 hours. The reaction mixture was diluted with a 10% NaHCO₃ aqueous solution and the pH was adjusted to 3 with 3N HCl aqueous solution and then extracted with EtOAc (4 times). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give (3R)-3-{[(tert-butoxy)carbonyl](methyl) amino}-3-(4- chlorophenyl)propanoic acid (Int-A4, 1.55 g, 100%) as an oil. LC/MS (ESI-): m/z 312.1 [M- H]-.¹H NMR (400 MHz, DMSO) δ 12.59 (s, 1H), 7.42 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 5.85 – 5.11 (m, 1H), 2.97 (dd, J = 15.5, 7.2 Hz, 1H), 2.88 – 2.71 (m, 1H), 2.58 (s, 3H), 1.39 (s, 9H). Preparation of Int-A5

To a solution of Int-A2 (1 eq., 1.24 g, 3.16 mmol) in DMF (7.9 mL) at room temperature were added HBTU (1.5 eq., 1.8 g, 4.74 mmol), 1H-1,2,3-benzotriazol-1-ol hydrate (1.5 eq., 0.73 g, 4.74 mmol) and DIPEA (3 eq., 1.65 mL, 9.48 mmol) before addition of a solution of Int-A4 (1.16 eq., 1.15 g, 3.67 mmol) in DMF (7.9 mL) and the resulting reaction was stirred at room temperature for 3 hours. The solution was diluted with a saturated NH4Cl aqueous solution and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to give a crude which was purified by normal phase LC (Stationary phase: irregular SiOH, 30 µm, Agela, 80 g, 0-10% MeOH in DCM, loaded with EtOAc). The obtained solid was taken in EtOAc (100 mL) and washed with aqueous NaHCO₃ saturated, dried over MgSO4, filtered, and concentrated to give methyl (2S,4S)-4- {[(benzyloxy)carbonyl]amino}-1-[(3R)-3-{[(tert-butoxy)carbonyl](methyl)amino}-3-(4- chlorophenyl)propanoyl]pyrrolidine-2-carboxylate (Int-A5, 580 mg, 32%) as a foaming solid. LC/MS (ESI+): m/z 572.3 [M-H]⁺. Preparation of Int-A6

To a solution of Int-A5 (1 eq., 560 mg, 0.98 mmol) in MeOH (3.3 mL) and H₂O (1.6 mL)at room temperature was added LiOH (2.5 eq., 102 mg, 2.44 mmol) and the reaction was stirred at room temperature for 1 hour. The solution was diluted with EtOAc and a 3N aqueous HCl solution. The layers were separated, and the organic layer was washed with brine, dried over MgSO₄, filtered, and concentrated to give(2S,4S)-4-{[(benzyloxy)carbonyl]amino}-1- [(3R)-3-{[(tert-butoxy)carbonyl](methyl)amino}-3-(4-chlorophenyl)propanoyl]pyrrolidine-2- carboxylic acid (Int-A6, 538 mg, 0.96 mmol, 98%) as a foaming solid. LC/MS (ESI-): m/z 558.4 [M-H]-. Preparation of Int-A7

To a solution of Int-A6 (1 eq., 289 mg, 0.52 mmol) in DMF (2.6 mL) at room temperature were added HBTU (1.5 eq., 294 mg, 0.77 mmol), 1H-1,2,3-benzotriazol-1-ol hydrate (1.5 eq., 119 mg, 0.77 mmol), butylamine (1.5 eq., 77.0 mL, 0.77 mmol) and DIPEA (3 eq., 0.27 mL, 1.55 mmol) and the resulting reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with a saturated NH4Cl aqueous solution and EtOAc. The layers were separated and the organic layer was washed with a 10% NaHCO₃ aqueous solution, brine, dried over MgSO₄, filtered and concentrated to give a crude which was purified by normal phase LC (Stationary phase: irregular SiOH, 30 µm, Agela, 4 g, loading in EtOAc, 0-70% EtOAc in Heptane) to give a residue which was taken in MeOH (1.4 mL) and H₂O (0.3 mL). LiOH (1 eq., 21.7 mg, 0.52 mmol) was added and the solution was stirred at room temperature for 30 minutes. The solution was diluted with EtOAc and a 10% NaHCO3 aqueous solution, the layers were separated, and the organic layer was washed with brine, dried over MgSO₄, filtered, and evaporated to give benzyl N-[(3S,5S)-1-[(3R)-3-{[(tert- butoxy)carbonyl](methyl)amino}-3-(4-chlorophenyl) propanoyl]-5- (butylcarbamoyl)pyrrolidin-3-yl]carbamate (Int-A7, 192 mg, 60%) as an oil. LC/MS (ESI-): m/z 613.4 [M-H]-. Preparation of Int-A8

In an adapted vial for hydrogenation was added Int-A7 (1 eq., 192 mg, 0.31 mmol) in MeOH (3.1 mL). The vial was flushed with nitrogen and Pd/C (10%) (0.1 eq., 33 mg, 0.031 mmol) was added to the mixture. Then the reaction was placed under 15 bar of H2 and was stirred at room temperature for 3 hours. The solution was diluted with MeOH (30 mL), filtered over a pad of celite and evaporated under reduced pressure to give tert-butyl N-[(1R)-3- [(2S,4S)-4-amino-2-(butylcarbamoyl)pyrrolidin-1-yl]-3-oxo-1-phenylpropyl]-N- methylcarbamate (Int-A8, 137 mg, 98%) as a powder. LC/MS (ESI+): m/z 447.4 [M+H]⁺. Example 7: Preparation of precursor of urea Preparation of Int-A9

To a solution of (2S)-2-aminopropanamide hydrochloride (1 eq., 500 mg, 4.01 mmol) in THF (16 mL) at room temperature were added Et3N (2.5 eq., 1.39 mL, 10 mmol) and phenyl chloroformate (1.2 eq., 0.606 mL, 4.82 mmol) and the resulting reaction mixture was stirred at room temperature for 16 hours. The solution was diluted with a saturated NH₄Cl aqueous solution and EtOAc. The layers were separated and the organic layer was washed with a 10% NaHCO3 aqueous solution, brine, dried over MgSO4, filtered and concentrated to give a crude which was purified by normal phase LC (Stationary phase: irregular SiOH, 30 µm, Agela, 12 g, liquid loading (EtOAc), 0-100% EtOAc in Heptane) to give phenyl N-[(1S)-1- carbamoylethyl]carbamate (Int-A9, 229 mg, 27%) as a solid. LC/MS (ESI-): m/z 207.0 [M- H]-.¹H NMR (400 MHz, DMSO) δ 7.86 (d, J = 7.6 Hz, 1H), 7.38 (dd, J = 15.9, 8.2 Hz, 3H), 7.19 (t, J = 7.5 Hz, 1H), 7.10 (d, J = 7.9 Hz, 2H), 7.03 (s, 1H), 4.02 (t, J = 7.3 Hz, 1H), 1.28 (d, J = 7.2 Hz, 3H). Preparation of Int-A10

To a solution of 1,1'-carbonyldiimidazole (1.1 eq., 263 mg, 1.62 mmol) in DMF (4.92 mL) at room temperature were Et3N (2.1 eq., 0.43 mL, 3.1 mmol) and 1-(1H-1,2,3,4-tetrazol- 5-yl)methanamine hydrochloride (1 eq., 200 mg, 1.48 mmol) and the resulting reaction mixture was stirred at room temperature for 20 hours. The solution was diluted with EtOAc (30 mL). The precipitate was removed by filtration and the filtrate was concentrated and was diluted with acetone (20 mL) to give a suspension. The supernatant was removed and the solid was dried under vacuum to give 1H-imidazol-3-ium; 5-{[(1H-imidazole-1- carbonyl)amino]methyl}-1H-1,2,3,4-tetrazol-1-ide (Int-A10, 149 mg, 39%) as a powder. LC/MS (ESI-): m/z 192.1[M-H]-.¹H NMR (400 MHz, DMSO) δ 9.26 (t, J = 5.6 Hz, 1H), 8.28 (t, J = 1.1 Hz, 1H), 7.88 (d, J = 1.1 Hz, 1H), 7.70 (t, J = 1.5 Hz, 1H), 7.13 (d, J = 1.1 Hz, 2H), 7.07 – 7.02 (m, 1H), 4.75 (d, J = 5.5 Hz, 2H). Example 8: Synthesis of targets for series 2 Preparation of Int-A11

To a solution of Int-A8 (1 eq., 45 mg, 0.10 mmol) in THF (0.5 mL) at room temperature were added Int-A9 (1.1 eq.23.1 mg, 0.11 mmol) and Et3N (1.5 eq., 0.021 mL, 0.15 mmol) was added and the reaction was left at room temperature for 3 days. The solution was diluted with a saturated NH₄Cl aqueous solution and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to give a crude which was purified by normal phase LC (Stationary phase: irregular SiOH, 30 µm, Agela, 4 g, direct loading (EtOAc), 0-10% MeOH in DCM) to give tert-butyl N-[(1R)-3-[(2S,4S)-2-(butylcarbamoyl)-4-({[(1S)-1- carbamoylethyl]carbamoyl}amino)pyrrolidin-1-yl]-3-oxo-1-phenylpropyl]-N- methylcarbamate (Int-A11, 30 mg, 53%) as a solid. The compounds reported in the following table were prepared via an analogous procedure.

Synthesis of Compound 800

To a reaction tube was added Int-A11 (1 eq., 15 mg, 0.027 mmol) and DCM (0.27 mL). TFA (5 eq., 0.01 mL, 0.13 mmol) was added and the reaction was stirred at room temperature for 1 h. The solution was diluted with aqueous NaHCO310% and EtOAc (3 mL each). The aqueous layer was extracted with EtOAc again and the combined organic layers were dried over MgSO4, filtered, and evaporated under vacuum. The residue was taken in ACN (1 mL) and H₂O (2 mL) and freeze-dried to give (2S,4S)-N-butyl-4-({[(1S)-1- carbamoylethyl]carbamoyl}amino)-1-[(3R)-3-(methylamino)-3- phenylpropanoyl]pyrrolidine-2-carboxamide (Compound 800, 4.5 mg, 37%) as flakes. The compounds in the following table were prepared via an analogous procedure.

Example 9: Preparation of aniline intermediates Preparation of Int-A13

To a solution of m-nitroaniline (1 eq., 1.50 g, 10.9 mmol) in EtOAc (3 mL) at 0 °C were added pyridine (1.1 eq., 0.97 mL, 11.9 mmol) and Phenyl chloroformate (1.1 eq., 1.50 mL, 11.9 mmol) and the resulting reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with water, dried over Na2SO4, filtered, and concentrated to give a crude which was purified by normal phase LC (Stationary phase: irregular SiOH, 30 µm, 0-100% EtOAc in Heptane) to give phenyl N-(3- nitrophenyl)carbamate as a powder (Int-A13, 2.1 g, 75%).¹H NMR (500 MHz, CDCl₃) δ 8.37 (t, J = 2.2 Hz, 1H), 7.99 – 7.95 (m, 1H), 7.86 – 7.81 (m, 1H), 7.52 (t, J = 8.2 Hz, 1H), 7.45 – 7.39 (m, 2H), 7.29 (d, J = 7.7 Hz, 1H), 7.23 – 7.18 (m, 2H), 7.16 – 7.10 (m, 1H). Preparation of Int-A14

To a solution of Int-A13 (1 eq., 400 mg, 1.55 mmol) in DMF (8 mL) at room temperature were added DIPEA (2 eq., 0.54 mL, 3.1 mmol), butylamine (1 eq., 0.15 mL, 1.55 mmol) and the resulting reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give a crude which was purified by normal phase LC (Stationary phase: irregular SiOH, 30 µm, 0-100% EtOAc in Heptane) to give 3-butyl-1-(3- nitrophenyl)urea as a powder (Int-A14, 315 mg, 43%). The compounds reported in the following table were prepared via an analogous procedure.

Preparation of Int-A19

To a solution of Int-A14 (1 eq., 315 mg, 1.33 mmol) in MeOH (10 mL) under N2 atmosphere was added Pd/C (10%) (0.05 eq., 70.6 mg, 0.066 mmol). The atmosphere was exchanged with H2 (5 bar), and the reaction mixture was stirred at room temperature for 1 hour. The crude mixture was filtered on a pad of celite, and the filtrate was concentrated to give 3- butyl-1-(3-nitrophenyl)urea (Int-A19, 240 mg, 87%) as a solid without any further purification. LC/MS: (ESI+) m/z 208.2 [M+H]⁺; (ESI-) m/z 206.2 [M-H]-.¹H NMR (500 MHz, MeOD) δ 6.97 (t, J = 8.0 Hz, 1H), 6.81 (t, J = 2.1 Hz, 1H), 6.62 (ddd, J = 8.1, 2.1, 0.9 Hz, 1H), 6.37 (ddd, J = 8.0, 2.2, 0.9 Hz, 1H), 3.17 (t, J = 7.0 Hz, 2H), 1.54 – 1.46 (m, 2H), 1.43 – 1.33 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H). The compounds reported in the following table were prepared via an analogous procedure.

Example 10: Preparation of Compounds 806-812 Synthesis of Compound 806

To a solution of Int-C4 (1.2 eq., 203 mg, 0.69 mmol) DCM (1,66 mL) at room temperature were added HATU (1.2 eq., 264 mg, 0.69 mmol), DIPEA (5 eq., 374 mg, 504 mL, 2.89 mmol) and the resulting reaction mixture was stirred at room temperature for 15 minutes before addition of Int-A19 (1 eq., 120 mg, 0.58 mmol) and the resulting reaction mixture was stirred at room temperature for 7 hours and concentrated to give a crude which was purified by normal phase LC (Stationary phase: irregular SiOH, 30 µm, 0-10% MeOH in DCM) to afford (3S,4R)-N-{3-[(butylcarbamoyl)amino]phenyl}-4-(4-chlorophenyl)-1-methylpyrrolidine-3- carboxamide as a powder (Compound 806, 67 mg, 27%). The compounds in the following table were prepared via an analogous procedure.

Example 11: Synthesis of Compounds 814-825 Representative procedure for the peptidic coupling:

To a solution of Int-C5 (1.2 eq., 1.2 g, 4.99 mmol) in DMF (12 mL) at room temperature were added ethyl 3-aminobenzoate (1 eq., 0.69 g, 0.62 mL, 4.15 mmol) DIPEA (3 eq., 1.61 g, 2.17 mL, 12.5 mmol) and HATU (1.5 eq., 2.37 g, 6.23 mmol) and the resulting reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with Water and EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with water (3x), brine, dried over Na₂SO₄, filtered, and concentrated to give an oil which was purified normal phase LC (Stationary phase: irregular SiOH, 30 µm, Interchim, 80 g, solid loading on celite, 0-10% MeOH in DCM) to give (Int- A24, 750 mg, 47%) as a solid. The compounds reported in the following table were prepared via an analogous procedure.

Representative procedure for the saponification

To a solution of Int-A24 (1 eq., 1.05 g, 2.71 mmol), MeOH (9 mL), THF (2.1 mL) and H₂O (4.5 mL) at room temperature was added LiOH (2.5 eq., 284.7 mg, 6.8 mmol) and the reaction was stirred at room temperature for 18 hours. The reaction mixture was concentrated to dryness then taken up in the minimum amount of water and the pH was adjusted to 6 with a 1 N HCl aqueous solution. The aqueous layer was saturated with NaCl and then extracted with a mixture of CHCl₃/i-PrOH (3/1) (3x). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give a residue which was triturated in Et2O, filtered, and dried under high vacuum at 45 °C for 30 minutes to give Int-A26 (900 mg, 92%) as a solid. The compounds reported in the following table were prepared via an analogous procedure.

Synthesis of Fmoc protected amines intermediates Method A: To a solution of (2S)-2-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)hexanoic acid (1 eq., 1.0 g, 2.83 mmol) in DMF (10 mL) at 0 °C were added HOBt (2 eq., 0.76 g, 5.66 mmol) and HBTU (2 eq., 2.15 g, 5.66 mmol) before addition of MeNH₂ (2 M in THF, 2 eq., 2.83 mL, 5.66 mmol) and DIPEA (3 eq., 1.48 mL, 8.49 mmol) and the resulting mixture was stirred from 0 °C to room temperature over 16 hours. The reaction mixture was diluted with NaHCO₃ and EtOAc, the layers were separated, and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated to give a crude which was purified by normal phase LC (irregular SiOH, 15 µm, interchim 20 g, 0-100% EtOAc (1% Et3N) in Heptane) to give (9H-fluoren-9-yl)methyl N-[(1S)-1-(methylcarbamoyl)pentyl]carbamate (801 mg, 77%) as a powder. Method B: To a solution of (2S)-2-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)hexanoic acid (1 eq., 1 g, 2.83 mmol) in DMF (10 mL) at room temperature was added DIPEA (3 eq., 1.10 g, 1.48 mL, 8.49 mmol), HATU (1.5 eq., 1.61 g, 4.24 mmol) and Me2NH (2 eq., 2.83 mL, 5.66 mmol) and the resulting reaction mixture was stirred at room temperature for 60 minutes. The reaction mixture was diluted with EtOAc and a saturated NaHCO₃ aqueous solution. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with a saturated NaHCO3 aqueous solution (4x), brine, dried over Na2SO4, filtered, and concentrated to give a residue which was taken up in Et2O, triturated and filtrated. The filtrate was concentrated to give a crude which was purified normal phase LC (Stationary phase: irregular SiOH, 30 µm, Interchim, 40 g, liquid loading in DCM, 0-10% MeOH in DCM) to give a residue which was coevaporated with Et2O to give (9H-fluoren-9-yl)methyl N-[(1S)- 1-(dimethylcarbamoyl)pentyl]carbamate (868 mg, 81%) as a solid. Method C: To a solution of (2S)-2-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)-3- phenylpropanoic acid (1 eq., 1 g, 2.58 mmol) in THF (10 mL) at room temperature was added ethyl chloroformate (1.4 eq., 0.39 g, 0.35 mL, 3.61 mmol) and Et₃N (3 eq., 0.78 g, 1.076 mL, 7.74 mmol). The resulting suspension was stirred at room temperature for 1 hour before addition of NH4Cl (1.5 eq., 3.87 mL, 3.87 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction was diluted with a saturated NaHCO3 aqueous solution and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated to give a crude which was purified by normal phase LC (irregular SiOH, 15 µm, interchim 20 g, 0-100% EtOAc (1% Et₃N) in Heptane) to give (9H- fluoren-9-yl)methyl N-[(1S)-1-carbamoyl-2-phenylethyl]carbamate (450 mg, 45%) as a powder. The compounds reported in the following table were prepared via analogous procedures.

Preparation of Compounds 814-825, from Int-C4 and Int-C5

Synthesis of Compound 825 N To a solution of Int-A28

(1 eq., 190 mg, 0.5 mmol) in DMF (1 mL) at room temperature was added TBAF (2 eq., 1 mL, 1 mmol) and the resulting reaction mixture was stirred at room temperature for until completion of Fmoc deprotection (0.5 to 92 hours). In a separated flask, to a solution of 3-[(3S,4R)-4-(4-chlorophenyl)-1-methylpyrrolidine-3-amido]benzoic acid (1 eq., 50 mg, 0.14 mmol) in DMF (0.5 mL) at room temperature was added DIPEA (3.3 eq., 59.4 mg, 0.08 mL, 0.46 mmol), HATU (1.5 eq., 79.5 mg, 0.21 mmol) and half of the previously prepared solution of (2S)-2-amino-N,N-dimethylhexanamide (1.79 eq., 1 mL, 0.25 mmol) and the resulting reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc and a saturated NaHCO3 aqueous solution. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with a half saturated NaHCO₃ aqueous solution (3x), brine, dried over Na₂SO₄, filtered and concentrated to give a residue which was taken up in DCM filtered and purified by normal phase LC (Stationary phase: irregular SiOH, 30 µm, Interchim, 12 g, liquid loading in DCM, 0-20% MeOH (+5% NH₃ aqueous solution) in DCM) to give a residue which was co- evaporated with Et₂O to give (3S,4R)-4-(4-chlorophenyl)-N-(3-{[(1S)-1- (dimethylcarbamoyl)pentyl]carbamoyl}phenyl)-1-methylpyrrolidine-3-carboxamide (Compound 825, 42.5 mg, 0.085 mmol, 61%) as a solid. The compounds in the following table were prepared via an analogous procedure.

Example 12: Potency Evaluation in Human MCRs in Transient Assays The example set forth below describes a transient assay to determine potency of melanocortin receptor (MCR) agonists (24 peptide and 98 small molecule) modulating cellular cyclic adenosine triphosphate (cAMP) levels in MCRs transfected HEK 293 cells. As members of GPCRs, MCRs can signal through Gs proteins to activate adenylyl cyclase. This leads to increased synthesizes of cAMP and leads to an accumulation of the second messenger and is reflective of Gs activation. The cellular accumulation of cAMP can be quantified using a commercially available time-resolved FRET (TR-FRET) assay kit (cAMP-Gs Dynamic Kit; Cisbio; cat# 62AM4PEC). Briefly, modulation of MCR activity was determined according to the following general experimental method employing Human Embryonic Kidney (HEK) 293 cells. On the first day of the assay, HEK-293 cells were trypsined, counted and seeded on 1% Matrigel coated 384 well plates at a density of 5,000 cells/well. After 1 day incubation, cells were transfected with either MC1R, MC2R, MC3R, MC4R or MC5R with Invitrogen Lipofectamine 3000.2 ng plasmid, 0.05 µl Lipofectamine 3000, 0.004µl P3000 reagent, 4.9 µl Opti-MEM were mixed and added to cells after 15 min of room temperature incubation. MC1R was purchased from OriGene. MC2R, MC3R, MC4R, and MC5R was generated by GenScript. All plasmids were Maxiprep from Eton Bio. Cell medium was discarded on the third day and replaced with 20 µl stimulation buffer with 0.5 mM IBMX. Compounds were added with Echo according to the plate map. Plates were then incubated for 30 min at 37^oC. The cells were subsequently lysed for detection of accumulated cAMP via the homogeneous TR-FRET assay. The activity against human MC4R was assessed and the results are summarized in Table X below. In this table, compounds with activity equal to or less than 5 µM are annotated as “++,” and compounds with activity greater than 5 µM are annotated as “+.”

EQUIVALENTS The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety. While this invention has been disclosed with reference to specific aspects, it is apparent that other aspects and variations of this invention may be devised by others skilled in the art without departing from the true spirit and scope of the invention. The appended claims are intended to be construed to include all such aspects and equivalent variations.

Claims

CLAIMS 1. A method of treating a disease, disorder, or condition in a subject, comprising administering to the subject a melanocortin-4 receptor (MC4R) agonist, wherein the subject: (i) has or is identified as having a non-genetic obesity; (ii) has or is identifying as having damage to the brain tissue; and/or (iii) has or is identified as having a proliferative brain disease. 2. The method of claim 1, comprising (i). 3. The method of claim 1, comprising (ii). 4. The method of claim 1, comprising (iii). 5. The method of claim 1, wherein the non-genetic obesity comprises obesity is caused by a neurodevelopmental abnormality or a brain malformation. 6. The method of claim 1, wherein the damage to the brain tissue is present in the hypothalamus. 7. The method of claim 6, wherein the damage to the brain tissue is present in the paraventricular hypothalamic nucleus, ventromedial hypothalamic nucleus, or arcuate hypothalamic nucleus. 8. The method of claim 7, wherein the damage or trauma in the brain occurs in the ventromedial nucleus. 9. The method of claim 1, wherein the disease, disorder, or condition comprises hypothalamic obesity.

10. The method of claim 1, wherein the proliferative brain disease comprises a benign tumor, a benign lesion, or a malignant tumor (e.g., cancer). 11. The method of claim 10, wherein the proliferative brain disease is present in the hypothalamus. 12. The method of any one of claims 10 or 11, wherein the proliferative brain disease is present in the paraventricular hypothalamic nucleus, ventromedial hypothalamic nucleus, or arcuate hypothalamic nucleus. 13. The method of claim 10, wherein the proliferative brain disease comprises craniopharyngioma or astrocytoma. 14. The method of claim 1, wherein the subject has undergone a surgery (e.g., tumor removal or bariatric surgery) or received radiation. 15. The method of claim 1, wherein the subject is obese, e.g., severely obese. 16. The method of claim 1, wherein the subject is hyperphagic. 17. The method of claim 1, wherein the subject has a body mass index (BMI) greater than 35 kg/m² (e.g., ≥36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg/m² or greater) prior to administration of the MC4R agonist, e.g., at the time the MC4R agonist is prescribed, or at the time of the first administration. 18. The method of claim 1, wherein the subject has failed one or more previous therapies, e.g., exercise, diet, or behavioral therapies, prior to administration of the MC4R agonist, e.g., at the time the MC4R agonist is prescribed, or at the time of the first administration. 19. 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), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), or (XXXVI) (e.g., as described herein). 20. The method of claim 1, wherein the MC4R agonist is a peptide or a small molecule, or a pharmaceutically acceptable salt thereof. 21. The method of claim 1, wherein the MC4R agonist is a peptide, e.g., selected from any one of SEQ ID NOs: 1-915. 22. The method of claim 1, wherein the MC4R agonist is not Ac-Arg-c(Cys-D-Ala-His- D-Phe-Arg-Trp-Cys)-NH₂ (SEQ ID NO: 140). 23. The method of claim 1, wherein the MC4R agonist is a small molecule, or a pharmaceutically acceptable salt thereof. 24. The method of claim 20, wherein the MC4R agonist is selected from any one of Compound Nos.100-825, or a pharmaceutically acceptable salt thereof. 25. The method of claim 20, wherein the MC4R agonist is a compound of any one of Formulas (XIV)-(XXXVI), or a pharmaceutically acceptable salt thereof. 26. The method of claim 20, wherein the MC4R agonist is a compound of Formula (XIV), or a pharmaceutically acceptable salt thereof. 28. The method of claim 20, wherein the MC4R agonist is selected from any one of Compounds 100-221, or a pharmaceutically acceptable salt thereof. 29. The method of claim 20, wherein the MC4R agonist is a compound of Formula (XV), or a pharmaceutically acceptable salt thereof.

30. The method of claim 29, wherein the MC4R agonist is selected from any one of Compounds 300-383, or a pharmaceutically acceptable salt thereof 31. The method of claim 20, wherein the MC4R agonist is a compound of Formula (XVI), or a pharmaceutically acceptable salt thereof. 32. The method of claim 31, wherein the MC4R agonist is selected from any one of Compounds 390-394, or a pharmaceutically acceptable salt thereof 33. The method of claim 20, wherein the MC4R agonist is a compound of Formula (XVII), or a pharmaceutically acceptable salt thereof. 34. The method of claim 33, wherein the MC4R agonist is selected from any one of Compounds 400-403, or a pharmaceutically acceptable salt thereof. 35. The method of claim 20, wherein the MC4R agonist is a compound of Formula (XX), or a pharmaceutically acceptable salt thereof. 36. The method of claim 36, wherein the MC4R agonist is selected from any one of Compounds 410-449, or a pharmaceutically acceptable salt thereof. 37. The method of claim 20, wherein the MC4R agonist is a compound of Formula (XXI), or a pharmaceutically acceptable salt thereof. 38. The method of claim 37, wherein the MC4R agonist is selected from any one of Compounds 460-481, or a pharmaceutically acceptable salt thereof. 39. The method of claim 20, wherein the MC4R agonist is a compound of Formula (XXIV), or a pharmaceutically acceptable salt thereof.

40. The method of claim 39, wherein the MC4R agonist is selected from any one of Compounds 550-576, or a pharmaceutically acceptable salt thereof. 41. The method of claim 20, wherein the MC4R agonist is Compound 580, or a pharmaceutically acceptable salt thereof. 42. The method of claim 20, wherein the MC4R agonist is selected from any one of Compounds 600-626, or a pharmaceutically acceptable salt thereof. 43. The method of claim 20, wherein the MC4R agonist is a compound of any of Formulas (XXVIII), (XXVIIIa), (XXVIIIb), (XXVIIIc), and (XXVIIId) or a pharmaceutically acceptable salt thereof. 44. The method of claim 43, wherein the MC4R agonist is selected from any one of Compounds 650-682, or a pharmaceutically acceptable salt thereof. 45. The method of claim 20, wherein the MC4R agonist is a compound of any of Formulas (XXVIII), (XXVIIIa), (XXVIIIb), (XXVIIIc), (XXVIIId), (XXVIIIe), and (XXVIIIf) or a pharmaceutically acceptable salt thereof. 46. The method of claim 45, wherein the MC4R agonist is selected from any one of Compounds 690-693, or a pharmaceutically acceptable salt thereof. 47. The method of claim 20, wherein the MC4R agonist is a compound of any of Formulas (XXIX), (XXIXa), (XXIXb), (XXIXc), (XXIXd), (XXIXe), and (XXIXf) or a pharmaceutically acceptable salt thereof. 48. The method of claim 47, wherein the MC4R agonist is selected from any one of Compounds 700-737, or a pharmaceutically acceptable salt thereof.

49. The method of claim 20, wherein the MC4R agonist is a compound of Formula (XXX) or a pharmaceutically acceptable salt thereof. 50. The method of claim 49, wherein the MC4R agonist is selected from any one of Compounds 740-741, or a pharmaceutically acceptable salt thereof. 51. The method of claim 20, wherein the MC4R agonist is selected from any one of Compounds 742-751, or a pharmaceutically acceptable salt thereof. 52. The method of claim 20, wherein the MC4R agonist is selected from any one of Compounds 760-762, or a pharmaceutically acceptable salt thereof. 53. The method of claim 20, wherein the MC4R agonist is a compound of any one of Formulas (XXXIV)-(XXXVI) or a pharmaceutically acceptable salt thereof. 54. The method of claim 53, wherein the MC4R agonist is selected from any one of Compounds 1000-1013, or a pharmaceutically acceptable salt thereof. 55. The method of claim 20, wherein the MC4R agonist is selected from any one of Compounds 800-825, or a pharmaceutically acceptable salt thereof. 56. The method of claim 1, wherein the MC4R agonist is formulated as a pharmaceutical composition. 57. The method of claim 56, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable excipient. 58. The method of claim 57, wherein the pharmaceutical composition comprises a polyethylene glycol (e.g., a modified polyethylene glycol, e.g., mPEG-DSPE, e.g., mPEG- 2,000-DSPE).

59. The method of claim 1, comprising administering the MC4R agonist in a unit dosage suitable for injection, e.g., subcutaneous injection, to the subject. 60. The method of claim 59, wherein the unit dosage form is disposed within a delivery device, e.g., a syringe (e.g., prefilled syringe), an implantable device, a needleless hypodermic injection device, an infusion pump (e.g., implantable infusion pump), or an osmotic delivery system. 61. The method of claim 1, wherein the MC4R agonist is administered subcutaneously, e.g., by subcutaneous injection. 62. The method of claim 1, comprising administering the MC4R agonist in a unit dosage suitable for oral delivery to the subject. 63. The method of claim 1, wherein the subject is a human. 64. The method of claim 1, wherein the subject is an adult (e.g., over the age of 18 years old). 65. The method of claim 1, wherein the subject is a pediatric subject, e.g., a child (e.g., under the age of 18, 16, 14, 12, 10, 8, 6, or 4 years). 66. The method of claim 1, wherein prior to administration of the MC4R agonist, the subject has previously received treatment for obesity, e.g., a non-genetic obesity, e.g., hypothalamic obesity. 67. The method of claim 1, wherein after a first administration of the MC4R agonist (e.g., at least 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 4 months, 5 months, 6 months, 8 months, 10 months, 1 year, or longer), the subject exhibits a reduction in BMI.

68. The method of claim 67, wherein the reduction of BMI in the subject is greater than 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14% 16%, 18%, 20%, or more, e.g., relative to a reference standard (e.g., BMI prior to administration of the MC4R agonist). 69. The method of claim 1, wherein the subject is administered an additional agent (e.g., an additional therapeutic agent).