Use of melanocortin-4 receptor agonists for the treatment of PCSK1 deficiency indications

Abstract

The present invention relates to the use of a compound of Formula 1 below or a pharmaceutically acceptable salt thereof for the purpose of preventing or treating obesity, particularly a rare genetic obesity disease associated with Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1) deficiency, which is related to the melanocortin-4 receptor (MC4R) pathway and the mechanism of action thereof.

Description

[0001] USE OF MELANOCORTIN-4 RECEPTOR AGONISTS FOR THE TREATMENT OF PCSK1 DEFICIENCY INDICATIONS CLAIM OF PRIORITY This application claims priority to KR Patent Application No. 10-2023-0130273, filed on September 27, 2023. The entire contents of the application as filed is incorporated herein by reference. TECHNICAL FIELD The present invention relates to the use of a compound of Formula 1 or a pharmaceutically acceptable salt thereof for the purpose of preventing or treating a rare genetic obesity disease associated with deficiency of Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1), which is related to the melanocortin-4 receptor (MC4R) pathway and the mechanism of action thereof: [Formula 1] In Formula 1 above, R1 is C2-C5alkyl. BACKGROUND Proprotein convertase subtilisin / kexin type 1(PCSK1) is a member of the subtilisin-like proprotein convertase family, which includes proteases that process peptide precursors and is involved in the processing of hormones and other protein precursors. Substrates include pro- opiomelanocortin (POMC), renin, enkephalin, dynorphin, somatostatin, insulin, and AGRP. PCSK1 activity is essential for the cleavage activation of many peptide hormone precursors such as proopiomelanocortin, proinsulin, proglucagon, and proghrelin, which are involved in the regulation of food intake, glucose homeostasis, and energy homeostasis. Proopiomelanocortin is derived from the POMC gene and is mainly expressed in the hypothalamus pituitary gland, brain, and stem, and the like of the brain, and is post-translationally and enzymatically modified to become neuropeptides such as α-melanocyte stimulating hormone (MSH), β-MSH, γ-MSH, adrenocorticotrophic hormone, or the like, which exert physiological effects. Melanocortin peptides regulate various physiological phenomena depending on their affinity for each MCR, and these physiological phenomena are known to include skin pigmentation, body temperature, inflammation, appetite, behavior control functions, and the like (Reference: Mountjoy KG, et al., Mol Cell Endocrinol 1997, 128, 171; Haskell-Luevano C. et al., Drug News Perspect 1999, 12, 197; Wikberg, JES, et al., Pharmacol Res 2000, 42, 393). Melanocortin receptor (MCR) is a type of G-protein coupled receptor (GPCR), whose main role is to activate secondary messengers to transmit signals and regulate cellular responses to many physiological stimuli. A total of five types of melanocortin receptors have been identified as melanocortin receptors to date. MC1R is expressed in melanocytes and macrophages, and determines skin and hair color by regulating melanin pigment in melanocytes. MC2R is expressed in the adrenal gland and adipose tissue, and the function thereof in mediating the regulation of adrenal hormone secretion by adrenocorticotropic hormone in the adrenal gland is well known. MC3R, MC4R, and MC5R are expressed not only in nerve terminals but also in the brain and are thought to mediate central nervous system actions by melanocortin peptides that result in effects on behavior, learning, memory, appetite, and neurogenesis and regeneration. To date, MC3R is known to be involved in erectile dysfunction and inflammatory responses, and MC4R is known to be involved in obesity and diabetes, and research on the specificity of action of each receptor is actively being conducted (MacNeil DJ et al., Eur J Pharmacol 2002, 450, 93). As a result, genetic studies in humans with active obesity have shown that MC4R is deeply involved, and knockout mice with MC4R deletion have been shown to develop obesity due to overeating, proving that this receptor plays an important role in appetite control (Lu D, Willard D et al., Nature 1994, 371(6500), 799; Huszar D et al., Cell 1997,88(1), 131; Hinney A et al., J Clin Endocrinol Metab 1990, 84(4), 1483). The main obesity treatment drugs developed to date are appetite suppressants that act on the central nervous system, and most of them are drugs that regulate the action of neurotransmitters. Examples include noradrenalin agents (phentermine and mazindol) and fluoxetine and sibutramine, which are serotonergic agents. However, the above neurotransmitter regulators have a wide range of effects on various physiological functions in addition to appetite suppression through numerous subtype receptors. Therefore, the above regulators have a major disadvantage of lacking selectivity for each subtype and cause various side effects when administered for a long period of time. On the other hand, melanocortin agonists are neuropeptides rather than neurotransmitters, and considering the fact that all other functions other than energy metabolism are normal in MC4R gene KO mice, melanocortin agonists may have an advantage as a point of action in being capable of only inducing weight loss through appetite suppression without affecting other physiological functions. In particular, the receptor is a G-protein coupled receptor (GPCR), which belongs to the most successful category of new drug action points developed to date, and is significantly different from existing action points in that it is relatively easy to secure selectivity for subtype receptors. As examples of utilizing these melanocortin receptors as the point of action, International Publication Nos. WO 2008 / 007930 and WO 2010 / 056022 disclose compounds as agonists of the melanocortin receptors. DETAILED DESCRIPTION The present invention aims to provide a use of the compound of Formula 1 or a pharmaceutically acceptable salt thereof for preventing and treating obesity, including rare genetic obesities. In particular, the present disclosure features methods for preventing and treating obesity in a subject associated with the melanocortin-4 receptor (MC4R) pathway, especially associated with a Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK 1) deficiency The present invention provides methods and composition for preventing or treating obesity, such as a rare genetic obesity associated with Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1) deficiency, containing a therapeutically effective amount of a compound of Formula 1 below or a pharmaceutically acceptable salt thereof: [Formula 1] . In Formula 1 above, R1 is C2-C5alkyl. In addition, the present invention provides a pharmaceutical composition for preventing or treating a rare genetic obesity disease associated with Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1) deficiency, containing a therapeutically effective amount of a compound of Formula 1 above or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In addition, the present invention provides a method for preventing or treating a rare genetic obesity disease associated with Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1) deficiency, by including administering to a subject a therapeutically effective amount of a compound of Formula 1 above or a pharmaceutically acceptable salt thereof. In addition, the present invention provides a use of a therapeutically effective amount of the compound of Formula 1 above or a pharmaceutically acceptable salt thereof for preventing or treating a rare genetic obesity disease associated with Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1) deficiency. According to one aspect of the present invention, a pharmaceutical composition for preventing or treating a rare genetic obesity disease associated with Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1) deficiency is provided, containing a therapeutically effective amount of a compound of Formula 1 below or a pharmaceutically acceptable salt thereof. According to another aspect of the present invention, a pharmaceutical composition for preventing or treating a rare genetic obesity disease associated with Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1) deficiency is provided, containing a therapeutically effective amount of a compound of the Formula 1 above or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In one embodiment, the rare genetic obesity disease associated with Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1) deficiency is characterized by being homozygous (PCSK1- / -) or heterozygous (PCSK1+ / -). In one embodiment, the compound of Formula 1 above is N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4- (4- Chlorophenyl)pyrrolidin-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4- methylcyclohexyl)Isobutyramide of Formula 2 below: [Formula 2] . In one embodiment, a method for preparing a compound of Formula 1 is provided. Hereinafter, to help understand the present invention, a method for preparing a compound of Formula 1 will be described based on an exemplary reaction formula. However, a person skilled in the art can prepare the compound of Formula 1 using various methods based on the structure of Formula 1, and all of these methods should be interpreted as falling within the scope of the present invention. In other words, the compound of Formula 1 can be prepared by arbitrarily combining various synthetic methods described herein or disclosed in the prior art, and this will be understood as falling within the scope of the present invention, and the method for preparing the compound of Formula 1 is not limited to that described below. In one embodiment, the hydrochloride salt of the compound of Formula 1 of the present invention can be prepared according to Reaction Formula 1 below. [Reaction Formula 1] In Reaction Formula 1 above, R2is C1-C5alkyl; R3 is C3-C8 cycloalkyl unsubstituted or substituted with 1 or 2 C1-C5 alkyl; and R4 and R5 are each independently hydrogen or halogen. In defining the compound represented by Formula 1 throughout this specification, the concepts defined as below are used. The following definitions also apply to terms used individually or as part of larger groups throughout this specification, unless specifically indicated otherwise. Terms and abbreviations used herein have their original meanings unless otherwise defined. As used herein, the term “substitution” may mean that a hydrogen atom bonded to each substituent listed in the compound or the above substituent group is replaced and bonded with any substituent At this time the position to be substituted is not limited as long as it is a position in which a hydrogen atom bonded to each substituent listed in the compound or the above substituent group exists, that is, a position in which the hydrogen atom can be substituted with a substituent. When two or more are substituted, the two or more substituents may be the same or different from each other. Conversely, “unsubstituted” can mean that no hydrogen atom bonded to a carbon atom has been replaced by any substituent. Any substituent applicable to the above “substitution” may be appropriately selected from the substituents listed in the substituent group as described herein, but the scope of substituents available for substitution is not limited to this substituent group. When a substituent is not separately described or mentioned in the chemical formula described herein, it may be considered that hydrogen is bonded, and in some cases, the substituent may be absent depending on the ring member forming the heterocycle. As used herein, the term “alkyl” by itself or as part of another substituent, unless otherwise stated, means a straight- chain or branched-chain monovalent hydrocarbon having the number of carbon atoms indicated (that is, C1-C5 means 1 to 5 carbons). Examples of the above alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, 1-methyl-butyl, 1-ethyl-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and the like, but these are non-limiting examples, and the scope of the present invention is not limited thereto. As used herein, the term “cycloalkyl” refers to a monovalent aliphatic carbocycle in which one hydrogen atom is missing from any position among the carbon atoms constituting the ring. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 3-methylcyclopentyl, 2,3-dimethylcyclopentyl, cyclohexyl, cyclohexylene 3- methylcyclohexyl, 4-methylcyclohexyl, 2,3-dimethylcyclohexyl, 3,4,5-trimethylcyclohexyl, 4-tert- butylcyclohexyl, cycloheptyl, cyclooctyl, and the like. As used herein, the term “halogen” includes, but is not limited to, for example, fluoro, chloro, bromo, or iodo. According to the present invention, the compound of the above Formula 1 can efficiently prevent or treat a rare genetic obesity disease associated with Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1) deficiency, but is not limited thereto. Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1) is a member of the subtilisin-like precursor protein convertase family, which includes proteases that process peptide precursors, and has proopiomelanocortin (POMC) as a substrate. POMC is a precursor polypeptide having 241 amino acid residues, which is synthesized in the anterior and intermediate pituitary gland and serve as a precursor of several peptide hormones such as melanocyte stimulating hormone (MSH), endorphin, and corticotrophin. Alpha-MSH, which is a ligand of the melanocortin-4 receptor (MC4R), acts in the upstream of MC4R and when the PCSK1 gene is deficient and not expressed normally, POMC is not converted to alpha-MSH, which can cause severe early-onset obesity. As used herein, the term "therapeutically effective amount" means an amount sufficient to achieve the above pharmacological effect, that is, a therapeutic effect, and the amount of the compound will vary depending on the condition of the subject and the severity thereof, the mode of administration, and the age of the subject to be treated, can be determined by those skilled in the art based on the own knowledge thereof. In one embodiment, a therapeutically effective dose of the compound of Formula 1 above, for example, a dose required to treat adults, typically ranges from approximately 0.1 to 500 mg per day depending on the frequency and intensity of administration. When administered intramuscularly or intravenously to adults, a total dose of approximately 0.1 to 300 mg per day, divided into single doses, will usually be sufficient, but higher daily doses may be desirable for some patients. In one embodiment, the compound of Formula 1 may be administered at a dose of 10 mg / kg or 30 mg / kg. As used herein, the term “carrier” refers to a compound that facilitates introduction of a compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a common carrier that facilitates the introduction of many organic compounds into the cells or tissues of an organism. In one embodiment, the pharmaceutically acceptable carrier can include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral oil, and the like. As used herein, the term “diluent” refers to a compound that is diluted in water to not only stabilize the biologically active form of the subject compound, but also to dissolve the compound. Salts dissolved in buffer solutions are used as diluents in the field of art. A commonly used buffer solution is phosphate buffered saline, which mimics the salt form of human body fluids. Buffer salts can control the pH of a solution at low concentrations, and thus it is rare for buffer diluents to modify the biological activity of a compound. As used herein, the term “pharmaceutically acceptable” refers to a property that does not impair the biological activity and physical properties of a compound. In one embodiment, the pharmaceutically acceptable salts include, but are not limited to acid addition salts formed by inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, and hydroiodic acid, organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, and maleic acid, sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and naphthalenesulfonic acid, or the like. In one embodiment, the pharmaceutically acceptable salt may be selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, and hydroiodic acid. In one embodiment, the pharmaceutically acceptable salt is hydrochloride salt. In the present invention, the compound can be formulated into various pharmaceutical dosage forms depending on the purpose. When preparing a pharmaceutical composition according to the present invention, an active ingredient, specifically the compound of Formula 1 or a pharmaceutically acceptable salt thereof, is mixed with various pharmaceutically acceptable carriers that can be selected depending on the formulation to be prepared. For example, a medicament or pharmaceutical composition according to the present invention may be formulated as an injectable formulation, an oral formulation, or the like, depending on the intended purpose. In one embodiment, the medicament or pharmaceutical composition is characterized in being an oral dosage form. The compound of the present invention can be formulated by well-known methods using well- known pharmaceutical carriers and excipients and placed in unit dosage form or multi-dose containers. The form of the formulation may be in the form of a solution, suspension or emulsion in an oil or aqueous medium and may contain conventional dispersing, suspending or stabilizing agents. Additionally, for example, it may be in the form of a dry powder that is dissolved in sterile, pyrogen- free water before use. The compounds of the present invention may also be formulated in suppository form using conventional suppository bases such as cocoa butter or other glycerides. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules, and capsules and tablets are particularly useful. Tablets and pills are preferably manufactured as enteric coating agents. Solid dosage forms can be prepared by mixing the compound of the present invention with one or more inert diluents such as sucrose, lactose, starch, and the like and carriers such as lubricants such as magnesium stearate, disintegrants, binders, and the like. Additionally, it may be formulated in a transdermal dosage form, for example, as a lotion, ointment, gel, cream, patch, or spray. In another embodiment according to the present invention, the medicament or pharmaceutical composition may be in an oral dosage form. In one embodiment, the pharmaceutical composition of the present invention can be administered to mammals such as rats, mice, livestock, and humans by various routes, for example, orally, intraperitoneally, rectally, or intravenously, intramuscular, subcutaneously, intrauterine, or intracerebrovascular injection. As used herein, the term “prevention” means reducing or eliminating the possibility of contracting a disease. As used herein, the term “treatment” when used on a subject showing symptoms of disease refers to stopping, delaying, or alleviating the progression of a disease. The medicament or pharmaceutical composition according to the present invention can effectively prevent or treat a rare genetic obesity disease associated with Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1) deficiency, which is related to the melanocortin-4 receptor (MC4R) pathway and the mechanism of action thereof. BRIEF EXPLANATION OF DRAWINGS FIGS. 1A-C are graphs showing the body weight change over 28 days and the body weight measured on the 28th (last) day of administration in the compound administration experimental group of Example 1 (Compound 10010 mg / kg and Compound 10030 mg / kg, respectively) and the solvent administration control group (Vehicle) in a PCSK1 heterozygous deficient mouse model induced with obesity by a high-fat diet. FIG. 2 is a graph showing the cumulative food intake for the first week of the compound administration experimental group of Example 1 (Compound 10010 mg / kg and Compound 10030 mg / kg, respectively) and the solvent administration control group (Vehicle) in a PCSK1 heterozygous deficiency mouse model for which obesity is induced by a high-fat diet. FIGS. 3A-C are graphs showing the body weight change over 28 days and the body weight measured on the 28th(last) day of administration in the compound administration experimental group of Example 1 (Compound 10010 mg / kg and Compound 10030 mg / kg, respectively) and the solvent administration control group (Vehicle) in a PCSK1 homozygous deficient mouse model for which obesity is induced by a high-fat diet. FIG. 4 is a graph showing the cumulative food intake for the first week of the compound administration experimental group of Example 1 (Compound 10010 mg / kg and Compound 10030 mg / kg, respectively) and the solvent administration control group (Vehicle) in a PCSK1 homozygous deficiency mouse model for which induced by a high-fat diet. DETAILED DESCRIPTION Hereinafter, the present invention will be described in more detail through preparation examples, examples, and experimental examples to help understand the present invention. At this time, the terms or words used in this specification and scope of claims should not be interpreted as limited to their usual or dictionary meanings, and should be interpreted as meanings and concepts that conform to the technical idea of the present invention based on the principle that the inventor can appropriately define the concept of the term in order to explain his or her own invention in the best way. The present disclosure provides methods for treating rare genetic obesity comprising administering a compound of Formula 1, or a pharmaceutically acceptable salt thereof, to a subject. In some embodiments, the subject has a rare genetic obesity characterized by a proprotein convertase subtilisin / Kexin type 1 (PCSK1) deficiency. In some embodiments, the subject has a mutation (N222D) in the PCSK1 gene. In some embodiments, the subject is homozygous (PCSK1 (- / -)) for the mutation (N222D) in the PCSK1 gene. In some embodiments, the subject is heterozygous (PCSK1 (+ / -)) for the mutation (N222D) in the PCSK1 gene. In some embodiments, the subject is a mammal, e.g., a mouse or a human. In some embodiments, the subject is a mouse, e.g., a PCSK1-deficient mouse. In some embodiments, the subject is a human. Upon administration of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, the subject can be obese, e.g., severely obese. In some embodiments, the subject is hyperphagic. In some embodiments, the subject has a body mass index greater than 35 kg / m2(e.g., ≥36, 37, 38, 39, 40, 41, 42, 43, 44, 45 kg / m2or greater), prior to administration of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, or at the time of the first administration. In some embodiments, the subject has a body mass index greater than 40 kg / m2(e.g., ≥41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg / m2or greater), prior to administration of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, or at the time of the first administration. In some embodiments, the subject has a body mass index greater than 45 kg / m2(e.g., ≥46, 47, 48, 49, 50, 51, 52, 53, 54, 55 kg / m2or greater), prior to administration of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, or at the time of the first administration. The subject may have an additional genetic deficiency, e.g., an additional genetic metabolic deficiency. In some embodiments, the subject has diabetes or a diabetological condition, e.g., pre- diabetes, diabetes mellitus type 1, diabetes mellitus type 2, hyperglycemia, hypoglycemia, or hyperinsulinemia. In some embodiments, the subject is hypertensive (i.e., the subject has high blood pressure). In some embodiments, the subject has failed one or more previous therapies comprising exercise, diet, or behavioral therapies prior to administration of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, or at the time of the first administration. The compound of Formula 1, or a pharmaceutically acceptable salt thereof, may be administered orally. In some embodiments, the administration occurs daily, weekly, or monthly. In some embodiments, the administration occurs once weekly, twice weekly, or three times weekly. In some embodiments, the oral administration is repeated daily, twice daily, or three times daily for the duration of the treatment period. In some embodiments, the oral administration is repeated daily for the duration of the treatment period. In an aspect, the method comprises administering the compound of Formula 1, or a pharmaceutically acceptable salt thereof, for 7 days, 14 days, 21 days, 28 days, or longer. In some embodiments, the duration of administration is 7 days. In some embodiments, the duration of administration is 14 days. In some embodiments, the duration of administration is 21 days. In some embodiments, the duration of administration is 28 days. The compound of Formula 1, or a pharmaceutically acceptable salt thereof, can be administered at a dose between about 0.1 mg to about 500 mg. In some embodiments, the dose is about 1 mg to about 400 mg. In some embodiments, the dose is about 1 mg to about 300 mg. In some embodiments, the dose is about 1 mg to about 200 mg. In some embodiments, the dose is about 1 mg to about 100 mg. In some embodiments, the dose is about 1 mg to about 90 mg. In some embodiments, the dose is about 1 mg to about 80 mg. In some embodiments, the dose is about 1 mg to about 70 mg. In some embodiments, the dose is about 1 mg to about 60 mg. In some embodiments, the dose is about 1 mg to about 50 mg. In some embodiments, the dose is about 10 mg to about 30 mg. In some embodiments, the compound of Formula 1, or a pharmaceutically acceptable salt thereof, is provided as an oral dosage form. The compound of Formula 1 can be administered at a dose of about 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, or 500 mg. In some embodiments, the dose is about 0.1 mg. In some embodiments, the dose is about 1 mg. In some embodiments, the dose is about 2 mg. In some embodiments, the dose is about 3 mg. In some embodiments, the dose is about 4 mg. In some embodiments, the dose is about 5 mg. In some embodiments, the dose is about 6 mg. In some embodiments, the dose is about 7 mg. In some embodiments, the dose is about 8 mg. In some embodiments, the dose is about 9 mg. In some embodiments, the dose is about 10 mg. In some embodiments, the dose is about 15 mg. In some embodiments, the dose is about 20 mg. In some embodiments, the dose is about 25 mg. In some embodiments, the dose is about 30 mg. In some embodiments, the dose is about 40 mg. In some embodiments, the dose is about 50 mg. In some embodiments, the dose is about 60 mg. In some embodiments, the dose is about 70 mg. In some embodiments, the dose is about 80 mg. In some embodiments, the dose is about 90 mg. In some embodiments, the dose is about 100 mg. In some embodiments, the dose is about 200 mg. In some embodiments, the dose is about 300 mg. In some embodiments, the dose is about 400 mg / kg. In some embodiments, the dose is about 500 mg. In some embodiments, the compound of Formula 1, or a pharmaceutically acceptable salt thereof, is provided as an oral dosage form. The compound of Formula 1, or a pharmaceutically acceptable salt thereof, can be administered at a dose between about 0.1 mg / kg to about 500 mg / kg. In some embodiments, the dose is about 1 mg / kg to about 400 mg / kg. In some embodiments, the dose is about 1 mg / kg to about 300 mg / kg. In some embodiments, the dose is about 1 mg / kg to about 200 mg / kg. In some embodiments, the dose is about 1 mg / kg to about 100 mg / kg. In some embodiments, the dose is about 1 mg / kg to about 90 mg / kg. In some embodiments, the dose is about 1 mg / kg to about 80 mg / kg. In some embodiments, the dose is about 1 mg / kg to about 70 mg / kg. In some embodiments, the dose is about 1 mg / kg to about 60 mg / kg. In some embodiments, the dose is about 1 mg / kg to about 50 mg / kg. In some embodiments, the dose is about 10 mg / kg to about 30 mg / kg. In some embodiments, the compound of Formula 1, or a pharmaceutically acceptable salt thereof, is provided as an oral dosage form. The compound of Formula 1 can be administered at a dose of about 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, or 500 mg / kg. In some embodiments, the dose is about 0.1 mg / kg. In some embodiments, the dose is about 1 mg / kg. In some embodiments, the dose is about 2 mg / kg. In some embodiments, the dose is about 3 mg / kg. In some embodiments, the dose is about 4 mg / kg. In some embodiments, the dose is about 5 mg / kg. In some embodiments, the dose is about 6 mg / kg. In some embodiments, the dose is about 7 mg / kg. In some embodiments, the dose is about 8 mg / kg. In some embodiments, the dose is about 9 mg / kg. In some embodiments, the dose is about 10 mg / kg. In some embodiments, the dose is about 15 mg / kg. In some embodiments, the dose is about 20 mg / kg. In some embodiments, the dose is about 25 mg / kg. In some embodiments, the dose is about 30 mg / kg. In some embodiments, the dose is about 40 mg / kg. In some embodiments, the dose is about 50 mg / kg. In some embodiments, the dose is about 60 mg / kg. In some embodiments, the dose is about 70 mg / kg. In some embodiments, the dose is about 80 mg / kg. In some embodiments, the dose is about 90 mg / kg. In some embodiments, the dose is about 100 mg / kg. In some embodiments, the dose is about 200 mg / kg. In some embodiments, the dose is about 300 mg / kg. In some embodiments, the dose is about 400 mg / kg. In some embodiments, the dose is about 500 mg / kg. In some embodiments, the compound of Formula 1, or a pharmaceutically acceptable salt thereof, is provided as an oral dosage form. Upon administration of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, the subject can exhibit a weight loss effect. In some embodiments, the weight loss is equal to or greater than 1% of the subject’s body weight (e.g., ≥1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or greater prior to administration of the compound of Formula 1, or a pharmaceutically acceptable thereof. In some embodiments, the weight loss is equal to or greater than 1% of the subject’s body weight (e.g., ≥1% 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or greater) prior to administration of the compound of Formula 1, or a pharmaceutically acceptable thereof, at an oral daily dose of 10 mg / kg after 28 days or longer. In some embodiments, the weight loss is equal to or greater than 1% of the subject’s body weight (e.g., ≥1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%) or greater prior to administration of the compound of Formula 1, or a pharmaceutically acceptable thereof, at an oral daily dose of 30 mg / kg after 28 days or longer. In some embodiments, the weight loss is equal to about 6.23% of the subject’s body weight prior to administration of the compound of Formula 1, or a pharmaceutically acceptable thereof, at an oral daily dose of 10 mg / kg after 28 days or longer. In some embodiments, the weight loss is equal to about 13.4% of the subject’s body weight prior to administration of the compound of Formula 1, or a pharmaceutically acceptable thereof, at an oral daily dose of 30 mg / kg after 28 days or longer. In some embodiments, the subject is administered a high fat diet (e.g., a diet with 60% kcal% fat) during the duration of administration. In some embodiments, the subject is a mouse, e.g., a PCSK1-deficient mouse, e.g., a PCSK1(- / -) or a PCSK1(+ / -) mouse. Upon administration of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, the subject can exhibit an appetite suppressing effect. In some embodiments, the appetite suppressing effect is about 1% or greater (e.g., ≥1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%), compared to the solvent-administered control group (Vehicle). In some embodiments, the appetite suppressing effect is about 1% or greater (e.g., ≥ 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%), compared to the solvent-administered control group (Vehicle), at an oral daily dose of 10 mg / kg after 28 days or longer. In some embodiments, the appetite suppressing effect is about 1% or greater (e.g., ≥ 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%), compared to the solvent-administered control group (Vehicle), at an oral daily dose of 30 mg / kg after 28 days or longer. In some embodiments, the appetite suppressing effect is about -5.2% compared to the solvent-administered control group (Vehicle), at an oral daily dose of 10 mg / kg after 28 days or longer. In some embodiments, the appetite suppressing effect is about -10.1% compared to the solvent-administered control group (Vehicle), at an oral daily dose of 10 mg / kg after 28 days or longer. In some embodiments, the subject is administered a high fat diet (e.g., a diet with 60% kcal% fat) during the duration of administration. In some embodiments, the subject is a mouse, e.g., a PCSK1-deficient mouse, e.g., a PCSK1(- / -) or a PCSK1(+ / -) mouse. Upon administration of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, the subject can exhibit a decrease in food intake. In some embodiments, the decrease in food intake is about 1% or greater (e.g., ≥ 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, or greater), compared to the solvent-administered control group (Vehicle). In some embodiments, the decrease in food intake is about 1% or greater (e.g., ≥ 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, or greater), compared to the solvent-administered control group (Vehicle), at an oral daily dose of 10 mg / kg after 28 days or later. In some embodiments, the decrease in food intake is about 1% or greater (e.g., ≥ 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, or greater), compared to the solvent-administered control group (Vehicle), at an oral daily dose of 10 mg / kg after 28 days or longer. In some embodiments, the decrease in food intake is about 1% or greater (e.g., ≥ 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, or greater), compared to the solvent-administered control group (Vehicle), at an oral daily dose of 30 mg / kg after 28 days or longer. In some embodiments, the subject is administered a high fat diet (e.g., a diet with 60% kcal% fat) during the duration of administration. In some embodiments, the subject is a mouse, e.g., a PCSK1-deficient mouse, e.g., a PCSK1(- / -) or a PCSK1(+ / -) mouse. The compound of Formula 1 may be selected from N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4- chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4- methylcyclohexyl)isobutyramide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4- chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4- methylcyclohexyl)pivalamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine- 3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4- methylcyclohexyl)propionamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4- chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4- methylcyclohexyl)butyramide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine- 3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4- methylcyclohexyl)pentanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4- chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4- methylcyclohexyl)hexanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4- chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-2-methyl-N- ((1s,4R)-4-methylcyclohexyl)butanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4- chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-2-methyl-N- ((1s,4R)-4-methylcyclohexyl)pentanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4- chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-2,2-dimethyl-N- ((1s,4R)-4-methylcyclohexyl)butanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4- chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-3-methyl-N- ((1s,4R)-4-methylcyclohexyl)pentanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4- chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-3,3-dimethyl-N- ((1s,4R)-4-methylcyclohexyl)butanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4- chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-2,3-dimethyl-N- ((1s,4R)-4-methylcyclohexyl)butanamide; and N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4- chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-3-methyl-N- ((1s,4R)-4-methylcyclohexyl)pentanamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula 1 is selected from N-((3S,5S)-1-((3S,4R)-1- (tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)- N-((1s,4R)-4-methylcyclohexyl)isobutyramide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4- chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4- methylcyclohexyl)propionamide; and N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4- chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4- methylcyclohexyl)pivalamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula 1 is N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4- (4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4- methylcyclohexyl)isobutyramide, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula 1 is N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4- chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4- methylcyclohexyl)isobutyramide hydrochloride. In some embodiments, the compound of Formula 1 is selected from a compound, or a pharmaceutically acceptable salt thereof, having the following structural formulas: Preparation Example 1: Preparation of methyl (2S, 4S)-4-(N-((1s, 4R)-4- methylcyclohexyl)isobutyramido)pyrrolidine-2-carboxylate hydrochloride The title compound was obtained using the method described in International Publication No. WO 2009 / 007930. Specifically, the title compound was obtained through the following steps A, B, C, D, and E. Step A: Preparation of 1-(tert-butyl)2-methyl (2S,4S)-4-azidopyrrolidine-1,2-dicarboxylate 1-(tert-butyl)2-methyl (2S,4R)-4-((methylsulfonyl)oxy)pyrrolidine-1,2-dicarboxylate (48.5 g, 150 mmol) was dissolved in N,N'-dimethylformamide (250 ml) under a nitrogen atmosphere, and sodium azide (19.5 g, 300 ml) was added. After stirring at 80°C for 16 hours and concentrating the reaction solvent under reduced pressure, water was added and extraction was performed twice using ethyl acetate. The organic layer was washed with aqueous sodium chloride solution and water, then dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude (39.59 g, 98%), which was used in the next step without purification. MS [M+H] = 271 (M+1) 4.37 (m, 1H), 4.35-4.27 (br, 1H), 3.77 (s, 1.8H), 3.76 (s, 1.2H), 3.73-3.66 (m, 1H), 3.44-3.38 (m, 1H), 2.63-2.49 (m, 1H), 2.19-2.11 (m, 1H), 1.50 (s, 4.5H), 1.44 (s, 4.5H) Step B: Preparation of 1-(tert-butyl)2-methyl (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate After 1-(tert-butyl) 2-methyl (2S, 4S)-4-azidopyrrolidine-1,2-dicarboxylate (24.59 g, 91.0 mmol) obtained in step A above was dissolved in tetrahydrofuran (180 ml), 1M trimethylphosphine tetrahydro solution (109.2 ml, 109.2 mmol) was slowly added at 0°C. Stirring was performed at the same temperature for 1 hour, then at room temperature for 3 hours. After concentrating the reaction solvent under reduced pressure, dichloromethane (100 ml) and water (150 ml) were added and stirred for about 30 minutes. After separating the layers and extracting once more using dichloromethane, the organic layer was dried and filtered over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure to obtain a crude (20.62 g, 93%), which was used in the next step without purification. MS [M+H] = 245 (M+1) 1H NMR (400 MHz,CD3OD) δ 4.27 (m, 1H), 3.77 (s, 1.8H), 3.76 (s, 1.2H), 3.75-3.67 (m, 1H), 3.50-3.42 (m, 1H), 3.22-3.17 (m, 1H), 2.58-2.47 (m, 1H), 1.82-1.71 (m, 1H), 1.48 (s, 4.5H), 1.42 (s, 4.5H) Step C: Preparation of 1-(tert-butyl)2-methyl (2S,4S)-4-(((1s,4R)-4- methylcyclohexyl)amino)pyrrolidine-1,2-dicarboxylate 1-(tert-butyl)2-methyl (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate (20.62 g, 84.4 mmol) obtained in step B above was dissolved in dichloroethane (150 ml) and 4-methylcyclohexanone (9.5 ml, 101.3 mmol) was added. Sodium triacetoxyborohydride (26.8 g, 126.6 mmol) was added at 0°C, and stirred at room temperature for 16 hours. The reaction solvent was concentrated under reduced pressure, water was added, and extraction was performed twice using ethyl acetate. The organic layer was washed with aqueous sodium chloride solution, then dried and filtered over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure and purified by column chromatography to obtain the title compound (22.9 g, 80%). MS [M+H] = 341 (M+1) 1H NMR (400 MHz,CD3OD) δ 4.26 (m, 1H), 3.76 (s, 1.8H), 3.75 (s, 1.2H), 3.78-3.71 (m, 1H), 3.49-3.40 (m, 1H), 3.22-3.16 (m, 1H), 2.69-2.60 (br, 1H), 2.58-2.46 (m, 1H), 1.87-1.77 (m, 1H), 1.73-1.63 (m, 1H), 1.62-1.35 (m, 8H), 1.48 (s, 4.5H), 1.42 (s, 4.5H), 0.96 (d, 3H) Step D: Preparation of 1-(tert-butyl)2-methyl (2S,4S)-4-(N-((1s,4R)-4-- methylcyclohexyl)isobutyramido)pyrrolidine-1,2-dicarboxylate 1-(tert-butyl)2-methyl (2S,4S)-4-(((1s,4R)-4-methylcyclohexyl)amino)pyrrolidine-1,2- dicarboxylate (37.29 g, 109.5 mmol) obtained in step C above was dissolved in dichloromethane (500 ml), triethyl amine (61.1 ml, 438.1 mmol) was added, and then isobutyryl chloride (11.7 ml, 219 mmol) was slowly added at 0°C. After stirring at room temperature for 16 hours, the reaction solvent was concentrated under reduced pressure, then sodium bicarbonate aqueous solution was added and extracted twice using ethyl acetate. The organic layer was washed with aqueous sodium chloride solution and water, then dried and filtered over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure and purified by column chromatography to obtain the title compound (38.79 g, 86%). MS [M+H] = 411 (M+1) 1H NMR (400 MHz,CD3OD) δ 4.27 (m, 1H), 3.76 (s, 1.8H), 3.75 (s, 1.2H), 3.78-3.72 (m, 1H), 3.50-3.41 (m, 1H), 3.33-3.14 (m, 1H), 2.69-2.60 (m, 2H), 2.57-2.43 (m, 1H), 1.87-1.79 (m, 1H), 1.70- 1.61 (m, 1H), 1.60-1.32 (m, 8H), 1.47 (s, 4.5H), 1.41 (s, 4.5H), 1.10 (dd, 6H), 0.99 (d, 3H) Step E: Preparation of methyl (2S,4S)-4- -4- methylcyclohexyl)isobutyramido)pyrrolidine-2-carboxylate hydrochloride After 1-(tert-butyl)2-methyl (2S,4S)-4-(N-((1s,4R)-4- methylcyclohexyl)isobutyramido)pyrrolidine-1,2-dicarboxylate (34.0 g, 82.8 mmol) obtained in step D above was dissolved in dichloromethane (200 ml), 4N hydrochloric acid 1,4-dioxane solution (82.8 ml, 331.3 mmol) was added at 0°C. After stirring at room temperature for 6 hours, the reaction solvent was concentrated under reduced pressure to obtain a crude (28.7 g, 99%), which was used in the next step without purification. MS [M+H] = 311 (M+1) Preparation Example 2: Preparation of (3S,4R)-1-(tert-butyl)-4-(4- chlorophenyl)pyrrolidine-3-carboxylic acid The title compound was obtained using the method described in International Publication No. WO 2004 / 092126. MS [M+H] = 282 (M+1) 1H NMR (400 MHz,CD3OD) δ 7.43-7.33 (m, 4H), 3.90-3.69 (m, 3H), 3.59 (dd, J = 11.2, 10.0 Hz, 1H), 3.29 (dd, J = 11.2, 11.2 Hz, 1H), 3.18-3.09 (m, 1H), 1.44 (s, 9H) Preparation Example 3: Preparation of methyl (2S,4S)-4-(N-((1s,4R)-4- methylcyclohexyl)propioneamido)pyrrolidine-2-carboxylate hydrochloride The title compound was obtained through the following steps A and B. Step A: Preparation of (tert-butyl)2-methyl (2S,4S)-4-(N-((1s,4R)-4-- methylcyclohexyl)propionamido)pyrrolidine-12-dicarboxylate The title compound (0.98 g, 84%) was obtained using the same method as in Step D of Preparation Example 1, using 1-(tert-butyl) 2-methyl (2S,4S)-4-(((1s,4R)-4- methylcyclohexyl)amino)pyrrolidine-1,2-dicarboxylate (1.0 g, 2.9 mmol) obtained in Step C of Preparation Example 1 and propionyl chloride (0.33 g, 3.5 mmol). MS [M+Na] = 419.5 (M+23) 1H NMR (400 MHz,CD3OD) δ 4.33 (m, 1H), 4.00-3.80 (m, 2H), 3.75 (m, 3H), 3.58 (m, 1H), 3.47 (m, 1H), 2.85-2.68 (m, 1H), 2.38 (q, 2H), 2.31 (m, 1H), 1.93 (m, 1H), 1.80 (m, 2H), 1.72-1.55 (m, 4H), 1.45 (m, 2H), 1.45-1.41 (m, 9H), 1.07 (m, 6H) Step B: Preparation of methyl (2S,4S)-4-(N-((1s,4R)-4- methylcyclohexyl)propionamido)pyrrolidine-2-carboxylate hydrochloride The title compound (0.76 g, 93%) was obtained using the same method as in Step E of Preparation Example 1, using 1-(tert-butyl)2-methyl(2S,4S)-4-(N-((1s,4R)-4- methylcyclohexyl)propionamido)pyrrolidine-1,2-dicarboxylate (0.98 g, 2.4 mmol) obtained in step A above. MS [M+H] = 297.4 (M+1) NMR (400 MHz, DMSO-d6) δ 9.95 (brs, 1H), 8.63 (brs, 1H), 4.38 (m, 1H), 4.21 (m, 1H), 3.77 (s, 3H), 3.53 (m, 1H), 3.40 (m, 2H), 2.53 (m, 1H), 2.37 (q, 2H), 2.24 (m, 1H), 1.88 (m, 1H), 1.68- 1.55 (m, 4H), 1.52 (m, 2H), 1.40 (m, 2H), 0.97 (m, 6H) Preparation Example 4: Preparation of methyl (2S,4S)-4-(N-((1s,4R)-4- methylcyclohexyl)pivalamido)pyrrolidine-2-carboxylate hydrochloride The title compound was obtained through the following steps A and B. Step A: Preparation of 1-(tert-butyl)2-methyl (2S,4S)-4-(N-((1s,4R)-4-- methylcyclohexyl)pivalamido)pyrrolidine-1,2-dicarboxylate The title compound was obtained using the method described in International Publication No. WO 2008 / 007930. MS [M+Na] = 447.5 (M+23) 1H NMR (400 MHz,CD3OD) δ 4.34 (m, 1H), 3.90-3.75 (m, 2H), 3.73 (m, 3H), 3.45 (m, 2H), 2.75-2.60 (m, 1H), 2.30 (m, 1H), 1.95 (m, 1H), 1.85 (m, 2H), 1.66 (m, 4H), 1.50 (m, 2H), 1.45-1.41 (m, 9H), 1.25-1.20 (m, 9H), 1.05 (d, 3H) Step B: Preparation of methyl (2S,4S)-4-(N-((1s,4R)-4- methylcyclohexyl)pivalamido)pyrrolidine-2-carboxylate hydrochloride The title compound (0.68 g, 99%) was obtained using the same method as in Step E of Preparation Example 1, using 1-(tert-butyl)2-methyl(2S,4S)-4-(N-((1s,4R)-4- methylcyclohexyl)pivalamido)pyrrolidine-1,2-dicarboxylate (0.80 g, 1.88 mmol) obtained in Step A above. MS [M+H] = 325.4 (M+1) 1H NMR (400 MHz, DMSO-d6) δ 10.24 (brs, 1H), 8.60 (brs, 1H), 4.41 (m, 1H), 4.22 (m, 1H), 3.77 (m, 3H), 3.40-3.28 (m, 3H), 2.55 (m, 1H), 2.20 (m, 1H), 1.87 (m, 1H), 1.70-1.50 (m, 6H), 1.40 (m, 2H), 1.21-1.10 (m, 9H), 1.00 (m, 3H) Example 1: Preparation of N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4- chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)- 4-methylcyclohexyl)isobutyramide hydrochloride The title compound was obtained through the following steps A, B, C, and D. Step A: Preparation of methyl (2S,4S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3- carbonyl)-4-(N-((1s,4R)-4-methylcyclohexyl)isobutyramido)pyrrolidine-2-carboxylate Methyl (2S,4S)-4-(N-((1s,4R)-4-methylcyclohexyl)isobutyramido)pyrrolidine-2-carboxylate hydrochloride (28.7 g, 82.73 mmol) obtained in Preparation Example 1, (3S,4R)-1-(tert-butyl)-4-(4- chlorophenyl)pyrrolidine-3-carboxylic acid (24.5 g, 86.87 mmol) obtained in Preparation Example 2, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (22.2 g, 115.83 mmol), and 1- hydroxybenzotriazole hydrate (15.7 g, 115.83 mmol) were dissolved in N,N'-dimethyformamide (400ml) and N,N'-diisopropylethylamine (72.0 ml, 413.66 mmol) was slowly added. After stirring at room temperature for 16 hours and concentrating the reaction solvent under reduced pressure, 0.5N aqueous sodium hydroxide solution was added and extraction was performed twice using ethyl acetate. The organic layer was washed twice with aqueous sodium chloride solution and water, then dried and filtered over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure and purified by column chromatography to obtain the title compound (41.19 g, 87%). MS [M+H] = 575 (M+1) Step B: Preparation of (2S,4S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3- carbonyl)-4-(N-((1s,4R)-4-methylcyclohexyl)isobutyramido)pyrrolidine-2-carboxylic acid After methyl (2S,4S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-4-(N- ((1s,4R)-4-methylcyclohexyl)isobutyramido)pyrrolidine-2-carboxylate (39.4 g, 68.62 mmol) obtained in step A above was dissolved in methanol (450 ml), 6N aqueous sodium hydroxide solution (57.2 ml, 343.09 mmol) was added. After stirring at room temperature for 16 hours and adjusting the pH to about 5 using a 6N aqueous hydrochloric acid solution, the reaction solution was concentrated under reduced pressure. After dissolving the concentrate in dichloromethane, the insoluble solid was filtered through a paper filter. The filtrate was concentrated under reduced pressure to obtain a crude (38.4 g, 99%), which was used in the next step without purification. MS [M+H] = 561 (M+1) Step C: Preparation of N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3- carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4- methylcyclohexyl)isobutyramide (2S,4S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)- 4-(N-((1s,4R)-4- methylcyclohexyl)isobutyramido)pyrrolidine-2-carboxylic acid (38.4 g, 68.60 mmol) obtained in step B above, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (18.4 g, 96.04 mmol), and 1-hydroxybenzotriazole hydrate (13.0 g, 96.04 mmol) were dissolved in N,N'- dimethylformamide (200 ml) and then sequentially morpholine (5.9 ml, 68.80 mmol) and N,N'- diisopropylethylamine (59.7 ml, 343.02 mmol) were slowly added. After stirring at room temperature for 16 hours, the reaction solution was concentrated under reduced pressure, 0.5 N sodium hydroxide aqueous solution was added, and extraction was performed twice using ethyl acetate. The organic layer was washed twice with aqueous sodium chloride solution and water, then dried and filtered over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure and purified by column chromatography to obtain the title compound (37.05 g, 86%). MS [M+H] = 630 (M+1) Step D: Preparation of N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3- carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4- methylcyclohexyl)isobutyramide hydrochloride After N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5- (morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide (5.0 g, 7.95 mmol ) obtained in step C above was dissolved in ethyl acetate (50 ml), 2N hydrochloric acid ethyl acetate solution (3.97 ml, 15.89 mmol) was slowly added. After stirring at room temperature for 30 minutes, the reaction solvent was concentrated under reduced pressure. The resulting crude solid was purified by trituration using hexane and diethyl ether to obtain the title compound (5.23 g, 99%). MS [M+H] = 630 (M+1) 1H NMR (500 MHz,CD3OD) δ 7.49-7.44 (m, 4H), 4.83 (m, 1H), 4.23-4.20 (m, 1H), 3.95-3.91 (m, 2H), 3.79-3.47 (m, 14H), 3.03-3.00 (m, 1H), 2.86-2.82 (m, 1H), 2.73-2.67 (m, 1H), 2.20-2.14 (m, 1H), 1.97 (m, 1H), 1.80-1.62 (m, 5H), 1.50 (s, 9H), 1.44-1.27 (m, 3H), 1.06-1.04 (m, 9H) Example 2: Preparation of N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4- chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)- 4-methylcyclohexyl)propionamide hydrochloride The title compound was obtained through the following steps A, B, C, and D. Step A: Preparation of methyl (2S,4S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3- carbonyl)-4-(N-((1s,4R)-4-methylcyclohexyl)propionamido)pyrrolidine-2-carboxylate The title compound (0.45 g, 35%) was obtained using the same method as in Step A of Example 1, using methyl (2S, 4S)-4-(N-((1s,4R)-4-methylcyclohexyl)propionamido)pyrrolidine-2-carboxylate hydrochloride (0.76 g, 2.28 mmol) obtained in Preparation Example 3 and (3S,4R)-1-(tert-butyl)-4- (4-chlorophenyl)pyrrolidine-3-carboxylic acid (0.64 g, 2.28 mmol) obtained in Preparation Example 2. MS [M+H] = 560.4 (M+1) 1H NMR (400 MHz,CD3OD) δ 7.39-7.30 (m, 4H), 4.45 (m, 1H), 4.04 (m, 1H), 3.71 (s, 3H), 3.65- 3.35 (m, 6H), 3.13 (m, 2H), 2.99 (m, 1H), 2.71 (m, 1H), 2.34 (q, 2H), 2.20 (m, 1H), 1.92 (m, 1H), 1.75-1.55 (m, 6H), 1.42 (m, 2H), 1.22 (m, 9H), 1.03 (m, 6H) Step B: Preparation of (2S,4S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3- carbonyl)-4-(N-((1s,4R)-4-methylcyclohexyl)propionamido)pyrrolidine-2-carboxylic acid The title compound (0.44 g, 99%) was obtained using the same method as in Step B of Example 1 using methyl (2S,4S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-4-(N- ((1s,4R)-4-methylcyclohexyl)propionamido)pyrrolidine-2-carboxylate (0.45 g, 0.80 mmol) obtained in step A above. MS [M+H] = 546.4 (M+1) Step C: Preparation of N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3- carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)propionamide The title compound (0.28g, 53%) was obtained using the same method as in Step C of Example 1 using (2S,4S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-4-(N-((1s,4R)- 4-methylcyclohexyl)propionamido)pyrrolidine-2-carboxylic acid (0.44 g, 0.80 mmol) obtained in Step B above. MS [M+H] = 615.5 (M+1) 1H NMR (400 MHz,CD3OD) δ 7.36 (m, 4H), 4.79 (m, 1H), 4.18 (m, 1H), 3.80-3.40 (m, 15H), 3.20 (m, 1H), 3.03 (m, 1H), 2.70 (m, 1H), 2.33 (q, 2H), 2.15 (m, 1H), 1.93 (m, 1H), 1.71-1.56 (m, 6H), 1.40-1.20 (m, 11H), 1.00 (m, 6H) Step D: Preparation of N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3- carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)propionamide hydrochloride The title compound (0.08 g, 94%) was obtained using the same method as in Step D of Example 1 using N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5- (morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)propionamide (0.08 g, 0.13 mmol) obtained in step C above. MS [M+H] = 615.5 (M+1) δ 7.43 (m, 4H), 4.82 (t, 1H), 4.20 (m, 1H), 4.06-3.40 (m, 15H), 2.97 (m, 1H), 2.69 (m, 1H), 2.33 (m, 2H), 2.15 (m, 1H), 1.93 (m, 1H), 1.80-1.53 (m, 5H), 1.47 (s, 9H), 1.50-1.25 (m, 4H), 1.01 (m, 6H) Example 3: Preparation of N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4- chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)- 4-methylcyclohexyl)pivalamide hydrochloride The title compound was obtained through the following steps A, B, C, and D. Step A: Preparation of methyl (2S,4S)-1-((3S,4R)-1- butyl)-4-(4-chlorophenyl)pyrrolidine-3- carbonyl)-4-(N-((1s,4R)-4-methylcyclohexyl)pivalamido)pyrrolidine-2-carboxylate The title compound (0.70 g, 66%) was obtained using the same method as in Step A of Example 1, using methyl (2S,4S)-4-(N-((1s,4R)-4-methylcyclohexyl)pivalamido)pyrrolidine-2-carboxylate hydrochloride (0.65 g, 1.8 mmol) obtained in Preparation Example 4 and (3S, 4R)-1-(tert-butyl)-4- (4-chlorophenyl)pyrrolidine-3-carboxylic acid (0.50 g, 1.8 mmol) obtained in Preparation Example 2. MS [M+H] = 588.5 (M+1) 7.30 (m, 4H), 4.49 (m, 1H), 4.00-3.50 (m, 4H), 3.71 (s, 3H), 3.40 (m, 3H), 3.20-3.05 (m, 2H), 3.00 (m, 1H), 2.70 (m, 1H), 2.27 (m, 1H), 1.90 (m, 1H), 1.73-1.60 (m, 6H), 1.60-1.35 (m, 2H), 1.25-1.17 (m, 18H), 1.01 (m, 3H) Step B: Preparation of (2S,4S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3- carbonyl)-4-(N-((1s,4R)-4-methylcyclohexyl)pivalamido)pyrrolidine-2-carboxylic acid The title compound (0.10 g, 99%) was obtained using the same method as in Step B of Example 1 using methyl (2S,4S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-4-(N- ((1s,4R)-4-methylcyclohexyl)pivalamido)pyrrolidine-2-carboxylate (0.10 g, 0.18 mmol) obtained in step A above. MS [M+H] = 574.4 (M+1) Step C: Preparation of N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3- carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)pivalamide

[0002] The title compound (0.020 g, 17%) was obtained using the same method as in Step C of Example 1 using (2S,4S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-4-(N-((1s,4R)- 4-methylcyclohexyl)pivalamido)pyrrolidine-2-carboxylic acid (0.10 g, 0.18 mmol) obtained in step B above. MS [M+H] = 643.5 (M+1) 7.30 (m, 4H), 4.79 (m, 1H), 4.17 (m, 1H), 3.80-3.40 (m, 15H), 3.10 (m, 1H), 2.96 (m, 1H), 2.71 (m, 1H), 2.15 (m, 1H), 1.90 (m, 1H), 1.80-1.35 (m, 8H), 1.21- 1.15 (m, 18H), 1.02 (m, 3H) Step D: Preparation of N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3- carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N -4-methylcyclohexyl)pivalamide hydrochloride The title compound (0.29 g, 83%) was obtained using the same method as in Step D of Example 1 using N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5- (morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)pivalamide (0.33 g, 0.51 mmol) obtained in step C above. MS [M+H] = 643.5 (M+1) 1H NMR (400 MHz,CD3OD) δ 7.41 (m, 4H), 4.80 (m, 1H), 4.13 (m, 1H), 3.90 (m, 2H), 3.80- 3.40 (m, 13H), 2.94 (m, 1H), 2.63 (m, 1H), 2.11 (m, 1H), 1.93 (m, 1H), 1.75 (m, 2H), 1.60 (m, 4H), 1.46 (s, 9H), 1.15 (s, 9H), 1.45-1.30 (m, 3H), 1.01 (m, 3H) Experimental Example 1: Pharmacology Mutations in the prohormone convertase 1 (PC1 or PCSK1) gene cause deficiency in POMC processing and impairment of the melanocortin pathway through disruption of MC4R signaling. Therefore, mice having a mutation (N222D) in the PCSK1 gene are an effective animal model reflecting the human genetic obesity disease, PC1 / PCSK1 deficiency obesity, and are mice that exhibit abnormal metabolic disease-related phenotypes such as hyperphagia and severe obesity. The pharmacological effects of N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4- chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)- N-((1s,4R)-4- methylcyclohexyl)isobutyramide hydrochloride (hereinafter referred to as "Compound 100" or “Cmpd. 100”) obtained in Example 1 in a rare genetic obesity disease associated with PCSK1 deficiency in a Pcsk1-deficient mouse model were evaluated in the obesity models as below. Experimental Example 1-1: Heterozygous (PCSK1+ / -) mouse obesity model The anti-obesity efficacy was confirmed by repeated oral administration of the Compound 100 of the present invention at a dose of 10 mg / kg or 30 mg / kg for about 28 days to PCSK1+ / - mice heterozygous for a mutation (N222D) in the PCSK1 gene while feeding a 60 kcal% high-fat diet (diet with 60 kcal% fat) and the results are shown in FIGS.1 and 2. As can be seen from FIG. 1, it was confirmed that the Compound 100 of the present invention exhibited a significant weight loss effect. As of day 28, Compound 100 in PCSK1+ / - mice when administered at doses of 10 mg / kg and 30 mg / kg caused weight gain inhibition of -6.23% and -13.4% compared to the solvent-administered control group (Vehicle), respectively, exhibiting a statistically significant weight loss effect. Additionally, as can be seen from FIG.2, it was confirmed that the Compound 100 of the present invention exhibited a significant appetite suppressing effect. Based on the cumulative feed intake for one week, when Compound 100 was administered at doses of 10 mg / kg and 30 mg / kg in PCSK1+ / - mice, food intake (g) decreased compared to the solvent-administered control group (Vehicle), exhibiting a statistically significant appetite suppressing effect. Experimental Example 1-2: Homozygous (PCSK1- / -) mouse obesity model The anti-obesity efficacy was confirmed by repeated oral administration of the Compound 100 of the present invention at a dose of 10 mg / kg or 30 mg / kg for approximately 28 days to PCSK1- / - mice homozygous for a mutation (N222D) in the PCSK1 gene while feeding a 60 kcal% high-fat diet (diet with 60 kcal% fat) and the results are shown in FIGS.3 and 4. As can be seen from FIG. 3, it was confirmed that the Compound 100 of the present invention exhibited a significant weight loss effect. As of day 28, when Compound 100 was administered to PCSK1- / - mice at doses of 10 mg / kg and 30 mg / kg, it caused weight gain inhibition of -5.2% and - 10.1%, respectively, compared to the solvent-administered control group (Vehicle), exhibiting a statistically significant weight loss effect. Additionally, as can be seen from FIG.4, it was confirmed that the Compound 100 of the present invention exhibited a significant appetite suppressing effect. Based on the cumulative feed intake for one week, when Compound 100 was administered at doses of 10 mg / kg and 30 mg / kg in PCSK1- / - mice, food intake (g) decreased compared to the solvent-administered control group (Vehicle), exhibiting a statistically significant appetite suppressing effect. The results of Experimental Examples 1-1 and 1-2 are due to the excellent melanocortin-4 receptor agonistic activity of the Compound 100 of Example 1, for which it is expected that significant differences will be visible even at low administration doses, and have exhibited equal or better efficacy compared to other obesity treatment agents having the same MC4R agonist as the point of action, and thus it is expected that it will be able to exhibit excellent constitutional improvement effects and safety when actually applied clinically. In addition, the Compound 100 of the present invention is a small molecule compound rather than a peptide, and thus there is the advantage that the Compound 100 can be used as an oral preparation in addition to an injectable preparation compared to peptidyl MC4R agonists.

Claims

CLAIMS 1. A method for treating obesity in a subject having a Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1) deficiency, wherein the method comprises administering to the subject a compound of Formula 1 or a pharmaceutically acceptable salt thereof:, wherein R1 is C2-C5 alkyl, thereby treating obesity in the subject.

2. The method of claim 1, wherein the Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1) deficiency is homozygous (PCSK1- / -) or heterozygous (PCSK1+ / -).

3. The method of claim 2, wherein the Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1) deficiency is homozygous (PCSK1- / -).

4. The method of claim 2, wherein the Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1) deficiency is heterozygous (PCSK1+ / -).

5. The method of claim 1, wherein the compound of Formula 1, or a pharmaceutically acceptable salt thereof, is formulated as a pharmaceutical composition, together with a pharmaceutically acceptable carrier.

6. The method of claim 1, wherein the pharmaceutical composition is formulated as a dosage form, e.g., a unit dosage form.

7. The method of claim 1, wherein the dosage form is a solid dosage form.

8. The method of claim 1, wherein the pharmaceutical composition is formulated as an oral dosage form.

9. The method of claim 1, wherein the oral dosage form comprises a capsule, a tablet, a pill, a powder, or a granule.

10. The method of claim 1, wherein the oral dosage form comprises a capsule.

11. The method of claim 1, herein the oral dosage form comprises a tablet.

12. The method of claim 1, wherein the dosage form is formulated as a transdermal dosage form.

13. The method of claim 1, wherein the transdermal dosage form comprises a lotion, ointment, gel, cream, patch or spray.

14. The method of claim 1, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is between about 0.1 mg to about 500 mg.

15. The method of claim 1, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is about 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, or 500 mg.

16. The method of claim 1, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is between about 1 mg to about 50 mg.

17. The method of claim 1, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is between about 10 mg to about 30 mg.

18. The method of claim 1, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is 10 mg.

19. The method of claim 1, wherein the dosage of Formula 1, or a pharmaceutically acceptablesalt thereof, administered to the subject is 30 mg.

20. The method of claim 1, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is between about 0.1 mg / kg to about 500 mg / kg.

21. The method of claim 1, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is about 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, or 500 mg / kg.

22. The method of claim 1, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is between about 1 mg / kg to about 50 mg / kg.

23. The method of claim 1, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is between about 10 mg / kg to about 30 mg / kg.

24. The method of claim 1, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is 10 mg / kg.

25. The method of claim 1, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is 30 mg / kg.

26. The method of claim 1, wherein administration occurs daily, weekly, or monthly.

27. The method of claim 1, wherein administration occurs once daily or twice daily.

28. The method of claim 1, wherein administration occurs once daily.

29. The method of claim 1, wherein administration occurs twice daily.

30. The method of claim 1, wherein administration occurs once weekly, twice weekly, or three times weekly.

31. The method of claim 1, wherein administration occurs once weekly.

32. The method of claim 1, wherein administration occurs twice weekly.

33. The method of claim 1, wherein administration occurs three times weekly.

34. The method of claim 1, wherein the subject is obese, e.g., severely obese.

35. The method of claim 1, wherein the subject is hyperphagic.

36. The method of claim 1, wherein the subject has a body mass index greater than 35 kg / m2(e.g., ≥36, 37, 38, 39, 40, 41, 42, 43, 44, 45 kg / m2or greater), prior to administration of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, or at the time of the first administration.

37. The method of claim 1, wherein the subject has a body mass index greater than 40 kg / m2(e.g., ≥41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg / m2or greater), prior to administration of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, or at the time of the first administration.

38. The method of claim 1, wherein the subject has a body mass index greater than 45 kg / m2(e.g., ≥46, 47, 48, 49, 50, 51, 52, 53, 54, 55 kg / m2or greater), prior to administration of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, or at the time of the first administration.

39. The method of claim 1, wherein the subject has an additional genetic deficiency, e.g., an additional genetic metabolic deficiency.

40. The method of claim 1, wherein the subject has diabetes or a diabetological condition, e.g., pre-diabetes, diabetes mellitus type 1, diabetes mellitus type 2, hyperglycemia, hypoglycemia, or hyperinsulinemia.

41. The method of claim 1, wherein the subject is hypertensive.

42. The method of claim 1, wherein the subject has failed one or more previous therapies comprising exercise, diet, or behavioral therapies prior to administration of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, or at the time of the first administration.

43. The method of claim 1, wherein the subject exhibits a weight loss equal to or greater than 1% of the subject’s body weight (e.g., ≥ 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or greater) prior to administration of the compound of Formula 1, or a pharmaceutically acceptable thereof, at an oral daily dose of 10 mg / kg after 28 days or longer.

44. The method of claim 1, wherein the subject exhibits a weight loss equal to or greater than 1% of the subject’s body weight (e.g., ≥ 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or greater) prior to administration of the compound of Formula 1, or a pharmaceutically acceptable thereof, at an oral daily dose of 30 mg / kg after 28 days or longer.

45. The method of claim 1, wherein the subject exhibits an appetite suppressing effect of about 1% or greater (e.g., ≥ 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%), compared to a solvent-administered control group (Vehicle), at an oral daily dose of 10 mg / kg after 28 days or longer.

46. The method of claim 1, wherein the subject exhibits an appetite suppressing effect is about 1% or greater (e.g., ≥ 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%), compared to a solvent-administered control group (Vehicle), at an oral daily dose of 30 mg / kg after 28 days or longer.

47. The method of claim 1, wherein the subject exhibits a decrease in food intake of about 1% or greater (e.g., ≥ 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, or greater), compared to a solvent-administered control group (Vehicle), at an oral daily dose of 10 mg / kg after 28 days or later.

48. The method of claim 1, wherein the subject exhibits a decrease in food intake of about 1%or greater (e.g., ≥ 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, or greater), compared to a solvent-administered control group (Vehicle), at an oral daily dose of 30 mg / kg after 28 days or later.

49. The method of claim 1, wherein the compound of Formula 1 is selected from one of the following compounds, or a pharmaceutically acceptable salt thereof: N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)pivalamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)propionamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)butyramide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)pentanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)hexanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-2-methyl-N-((1s,4R)-4-methylcyclohexyl)butanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-2-methyl-N-((1s,4R)-4-methylcyclohexyl)pentanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-2,2-dimethyl-N-((1s,4R)-4-methylcyclohexyl)butanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-3-methyl-N-((1s,4R)-4-methylcyclohexyl)pentanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-3,3-dimethyl-N-((1s,4R)-4-methylcyclohexyl)butanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-2,3-dimethyl-N-((1s,4R)-4-methylcyclohexyl)butanamide; and N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-3-methyl-N-((1s,4R)-4-methylcyclohexyl)pentanamide.

50. The method of claim 1, wherein the compound of Formula 1 is selected from a compound having one of the following structural formulas, or a pharmaceutically acceptable salt thereof :

51. The method of claim 1, wherein the compound of Formula 1 is N-((3S,5S)-1-((3S,4R)-1- (tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)- N-((1s,4R)-4-methylcyclohexyl)isobutyramide, or a pharmaceutically acceptable salt thereof.

52. The method of claim 1, wherein the compound of Formula 1 is selected from one of the following compounds, or a pharmaceutically acceptable salt thereof: N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)propionamide; and N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)pivalamide.

53. The method of claim 1, wherein the compound of Formula 1 is selected from one of the following compounds: N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide hydrochloride; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)propionamide hydrochloride; and N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)pivalamide hydrochloride.

54. The method of claim 1, wherein the compound of Formula 1 isN-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide hydrochloride.

55. A composition for use in treating obesity in a subject having a Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1) deficiency, wherein the composition comprises an effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof:, wherein R1 is C2-C5 alkyl.

56. The composition for use of claim 55, wherein the Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1) deficiency is homozygous (PCSK1- / -) or heterozygous (PCSK1+ / -).

57. The composition for use of claim 56, wherein the Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1) deficiency is homozygous (PCSK1- / -).

58. The composition for use of claim 56, wherein the Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1) deficiency is heterozygous (PCSK1+ / -).

59. The composition for use of claim 55, wherein the compound of Formula 1, or a pharmaceutically acceptable salt thereof, is formulated as a pharmaceutical composition, together with a pharmaceutically acceptable carrier.

60. The composition for use of claim 55, wherein the pharmaceutical composition is formulated as a dosage form, e.g., a unit dosage form.

61. The composition for use of claim 55, wherein the dosage form is a solid dosage form.

62. The composition for use of claim 55, wherein the pharmaceutical composition is formulated as an oral dosage form.

63. The composition for use of claim 55, wherein the oral dosage form comprises a capsule, a tablet, a pill, a powder, or a granule.

64. The composition for use of claim 55, wherein the oral dosage form comprises a capsule.

65. The composition for use of claim 55, wherein the oral dosage form comprises a tablet.

66. The composition for use of claim 55, wherein the dosage form is formulated as a transdermal dosage form.

67. The composition for use of claim 55, wherein the transdermal dosage form comprises a lotion, ointment, gel, cream, patch or spray.

68. The composition for use of claim 55, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is between about 0.1 mg to about 500 mg.

69. The composition for use of claim 55, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is about 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, or 500 mg.

70. The composition for use of claim 55, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is between about 1 mg to about 50 mg.

71. The composition for use of claim 55, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is between about 10 mg to about 30 mg.

72. The composition for use of claim 55, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is 10 mg.

73. The composition for use of claim 55, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is 30 mg.

74. The composition for use of claim 55, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is between about 0.1 mg / kg to about 500 mg / kg.

75. The composition for use of claim 55, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is about 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, or 500 mg / kg.

76. The composition for use of claim 55, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is between about 1 mg / kg to about 50 mg / kg.

77. The composition for use of claim 55, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is between about 10 mg / kg to about 30 mg / kg.

78. The composition for use of claim 55, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is 10 mg / kg.

79. The composition for use of claim 55, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is 30 mg / kg.

80. The composition for use of claim 55, wherein administration occurs daily, weekly, or monthly.

81. The composition for use of claim 55, wherein administration occurs once daily or twice daily.

82. The composition for use of claim 55, wherein administration occurs once daily.

83. The composition for use of claim 55, wherein administration occurs twice daily.

84. The composition for use of claim 55, wherein administration occurs once weekly, twice weekly, or three times weekly.

85. The composition for use of claim 55, wherein administration occurs once weekly.

86. The composition for use of claim 55, wherein administration occurs twice weekly.

87. The composition for use of claim 55, wherein administration occurs three times weekly.

88. The composition for use of claim 55, wherein the subject is obese, e.g., severely obese.

89. The composition for use of claim 55, wherein the subject is hyperphagic.

90. The composition for use of claim 55, wherein the subject has a body mass index greater than 35 kg / m2(e.g., ≥36, 37, 38, 39, 40, 41, 42, 43, 44, 45 kg / m2or greater), prior to administration of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, or at the time of the first administration.

91. The composition for use of claim 55, wherein the subject has a body mass index greater than 40 kg / m2(e.g., ≥41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg / m2or greater), prior to administration of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, or at the time of the first administration.

92. The composition for use of claim 55, wherein the subject has a body mass index greater than 45 kg / m2(e.g., ≥46, 47, 48, 49, 50, 51, 52, 53, 54, 55 kg / m2or greater), prior to administration of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, or at the time of the first administration.

93. The composition for use of claim 55, wherein the subject has an additional genetic deficiency, e.g., an additional genetic metabolic deficiency.

94. The composition for use of claim 55, wherein the subject has diabetes or a diabetological condition, e.g., pre-diabetes, diabetes mellitus type 1, diabetes mellitus type 2, hyperglycemia, hypoglycemia, or hyperinsulinemia.

95. The composition for use of claim 55, wherein the subject is hypertensive.

96. The composition for use of claim 55, wherein the subject has failed one or more previous therapies comprising exercise, diet, or behavioral therapies prior to administration of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, or at the time of the first administration.

97. The composition for use of claim 55, wherein the subject exhibits a weight loss equal to or greater than 1% of the subject’s body weight (e.g., ≥ 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or greater) prior to administration of the compound of Formula 1, or a pharmaceutically acceptable thereof, at an oral daily dose of 10 mg / kg after 28 days or longer.

98. The composition for use of claim 55, wherein the subject exhibits a weight loss equal to or greater than 1% of the subject’s body weight (e.g., ≥ 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or greater) prior to administration of the compound of Formula 1, or a pharmaceutically acceptable thereof, at an oral daily dose of 30 mg / kg after 28 days or longer.

99. The composition for use of claim 55, wherein the subject exhibits an appetite suppressing effect of about 1% or greater (e.g., ≥ 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%), compared to a solvent-administered control group (Vehicle), at an oral daily dose of 10 mg / kg after 28 days or longer.

100. The composition for use of claim 55, wherein the subject exhibits an appetite suppressing effect is about 1% or greater (e.g., ≥ 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%), compared to a solvent-administered control group (Vehicle), at an oral daily dose of 30 mg / kg after 28 days or longer.

101. The composition for use of claim 55, wherein the subject exhibits a decrease in food intake of about 1% or greater (e.g., ≥ 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, or greater), compared to a solvent-administered control group (Vehicle), at an oral daily dose of 10 mg / kg after 28 days or later.

102. The composition for use of claim 55, wherein the subject exhibits a decrease in food intake of about 1% or greater (e.g., ≥ 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, or greater), compared to a solvent-administered control group (Vehicle), at an oral daily dose of 30 mg / kg after 28 days or later.

103. The composition for use of claim 55, wherein the compound of Formula 1 is selected from one of the following compounds, or a pharmaceutically acceptable salt thereof: N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)pivalamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)propionamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)butyramide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)pentanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)hexanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-2-methyl-N-((1s,4R)-4-methylcyclohexyl)butanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-2-methyl-N-((1s,4R)-4-methylcyclohexyl)pentanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-2,2-dimethyl-N-((1s,4R)-4-methylcyclohexyl)butanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-3-methyl-N-((1s,4R)-4-methylcyclohexyl)pentanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-3,3-dimethyl-N-((1s,4R)-4-methylcyclohexyl)butanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-2,3-dimethyl-N-((1s,4R)-4-methylcyclohexyl)butanamide; and N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-3-methyl N ((1s4R) 4 methylcyclohexyl)pentanamide.

104. The composition for use of claim 55, wherein the compound of Formula 1 is selected from a compound having one of the following structural formulas, or a pharmaceutically acceptable salt thereof :

105. The composition for use of claim 55, wherein the compound of Formula 1 is N-((3S,5S)-1- ((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide, or a pharmaceutically acceptable salt thereof.

106. The composition for use of claim 55, wherein the compound of Formula 1 is selected from one of the following compounds, or a pharmaceutically acceptable salt thereof: N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)propionamide; and N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)pivalamide.

107. The composition for use of claim 55, wherein the compound of Formula 1 is selected from one of the following compounds:N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide hydrochloride; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)propionamide hydrochloride; and N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)pivalamide hydrochloride.

108. The composition for use of claim 55, wherein the compound of Formula 1 is N-((3S,5S)-1- ((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide hydrochloride.

109. A medicament for treating obesity associated with Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1) deficiency, comprising a therapeutically effective amount of the compound of Formula 1 below or a pharmaceutically acceptable salt thereof: [Formula 1], wherein R1 is C2-C5 alkyl.

110. The medicament of claim 109, wherein the Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1) deficiency is homozygous (PCSK1- / -) or heterozygous (PCSK1+ / -).

111. The medicament of claim 110, wherein the Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1) deficiency is homozygous (PCSK1- / -).

112. The medicament of claim 110, wherein the Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1) deficiency is heterozygous (PCSK1+ / -).

113. The medicament of claim 109, wherein the compound of Formula 1, or a pharmaceutically acceptable salt thereof, is formulated as a pharmaceutical composition, together with a pharmaceutically acceptable carrier.

114. The medicament of claim 109, wherein the pharmaceutical composition is formulated as a dosage form, e.g., a unit dosage form.

115. The medicament of claim 109, wherein the dosage form is a solid dosage form.

116. The medicament of claim 109, wherein the pharmaceutical composition is formulated as an oral dosage form.

117. The medicament of claim 109, wherein the oral dosage form comprises a capsule, a tablet, a pill, a powder, or a granule.

118. The medicament of claim 109, wherein the oral dosage form comprises a capsule.

119. The medicament of claim 109, wherein the oral dosage form comprises a tablet.

120. The medicament of claim 109, wherein the dosage form is formulated as a transdermal dosage form.

121. The medicament of claim 109, wherein the transdermal dosage form comprises a lotion, ointment, gel, cream, patch or spray.

122. The medicament of claim 109, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is between about 0.1 mg to about 500 mg.

123. The medicament of claim 109, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is about 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, or 500 mg.

124. The medicament of claim 109, wherein the dosage of Formula 1, or a pharmaceuticallyacceptable salt thereof, administered to the subject is between about 1 mg to about 50 mg.

125. The medicament of claim 109, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is between about 10 mg to about 30 mg.

126. The medicament of claim 109, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is 10 mg.

127. The medicament of claim 109, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is 30 mg.

128. The medicament of claim 109, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is between about 0.1 mg / kg to about 500 mg / kg.

129. The medicament of claim 109, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is about 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, or 500 mg / kg.

130. The medicament of claim 109, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is between about 1 mg / kg to about 50 mg / kg.

131. The medicament of claim 109, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is between about 10 mg / kg to about 30 mg / kg.

132. The medicament of claim 109, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is 10 mg / kg.

133. The medicament of claim 109, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is 30 mg / kg.

134. The medicament of claim 109, wherein administration occurs daily, weekly, or monthly.

135. The medicament of claim 109, wherein administration occurs once daily or twice daily.

136. The medicament of claim 109, wherein administration occurs once daily.

137. The medicament of claim 109, wherein administration occurs twice daily.

138. The medicament of claim 109, wherein administration occurs once weekly, twice weekly, or three times weekly.

139. The medicament of claim 109, wherein administration occurs once weekly.

140. The medicament of claim 109, wherein administration occurs twice weekly.

141. The medicament of claim 109, wherein administration occurs three times weekly.

142. The medicament of claim 109, wherein the subject is obese, e.g., severely obese.

143. The medicament of claim 109, wherein the subject is hyperphagic.

144. The medicament of claim 109, wherein the subject has a body mass index greater than 35 kg / m2(e.g., ≥36, 37, 38, 39, 40, 41, 42, 43, 44, 45 kg / m2or greater), prior to administration of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, or at the time of the first administration.

145. The medicament of claim 109, wherein the subject has a body mass index greater than 40 kg / m2(e.g., ≥41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg / m2or greater), prior to administration of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, or at the time of the first administration.

146. The medicament of claim 109, wherein the subject has a body mass index greater than 45 kg / m2(e.g., ≥46, 47, 48, 49, 50, 51, 52, 53, 54, 55 kg / m2or greater), prior to administration of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, or at the time of the first administration.

147. The medicament of claim 109, wherein the subject has an additional genetic deficiency, e.g., an additional genetic metabolic deficiency.

148. The medicament of claim 109, wherein the subject has diabetes or a diabetological condition, e.g., pre-diabetes, diabetes mellitus type 1, diabetes mellitus type 2, hyperglycemia, hypoglycemia, or hyperinsulinemia.

149. The medicament of claim 109, wherein the subject is hypertensive.

150. The medicament of claim 109, wherein the subject has failed one or more previous therapies comprising exercise, diet, or behavioral therapies prior to administration of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, or at the time of the first administration.

151. The medicament of claim 109, wherein the subject exhibits a weight loss equal to or greater than 1% of the subject’s body weight (e.g., ≥ 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or greater) prior to administration of the compound of Formula 1, or a pharmaceutically acceptable thereof, at an oral daily dose of 10 mg / kg after 28 days or longer.

152. The medicament of claim 109, wherein the subject exhibits a weight loss equal to or greater than 1% of the subject’s body weight (e.g., ≥ 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or greater) prior to administration of the compound of Formula 1, or a pharmaceutically acceptable thereof, at an oral daily dose of 30 mg / kg after 28 days or longer.

153. The medicament of claim 109, wherein the subject exhibits an appetite suppressing effect of about 1% or greater (e.g., ≥ 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%), compared to a solvent-administered control group (Vehicle), at an oral daily dose of 10 mg / kg after 28 days or longer.

154. The medicament of claim 109, wherein the subject exhibits an appetite suppressing effect is about 1% or greater (e.g., ≥ 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%,15%), compared to a solvent-administered control group (Vehicle), at an oral daily dose of 30 mg / kg after 28 days or longer.

155. The medicament of claim 109, wherein the subject exhibits a decrease in food intake of about 1% or greater (e.g., ≥ 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, or greater), compared to a solvent-administered control group (Vehicle), at an oral daily dose of 10 mg / kg after 28 days or later.

156. The medicament of claim 109, wherein the subject exhibits a decrease in food intake of about 1% or greater (e.g., ≥ 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, or greater), compared to the solvent-administered control group (Vehicle), at an oral daily dose of 30 mg / kg after 28 days or later.

157. The medicament of claim 109, wherein the compound of Formula 1 is selected from one of the following compounds, or a pharmaceutically acceptable salt thereof: N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)pivalamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)propionamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)butyramide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)pentanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)hexanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-2-methyl-N-((1s,4R)-4-methylcyclohexyl)butanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-2-methyl-N-((1s,4R)-4-methylcyclohexyl)pentanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-2,2-dimethyl-N-((1s,4R)-4-methylcyclohexyl)butanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-3-methyl-N-((1s,4R)-4-methylcyclohexyl)pentanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-3,3-dimethyl-N-((1s,4R)-4-methylcyclohexyl)butanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-2,3-dimethyl-N-((1s,4R)-4-methylcyclohexyl)butanamide; and N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-3-methyl-N-((1s,4R)-4-methylcyclohexyl)pentanamide.

158. The medicament of claim 109, wherein the compound of Formula 1 is selected from a compound having one of the following structural formulas, or a pharmaceutically acceptable salt thereof :

159. The medicament of claim 109, wherein the compound of Formula 1 is N-((3S,5S)-1- ((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide, or a pharmaceutically acceptable salt thereof.

160. The medicament of claim 109, wherein the compound of Formula 1 is selected from one of the following compounds, or a pharmaceutically acceptable salt thereof: N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide;N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)propionamide; and N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)pivalamide.

161. The medicament of claim 109, wherein the compound of Formula 1 is selected from one of the following compounds: N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide hydrochloride; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)propionamide hydrochloride; and N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)pivalamide hydrochloride.

162. The medicament of claim 109, wherein the compound of Formula 1 is N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide hydrochloride.

163. A pharmaceutical composition for use in treating obesity in a subject having a Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1) deficiency, wherein the pharmaceutical composition comprises a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof:, wherein R1 is C2-C5alkyl.

164. The pharmaceutical composition for use of claim 163, wherein the Proprotein ConvertaseSubtilisin / Kexin Type 1 (PCSK1) deficiency is homozygous (PCSK1- / -) or heterozygous (PCSK1+ / -).

165. The pharmaceutical composition for use of claim 164, wherein the Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1) deficiency is homozygous (PCSK1- / -).

166. The pharmaceutical composition for use of claim 164, wherein the Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1) deficiency is heterozygous (PCSK1+ / -).

167. The pharmaceutical composition for use of claim 163, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

168. The pharmaceutical composition for use of claim 163, wherein the pharmaceutical composition is formulated as a dosage form, e.g., a unit dosage form.

169. The pharmaceutical composition for use of claim 163, wherein the dosage form is a solid dosage form.

170. The pharmaceutical composition for use of claim 163, wherein the pharmaceutical composition is formulated as an oral dosage form.

171. The pharmaceutical composition for use of any of the preceding claims, wherein the oral dosage form comprises a capsule, a tablet, a pill, a powder, or a granule.

172. The pharmaceutical composition for use of claim 163, wherein the oral dosage form comprises a capsule.

173. The pharmaceutical composition for use of claim 163, wherein the oral dosage form comprises a tablet.

174. The pharmaceutical composition for use of claim 163, wherein the dosage form is formulated as a transdermal dosage form.

175. The pharmaceutical composition for use of claim 163, wherein the transdermal dosage form comprises a lotion, ointment, gel, cream, patch or spray.

176. The pharmaceutical composition for use of claim 163, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is between about 0.1 mg to about 500 mg.

177. The pharmaceutical composition for use of claim 163, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is about 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, or 500 mg.

178. The pharmaceutical composition for use of claim 163, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is between about 1 mg to about 50 mg.

179. The pharmaceutical composition for use of claim 163, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is between about 10 mg to about 30 mg.

180. The pharmaceutical composition for use of claim 163, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is 10 mg.

181. The pharmaceutical composition for use of claim 163, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is 30 mg.

182. The pharmaceutical composition for use of claim 163, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is between about 0.1 mg / kg to about 500 mg / kg.

183. The pharmaceutical composition for use of claim 163, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is about 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, or 500 mg / kg.

184. The pharmaceutical composition for use of claim 163, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is between about 1 mg / kg to about 50 mg / kg.

185. The pharmaceutical composition for use of claim 163, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is between about 10 mg / kg to about 30 mg / kg.

186. The pharmaceutical composition for use of claim 163, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is 10 mg / kg.

187. The pharmaceutical composition for use of any of the preceding claims, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is 30 mg / kg.

188. The pharmaceutical composition for use of claim 163, wherein administration occurs daily, weekly, or monthly.

189. The pharmaceutical composition for use of claim 163, wherein administration occurs once daily or twice daily.

190. The pharmaceutical composition for use of claim 163, wherein administration occurs once daily.

191. The pharmaceutical composition for use of claim 163, wherein administration occurs twice daily.

192. The pharmaceutical composition for use of claim 163, wherein administration occurs once weekly, twice weekly, or three times weekly.

193. The pharmaceutical composition for use of claim 163, wherein administration occurs once weekly.

194. The pharmaceutical composition for use of claim 163, wherein administration occurs twiceweekly.

195. The pharmaceutical composition for use of claim 163, wherein administration occurs three times weekly.

196. The pharmaceutical composition for use of claim 163, wherein the subject is obese, e.g., severely obese.

197. The pharmaceutical composition for use of claim 163, wherein the subject is hyperphagic.

198. The pharmaceutical composition for use of claim 163, wherein the subject has a body mass index greater than 35 kg / m2(e.g., ≥36, 37, 38, 39, 40, 41, 42, 43, 44, 45 kg / m2or greater), prior to administration of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, or at the time of the first administration.

199. The pharmaceutical composition for use of claim 163, wherein the subject has a body mass index greater than 40 kg / m2(e.g., ≥41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg / m2or greater), prior to administration of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, or at the time of the first administration.

200. The pharmaceutical composition for use of claim 163, wherein the subject has a body mass index greater than 45 kg / m2(e.g., ≥46, 47, 48, 49, 50, 51, 52, 53, 54, 55 kg / m2or greater), prior to administration of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, or at the time of the first administration.

201. The pharmaceutical composition for use of claim 163, wherein the subject has an additional genetic deficiency, e.g., an additional genetic metabolic deficiency.

202. The pharmaceutical composition for use of claim 163, wherein the subject has diabetes or a diabetological condition, e.g., pre-diabetes, diabetes mellitus type 1, diabetes mellitus type 2, hyperglycemia, hypoglycemia, or hyperinsulinemia.

203. The pharmaceutical composition for use of claim 163, wherein the subject is hypertensive.

204. The pharmaceutical composition for use of claim 163, wherein the subject has failed one or more previous therapies comprising exercise, diet, or behavioral therapies prior to administration of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, or at the time of the first administration.

205. The pharmaceutical composition for use of claim 163, wherein the subject exhibits a weight loss equal to or greater than 1% of the subject’s body weight (e.g., ≥ 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or greater) prior to administration of the compound of formula 1, or a pharmaceutically acceptable thereof, at an oral daily dose of 10 mg / kg after 28 days or longer.

206. The pharmaceutical composition for use of claim 163, wherein the subject exhibits a weight loss equal to or greater than 1% of the subject’s body weight (e.g., ≥ 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or greater) prior to administration of the compound of formula 1, or a pharmaceutically acceptable thereof, at an oral daily dose of 30 mg / kg after 28 days or longer.

207. The pharmaceutical composition for use of claim 163, wherein the subject exhibits an appetite suppressing effect of about 1% or greater (e.g., ≥ 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%), compared to the solvent-administered control group (Vehicle), at an oral daily dose of 10 mg / kg after 28 days or longer.

208. The pharmaceutical composition for use of claim 163, wherein the subject exhibits an appetite suppressing effect is about 1% or greater (e.g., ≥ 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%), compared to the solvent-administered control group (Vehicle), at an oral daily dose of 30 mg / kg after 28 days or longer.

209. The pharmaceutical composition for use of claim 163, wherein the subject exhibits a decrease in food intake of about 1% or greater (e.g., ≥ 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, or greater), compared to the solvent-administered control group (Vehicle), at an oral daily dose of 10 mg / kg after 28 days or later.

210. The pharmaceutical composition for use of claim 163, wherein the subject exhibits a decrease in food intake of about 1% or greater (e.g., ≥ 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, or greater), compared to the solvent-administered control group (Vehicle), at an oral daily dose of 30 mg / kg after 28 days or later.

211. The pharmaceutical composition for use of claim 163, wherein the compound of Formula 1 is selected from one of the following compounds, or a pharmaceutically acceptable salt thereof: N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)pivalamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)propionamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)butyramide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)pentanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)hexanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-2-methyl-N-((1s,4R)-4-methylcyclohexyl)butanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-2-methyl-N-((1s,4R)-4-methylcyclohexyl)pentanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-2,2-dimethyl-N-((1s,4R)-4-methylcyclohexyl)butanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-3-methyl-N-((1s,4R)-4-methylcyclohexyl)pentanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-3,3-dimethyl-N-((1s,4R)-4-methylcyclohexyl)butanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-2,3-dimethyl-N-((1s,4R)-4-methylcyclohexyl)butanamide; and N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-3-methyl-N-((1s,4R)-4-methylcyclohexyl)pentanamide.

212. The pharmaceutical composition for use of claim 163, wherein the compound of Formula 1 is selected from a compound having one of the following structural formulas, or a pharmaceutically acceptable salt thereof :

213. The pharmaceutical composition for use of claim 163, wherein the compound of formula 1 is N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine- 4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide, or a pharmaceutically acceptable salt thereof.

214. The pharmaceutical composition for use of claim 163, wherein the compound of formula 1 is selected from one of the following compounds, or a pharmaceutically acceptable salt thereof: N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)propionamide; and N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)pivalamide.

215. The pharmaceutical composition for use of claim 163, wherein the compound of formula 1 is selected from one of the following compounds:N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide hydrochloride; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)propionamide hydrochloride; and N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)pivalamide hydrochloride.

216. The pharmaceutical composition for use of claim 163, wherein the compound of formula 1 is Compound 100, N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide hydrochloride.

217. Use of a composition in the manufacture of a medicament for treating obesity in a subject having a Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1) deficiency, wherein the medicament comprises a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof:, wherein R1 is C2-C5alkyl.

218. The use of claim 217, wherein the Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1) deficiency is homozygous (PCSK1- / -) or heterozygous (PCSK1+ / -).

219. The use of claim 218, wherein the Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1) deficiency is homozygous (PCSK1- / -).

220. The use of claim 218, wherein the Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1) deficiency is heterozygous (PCSK1+ / -).

221. The use of claim 217, wherein the compound of Formula 1, or a pharmaceutically acceptable salt thereof, is formulated as a pharmaceutical composition, together with a pharmaceutically acceptable carrier.

222. The use of claim 217, wherein the pharmaceutical composition is formulated as a dosage form, e.g., a unit dosage form.

223. The use of claim 217, wherein the dosage form is a solid dosage form.

224. The use of claim 217, wherein the pharmaceutical composition is formulated as an oral dosage form.

225. The use of claim 217, wherein the oral dosage form comprises a capsule, a tablet, a pill, a powder, or a granule.

226. The use of claim 217, wherein the oral dosage form comprises a capsule.

227. The use of claim 217, wherein the oral dosage form comprises a tablet.

228. The use of claim 217, wherein the dosage form is formulated as a transdermal dosage form.

229. The use of claim 217, wherein the transdermal dosage form comprises a lotion, ointment, gel, cream, patch or spray.

230. The use of claim 217, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is between about 0.1 mg to about 500 mg.

231. The use of claim 217, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is about 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, or 500 mg.

232. The use of claim 217, wherein the dosage of Formula 1, or a pharmaceutically acceptablesalt thereof, administered to the subject is between about 1 mg to about 50 mg.

233. The use of claim 217, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is between about 10 mg to about 30 mg.

234. The use of claim 217, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is 10 mg.

235. The use of any of the preceding claims, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is 30 mg.

236. The use of claim 217, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is between about 0.1 mg / kg to about 500 mg / kg.

237. The use of claim 217, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is about 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, or 500 mg / kg.

238. The use of claim 217, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is between about 1 mg / kg to about 50 mg / kg.

239. The use of claim 217, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is between about 10 mg / kg to about 30 mg / kg.

240. The use of claim 217, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is 10 mg / kg.

241. The use of claim 217, wherein the dosage of Formula 1, or a pharmaceutically acceptable salt thereof, administered to the subject is 30 mg / kg.

242. The use of claim 217, wherein administration occurs daily, weekly, or monthly.

243. The use of claim 217, wherein administration occurs once daily or twice daily.

244. The use of claim 217, wherein administration occurs once daily.

245. The use of claim 217, wherein administration occurs twice daily.

246. The use of claim 217, wherein administration occurs once weekly, twice weekly, or three times weekly.

247. The use of claim 217, wherein administration occurs once weekly.

248. The use of claim 217, wherein administration occurs twice weekly.

249. The use of claim 217, wherein administration occurs three times weekly.

250. The use of claim 217, wherein the subject is obese, e.g., severely obese.

251. The use of claim 217, wherein the subject is hyperphagic.

252. The use of claim 217, wherein the subject has a body mass index greater than 35 kg / m2(e.g., ≥36, 37, 38, 39, 40, 41, 42, 43, 44, 45 kg / m2or greater), prior to administration of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, or at the time of the first administration.

253. The use of claim 217, wherein the subject has a body mass index greater than 40 kg / m2(e.g., ≥41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg / m2or greater), prior to administration of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, or at the time of the first administration.

254. The use of claim 217, wherein the subject has a body mass index greater than 45 kg / m2(e.g., ≥46, 47, 48, 49, 50, 51, 52, 53, 54, 55 kg / m2or greater), prior to administration of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, or at the time of the first administration.

255. The use of claim 217, wherein the subject has an additional genetic deficiency, e.g., an additional genetic metabolic deficiency.

256. The use of claim 217, wherein the subject has diabetes or a diabetological condition, e.g., pre-diabetes, diabetes mellitus type 1, diabetes mellitus type 2, hyperglycemia, hypoglycemia, or hyperinsulinemia.

257. The use of claim 217, wherein the subject is hypertensive.

258. The use of claim 217, wherein the subject has failed one or more previous therapies comprising exercise, diet, or behavioral therapies prior to administration of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, or at the time of the first administration.

259. The use of claim 217, wherein the subject exhibits a weight loss equal to or greater than 1% of the subject’s body weight (e.g., ≥ 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or greater) prior to administration of the compound of formula 1, or a pharmaceutically acceptable thereof, at an oral daily dose of 10 mg / kg after 28 days or longer.

260. The use of claim 217, wherein the subject exhibits a weight loss equal to or greater than 1% of the subject’s body weight (e.g., ≥ 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or greater) prior to administration of the compound of formula 1, or a pharmaceutically acceptable thereof, at an oral daily dose of 30 mg / kg after 28 days or longer.

261. The use of claim 217, wherein the subject exhibits an appetite suppressing effect of about 1% or greater (e.g., ≥ 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%), compared to the solvent-administered control group (Vehicle), at an oral daily dose of 10 mg / kg after 28 days or longer.

262. The use of claim 217, wherein the subject exhibits an appetite suppressing effect is about 1% or greater (e.g., ≥ 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%), compared to the solvent-administered control group (Vehicle), at an oral daily dose of 30 mg / kg after 28 days or longer.

263. The use of claim 217, wherein the subject exhibits a decrease in food intake of about 1% or greater (e.g., ≥ 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, or greater), compared to the solvent-administered control group (Vehicle), at an oral daily dose of 10 mg / kg after 28 days or later.

264. The use of claim 217, wherein the subject exhibits a decrease in food intake of about 1% or greater (e.g., ≥ 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, 25%, 30%, or greater), compared to the solvent-administered control group (Vehicle), at an oral daily dose of 30 mg / kg after 28 days or later.

265. The use of claim 217, wherein the compound of Formula 1 is selected from one of the following compounds, or a pharmaceutically acceptable salt thereof: N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)pivalamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)propionamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)butyramide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)pentanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)hexanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-2-methyl-N-((1s,4R)-4-methylcyclohexyl)butanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-2-methyl-N-((1s,4R)-4-methylcyclohexyl)pentanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-2,2-dimethyl-N-((1s,4R)-4-methylcyclohexyl)butanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-3-methyl-N-((1s,4R)-4-methylcyclohexyl)pentanamide;N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-3,3-dimethyl-N-((1s,4R)-4-methylcyclohexyl)butanamide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-2,3-dimethyl-N-((1s,4R)-4-methylcyclohexyl)butanamide; and N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-3-methyl-N-((1s,4R)-4-methylcyclohexyl)pentanamide.

266. The use of claim 217, wherein the compound of Formula 1 is selected from a compound having one of the following structural formulas, or a pharmaceutically acceptable salt thereof :

267. The use of claim 217, wherein the compound of Formula 1 is N-((3S,5S)-1-((3S,4R)-1-(tert- butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N- ((1s,4R)-4-methylcyclohexyl)isobutyramide, or a pharmaceutically acceptable salt thereof.

268. The use of claim 217, wherein the compound of Formula 1 is selected from one of the following compounds, or a pharmaceutically acceptable salt thereof: N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)propionamide; and N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)pivalamide.

269. The use of claim 217, wherein the compound of Formula 1 is selected from one of the following compounds: N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide hydrochloride; N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)propionamide hydrochloride; and N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)pivalamide hydrochloride.

270. The use of claim 217, wherein the compound of Formula 1 is N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide hydrochloride.

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