Treatment of Prader-Willi Syndrome

Abstract

The present disclosure relates generally to a compound of Formula I, II, III or IV, or a pharma- ceutically acceptable salt, hydrate, stereoisomer or prodrug thereof, and methods for treating Prader-Willi syndrome (PWS) in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula I, II, III or IV, or a pharma- ceutically acceptable salt, hydrate, stereoisomer or prodrug thereof, and their use in the manufacture of a medicament as described herein.

Description

[Technical field]

[0001] The present disclosure relates generally to the field of pharmacological treatment of Prader-Willi syndrome. More specifically, the present disclosure relates to the use of bicyclic compounds in the treatment of Prader-Willi syndrome. [Background technology]

[0002] Prader-Willi syndrome (PWS) is a rare genetic disorder caused by loss of function of the 15q11-q13 region on the paternal copy of chromosome 15. Approximately 70% of cases result from a deletion of part of the paternal copy of chromosome 15, and approximately 25% result from a duplication of the maternal copy of chromosome 15 (uniparental disomy UPD). In the United States, the birth incidence of PWS is estimated to be 1:10,000-1:30,000, with an estimated survival of approximately 10,000-20,000 individuals. PWS can affect both males and females and can affect individuals of any ethnic and racial background (Bohonowych et al., 2019).

[0003] PWS is characterized by early failure to thrive followed by the development of excessive appetite (hyperphagia), which often leads to obesity, type 2 diabetes, and metabolic syndrome. Other features include multiple endocrine disorders, hypotonia, hypogonadism, sleep disorders, a challenging neurobehavioral phenotype, self-injury, mild to moderate intellectual and learning disabilities, and distinctive facial features (Bohonowych et al., 2019). Summary of the Invention

[0004] Treatments for Prader-Willi syndrome are currently limited. Human growth hormone can improve muscle tone and reduce body fat. Testosterone can be used to treat men, and estrogen and progesterone can be used to treat women to reduce the risk of osteoporosis. Sleep apnea and other sleep disorders can be treated to improve behavioral problems. Behavioral therapy can help control behavioral problems.

[0005] Several medications may be offered. Physical, speech, and developmental therapies can help improve social and interpersonal skills. Treatments for PWS are currently limited and have so far focused on treating endocrine abnormalities with growth hormone therapy (Bohonowych et al., 2019).

[0006] Therefore, there remains a need for alternative and effective therapies to treat Prader-Willi syndrome and / or symptoms associated with Prader-Willi syndrome.

[0007] The subject matter of the present disclosure is based in part on the surprising discovery that a compound of formula I, or a pharma- ceutically acceptable salt, hydrate, stereoisomer or prodrug thereof, can treat Prader-Willi syndrome and / or symptoms associated with Prader-Willi syndrome.

[0008] Thus, in a first aspect, there is provided a method for treating Prader-Willi syndrome in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula I, or a pharma- ceutically acceptable salt, hydrate, stereoisomer or prodrug thereof. [ka] (In the formula, X 1 is selected from the group consisting of NR′, O and S; X 2 is CH 2 , NR′, O and S; R 1 , R 2 , R 3 , R 4 , and R 5 are independently hydrogen, halogen, -OR', -SR', -NR'R', -NO 2, -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', alkyl, heteroalkyl, alkenyl, alkynyl, 3- to 10-membered carbocyclic ring, and 3- to 10-membered heterocyclic ring, each of which is unsubstituted or halogen, -OR', -SR', -NR'R', -NO 2 , -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', alkyl, heteroalkyl, alkenyl, alkynyl, 3- to 10-membered carbocyclic ring, and 3- to 10-membered heterocyclic ring, where each R' is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, 3- to 10-membered carbocyclic ring, and 3- to 10-membered heterocyclic ring, or R 4 and R 5 Together, -CH 2 -(CH 2 ) n -CH 2 -, n is an integer from 0 to 6, or R 2 and R 3 Together, -CH 2 -(CH 2 ) n -CH 2 -, n is an integer from 0 to 6, provided that R 1 CH 3 and R 2 is hydrogen and R 3 is hydrogen and R 4 If is hydrogen, R 5 is not benzyl, but R 1 If is hydrogen, R 2 and R 3 At least one of them is not hydrogen.)

[0009] In another aspect, there is provided the use of a compound of Formula I, or a pharma- ceutically acceptable salt, hydrate, stereoisomer, or prodrug thereof, in the manufacture of a medicament for treating Prader-Willi syndrome. [ka] (In the formula, X 1 is selected from the group consisting of NR′, O and S; X 2 is CH 2 , NR′, O and S; R 1 , R 2 , R 3 , R 4 , and R 5 are independently hydrogen, halogen, -OR', -SR', -NR'R', -NO 2 , -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', alkyl, heteroalkyl, alkenyl, alkynyl, 3- to 10-membered carbocyclic ring, and 3- to 10-membered heterocyclic ring, each of which is unsubstituted or selected from the group consisting of halogen, -OR', -SR', -NR'R', -NO 2 , -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', alkyl, heteroalkyl, alkenyl, alkynyl, 3- to 10-membered carbocyclic ring, and 3- to 10-membered heterocyclic ring, where each R' is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, 3- to 10-membered carbocyclic ring, and 3- to 10-membered heterocyclic ring, or R 4 and R 5 Together, -CH 2 -(CH 2 ) n -CH 2 -, n is an integer from 0 to 6, or R 2 and R 3 Together, -CH 2 -(CH 2 ) n -CH 2 -, n is an integer from 0 to 6, provided that R 1 CH 3 and R 2 is hydrogen and R 3 is hydrogen and R 4 If is hydrogen, R 5is not benzyl, but R 1 If is hydrogen, R 2 and R 3 At least one of them is not hydrogen.)

[0010] In another aspect, there is provided a compound of Formula I, or a pharma- ceutically acceptable salt, hydrate, stereoisomer, or prodrug thereof, for treating Prard-Willi syndrome. [ka] (In the formula, X 1 is selected from the group consisting of NR′, O and S; X 2 is CH 2 , NR′, O, and S; R 1 , R 2 , R 3 , R 4 , and R 5 are independently hydrogen, halogen, -OR', -SR', -NR'R', -NO 2 , -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', alkyl, heteroalkyl, alkenyl, alkynyl, 3- to 10-membered carbocyclic ring, and 3- to 10-membered heterocyclic ring, each of which is unsubstituted or selected from the group consisting of halogen, -OR', -SR', -NR'R', -NO 2 , -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', alkyl, heteroalkyl, alkenyl, and alkynyl, where each R' is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, 3- to 10-membered carbocyclic ring, and 3- to 10-membered heterocyclic ring; or R 4 and R 5 Together, -CH 2 -(CH 2 ) n -CH 2 -, n is an integer from 0 to 6, or R 2and R 3 Together, -CH 2 -(CH 2 ) n -CH 2 -, n is an integer from 0 to 6, provided that R 1 CH 3 and R 2 is hydrogen and R 3 is hydrogen and R 4 If is hydrogen, R 5 is not benzyl, but R 1 If is hydrogen, R 2 and R 3 At least one of them is not hydrogen.)

[0011] It is understood that other aspects, embodiments, and examples of the compounds, pharmaceutical compositions, methods, or uses are further described herein. [Brief description of the drawings]

[0012] While it will be understood that various embodiments of the present disclosure may be utilized, several examples of the present disclosure will now be described with reference to the accompanying drawings, in which: [Figure 1] FIG. 1 shows the chemical structure of cG-2-allylP (also referred to as "NNZ2591"). [Diagram 2] FIG. 2 shows a graph of the results of an open field study on the effect of cG-2-allyl P or vehicle on hypoactivity (distance traveled) in Magel2-null mice compared to wild-type mice. [Diagram 3] FIG. 3 shows a graph of the results of an open field study on the effect of cG-2-allyl P or vehicle on hypoactivity (activity time) in Magel2-null mice compared to wild-type mice. [Figure 4] FIG. 4 shows a graph of the results of a study of the effects of cG-2-allele P or vehicle on daily living (nesting) activities in Magel2-null mice compared to wild-type mice. [Diagram 5]FIG. 5 shows the results of a study on the effect of cG-2-Allele P or vehicle on social preference in Magel-null mice compared to wild-type mice. [Figure 6] FIG. 6 shows a graph of the results of a study on the effect of cG-2-allele P or vehicle on social interaction in Magel2-null mice compared with wild-type mice. [Figure 7] FIG. 7 shows a graph of the results of a study of the effects of cG-2-allele P or vehicle on cognition (novel object exploration) in Magel2-null mice compared to wild-type mice. [Figure 8] FIG. 8 shows a graph of the results of a study on the effect of cG-2-AllylP or vehicle on anxiety (elevated plus maze: time spent in open arms) in Magel2-null mice compared to wild-type mice. [Figure 9] FIG. 9 shows a graph of the results of a study on the effect of cG-2-AllylP or vehicle on fat mass in Magel2-null mice compared to wild-type mice. [Figure 10] FIG. 10 shows a graph of the results of a study on the effect of cG-2-Allyl P or vehicle on circulating IGF-1 levels in Magel2 null mice compared to wild type mice. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] General definition Unless otherwise defined, all technical and scientific terms used herein are assumed to have the same meaning as commonly understood by one of ordinary skill in the art (e.g., chemistry, biochemistry, medicinal chemistry, microbiology, etc.).

[0014] As used herein, the term "and / or", e.g., "X and / or Y" is to be understood as meaning "X and Y" or "X or Y", and A and / or B should be understood as clearly supporting two meanings or either meaning, such as including the options i) A, ii) B, or iii) A and B.

[0015] As used herein, unless otherwise specified, the term "about" refers to + / - 20%, typically + / - 10%, typically + / - 5% of the specified value.

[0016] As used herein, the terms "a," "an," and "the" include both numerical and plural aspects unless the context clearly indicates otherwise.

[0017] It should be understood that certain features that are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features that are described in the context of a single embodiment may also be provided alone or in any subcombination for brevity.

[0018] Throughout this specification, various aspects and components of the invention may be expressed in a range format. The range format is included for convenience and should not be construed as an inflexible limitation on the scope of the invention. Thus, unless otherwise indicated, the description of a range should be considered to have specifically disclosed all possible subranges and individual numerical values ​​within that range. For example, a description of a range such as 1-5 should be considered to have specifically disclosed subranges such as 1-3, 1-4, 1-5, 2-4, 2-5, 3-5, etc. Individual and partial numbers within the recited ranges are included, such as 1, 2, 3, 4, 5, 5.5, 6, unless an integer is required or implied by context. This applies regardless of the breadth of the range disclosed. If a specific value is required, the specification will state so.

[0019] Throughout this specification, variations of words such as "comprise" or "comprising" or "comprising" will be understood to imply the inclusion of an element, integer, step, or group of elements, integers, steps, but not the exclusion of other elements, integers, steps, or groups of elements, integers, steps.

[0020] The phrase "consisting of" refers to the listed elements and to no other elements.

[0021] The phrase "consisting essentially of" means the recited elements and equivalents thereof.

[0022] Although a number of prior art documents have been cited herein, it should be expressly understood that the citation is not an admission that any of these documents form part of the public knowledge of those skilled in the art in the United States, Australia or any other country.

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art of the present invention.In carrying out or testing the present invention, methods and materials similar or equivalent to those described herein can be used, but the following describes suitable methods and materials.In the event of discrepancy, this specification (including definitions) shall prevail.In addition, the materials, methods and examples are merely illustrative and not limiting.

[0024] As used herein, the term "subject" refers to any organism susceptible to a disease or condition. The subject may be, for example, a mammal, a primate, a livestock animal (e.g., sheep, cow, horse, pig), a companion animal (e.g., dog, cat), or a laboratory animal (e.g., mouse, rabbit, rat, guinea pig, hamster). In one embodiment, the subject is a mammal. In one example, the subject is a human. In one embodiment, the disease or condition is Prader-Willi syndrome.

[0025] As used herein, the term "treatment" includes improving, alleviating, reducing, or eliminating one or more symptoms associated with a particular disorder or condition. In one embodiment, the disease or condition is Prader-Willi syndrome. For example, as used herein, the phrase "treating Prader-Willi syndrome" includes improving, alleviating, reducing, or eliminating one or more symptoms associated with Prader-Willi syndrome.

[0026] As used herein, the term "prevention" includes prevention of a particular disorder or condition, or prevention of one or more symptoms associated with a particular disorder or condition. In one embodiment, the one or more symptoms are one or more symptoms associated with Prader-Willi syndrome. For example, as used herein, the phrase "preventing Prader-Willi syndrome" refers to preventing the onset or persistence of one or more symptoms associated with Prader-Willi syndrome. In some embodiments, the phrase "preventing Prader-Willi syndrome" refers to slowing or halting the progression of one or more symptoms of Prader-Willi syndrome. Prevention may be absolute (e.g., a particular symptom does not appear), may be effective only in certain individuals, may be effective to some extent, or may be effective for a limited period of time.

[0027] The present disclosure relates to compounds of formula I, their pharma- ceutically acceptable salts, hydrates, stereoisomers, and prodrugs.

[0028] Salts may be formed in the case of embodiments of the compounds of formula I which contain suitable acidic or basic groups. Suitable salts of the compounds of formula I include salts formed with organic or inorganic acids or bases.

[0029] As used herein, "pharmaceutically acceptable salts" or similar terms refer to pharmaceutically acceptable organic or inorganic salts. It is understood that references herein to "salts" can include "pharmaceutically acceptable salts." Exemplary acid addition salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, hydrogensulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-tosylate, and pamoate (i.e., 1,1'-methylenebis-(2-hydroxy-3-naphthoic acid)) salts. Examples of base addition salts include, but are not limited to, ammonium salts, alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts with organic bases such as dicyclohexylamine, N-methyl-D-glucamine, morpholine, thiomorpholine, piperidine, pyrrolidine, mono-, di- or tri-lower alkylamines such as ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl-, dimethylpropylamine-, or mono-, di- or trihydroxyl lower alkylamines such as mono-, di- or triethanolamine. Pharmaceutically acceptable salts may contain other molecules such as acetate ions, succinate ions or other counter ions. The counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. In addition, a pharma-ceutically acceptable salt may have one or more charged atoms in its structure. When multiple charged atoms are part of a pharma-ceutically acceptable salt, it may have multiple counter ions. Hence, a pharma- ceutically acceptable salt can have one or more charged atoms and / or one or more counter ion.It should also be understood that non-pharmacologically acceptable salts are included within the scope of the disclosure since they may be used as intermediates for preparing pharma-ceutically acceptable salts, or for storage or transportation purposes.

[0030] Those skilled in the art of organic and / or medicinal chemistry will appreciate that many organic compounds can form complexes with solvents and react, precipitate, or crystallize in solvents. These complexes are referred to as "solvates." For example, a complex with water is referred to as a "hydrate." As used herein, the phrase "a pharmaceutically acceptable solvate" or "solvate" refers to an association of one or more solvent molecules with a compound of the present disclosure. Examples of solvents that form pharmaceutically acceptable solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. It should be understood that the present disclosure includes solvated forms of the compounds of formula I and their salts, including hydrates.

[0031] The compounds of the present disclosure may contain chiral (asymmetric) centers or the entire molecule may be chiral. The individual stereoisomers (enantiomers and diastereomers) and mixtures thereof are within the scope of the present disclosure.

[0032] As used herein, the term "stereoisomers" refers to compounds that have the same molecular formula and bonded atomic sequences (atomic connectivity) despite differing three-dimensional orientation of the atoms in space. As used herein, the term "enantiomers" refers to two compounds that are stereoisomers in that they are non-superimposable mirror images of one another. The relevant stereocenters may be designated as either (R)- or (S)-configuration.

[0033] Those skilled in the art of organic and / or medicinal chemistry will understand that the compounds of formula I and their salts can exist in amorphous or crystalline form. It should be understood that the present disclosure includes all forms and polymorphs of the compounds of formula I and their salts.

[0034] As used herein, the term "protecting group" has the meaning commonly associated with it in organic synthesis / medicinal chemistry, i.e., a chemical group that selectively blocks one or more reactive sites of a multifunctional compound allowing a chemical reaction to proceed selectively at an otherwise unprotected reactive site, yet allows for easy removal after the selective reaction is complete.

[0035] As will be appreciated by those of skill in the art, the compound of formula I, or a salt, solvate or stereoisomer thereof, is administered in a therapeutically effective amount. As used herein, the term "therapeutically effective amount" refers to a compound administered in an amount sufficient to alleviate or prevent to some extent one or more symptoms of a disorder or condition in the treated subject, resulting in reduction and / or alleviation of the signs, symptoms or causes of a disease or condition, or other desired alteration of a biological system. In one embodiment, the term "therapeutically effective amount" refers to a compound of formula I, or a salt thereof, administered in an amount sufficient to treat and / or prevent one or more symptoms associated with Prader-Willi syndrome to provide a therapeutic result.

[0036] Implicit hydrogen atoms (such as those present on the pyrrole ring) have been omitted from the formula for clarity, but will be understood to be present by one of ordinary skill in the art.

[0037] As used herein, the term "halogen" means fluorine, chlorine, bromine or iodine.

[0038] As used herein, the term "alkyl" encompasses both straight-chain (i.e., linear) and branched hydrocarbon groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, s-butyl, pentyl, and hexyl groups. In one embodiment, an alkyl group is an alkyl group having 1 to 6 carbon atoms (i.e., C 1~6 alkyl).

[0039] As used herein, the term "haloalkyl" refers to an "alkyl" group substituted with one or more "halogen" groups according to any of the examples described above or individually herein.

[0040] As used herein, the term "alkenyl" refers to both straight-chain and branched unsaturated hydrocarbon groups having at least one carbon-carbon double bond. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, and hexenyl groups. In one example, an alkenyl group is an alkyl group having 2 to 6 carbon atoms (i.e., C 2~6 alkenyl).

[0041] As used herein, the term "haloalkenyl" refers to an "alkenyl" group substituted with one or more "halogen" groups according to the embodiments described above or individually herein.

[0042] As used herein, the term "alkynyl" refers to both straight-chain and branched unsaturated hydrocarbon groups having at least one carbon-carbon triple bond. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentanyl, and hexynyl groups. In one example, an alkynyl group is an alkyl group having 2 to 6 carbon atoms (i.e., C 2~6 alkynyl).

[0043] As used herein, "carbocyclyl," "carbocycle," "carbocyclic" or similar terms refer to an aromatic or non-aromatic cyclic group of carbon atoms. A carbocyclyl group may be, for example, monocyclic or polycyclic (i.e., bicyclic, tricyclic). Polycyclic carbocyclyl groups may contain fused rings. In one example, a carbocyclyl group is a ring system having 3 to 10 carbon atoms (i.e., C 3~10 In one example, the carbocyclyl group is a cyclic alkyl group having 3 to 7 carbon atoms (i.e., C 3~7Examples of monocyclic non-aromatic carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl groups. Examples of monocyclic saturated carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. Aromatic carbocyclyl groups include phenyl and naphthalenyl.

[0044] As used herein, the term "heterocyclyl" refers to an aromatic or non-aromatic ring group similar to carbocyclyl, but where one to three carbon atoms are replaced by one or more heteroatoms selected from nitrogen, oxygen, or sulfur. Heterocyclyl groups may be, for example, monocyclic or polycyclic (e.g., bicyclic). Polycyclic heterocyclyls may, for example, contain fused rings. In bicyclic heterocyclyl groups, there may be one or more heteroatoms in each ring, or there may be heteroatoms in only one ring. The heteroatom may be nitrogen, oxygen, or sulfur. Heterocyclyl groups containing suitable nitrogen atoms include the corresponding N-oxides. In one example, the heterocyclyl group is 3 to 10 atoms (i.e., 3-10 membered heterocyclyl). In one example, the heterocyclyl group is 3 to 7 atoms (i.e., 3-7 membered heterocyclyl). Examples of monocyclic non-aromatic heterocyclyl groups include aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and azepanyl. Examples of bicyclic heterocyclyl groups in which one ring is non-aromatic include dihydrobenzofuranyl, indanyl, indolinyl, isoindolinyl, tetrahydroisoquinolinyl, tetrahydroquinolyl and benzazepanyl. Examples of monocyclic aromatic heterocyclyl groups (also called monocyclic heteroaryl groups) include furanyl, thienyl, pyrrolyl, oxazolidinyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, isothiazolyl, isoxazolidinyl, pyrazinyl, pyrazolyl and pyrimidinyl. Examples of bicyclic aromatic heterocyclyl groups (also called bicyclic heteroaryl groups) include quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolidinyl, benzothiophenyl, benzimidazolyl, naphthyridinyl, quinolinyl, benzofuranyl, indolyl, benzothiazolyl, oxazolidinyl[4,5-b]pyridyl, pyridopyrimidinyl, isoquinolinyl, and benzohydroxyoxazole.

[0045] As used herein, the term "saturated" refers to a group in which all available valence bonds of main chain atoms are attached to other atoms. Representative examples of saturated groups include, but are not limited to, butyl, cyclohexyl, piperidine groups, and the like.

[0046] As used herein, the term "substituted" refers to a group in which one or more hydrogen or other atoms have been removed from a carbon or suitable heteroatom and replaced with a further group (i.e., a substituent).

[0047] As used herein, the term "unsubstituted" refers to a group that is not attached or substituted by an additional group.

[0048] All documents cited or referenced herein, and all documents cited or referenced in documents cited or referenced herein, are hereby incorporated in their entirety, along with manufacturer's instructions, descriptions, product specifications, and product sheets for all products mentioned herein or any documents incorporated herein by reference. Prader-Willi syndrome

[0049] The most common endocrine disorder is growth hormone deficiency (GHD), which reportedly occurs in 40–100% of patients. Dysregulation of the GH-IGF-1 axis is thought to be universal in PWS (Heksch et al., 2017), and it has been reported that serum IGF-1 levels are lower than normal in almost 100% of people with PWS. The exact etiology of GHD and the disruption of the GH-IGF-1 axis have not yet been fully elucidated. The degree of GH-IGF-1 dysregulation varies to some extent depending on the underlying genetic cause, but showed significant variation within groups. Recombinant human growth hormone (rhGH) is approved as a treatment for GHD and is usually prescribed soon after diagnosis, regardless of whether GH levels are subnormal or not. In rhGH-treated PWS patients, IGF-1 levels in the peripheral circulation are usually much higher than in children with primary GHD and untreated PWS. Bakker et al. (2015) found that serum IGF-binding protein-3 (IGFBP3) and acid-labile subunit (ALS) were also elevated, suggesting that large amounts of IGF-1 are sequestered in the IGF-1 / ALS / IGFBP3 complex. It is unclear to what extent PWS affects the expression and / or bioavailability of endogenous IGF-1 in the brain. Chronic neuroinflammation has also been reported in PWS (Krefft et al., 2020). It also significantly elevated interleukin (IL)-1β and IL-13 levels, and a significant positive correlation was found between IL-1β levels and standardized measures of psychopathological behavior. Transcriptome analysis of postmortem tissue showed that genes in microglial cells associated with inflammation were upregulated, while genes associated with synaptic plasticity and neurogenesis were downregulated (Bochukova et al., 2018).

[0050] PWS is associated with a constellation of symptoms that have a significant negative impact on the quality of life of affected individuals and their families. The initial clinical course of PWS is characterized by hypotonia in infants with reduced motor activity, lethargy, feeding difficulties, and failure to thrive. One of the defining features of PWS is a change in appetite over time, with the emergence of bulimia (persistent, pathological excessive appetite) at some point after toddlerhood. Infants with PWS do not show normal signs of hunger and often require feeding via a nasogastric tube or other supportive means, but feeding improves in toddlers and then progresses to bulimia during childhood. Unless strict environmental controls that limit food intake are implemented, adolescents and adults with PWS will become morbidly obese. Other abnormalities associated with PWS include hormone deficiencies, hypogonadotropic hypogonadism, sleep abnormalities, decreased pain sensitivity, impaired bone health, reduced gastrointestinal motility, and scoliosis. Central adrenal insufficiency, seizures, hypothyroidism, and hypoglycemia occur more frequently than in unaffected groups, but are not present in all individuals ( Bohonowych et al., 2019 ).

[0051] In addition to physical symptoms, intellectual disability (ID) and neuropsychiatric problems are present to some degree in all individuals with PWS. Individuals with PWS commonly exhibit cognitive rigidity, heightened anxiety, severe tantrums, obsessive compulsive behaviors, and self-harming behaviors. Adolescents and adults are at risk for psychiatric disorders, and autistic symptoms are common, especially in individuals with PWS due to UPD. Binge-eating behaviors include food-seeking behaviors, food hoarding and scavenging, inappropriate food intake, stealing food or money to buy food, and intense psychological stress and behavioral disorders associated with food refusal. Behavioral problems and inability to control food intake are major obstacles to independent living in individuals with PWS, and opportunities for community participation, employment, independent living, and social activities are severely limited by these problems (Bohonowych et al., 2019). Treatment method

[0052] The present disclosure provides compounds for the treatment of Prader-Willi syndrome.

[0053] In one aspect, a method is provided for treating Prader-Willi syndrome in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula I, or a pharma- ceutically acceptable salt, hydrate, or prodrug thereof. [ka] (In the formula, X 1 is selected from the group consisting of NR′, O and S; X 2 is CH 2 , NR′, O and S; R 1 , R 2 , R 3 , R 4 , and R 5 are independently -H, halogen, -OR', -SR', -NR'R', -NO 2 , -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', alkyl, heteroalkyl, alkenyl, alkynyl, a 3- to 10-membered carbocyclic ring, and a 3- to 10-membered heterocyclic ring; Here, alkyl, heteroalkyl, alkenyl, alkynyl, 3- to 10-membered carbocyclic ring and 3- to 10-membered heterocyclic ring are each unsubstituted or substituted with halogen, -OR', -SR', -NR'R', -NO 2 , -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', alkyl, heteroalkyl, alkenyl, and alkynyl; wherein each R' is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, a 3- to 10-membered carbocyclic ring, and a 3- to 10-membered heterocyclic ring; or R 4 and R 5 Let's get together -CH 2 -(CH 2 ) n -CH 2 where n is an integer from 0 to 6; or R 2 and R 3Together, -CH 2 -(CH 2 ) n -CH 2 -, and n is an integer from 0 to 6.

[0054] In some embodiments of the above aspects, provided that R 1 CH 3 and R 2 is hydrogen and R 3 is hydrogen and R 4 If is hydrogen, R 5 is not benzyl, but R 1 If is hydrogen, R 2 and R 3 At least one of them is not hydrogen.

[0055] In one embodiment, the method of treatment provides for the treatment of one or more symptoms associated with an abnormality in chromosome 15. In one embodiment, the method of treatment provides for the treatment of one or more symptoms associated with Prader-Willi syndrome.

[0056] Many of the symptoms are associated with Prader-Willi syndrome. Examples of physical symptoms include, but are not limited to, early growth failure, excessive appetite (bulimia), obesity, type 2 diabetes, metabolic syndrome, multiple endocrine disorders, hypotonia, hypogonadism, sleep disorders, sleep apnea, speech disorders, decreased pain sensitivity, impaired bone health, strabismus, hypopigmentation, gastrointestinal hypomotility, scoliosis, adrenal insufficiency, seizures, hypothyroidism, hypoglycemia, hypogonadotropic hypogonadism, and characteristic facies.

[0057] Thus, in some embodiments, a method for treating a symptom or finding associated with Prader-Willi syndrome is provided comprising administering to a subject a therapeutically effective amount of a compound of formula I, or a pharma- ceutically acceptable salt, hydrate, or prodrug thereof, wherein the symptom is selected from the group consisting of early growth retardation, excessive appetite (bulimia), obesity, type 2 diabetes, metabolic syndrome, polyendocrine disorder, hypotonia, hypogonadism, sleep disorders, sleep apnea, speech disorders, decreased pain sensitivity, impaired bone health, strabismus, hypopigmentation, gastrointestinal hypomotility, scoliosis, adrenal insufficiency, seizures, hypothyroidism, hypoglycemia, gonadotropic hypogonadism, and characteristic facies. In one example, the symptom associated with Prader-Willi syndrome is bulimia. In one example, the symptom associated with Prader-Willi syndrome is obesity. In one example, the finding associated with Prader-Willi syndrome is elevated blood insulin. In one example, the symptom associated with Prader-Willi syndrome is bulimia.

[0058] In addition to physical symptoms, intellectual disability and neuropsychiatric problems may be present as symptoms of Prader-Willi syndrome. In some embodiments, the intellectual disability and / or neuropsychiatric symptoms are selected from the group consisting of mild to moderate intellectual disability and learning disabilities, cognitive impairment, neurobehavioral disorders, intellectual disability, cognitive rigidity, heightened anxiety, severe tantrums, obsessive-compulsive behaviors, and self-harming behaviors. Adolescents and adults are at risk of developing psychiatric and autistic symptoms.

[0059] Thus, in some embodiments, there is provided a method for treating a symptom associated with Prader-Willi syndrome in a subject comprising administering to the subject a therapeutically effective amount of a compound of formula I above, or a pharma- ceutically acceptable salt, hydrate, stereoisomer or prodrug thereof, wherein the symptom is selected from the group consisting of mild to moderate intellectual and learning disabilities, cognitive impairment, neurobehavioral disorders, intellectual disability, cognitive rigidity, heightened anxiety, severe tantrums, obsessive-compulsive behavior, self-injury, psychiatric disorders, and autism.

[0060] The most common endocrine disorder is growth hormone deficiency (GHD), which causes a deficiency of IGF-1. One example of a condition associated with Prader-Willi syndrome is a deficiency of IGF-1. In some embodiments, a method is provided for treating a condition associated with Prader-Willi syndrome in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula I above, or a pharma- ceutically acceptable salt, hydrate, or prodrug thereof, wherein the condition is a deficiency of IGF-1.

[0061] In a further aspect, there is provided the use of a compound of Formula I, or a pharma- ceutically acceptable salt, hydrate, stereoisomer or prodrug thereof, in the manufacture of a medicament for treating Prader-Willi syndrome. [ka] (In the formula, X 1 is selected from the group consisting of NR′, O and S; X 2 is CH 2 , NR′, O and S; R 1 , R 2 , R 3 , R 4 , and R 5 are independently -H, halogen, -OR', -SR', -NR'R', -NO 2 , -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', alkyl, heteroalkyl, alkenyl, alkynyl, a 3- to 10-membered carbocyclic ring, and a 3- to 10-membered heterocyclic ring; wherein alkyl, heteroalkyl, alkenyl, alkynyl, 3- to 10-membered carbocyclic ring and 3- to 10-membered heterocyclic ring are each unsubstituted or halogen, -OR', -SR', -NR'R', -NO 2 , -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', alkyl, heteroalkyl, alkenyl, and alkynyl; wherein each R' is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, a 3- to 10-membered carbocyclic ring, and a 3- to 10-membered heterocyclic ring; or R 4 and R 5 Together, -CH 2 -(CH 2 ) n -CH 2 where n is an integer from 0 to 6; or R 2 and R 3 Together, -CH 2 -(CH 2 ) n -CH 2 -, and n is an integer from 0 to 6.

[0062] In some embodiments of the above aspects, provided that R 1 CH 3 and R 2 is hydrogen and R 3 is hydrogen and R 4 If is hydrogen, R 5 is not benzyl, but R 1 If is hydrogen, R 2 and R 3 At least one of them is not hydrogen.

[0063] In a further aspect, there is provided a compound of Formula I, or a pharma- ceutically acceptable salt, hydrate, stereoisomer or prodrug thereof, for treating Prader-Willi syndrome. [ka] (In the formula, X 1 is selected from the group consisting of NR′, O and S; X 2 is CH 2 , NR′, O and S; R 1 , R 2 , R 3 , R 4 , and R 5are independently -H, halogen, -OR', -SR', -NR'R', -NO 2 , -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', alkyl, heteroalkyl, alkenyl, alkynyl, a 3- to 10-membered carbocyclic ring, and a 3- to 10-membered heterocyclic ring; wherein alkyl, heteroalkyl, alkenyl, alkynyl, 3- to 10-membered carbocyclic ring and 3- to 10-membered heterocyclic ring are each unsubstituted or halogen, -OR', -SR', -NR'R', -NO 2 , -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', alkyl, heteroalkyl, alkenyl, and alkynyl; wherein each R' is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, a 3- to 10-membered carbocyclic ring, and a 3- to 10-membered heterocyclic ring; or R 4 and R 5 Together, -CH 2 -(CH 2 ) n -CH 2 where n is an integer from 0 to 6; or R 2 and R 3 Together, -CH 2 -(CH 2 ) n -CH 2 -, and n is an integer from 0 to 6.

[0064] In some embodiments of the above aspects, provided that R 1 CH 3 and R 2 is hydrogen and R 3 is hydrogen and R 4 If is hydrogen, R 5 is not benzyl, but R 1 If is hydrogen, R 2 and R 3 At least one of them is not hydrogen.

[0065] One aspect is a method or use for treating any of the above or below described aspects of Prader-Willi syndrome in a subject comprising administering to the subject a therapeutically effective amount of a compound of formula I, II, III or IV, or a pharma-ceutically acceptable salt, hydrate, stereoisomer or prodrug thereof. [ka] (In the formula, X 1 is selected from the group consisting of NR′, O and S; X 2 is CH 2 , NR′, O and S; R 1 , R 2 , R 3 , R 4 , and R 5 are independently hydrogen, halogen, -OR', -SR', -NR'R', -NO 2 , -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', alkyl, heteroalkyl, alkenyl, alkynyl, a 3- to 10-membered carbocyclic ring, and a 3- to 10-membered heterocyclic ring; wherein alkyl, heteroalkyl, alkenyl, alkynyl, 3- to 10-membered carbocyclic ring and 3- to 10-membered heterocyclic ring are each unsubstituted or halogen, -OR', -SR', -NR'R', -NO 2 , -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', alkyl, heteroalkyl, alkenyl, and alkynyl; wherein each R' is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, a 3- to 10-membered carbocyclic ring, and a 3- to 10-membered heterocyclic ring; or R 4 and R 5 Together, -CH 2 -(CH 2 ) n -CH 2where n is an integer from 0 to 6; or R 2 and R 3 Together, -CH 2 -(CH 2 ) n -CH 2 -, and n is an integer from 0 to 6.

[0066] In some embodiments of the above aspects, provided that R 1 CH 3 and R 2 is hydrogen and R 3 is hydrogen and R 4 If is hydrogen, R 5 is not benzyl, but R 1 If is hydrogen, then 2 and R 3 At least one of them is not hydrogen.

[0067] In one embodiment, R 1 is hydrogen, -CH 3 and -CH 2 CHCH 2 The method or use according to any of the preceding or following embodiments, wherein the method or use is selected from the group consisting of:

[0068] In one embodiment, R 2 is hydrogen and -CH 3 The method or use according to any of the preceding or following embodiments, wherein the method or use is selected from the group consisting of:

[0069] In one embodiment, R 3 is hydrogen and -CH 3 The method or use according to any of the preceding or following embodiments, wherein the method or use is selected from the group consisting of:

[0070] In one embodiment, X 1 The method or use according to any of the preceding or following embodiments, wherein

[0071] In one embodiment, X 2 CH 2and S is selected from the group consisting of:

[0072] In one embodiment, R 4 and R 5 are each hydrogen or together are -CH 2 -(CH 2 ) 3 -CH 2 - and -CH 2 -(CH 2 ) 2 -CH 2 - the method or use according to any of the preceding or following embodiments, wherein the method or use is selected from the group consisting of:

[0073] It should be understood that any one or more of the above aspects, embodiments, and / or examples may be combined with each other to provide any one or more further aspects, embodiments, and / or examples. For example, in formula I above, R 1 is alkyl or alkenyl, R 2 is hydrogen, and R 3 is hydrogen, and R 4 and R 5 are each hydrogen or together are C 3~10 A carbocyclic ring, X 1 is NH and X 2 CH 2 and alkyl, alkenyl and C 3~10 The carbocyclic rings may each be unsubstituted, halogen, -OR', -SR', -NR'R', -NO 2 , -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', alkyl, haloalkyl, alkenyl, and haloalkenyl, where each R' is independently selected from the group consisting of hydrogen, alkyl, and alkenyl. 1 is C 1~6 Alkyl (e.g., -CH 3 ) or C 2~6 Alkenyl (e.g., -CH 2 -CH=CH2 ) In a further example, R 4 and R 5 is a monocyclic saturated C ring, which may be substituted or unsubstituted as defined above or herein. 3~10 Carbocyclic ring. Unsubstituted or substituted monocyclic saturated C 3~10 The carbocycle may be an unsubstituted or substituted cyclopentyl or cyclohexyl group. 3~10 Carbocycles can contain halogens, OH, -NO 2 , -NH 2 , -CN, -C(O)H, -C(O)OH, -C(O)NH 2 , substituted with one or more substituents selected from the group consisting of alkyl, haloalkyl, alkenyl, and haloalkenyl.

[0074] An embodiment is the method or use of any of the preceding or following embodiments, wherein the compound of formula I is selected from the group consisting of: [ka] [ka] [ka]

[0075] One aspect is the method or use of any of the preceding or following embodiments, wherein the compound of formula I is: [ka]

[0076] An embodiment is the method or use of any of the preceding or following embodiments, wherein the treating comprises preventing or reducing the likelihood or severity of one or more symptoms of Prader-Willi syndrome.

[0077] In one embodiment, the method or use of any of the preceding or following embodiments, wherein said Prader-Willi syndrome is assessed using one or more laboratory tests selected from the group consisting of genetic testing, serum IGF-1, total IGF-1, free IGF-1, IGF-1 (bound with IGFBP), IGF-1 in cerebrospinal fluid (CSF), total IGF-1, free IGF-1, IGFBP in serum, IGFBP-1, -2, -3, -4, -5, -6 in serum, IGFBP in CSF, IGFBP-1, -2, -3, -4, -5, -6, blood glucose, blood lipids (HDL, LDL, VLDL, triglycerides), homeostasis model assessment of insulin resistance (HOMA-IR), body mass index (BMI), and body fat assessment (BFA).

[0078] In one embodiment, the method or use of any of the preceding or following embodiments, wherein the severity of symptoms is assessed using one or more clinical tests selected from the group consisting of the Binge Eating Questionnaire Used in Clinical Trials (HQ-CT), Clinical Global Severity Index (CGI-S), Clinical Global Impression of Change (CGI-I), Caregiver Global Impression of Change (CaGI-I), Aberrant Behavior Checklist (ABC) and ABC subscales, Interpersonal Responsiveness Scale, Repetitive Behaviors Scale-Revised (RBS-R), PWS Anxiety and Distress Questionnaire (PADQ), Gut Microbiota Composition (16S or other sequencing method), Pediatric Yale-Brown Obsessive-Compulsive Scale (CY-BOCS), and Montefiore-Einstein Rigidity Scale-Revised PWS (MERS-R-PWS).

[0079] In one embodiment, the symptoms or findings associated with Prader-Willi syndrome are selected from the group consisting of early growth deficiency, excessive appetite (bulimia), obesity, type 2 diabetes, elevated blood insulin, metabolic syndrome, multiple endocrine disorders, hypotonia, hypogonadism, sleep disorders, sleep apnea, speech disorders, decreased pain sensitivity, impaired bone health, strabismus, hypopigmentation, gastrointestinal hypomotility, scoliosis, adrenal insufficiency, seizures, hypothyroidism, hypoglycemia, hypogonadotropic syndrome, characteristic facies, mild to moderate intellectual and learning disabilities, cognitive impairment, neurobehavioral disorders, intellectual disability, cognitive rigidity, increased anxiety, severe tantrums, obsessive-compulsive behavior, self-injury, psychiatric disorders, symptoms of autism, and growth hormone deficiency (GHD).

[0080] An embodiment is the method or use of any of the preceding or following embodiments, wherein the compound of formula I, II, III or IV is administered in combination with a therapeutic agent.

[0081] In one embodiment, the therapeutic agent is selected from the group consisting of recombinant human growth hormone (rhGH), human growth hormone, recombinant human IGF-1 (rhIGF-1), IGF-1, IGF-2, any IGF binding protein (IGFBP), IGFBP-3, insulin, any statin, any appetite suppressant, transforming growth factor-β1, activin, nerve growth factor, growth hormone binding protein, basic fibroblast growth factor, acidic fibroblast growth factor, hst / Kfgk gene product, FGF-3, FGF-4, FGF-6, keratinocyte growth factor, and fibroblast growth factor-induced growth factor, int-2, fibroblast growth factor, homologous factor-1 (FHF-1), FHF-2, FHF-3, FHF-4, keratinocyte growth factor 2, glial activating factor, FGF-10, FGF-16, ciliary neurotrophic factor, brain-derived nerve growth factor, neurotrophin 3, neurotrophin 4, bone morphogenetic protein 2 (BMP-2), glial activating factor, ... Lymphocyte-derived neurotrophic factor, activity-dependent neurotrophic factor, cytokines, leukemia inhibitory factor, oncostatin M, interleukins, α-interferon, β-interferon, γ-interferon, consensus interferon, TNF-α, clomethiazole, kynurenic acid, Semax, tacrolimus, L-threo-1-phenyl-2-decanoylamino-3,3-morpholino-1-propanol, adrenocorticotropic amines (4-9) The method or use of any of the preceding or following embodiments, wherein the therapeutic agent is selected from the group consisting of analog (4-9) (ORG2766), dizolcipine [MK-801], selegiline, NPS1506, GV1505260, MK-801, GV150526, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX), LY303070, LY300164, and anti-MAdCAM-1 antibody MECA-367.

[0082] An embodiment is the method or use of any of the preceding or following embodiments, wherein the therapeutic agent is recombinant human growth hormone (rhGH).

[0083] An embodiment is the method or use of any of the preceding or following embodiments, wherein the pharmaceutical composition is administered orally.

[0084] In one embodiment is the method or use of any of the preceding or following embodiments, wherein the compound of formula I, II, III or IV is administered at a dose of about 0.001 mg / kg to about 600 mg / kg.

[0085] An embodiment is the method or use of any of the preceding or following embodiments, wherein the subject is a mammal.

[0086] An embodiment is the method or use of any of the preceding or following embodiments, wherein the subject is a human.

[0087] An embodiment is the method or use of any of the preceding or following embodiments, wherein the compound of formula I, II, III or IV is administered in the form of a pharmaceutical composition comprising a pharma- ceutically acceptable excipient.

[0088] An embodiment is the method or use of any of the preceding or following embodiments, wherein the pharma- ceutically acceptable excipient is selected from the group consisting of binders, carriers, additives, adjuvants, microemulsions, coarse emulsions, and liquid crystals.

[0089] An embodiment is the method or use of any of the preceding or following embodiments, wherein the pharmaceutical composition is formulated as an oral solution, oral suspension, or a powder for preparing an oral solution or suspension.

[0090] An embodiment is the method or use of any of the preceding or following embodiments, wherein the pharmaceutical composition is formulated as a tablet or capsule.

[0091] One aspect is a compound of any of Formula I, II, III or IV, or a pharma- ceutically acceptable salt, hydrate, stereoisomer or prodrug thereof, for the manufacture of a medicament for treating Prader-Willi syndrome. [ka] (In the formula, X 1 is selected from the group consisting of NR′, O and S; X 2 is CH 2 , NR′, O and S; R 1 , R 2 , R 3 , R 4 , and R 5 are independently hydrogen, halogen, -OR', -SR', -NR'R', -NO 2 , -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', alkyl, heteroalkyl, alkenyl, alkynyl, a 3- to 10-membered carbocyclic ring, and a 3- to 10-membered heterocyclic ring; wherein alkyl, heteroalkyl, alkenyl, alkynyl, 3- to 10-membered carbocyclic ring and 3- to 10-membered heterocyclic ring are each unsubstituted or halogen, -OR', -SR', -NR'R', -NO 2 , -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', alkyl, heteroalkyl, alkenyl, and alkynyl; wherein each R' is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, a 3- to 10-membered carbocyclic ring, and a 3- to 10-membered heterocyclic ring; or R 4 and R 5 Together, -CH 2 -(CH 2 ) n -CH 2 where n is an integer from 0 to 6; or R 2 and R 3 Together, -CH 2 -(CH 2 ) n -CH 2 where n is an integer from 0 to 6; However, R 1 CH 3 and R 2 is hydrogen and R 3 is hydrogen and R 4 If is hydrogen, R5 is not benzyl, but R 1 If is hydrogen, R 2 and R 3 At least one of them is not hydrogen.)

[0092] One aspect is a compound of any of Formula I, II, III or IV, or a pharma- ceutically acceptable salt, hydrate, stereoisomer or prodrug thereof, for treating Prader-Willi syndrome. [ka] (In the formula, X 1 is selected from the group consisting of NR′, O and S; X 2 is CH 2 , NR′, O and S; R 1 , R 2 , R 3 , R 4 , and R 5 are independently hydrogen, halogen, -OR', -SR', -NR'R', -NO 2 , -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', alkyl, heteroalkyl, alkenyl, alkynyl, a 3- to 10-membered carbocyclic ring, and a 3- to 10-membered heterocyclic ring; wherein alkyl, heteroalkyl, alkenyl, alkynyl, 3- to 10-membered carbocyclic ring and 3- to 10-membered heterocyclic ring are each unsubstituted or halogen, -OR', -SR', -NR'R', -NO 2 , -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', alkyl, heteroalkyl, alkenyl, and alkynyl; wherein each R' is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, a 3- to 10-membered carbocyclic ring, and a 3- to 10-membered heterocyclic ring; or R 4 and R 5Together, -CH 2 -(CH 2 ) n -CH 2 where n is an integer from 0 to 6; or R 2 and R 3 Together, -CH 2 -(CH 2 ) n -CH 2 where n is an integer from 0 to 6; However, R 1 CH 3 and R 2 is hydrogen and R 3 is hydrogen and R 4 If is hydrogen, R 5 is not benzyl, but R 1 If is hydrogen, R 2 and R 3 At least one of them is not hydrogen.)

[0093] One aspect is the use of a compound of any of Formula I, II, III or IV to treat a subject suffering from Prader-Willi syndrome as described herein.

[0094] An embodiment is the method of any preceding or following embodiment, wherein the subject is a human.

[0095] One embodiment is the use of any of the preceding embodiments, wherein the subject is a human.

[0096] An embodiment is the method or use of any of the previous embodiments, wherein the compound is cG-2-allylP, cyclic cyclopentyl-G-2-MeP, or cyclic cyclohexyl-G-2-MeP.

[0097] In one embodiment, the compound is formulated in an aqueous solution. The method or use of

[0098] An embodiment is the method or use of any of the preceding or following embodiments, wherein the compound is cG-2-allylP, cyclic cyclopentyl-G-2-MeP, or cyclic cyclohexyl-G-2-MeP.

[0099] An embodiment is the method or use of any of the previous embodiments, wherein the compound is formulated in an aqueous solution.

[0100] In another embodiment, the dose of the compound is about 0.01 mg / kg to about 1000 mg / kg, about 0.1 mg / kg to about 500 mg / kg, about 0.1 mg / kg to about 200 mg / kg, about 0.01, 0.1, 1, 10, 20, 50, 75, 100, 500, 1000, or 5000 mg / kg of body weight. Clinical evaluation

[0101] Prader-Willi syndrome may be evaluated using laboratory tests including, for example, genetic testing, serum IGF-1, total IGF-1, free IGF-1, IGF-1 (bound with IGFBP), cerebrospinal fluid (CSF) IGF-1, total IGF-1, free IGF-1, serum IGFBP, serum IGFBP-1, -2, -3, -4, -5, -6, CSF IGFBP, IGFBP-1, -2, -3, -4, -5, -6, blood glucose, blood lipids (HDL, LDL, VLDL, triglycerides), homeostasis model assessment of insulin resistance (HOMA-IR), body mass index (BMI), and body fat assessment (BFA). The severity of symptoms associated with Prader-Willi syndrome may be assessed using clinical tests, including, for example, the Binge Eating Questionnaire used in clinical trials (HQ-CT), Clinical Global Severity Index (CGI-S), Clinical Global Impression of Change (CGI-I), Caregiver Global Impression of Change (CaGI-I), Aberrant Behavior Checklist (ABC) and ABC subscales, Interpersonal Responsiveness Scale, Repetitive Behavior Scale-Revised (RBS-R), PWS Anxiety and Distress Questionnaire (PADQ), gut microbiota composition (16S or other sequencing methods), Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS), and Montefiore-Einstein Rigidity Scale-Revised PWS (MERS-R-PWS). Compounds of Formula I

[0102] As described herein, a use or method for treating Prader-Willi syndrome comprising a compound of formula I, or a pharma- ceutically acceptable salt, hydrate, stereoisomer or prodrug thereof. [ka] In the above formula I, X 1 is selected from the group consisting of NR′, O and S, and in one embodiment, X 1 In one example, X is 1 is NH. In one example, X 1 is O. In one example, X 1 is S. In the above formula I, X 2 is CH 2 , NR′, O and S. In one example, X 2 is CH 2 In one embodiment, X 2 is NR'. In one example, X 2 is NH. In one example, X 2 is O. In one example, X 2 is S. In formula I, R 1 , R 2 , R 3 , R 4 , and R 5are independently hydrogen, halogen, -OR', -SR', -NR'R', -NO 2 , -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', alkyl, heteroalkyl, alkenyl, alkynyl, a 3- to 10-membered carbocyclic ring, and a 3- to 10-membered heterocyclic ring. That is, in the above formula I, R 1 is hydrogen, halogen, -OR', -SR', -NR'R', -NO 2 , -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', alkyl, heteroalkyl, alkenyl, alkynyl, 3- to 10-membered carbocyclic ring, and 3- to 10-membered heterocyclic ring. 1 is alkyl. In one embodiment, R 1 is C 1~6 In one example, R 1 is CH 3 In one embodiment, R 1 is alkenyl. In one embodiment, R 1 is C 2~6 alkenyl. In one example, R 1 -CH 2 CHCH 2 It is. In the above formula I, R 2 is hydrogen, halogen, -OR', -SR', -NR'R', -NO 2 , -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', alkyl, heteroalkyl, alkenyl, alkynyl, 3- to 10-membered carbocyclic ring, and 3- to 10-membered heterocyclic ring. 2 is hydrogen. In one embodiment, R 2 is alkyl. In one embodiment, R 2 is C 1~6 In one example, R 2 is CH 3 It is. In the above formula I, R 3 is hydrogen, halogen, -OR', -SR', -NR'R', -NO 2, -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', alkyl, heteroalkyl, alkenyl, alkynyl, 3- to 10-membered carbocyclic ring, and 3- to 10-membered heterocyclic ring. 3 is hydrogen. In one embodiment, R 3 is alkyl. In one embodiment, R 3 is C 1~6 In one example, R 3 is CH 3 It is. In the above formula I, R 4 is hydrogen, halogen, -OR', -SR', -NR'R', -NO 2 , -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', alkyl, heteroalkyl, alkenyl, alkynyl, 3- to 10-membered carbocyclic ring, and 3- to 10-membered heterocyclic ring. 4 is hydrogen. In the above formula I, R 5 is hydrogen, halogen, -OR', -SR', -NR'R', -NO 2 , -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', alkyl, heteroalkyl, alkenyl, alkynyl, 3- to 10-membered carbocyclic ring, and 3- to 10-membered heterocyclic ring. 5 is hydrogen. In the above formula I, in one embodiment, R 4 and R 5 Let's get together -CH 2 -(CH 2 ) n -CH 2 -, and n is 0, 1, 2, 3, 4, 5 or 6. In one example, R 4 and R 5 Together, -CH 2 -(CH 2 ) 2 -CH 2 That is, in one example, n is 2. In one example, R 4 and R 5 Together, -CH2 -(CH 2 ) 3 -CH 2 That is, in one example, n is 3. In one example, R 4 and R 5 are both hydrogen. In the above formula I, each R' is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, 3-10 membered carbocyclic ring, and 3-10 membered heterocyclic ring. In one example, R' is hydrogen, alkyl, or alkenyl. In one example, R' is hydrogen. In the above formula I, R 1 CH 3 and R 2 is hydrogen and R 3 is hydrogen and R 4 If is hydrogen, R 5 is not benzyl. In the above formula I, R 1 If is hydrogen, R 2 and R 3 At least one of them is not hydrogen.

[0103] It should be understood that any one or more of the above aspects, embodiments, and examples may be combined with each other to provide any one or more further specific embodiments and examples. For example, in formula I above, R 1 is alkyl or alkenyl, R 2 is hydrogen, and R 3 is hydrogen, and R 4 and R 5 are either hydrogen or together, C 3~10 A carbocyclic ring, X 1 is NH and X 2 CH 2 and alkyl, alkenyl and C 3~10 Each carbocycle may be unsubstituted or halogen, -OR', -SR', -NR'R', -NO 2, -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', alkyl, haloalkyl, alkenyl, and haloalkenyl, where each R' is independently selected from the group consisting of hydrogen, alkyl, and alkenyl. 1 is C 1~6 Alkyl (e.g., -CH 3 ) or C 2~6 Alkenyl (e.g., -CH 2 -CH=CH 2 ) In a further example, R 4 and R 5 is a monocyclic saturated C ring, which may be substituted or unsubstituted, as defined above or herein. 3~10 Carbocyclic ring. Unsubstituted or substituted monocyclic saturated C 3~10 The carbocycle may be an unsubstituted or substituted cyclopentyl or cyclohexyl group. 3~10 Carbocycles can contain halogens, OH, -NO 2 , -NH 2 , -CN, -C(O)H, -C(O)OH, -C(O)NH 2 , substituted with one or more substituents selected from the group consisting of alkyl, haloalkyl, alkenyl, and haloalkenyl.

[0104] In one example, the compound of formula I is selected from the group consisting of: [ka] [ka] [ka]

[0105] In one example, the compound of formula I is: [ka] "Cyclic glycyl-2-allylproline" or "Cyclic G-2-allyl P" or "NNZ2591" Formula II That is, in one example, in a compound of formula I, X 1 is NH and X 2 CH 2 and R 1 Ha-CH 2 CHCH 2 R 2 , R 3 , R 4 , and R 5 is hydrogen.

[0106] In one example, the compound of formula I is: [ka] "Cyclic cyclopentyl-G-2-MeP" Formula III

[0107] That is, in one example, in a compound of formula I, X 1 is NH and X 2 CH 2 and R 1 is CH 3 and R 2 and R 3 are hydrogen, and R 4 and R 5 Together, -CH 2 -(CH 2 ) 2 -CH 2 -It is.

[0108] In one example, the compound of formula I is: [ka] "Cyclic cyclohexyl-G-2-MeP" Formula IV

[0109] That is, in one example, in a compound of formula I, X 1 is NH and X 2 CH 2 and R 1 CH3 and R 2 and R 3 are hydrogen, and R 4 and R 5 Together, -CH 2 -(CH 2 ) 3 -CH 2 -It is. Pharmaceutical Compositions

[0110] In some embodiments, there is provided a use or method described herein, wherein a compound of Formula I, II, III or IV, or a pharma- ceutically acceptable salt, hydrate, stereoisomer or prodrug thereof, is administered in the form of a pharmaceutical composition.

[0111] Suitably, the pharma- ceutically acceptable carrier, diluent, and / or excipient may be one or more of a diluent, solvent, pH buffer, binder, carrier, additive, adjuvant, microemulsion, coarse emulsion, liquid crystal, filler, emulsifier, disintegrant, polymer, lubricant, oil, fat, wax, coating, viscosity modifier, glidant, etc. In some embodiments, methods are provided herein, wherein the compound of formula I, or a pharma- ceutically acceptable salt, hydrate or prodrug thereof, is administered in the form of a pharmaceutical composition comprising a pharma- ceutically acceptable excipient.

[0112] The diluents may include one or more of microcrystalline cellulose, lactose, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar, and the like. The binders may include one or more of povidone, starch, stearic acid, gum, hydroxypropyl methylcellulose, and the like. The disintegrants may include one or more of starch, cross-linked sodium carboxymethylcellulose, cross-linked povidone, sodium starch glycolate, and the like. The solvents may include one or more of ethanol, methanol, isopropanol, chloroform, acetone, methyl ethyl ketone, dichloromethane, water, and the like. The lubricants may include one or more of magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearoyl fumarate, hydrogenated vegetable oil, glyceryl behenate, and the like. The glidants may be one or more of colloidal silica, talc, corn starch, and the like. The buffers may include, but are not limited to, phosphate buffers, borate buffers, carbonate buffers. The filler may include one or more gels, including, but not limited to, gelatin, starch, and synthetic polymer gels. The coating may include one or more film formers, solvents, plasticizers, and the like. Suitable film formers may be one or more of hydroxypropylmethylcellulose, methylhydroxyethylcellulose, ethylcellulose, hydroxypropylcellulose, povidone, sodium carboxymethylcellulose, polyethylene glycol, acrylates, and the like. Suitable solvents may be one or more of water, ethanol, methanol, isopropanol, chloroform, acetone, methyl ethyl ketone, dichloromethane, and the like. Plasticizers may be one or more of propylene glycol, castor oil, glycerin, polyethylene glycol, polysorbitol esters, and the like.

[0113] See Pharmaceutical Excipients Handbook, 9th Edition, Edited by Sheskey, Hancock, Moss & Goldfarb (2020), which provides non-limiting examples of excipients that may be useful in accordance with the present disclosure. Other pharmaceutical excipients and / or additives suitable for compositions according to the present disclosure are found in Remington: The Science and Practice of Pharmacy, 23rd Edition, Edited by Ed. Adejare (2020), "Digital Reference for Prescribers" at www._pdr._net (2021), and Pharmaceutical Excipients Handbook, 3rd Edition, Edited by Ed. A.H. Kibbe, Pharmaceutical Journal, 2000.

[0114] It should be understood that the choice of pharma- ceutically acceptable carrier, diluent, and / or excipient will depend at least in part on the method of administration of the formulation.By way of example only, the composition may be in the form of a tablet, capsule, caplet, powder, oral solution or suspension, powder for preparing oral solution or suspension, liquid for injection, suppository, sustained release formulation, osmotic pump formulation, or other effective and safe form of administration.

[0115] Examples of pharmaceutical formulations may depend, for example, on the condition and disorder of the subject, but the most suitable routes include formulations suitable for oral administration, parenteral gastrointestinal administration (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), inhalation administration (including fine particle dusts or mists that can be generated by various metered amounts of pressurized aerosols), nebulizer or insufflator, rectal, intraperitoneal and topical administration (including cutaneous, buccal, sublingual and ocular). In one example, the compound of formula I, or a pharma- ceutically acceptable salt, hydrate or prodrug thereof, is administered orally.

[0116] Pharmaceutical preparations can be conveniently provided in unit dosage form and can be prepared by any method known in the pharmaceutical art.All methods include the step of combining the compound of formula I, its pharmaceutically acceptable salt, hydrate or prodrug with the excipient that constitutes one or more essential ingredients.Generally, preparations are prepared by uniformly and intimately associating active ingredient with liquid carrier or finely divided solid carrier or both, and then shaping the product into desired preparation as necessary.

[0117] In some embodiments, the composition is formulated for oral delivery. For example, the pharmaceutical formulation of the present disclosure suitable for oral administration may be provided as individual units, such as capsules, cachets, pills or tablets, each containing a predetermined amount of active ingredient, powders or granules, solutions or suspensions in aqueous or non-aqueous liquids, such as elixirs, tinctures, suspensions or syrups, or oil-in-water or water-in-oil liquid emulsions. The compound of formula I, or its pharma-ceutically acceptable salts, hydrates or prodrugs, may also be provided as a bolus, tablet or paste. In one example, the compound of formula I, or its pharma-ceutically acceptable salts, hydrates or prodrugs, is administered as an oral tablet. In one example, the compound of formula I, or its pharma-ceutically acceptable salts, hydrates or prodrugs, is administered as an oral capsule. In one example, the compound of formula I, or its pharma-ceutically acceptable salts, hydrates or prodrugs, is administered as an oral solution. In one example, the compound of formula I, a pharma- ceutically acceptable salt, hydrate or prodrug thereof, is administered as an oral suspension.

[0118] Tablets may be prepared, for example, by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing the active ingredient, as a powder or particles, optionally mixed with a binder, lubricant, inert diluent, lubricant, surfactant or dispersant, in a free-flowing form in a suitable machine. Molded tablets may be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. The tablets may be optionally coated or scored, and may be formulated to provide slow or controlled release of the compound of formula I, or a pharma-ceutically acceptable salt, hydrate or prodrug thereof. The compound of formula I, or a pharma-ceutically acceptable salt, hydrate or prodrug thereof, may be administered, for example, in a form suitable for immediate or sustained release. Immediate or sustained release may be achieved by using a suitable pharmaceutical composition containing the compound of formula I, or a pharma-ceutically acceptable salt, hydrate or prodrug thereof, or, particularly in the case of sustained release, by using a device such as a subcutaneous implant or an osmotic pump. The compounds of formula I, or a pharma- ceutically acceptable salt, hydrate or prodrug thereof, may also be administered liposomally.

[0119] It should be understood that in addition to the above-mentioned ingredients, other preparations conventionally used in the art may be included, for example, preparations suitable for oral administration may include flavoring agents. In one example, the compound of formula I, II, III or IV, or a pharma-ceutically acceptable salt, hydrate or prodrug thereof, is formulated as an oral solution. In one example, the compound of formula I, II, III or IV, or a pharma-ceutically acceptable salt, hydrate or prodrug thereof, is formulated as an oral suspension. In one example, the compound of formula I, II, III or IV, or a pharma-ceutically acceptable salt, hydrate or prodrug thereof, is formulated as a powder for preparing an oral solution or oral suspension. Solvates and hydrates

[0120] It may be convenient or desirable to prepare, purify, and / or handle the corresponding solvates of a compound. Those skilled in the art of organic and / or medicinal chemistry will appreciate that many organic compounds can form complexes with solvents in which they dissolve, react, or precipitate or crystallize. Such complexes are called "solvates," and as used herein, the term "solvate" refers to a complex of a solute (e.g., a compound, a salt of a compound) and a solvent. Examples of solvents that can form pharma-ceutically acceptable solvates include, but are not limited to, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. When the solvate is water, the solvate is conventionally referred to as a "hydrate." In some embodiments, the pharma-ceutically acceptable solvate is a pharma-ceutically acceptable hydrate. The hydrate may be, for example, a monohydrate, a dihydrate, a trihydrate, and the like. Unless otherwise stated herein, a reference to a particular compound also includes its solvates. Prodrug

[0121] It may be convenient or desirable to prepare, purify and / or handle a compound in the form of a prodrug. As used herein, the term "prodrug" refers to a compound that, when metabolized (e.g., in vivo), produces the desired active compound. Generally, prodrugs are inactive or less active than the desired active compound, but may offer advantageous handling, administration, or metabolic properties.

[0122] Also, as will be appreciated by those skilled in the art of organic and / or medicinal chemistry, some prodrugs are activated enzymatically to produce the active compound, or produce a compound that produces the active compound after further chemical reaction. For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative. dose

[0123] Of course, the amount of active ingredient required to achieve a therapeutic effect will vary depending on the particular compound, the route of administration, the subject being treated (e.g., patient type, species, age, weight, sex, medical condition, etc.), the renal and hepatic function of the subject being treated, and the particular disease, disorder, or condition being treated, and its severity. A physician or clinician of ordinary skill can readily determine and prescribe the effective amount of drug required to prevent or treat the disease, disorder, or condition.

[0124] The dosage of the compound of formula I, II, III or IV, or a pharma- ceutically acceptable salt, hydrate, stereoisomer or prodrug thereof, may be, for example, about 0.01 mg / kg body weight (mg / kg) to about 1000 mg / kg. In one example, the dosage of the compound of formula I, II, III or IV, or a pharma- ceutically acceptable salt, hydrate, stereoisomer or prodrug thereof, is about 0.01-1000, 0.1-500, 0.1-200, 1-200 mg / kg. In one example, the dosage of the compound of formula I, II, III or IV, or a pharma- ceutically acceptable salt, hydrate, stereoisomer or prodrug thereof, is about 0.01-1000 mg / kg. In one example, the dosage of the compound of formula I, II, III or IV, or a pharma- ceutically acceptable salt, hydrate, stereoisomer or prodrug thereof, is about 0.1-200 mg / kg. In one example, the dose of the compound of formula I, II, III or IV, or a pharma- ceutically acceptable salt, hydrate or prodrug thereof, is about 1-200 mg / kg. In one example, the dose of the compound of formula I, II, III or IV, or a pharma-ceutically acceptable salt, hydrate or prodrug thereof, is greater than about 0.01, 0.1, 1, 10, 20, 50, 75, 100, 500, 1000 mg / kg. In one example, the dose of the compound of formula I, II, III or IV, or a pharma-ceutically acceptable salt, hydrate, stereoisomer or prodrug thereof, is less than about 5000, 1000, 75, 50, 20, 10, 1, 0.1 mg / kg.

[0125] The compound of formula I, II, III or IV, or a pharma- ceutically acceptable salt, hydrate, stereoisomer or prodrug thereof, can be administered, for example, as a daily dose, or the total daily dose can be divided into two, three or four doses. In one example, the frequency of administration of the compound of formula I, II, III or IV, or a pharma- ceutically acceptable salt, hydrate or stereoisomer thereof, can be once a day or less, for example, once every 2, 3, 4, 5, 6 days, or once a week.

[0126] Thus, the dose of a compound of formula I, II, III or IV, or a pharma- ceutically acceptable salt, hydrate, stereoisomer or prodrug thereof, when used for the indicated effects, may be, for example, between about 0.01 mg / kg body weight / day (mg / kg / day) and about 1000 mg / kg / day, including 1000 mg / kg / day. In one example, the dose of a compound of formula I, II, III or IV, or a pharma- ceutically acceptable salt, hydrate, stereoisomer or prodrug thereof, is about 0.01-1000 mg / kg / day, 0.1-500 mg / kg / day, 0.1-200 mg / kg / day, or 1-200 mg / kg / day. In one example, the dose of a compound of formula I, II, III or IV, or a pharma- ceutically acceptable salt, hydrate, stereoisomer or prodrug thereof, is about 0.01-1000 mg / kg / day. In one example, the dose of the compound of formula I, or a pharma- ceutically acceptable salt, hydrate, or prodrug thereof, is about 0.1 to 200 mg / kg / day, or about 0.001 mg / kg to about 600 mg / kg. In one example, the dose of the compound of formula I, II, III, or IV, or a pharma- ceutically acceptable salt, hydrate, stereoisomer, or prodrug thereof, is about 1 to 200 mg / kg / day. In one example, the dose of the compound of formula I, or a pharma- ceutically acceptable salt, hydrate, stereoisomer, or prodrug thereof, is greater than about 0.01, 0.1, 1, 10, 20, 50, 75, 100, 500, 1000 mg / kg / day. In one example, the dose of a compound of Formula I, II, III or IV, or a pharma- ceutically acceptable salt, hydrate, stereoisomer or prodrug thereof, is less than about 5000, 1000, 75, 50, 20, 10, 1, 0.1 mg / kg / day, respectively.

[0127] It is to be understood that the above dosages apply to compounds of formula I, II, III and IV. Combination therapy

[0128] Although the compound of formula I, II, III or IV, or its pharma- ceutically acceptable salt, hydrate or prodrug, may be used as the only active agent in a medicament, the compound of formula I, II, III or IV, or its pharma- ceutically acceptable salt, hydrate or prodrug, may be used in combination with one or more additional therapeutic agents.Thus, in one example, the compound of formula I, or its pharma- ceutically acceptable salt, hydrate, stereoisomer or prodrug, is used in combination with one or more additional therapeutic agents.Thus, the present disclosure also provides a combination of the compound of formula I, II, III or IV, or its pharma- ceutically acceptable salt, hydrate or prodrug, and an additional therapeutic agent.The present disclosure also provides a pharmaceutical composition comprising a combination of the compound of formula I, II, III or IV, or its pharma- ceutically acceptable salt, hydrate or prodrug, an additional therapeutic agent, and a pharma- ceutically acceptable excipient.Such one or more additional therapeutic agents may be, for example, recombinant human growth hormone (rhGH), human growth hormone, recombinant human IGF-1 (rhIGF-1), IGF-1, IGF-2, any IGF binding protein (IGFBP), IGFBP-3, insulin, any statin, any appetite suppressant, transforming growth factor-β1, activin, nerve growth factor, growth hormone binding protein, basic fibroblast growth factor, acidic fibroblast growth factor, hst / Kfgk gene product, FGF-3, FGF-4, FGF-6, keratinocyte growth factor, and gonadotropin-induced growth factor, int-2, fibroblast growth factor, homologous factor-1 (FHF-1), FHF-2, FHF-3, FHF-4, keratinocyte growth factor 2, glial activating factor, FGF-10, FGF-16, ciliary neurotrophic factor, brain-derived nerve growth factor, neurotrophin 3, neurotrophin 4, neurotrophin 5, neurotrophin 6, neurotrophin 7, neurotrophin 8, neurotrophin 9, neurotrophin 10, neurotrophin 11, neurotrophin 12, neurotrophin 13, neurotrophin 14, neurotrophin 15, neurotrophin 16, neurotrophin 17, neurotrophin 18, neurotrophin 19, neurotrophin 20, neurotrophin 21, neurotrophin 22, neurotrophin 23, neurotrophin 24, neurotrophin 25, neurotrophin 26, neurotrophin 27, neurotrophin 28, neurotrophin 29, neurotrophin 30, neurotrophin 31, neurotrophin 32, neurotrophin 33, neurotrophin 34, neurotrophin 35, neurotrophin 36, neurotrophin 37, neurotrophin 38, neurotrophin 39, neurotrophin 40, neurotrophin 41, neurotrophin 42, neuro Lophin 4, bone morphogenetic protein 2 (BMP-2), glial cell line-derived neurotrophic factor, activity-dependent neurotrophic factor, cytokines leukemia inhibitory factor, oncostatin M, interleukins, a-interferon, beta-interferon, gamma-interferon, consensus interferon, TNF-a, clomethiazole; kynurenic acid, Semax, tacrolimus, L-threo-1-phenyl-2-decanoylamino-3, 3- Morpholino-1-propanol, corticotropin-(4-9) analog (4-9) (ORG2766), dizolcipine [MK-801], selegiline, NPS1506, GV1505260, MK-801, GV150526, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX), LY303070, LY300164, and the anti-MAdCAM-1 antibody MECA-367.

[0129] The compound of formula I, II, III or IV, or its pharmaceutically acceptable salt, hydrate, stereoisomer or prodrug, and one or more additional pharmaceutically active agents may be administered simultaneously, sequentially, or separately.For example, they may be administered as part of the same composition, or may be administered by separate compositions.In one example, the compound of formula I, II, III or IV, or its pharmaceutically acceptable salt, hydrate, stereoisomer or prodrug, is administered in combination with recombinant human growth hormone.

[0130] Additional therapeutic agents, when used in combination with a compound of Formula I, II, III or IV, or a pharma- ceutically acceptable salt, hydrate, stereoisomer or prodrug thereof, may be used, for example, in the amounts indicated in the Prescriber's Digital Reference or as otherwise determined by one of skill in the art. Synthesis of Compounds of Formula I

[0131] Many synthetic routes to compounds of formula I, II, III and IV can be devised by one skilled in the art, and the possible synthetic routes described below are not intended to be limiting. Where appropriate, the initially prepared compound of formula I can be converted into other compounds of formula I by known methods.

[0132] Starting materials and reagents for preparing compounds of formula I are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, WI), Bachem Co. (Torrance, CA), Sigma Co. (St. Louis, MO), or may be prepared by methods well known to those skilled in the art according to procedures described in references such as Fieser and Fieser, Reagents for Organic Synthesis, Vol. 1-17, John Wiley and Sons, New York, NY, 1991; Rodd, Chemistry of Carbon Compounds, Vol. 1-5 and supplementary materials, Elsevier Science Publishers, 1989; Organic Reactions, Vol. 1-40, John Wiley and Sons, New York, NY, 1991; March J; Advanced Organic Chemistry, 4th Ed. John Wiley and Sons, New York, NY, 1992; and Larock: Comprehensive Organic Transformations, VCH Publishers, 1989. In most cases, amino acids and their esters or amides, as well as protected amino acids, are widely available commercially. Moreover, the preparation of modified amino acids and their amides or esters has been widely described in the chemical and biochemical literature and is therefore well known to those of skill in the art.

[0133] The starting materials, intermediates, and final products of this disclosure may be isolated and purified using conventional techniques, including filtration, distillation, crystallization, chromatography, etc. They may be characterized using conventional methods, including physical constants and spectral data.

[0134] Cyclic G-2-allyl P is a type of cyclic dipeptide (bicyclic 2,5-diketopiperazine) and a member of the class of compounds called cyclic GP ("cGP"). In general, cGP and cyclic G-2-allyl P may be prepared by methods familiar to those skilled in the art of peptide and modified peptide synthesis, by methods following the reaction schemes described herein, or by other methods familiar to those skilled in the art of peptide and analogue synthesis. See, for example, Bodanzsky: Principles of Peptide Synthesis, Berlin, New York: Springer-Verlag 1993.

[0135] Synthesis of the diketopiperazine compounds of the present disclosure may be by solution phase synthesis or by solid phase synthesis methods exemplified by Merrifield et al. (1963 J. Amer. Chem. Soc.:85, 2149-2156.) Solid phase synthesis may be performed using a commercially available peptide synthesizer, such as the Applied Biosystems Model 430A, using protocols established for that instrument.

[0136] Specific examples of diketopiperazine synthesis can be found in Fischer, 2003, J. Peptide Science: 9:9-35 and references therein. Those of skill in the art will have no difficulty in developing a suitable method for synthesizing one or more of the compounds of the invention, given their skill and available knowledge, and this disclosure.

[0137] It is within the skill of the art to select the appropriate protecting group for the chosen method (solid phase or solution phase) and to select the appropriate substrate when using solid phase synthesis. Suitable protecting groups for peptide synthesis are tert-butoxycarbonyl (Boc), fluorenylmethyloxycarbonyl (Fmoc), benzyl (Bzl), tert-amyloxycarbonyl (Aoc), tosyl (Tos), benzyloxycarbonyl (Z or Cbz), o-bromobenzyloxycarbonyl (BrZ), etc. Additional protecting groups are described in "Synthesis of Peptides and Peptidomimetics" in Goodman M. (ed.), Methods of Organic Chemistry (Houben-Weyl) (Workbench Edition, E22a, b, c, d, e; 2004; Georg Thieme Verlag, Stuttgart, NY).

[0138] The choice of coupling agent for the chosen method is also within the skill of the art. Suitable coupling agents include DCC (N,N'-dicyclohexylcarbodiimide), Bop (benzotriazol-1-yl-oxy-tri-(dimethylamino)-phosphonium hexafluorophosphate), PyBop (benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate), BopCl (bis(2-oxo-3-oxazolidinyl)phosphinic chloride), 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP), and the like. Other compounds can be used in the synthesis to prevent racemization, such as HOBt (N-hydroxybenzotriazole) and HOAt (1-hydroxy-7-azabenzotriazole). Working Example

[0139] The present disclosure is further illustrated by the following examples, which are provided by way of illustration only and are not intended to limit the scope of the present disclosure. Overview: Materials and Methods

[0140] High performance chromatography was performed using Scharlau 60 (40-60 μm mesh) silica gel. Analytical thin-layer chromatography was performed on 0.20 mm precoated silica gel plates (ALUGRAM® SILG / UV254) and compounds were visualized using ultraviolet fluorescence or heating of the plates immersed in potassium permanganate in alkaline solution.

[0141] Melting points (degrees Celsius, °C) were determined with an Electrothermal® melting point apparatus and are uncorrected.

[0142] 10 -1 degcm 2 g -1 Measure the optical rotation at 20°C using a 10 cm path length cell on a Perkin Elmer 341 polarimeter, given in units of g / 100 cm. Prepare the sample in a solvent of given concentration (units of measurement are g / 100 cm). 3). Infrared spectra were recorded on a Perkin Elmer Spectrum One FT-IR spectrometer. Samples were prepared as thin films on sodium chloride disks or as solids on potassium bromide disks. The broad signal is denoted by br. The frequency (u) of the absorption maximum is expressed in wavenumbers (cm -1 ) is given by

[0143] NMR spectra were obtained using a Bruker AVANCE DRX400 ( 1 H, 400MHz; 13 C,100 MHz) or Bruker AVANCE 300( 1 H, 300MHz; 13 C, 75 MHz) at ambient temperature. 1 For H NMR data, the chemical shifts are SiMe 4 are expressed in parts per million downfield from and are reported successively as positions (δH), relative integrals, multiplet numbers (s=singlet, d=doublet, t=triplet, dd=doublet of doublets, m=multiplet, br=broad), coupling constants (J / Hz), and assignments. 13 For C NMR data, chemical shifts are in CDCl 3 are expressed in parts per million relative to the nucleotide sequence and are reported successively as position (δC), degree of hybridization as determined by DEPT experiments, and assignment. 1 HNMR spectrum of SiMe 4 (δ0.00) or CDCl 3 It is internally referenced using (δ7.26). 13 C NMR spectra were obtained using CDCl 3 (δ 77.0). When the NMR spectrum shows two sets of peaks due to different conformations around the glycine-proline amide bond, the chemical shifts of the secondary cis stereoisomer are marked with an asterisk (*).

[0144] Exact mass measurements are recorded on a VG-70SE mass spectrometer.

[0145] Hexane and dichloromethane are distilled prior to use. Methanol is dried using magnesium turnings and iodine and distilled under nitrogen. Triethylamine is dried over calcium hydride and distilled under nitrogen.

[0146] Example 1: (8aS)-Methyl-hexahydropyrrolo[1,2-a]pyrazine-1,-dione Synthesis of (cyclic G-2-MeP) [ka] Scheme 1: Reagents, conditions, and yields: (i) LDA, THF, -78 °C, iodomethane, -78-20 to 50 °C, 2 h (63%); (ii) SOCl 2 , C.H. 3 OH, reflux, N 2 , 2.5 hours (98%); (iii) Et 3 N, BoPCl, CH 2 Cl 2 , room temperature, N 2 , 20.5 hours (78%); (iv) 10%Pd / C, CH 3 OH, room temperature, 15 hours (98%) (2R,5S)-4-Methyl-2-trichloromethyl-1-aza-3-oxabicyclo[3.3.0]octan-4-one (9) Diisopropylamine (0.86 cm 3 , 6.14 mmol) in dry tetrahydrofuran (10 cm 3 ) was stirred at −78 °C under a nitrogen atmosphere. 3 , 6.14 mmol) was added dropwise. The solution was stirred for 5 min, warmed to 0 °C and stirred for 15 min. Next, oxazolidinone 8 (1.00 g, 4.09 mmol) was dissolved in dry tetrahydrofuran (20 cm 3 This solution was added dropwise to a solution of 1,000 ml of iodomethane (0.76 cm3) over 20 min at -78°C (the solution turned dark brown), and the solution was stirred for a further 30 min. 3 , 12.3 mmol) was added dropwise over 5 min and the solution was heated to -50°C for 2 h. Water (15 cm 3 ) and heat to room temperature. 3 The combined organic extracts were dried (MgSO 4), filtered and evaporated to dryness in vacuo to give a dark brown semi-solid. The residue was purified by flash column chromatography (15% ethyl acetate-hexanes) to give oxazolidinone 9 (0.67 g, 63%) as a pale yellow solid. mp 55-57 °C (lit., 57-60 °C); δH (300 MHz, CDCl 3 ) 1.53 (3H, s, CH 3 ), 1.72-2.02 (3H, m, Proβ-H and Proγ-H 2 ), 2.18-2.26 (1H, m, Proβ-H), 3.15-3.22 (1H, m, Proδ-H), 3.35-3.44 (1H, m, Proδ-H) and 4.99 (1H, s, NCH). L-2-Methylproline methyl ester hydrochloride (10) a) Use of acetyl chloride Under a nitrogen atmosphere, oxazolidinone 9 (0.60 g, 2.33 mmol) was dissolved in dry methanol (15 cm 3 ), and then acetyl chloride (0.33 cm 3 4.66 mmol) was added dropwise to the ice-cold solution. The solution was heated under reflux for 4.5 h, after which the solvent was removed under reduced pressure to give a brown oil which was purified by flash column chromatography (10% CH 3 OH-CH 2 Cl 2 ) to give the hydrochloride salt 10 (0.2 g, 48%) as a flaky white solid. mp 107-109°C (lit., 106-108°C); δH (300 MHz, CDCl 3 ) 1.81 (3H, s, CH 3 ), 1.93-2.14 (3H, m, Proβ-H A H B and Proγ-H 2 ), 2.33-2.39 (1H, m, Proβ-H A H B ), 3.52-3.56 (2H, m, Proδ-H 2 ) and 3.82 (3H, s, CO 2 CH 3 ). b) Use of thionyl chloride Dissolve oxazolidinone 9 (53 mg, 0.21 mmol) in dry methanol (1 cm 3 ) in thionyl chloride (0.045 cm 3 The solution was heated under reflux for 2.5 hours, then cooled and the solvent removed under reduced pressure to give a brown oil. This oil was dissolved in toluene (5 cm3) and concentrated to dryness to remove residual thionyl chloride and methanol, then purified by flash column chromatography (10% CH 3 OH-CH 2 Cl 2 ) to give the hydrochloride salt 10 (16 mg, 43%) as a flaky white solid. 1 1 H NMR assignments were consistent with those reported above. Methyl-N-benzyloxycarbonyl-glycyl-L-2-methylproline (12) A solution of the hydrochloride 10 (0.11 g, 0.61 mmol) and N-benzyloxycarbonyl-glycine 11 (98.5%) (0.17 g, 0.79 mmol) in dichloromethane (35 cm 3 ) was added to a solution of dry triethylamine (0.27 cm 3 , 1.96 mmol) was added dropwise. The reaction mixture was stirred for 10 min at room temperature under a nitrogen atmosphere. Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BoPCl, 97%) (0.196 g, 0.77 mmol) was added and the resulting colorless solution was stirred for 20.5 h. 10% aqueous hydrochloric acid (30 cm 3 ) and saturated aqueous sodium bicarbonate solution (30 cm 3 ) and dried (MgSO 4 The resulting residue was purified by flash column chromatography (50-80% ethyl acetate-hexanes; gradient elution) to give dipeptide 12 (0.18 g, 92%) as a colorless oil. 13 C NMR analysis showed that amide 12 exists as a 98:2 trans:cis mixture of conformers (the ratio is estimated from the relative intensities of the resonances assigned to the Pro γ-C atoms of the minor and major conformers at δ 20.8 and 23.5, respectively): [α]D - 33.0 (in MeOH c 1.0); νmax (film) / cm -1 3406, 2952, 1732, 1651, 1521, 1434, 1373, 1329, 1310, 1284, 1257, 1220, 1195, 1172, 1135, 1107, 1082, 1052, 1029, 986, 965, 907, 876, 829, 775, 738 and 699; δH (300 MHz, CDCl 3 ) 1.49 (3H, s, CH 3 ), 1.77 - 2.11 (4H, m, Proβ-H 2 and Proγ-H 2 ), 3.43 - 3.48 (2H, m, Proδ-H 2 ), 3.61 (3H, s, OCH 3 ), 3.85 - 3.89 (2H, m, Glyα-H 2 ), 5.04 (2H, s, PhCH 2 ), 5.76 (1H, br s, N-H) and 7.21 - 7.28 (5H, s, ArH); δC (75 MHz, CDCl 3 ) 13.8* (CH 3 , Proα-CH 3 ), 21.1 (CH 3 , Proα-CH 3 ), 20.8* (CH 2 , Proγ-C), 23.5 (CH 2 , Proγ-C), 38.0 (CH 2 , Proβ-C), 40.8* (CH 2 , Proβ-C), 43.3 (CH 2 , Glyα-C), 45.5* (CH 2 , Glyα-C), 46.6 (CH 2 , Proδ-C), 48.7* (CH 2 , Proδ-C), 51.9* (CH 3 , OCH 3 ), 52.1 (CH 3 , OCH3 ), 60.0* (quat., Proα-C), 66.0 (quat., Proα-C), 66.3 (CH 2 , PhCH 2 ), 68.6* (CH 2 , PhCH 2 ), 127.5 (CH, Ph), 127.6 (CH, Ph), 127.9* (CH, Ph), 128.1 (CH, Ph), 128.3* (CH, Ph), 136.2 (quat., Ph), 155.9 (quat., NCO 2 ), 166.0 (quat., Gly-CON), 169.4* (quat., Gly-CON) and 173.6 (quat., CO 2 CH 3 ); m / z (EI+) 334.1535 (M+.C 17 H 22 N 2 O 5 requires 334.1529). (8As)-Methyl-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (Cyclic G-2MeP) Dipeptide 12 (0.167 g, 0.51 mmol) in methanol (8.0 cm 3 To the solution was added 10% Pd on activated carbon (8.1 mg, 0.076 mmol) and the vessel was flushed with hydrogen gas. The resulting suspension was stirred vigorously under a hydrogen atmosphere for 15 h. The mixture was then filtered through a mat of diatomaceous earth followed by a short plug of silica gel with methanol and the solvent removed under reduced pressure to give Cyclic G-2MeP (83 mg, 98%) as a yellow solid; mp 133-135°C; [α] D -128.1 (in MeOH c 0.52 ); δH (300 MHz, CDCl 3 ) 1.36 (3H, s, CH 3 ), 1.87-2.01 (3H, m, Proβ- H A H B and Proγ-H 2 ), 2.07-2.21 (1H, m, Proβ-H AH B ), 3.45-3.64 (2H, m, Proδ-H 2 ), 3.82 (1H, dd, J 17.1 and 4.1, C H A H B NH), 3.99 (1H, d, J 17.1, CH A H B NH) and 7.66 (1H, br s, NH); δC (75 MHz, CDCl 3 ) 20.2 (CH 2 , Proγ-C), 23.2 (CH 3 , Proα-CH 3 ), 35.0 (CH 2 , Proβ-C), 44.7 (CH 2 , Proδ-C), 45.9 (CH 2 , C.H. 2 NH), 63.8 (quat., Proα-C), 163.3 (quat., NCO) and 173.3 (quat., CONH); m / 5 z (EI+) 168.08986 (M+.C 8 H 12 N 2 O 2 requires 168.08988).

[0147] Example 2: (8aS)-Methyl-spiro[cyclohexane-1,3(4H)-tetrahydropyrrolo[1,2-a]pyrazine]-1,4(2H)-dione Synthesis of (Cyclic Cyclohexyl-G-2-MeP) Formula IV [ka] Scheme 2: Reagents, conditions, and yields: (i) BnO 2 CCl, Na 2 CO 3 , H 2 O-Dioxane (3:1), 19 h, 96%; (ii) Et 3 N, HOAt, CIP, 1,2-dichloroethane, reflux, N 2 , 19 hours (23%); (iii) 10%Pd / C, CH3 OH, room temperature, 17 h (65%). N-Benzyloxycarbonyl-1-aminocyclohexane-1-carboxylic acid (14) A suspension of 1-aminocyclohexanecarboxylic acid 13 (0.72 g, 5.02 mmol) and sodium carbonate (1.6 g, 15.1 mmol) in water was added to dioxane (21 cm 3 , 3:1) was added dropwise, and benzyl chloroformate (0.79 cm 3 , 5.52 mmol) was added dropwise and the mixture was stirred at room temperature for 19.5 hours. The aqueous layer was diluted with diethyl ether (60 cm 3 ), acidified with 2M HCl and washed with ethyl acetate (2 × 60 cm 3 The organic layers were combined and dried (MgSO 4 ), filtered, and evaporated under reduced pressure to give a colorless oil which solidified on standing and was obtained crude as a white solid. Urethane 14 (1.23 g, 88%) was obtained. mp 152-154 °C (lit., 148-150 °C); δH (400 MHz, CDCl 3 ) 1.27-1.56 (3H, m, 3 x cyclohexyl-H), 1.59-1.73 (3H, m, 3 x cyclohexyl-H), 1.85-1.91 (2H, m, 2 x cyclohexyl-H), 2.05-2.09 (2H, m, 2 x cyclohexyl-H), 5.02 (1H, br s, NH), 5.12 (2H, s, OC H 2 Ph) and 7.27-7.36 (5H, s, Ph); δC (100 MHz, CDCl 3 ) 21.1 (CH 2 , 2 x Cyclohexyl-C), 25.1 (CH2, 2 x Cyclohexyl-C), 32.3 (CH 2 , cyclohexyl-C), 5 59.0 (quat.,1-C), 67.1 (CH 2 , O C H 2Ph), 128.1 (CH, Ph), 128.2 (CH, Ph), 128.5 (CH, Ph), 136.1 (quat., Ph), 155.7 (quat., NCO2) and 178.7 (quat., CO 2 H). Methyl-N-benzyloxycarbonyl-cyclohexyl-glycyl-L-2-methylproline (15) A solution of the hydrochloride salt 10 (84.0 mg, 0.47 mmol), the carboxylic acid 14 (0.17 g, 0.61 mmol) and 1-hydroxy-7-azabenzotriazole (16 mg, 0.12 mmol) in dry 1,2-dichloroethane (26 cm 3 , 1.5 mmol) was added to a solution of dry triethylamine (0.21 cm 3 2-Chloro-1,3-dimethylimidazolidine hexafluorophosphate (0.13 g, 0.47 mmol) was added and the resulting solution was heated under reflux for 21 hours, after which 10% aqueous hydrochloric acid (30 cm 3 ), saturated sodium bicarbonate solution (30 cm 3 ), dried (MgSO 4 The residue was purified by flash column chromatography (40-50% ethyl acetate-hexane; gradient elution) to give a 30 ml solution of 100 ml of ethyl acetate in hexane. Amide Obtained 15 (16 mg, 9%) as a white solid. 13 C NMR analysis showed that amide 15 exists in the form of an 11:1 trans:cis mixture of conformers (the ratio is estimated from the relative intensities of the resonances assigned to the Pro δ-C atoms of the minor and major conformers at δ 41.3 and 48.2, respectively): mp 219-222 °C; [α] D -44.9 (CH 2 Cl 2 In c 1.31); nmax (film) / cm -13239, 2927, 1736, 1707, 1617, 1530, 1450, 1403, 1371, 1281, 1241, 1208, 1194, 1165, 1150, 1132, 1089, 1071, 1028, 984, 912, 25 796, 749, 739 and 699; δH (400 MHz, CDCl 3 ) 1.24-2.10 (17H, m, Proα-CH 3 , Proβ-H 2 , Proγ-H 2 and 5 x Cyclohexyl-H 2 ), 3.25-3.48 (1H, br m, Prod- H A H B ), 3.61-3.87 (4H, br m, OCH 3 and Proδ-H A H B ), 4.92-5.19 (3H, m, NH and OC H 2 Ph) and 7.35-7.37 (5H, s, Ph); δC (100 MHz, CDCl 3 ) 21.26 (CH 2 , cyclohexyl-C), 21.33 (CH 2 , cyclohexyl-C), 21.7 (CH 3 , Proα-CH 3 ), 24.8 (CH 2 , Cyclohexyl-C), 25.0 (CH 2 , Proγ-C), 29.4* (CH 2 , Cyclohexyl-C), 29.7* (CH 2 , cyclohexyl-C), 31.1 (CH 2 , cyclohexyl-C), 31.6 (CH 2 , Cyclohexyl-C), 31.9* (CH 2 , Cyclohexyl-C), 32.2* (CH 2 , Cyclohexyl-C), 32.8* (CH 2, cyclohexyl-C), 37.3 (CH 2 , Proβ-C), 41.4* (CH 2 , Proδ-C), 48.2 (CH 2 , Proδ-C), 52.1 (CH 3 , OCH 3 ), 59.1 (quat., Glyα-C), 66.7 (CH 2 , O C H 2 Ph), 67.3* (CH 2 , O C H 2 Ph), 67.4 (quat., Proα-C), 128.0* (CH, Ph), 128.1* (CH, Ph), 128.3 (CH, Ph), 128.5 (CH, Ph), 128.7 (CH, Ph), 136.6 (quat., Ph), 153.7 (quat., NCO 2 ), 171.0 (quat., Gly-CO) and 174.8 (quat., C O 2 CH 3 ); m / z (EI+) 402.2151 (M + C 22 H 30 N 2 O 5 requires 402.2155). (8aS)-Methyl-spiro[cyclohexane-1,3(4H)-tetrahydropyrrolo[1,2-a]pyrazine]-1,4(2H)-dione (cyclic cyclohexyl-G-2MeP) Amide 15 (40 mg, 0.01 mmol) in methanol (3.3 cm 3 To the solution was added 10% Pd on activated carbon (1.6 mg, 0.015 mmol) and the vessel was flushed with hydrogen gas. The resulting suspension was stirred vigorously under an atmosphere of hydrogen gas for 61.5 h, after which it was diluted with methanol (15 cm 3 The mixture was filtered through a mat of diatomaceous earth (Celite®) using 0.1% CH. The filtrate was concentrated to dryness under reduced pressure to give a yellow semi-solid, which was purified by reverse-phase C18 flash column chromatography (0–10% CH 3 CN / H 2 0, gradient elution) and Cyclic cyclohexyl-G-2MeP(19 mg, 81%) was prepared as a white solid. mp 174-177°C; [α] D -63.8 (CH 2 Cl 2 In c 1.13); nmax (film) / cm -1 3215, 2925, 2854, 1667, 1646, 1463, 1427, 1276, 1232, 1171, 1085, 1014, 900, 868, 818, 783, 726 and 715; δH (400 MHz, CDCl 3 ) 1.31-1.89 (12H, m, 9 x cyclohexyl-H and 8a-CH 3 ), 1.94-2.15 (4H, m, 7-H2 and 8-H 2 ), 2.26 (1H, td, J 13.7 and 4.5, 1 x cyclohexyl-H), 3.44-3.51 (1H, m, 6- H A H B ), 3.79-3.86 (1H, m, 6-H A H B ) and 6.40 (1H, br s, NH); δC (100 MHz, CDCl 3 ) 19.5 (CH 2 , 7-C), 20.6 (CH 2 , cyclohexyl-C), 20.8 (CH 2 , cyclohexyl-C), 24.5 (CH 2 , Cyclohexyl-C), 25.0 (CH 3 , 8a-CH 3 ), 33.7 (CH 2 , cyclohexyl-C), 36.3 (CH 2 , 8-C), 36.5 (CH 2 , cyclohexyl-C), 44.7 (CH 2 , 6-C), 59.5 (quat., 8a-C), 64.0 (quat., 3-C), 168.1 (quat., 4-C) and 171.6 (quat., 1-C); m / z (EI + ) 236.15246 (M + C 13 H 20 N 2 O 2 requires 236.15248).

[0148] Example 3: (8aS)-Allyl-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (cyclic G-2-allyl P) Synthesis of [ka] Scheme 3: Reagents, conditions, and yields: (i) LDA, THF, -78 °C, allyl bromide, -78 to -30 °C, N 2、 4 h (60%); (ii) acetyl chloride, CH3OH, reflux, N2, 24 h (63%); (iii) Et3N, BoPCl, CH2Cl2, rt, N2, 19.5 h (45%); (iv) TFA, CH2Cl2, 1 h, then Et3N, CH2Cl2, 23 h (37%) 。 (2R,5S)-4-Allyl-2-trichloromethyl-1-aza-3-oxabicyclo[3.3.0]octan-4-one (17) Diisopropylamine (1.82 cm) was dissolved in water at −78°C under a nitrogen atmosphere. 3 , 13.0 mmol) of dry tetrahydrofuran (20 cm 3 ) in a stirred solution of n-BuLi (1.31 M, 9.93 cm 3 The solution was stirred for 5 min, warmed to 0° C., stirred for 15 min, and then added dropwise with dry tetrahydrofuran (40 cm 3 Ortho-oxazolidinone 16 (2.12 g, 8.68 mmol) was added dropwise over 20 min to the solution, which was then stirred for an additional 30 min, after which allyl bromide (2.25 cm 3 The solution was slowly warmed to -30°C over 4 hours and then cooled to -30°C for 5 hours. 2 O(30cmcm 3 ) and then cooled to room temperature. 3 The combined organic extracts were dried (MgSO 4), filtered, evaporated to dryness in vacuo, and purified by flash column chromatography (10-20% ethyl acetate-hexanes; gradient elution), Oxazolidinone 17 (1.48 g, 60%) was prepared as an orange oil by hardening at 0 °C. Its nmr data were consistent with those reported in the literature. δH (400 MHz, CDCl 3 ) 1.58-1.92 (2H, m, Proγ-H 2 ), 1.96-2.14 (2H, m, Proβ-H 2 ), 2.50-2.63 (2H, m, Proδ-H 2 ), 3.12-3.23 (2H, m, CH 2 -CH=CH 2 ), 4.97 (1H, s, NCH), 5.13-5.18 (2H, m, CH=CH 2 ) and 5.82-5.92 (1H, m, CH=CH 2 ); δC (100 MHz, CDCl 3 ) 25.1 (CH 2 , Proγ-C), 35.1 (CH 2 , Proβ-C), 41.5 (CH 2 , Proδ-C), 58.3 (CH 2 , C.H. 2 CH=CH 2 ), 71.2 (quat., Proα-C), 100.4 (quat., CCl 3 ), 102.3 (CH, NCH), 119.8 (CH 2 , C.H. 2 CH=CH 2 ), 131.9 (CH, CH 2 CH=CH 2 ) and 176.1 (quat., C=O); m / z (CI+) 284.0009 [(M+H) + .C 10 H 13 Cl 3 NO 2 requires 284.0012], 285.9980 [(M+H) + C 10 H13 35 Cl 37 Cl 3 NO 2は 285.9982 required], 287.9951 [(M+H) + .C 10 H 13 35 Cl 37 Cl 2 NO 2 requires 287.9953] and 289.9932 [(M+H) + .C 10 H 13 37 Cl 3 NO 2 requires 289.9923]. L-2-Allylproline methyl ester hydrochloride (18) Dissolve oxazolidinone 17 (0.64 g, 2.24 mmol) in dry methanol (15 cm 3 ) was added to an ice-cold solution of acetyl chloride (0.36 cm 3 , 5.0 mmol) of methanol (5 cm 3 A solution of 1,2-dichlorophenyl ether in toluene (40 cm) was added dropwise. The solution was heated under reflux for 24 h, then cooled and the solvent removed under reduced pressure. The resulting brown oil was diluted with toluene (40 cm). 3 ), concentrated to dryness to remove residual thionyl chloride and methanol, and then purified by flash column chromatography (5–10% CH 3 OH-CH 2 Cl 2 (gradient elution), Hydrochloride 18 (0.29 g, 63%) was obtained. Its NMR data were consistent with those reported in the literature. δH (300 MHz, CDCl 3 ) 1.72-2.25 (3H, m, Proβ- H A H B and Proγ-H 2 ), 2.32-2.52 (1H, m, Proβ-H A H B ), 2.72-3.10 (2H, m, Proδ-H 2 ), 3.31-3.78 (2H, m, CH 2 CH=CH 2 ), 3.84 (3H, s, CO 2 CH 3 ), 5.20-5.33 (2H, m, CH=C H 2 ), 5.75-5.98 (1H, m, C H =CH 2 ) and 8.06 (1H, br s, NH); m / z (CI+) 170.1183 [(M+H) + .C 9 H 16 NO 2 requires 170.1181]. Methyl-N-tert-butoxycarbonyl-glycyl-L-2-allylproline (20) Under a nitrogen atmosphere, at room temperature, dichloromethane chloride (35 cm 3 A solution of the hydrochloride salt 18 (0.13 g, 0.63 mmol) and N-tert-butoxycarbonyl-glycine 19 (0.14 g, 0.82 mmol) was added to dry triethylamine (0.28 cm 3 , 2.02 mmol) was added dropwise and stirred for 10 minutes. Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BoPCl, 97%) (0.20 g, 0.80 mmol) was added and stirred for 19.5 hours, after which a 10% aqueous hydrochloric acid solution (35 cm 3 ) and saturated aqueous sodium bicarbonate solution (35 cm 3 ), dried (MgSO 4 ), filtered and evaporated to dryness in vacuo. The resulting residue was purified by flash column chromatography (40% ethyl acetate-hexanes) to give Dipeptides 20 (0.09 g, 45%) was obtained as a pale yellow oil. D +33.8 (CH 2 Cl 2 In c 0.83); nmax (film) / cm -13419, 5 3075, 2977, 2930, 2874, 1739, 1715, 1656, 1499, 1434, 1392, 1366, 1332, 1268, 1248, 1212, 1168, 1122, 1051, 1026, 1003, 943, 919, 867, 830, 779, 739, 699 および679; δH (300 MHz, CDCl 3 ) 1.42 [9H, s, C(CH 3 ) 3 ], 1.93-2.08 (4H, m, Proβ-H 2 およびProγ-H 2 ), 2.59-2.67 (1H, m, C H A H B CH=CH 2 ), 3.09-3.16 (1H, m, CH A H B CH=CH 2 ), 3.35-3.44 (1H, m, Proδ- H A H B ), 3.56-3.62 (1H, m, Proδ-H A H B ), 3.70 (3H, s, OCH 3 ), 3.89 (2H, d, J 4.2, Glyα-H 2 ), 5.06-5.11 (2H, m, CH=C H 2 ), 5.42 (1H, br s, Gly-NH) および5.58-5.72 (1H, m, C H =CH 2 ); δC (75 MHz, CDCl 3 ) 23.7 (CH 2 , Proγ-C), 28.3 [CH 3 , C( C H 3 ) 3 ], 35.0 (CH 2 , Proβ-C), 37.6 (CH 2, C H 2 CH=CH 2 ), 43.3 (CH 2 , Glyα-C), 47.5 (CH 2 , Proδ-C), 52.5 (CH 3 , OCH 3 ), 68.8 (quat., Proα-C), 79.5 [quat., C (CH 3 ) 3 ], 119.4 (CH 2 , CH= C H 2 ), 132.9 (CH, C H=CH 2 ), 155.7 (quat., NCO 2 ), 166.9 (quat., Gly-CON) and 173.8 (quat., C O 2 CH 3 ); m / z (EI + ) 326.1845 (M + .C 16 H 26 N 2 O 5 requires 326.1842). (8aS)-Allyl-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (cyclic G-2 allyl P) Formula II Dipeptide 20 (0.09 g, 0.28 mmol) in dichloromethane (9 cm 3 ) solution with trifluoroacetic acid (1 cm 3 0.013 mmol) was added dropwise at room temperature and the reaction mixture was stirred under nitrogen for 1 h. The solution was evaporated under reduced pressure to give a colourless oil which was diluted with dichloromethane (10 cm 3 ) and dried triethylamine (0.096 cm 3 , 0.69 mmol) was added, and the mixture was stirred for 4.5 hours. Then, triethylamine (0.096 cm 3 , 0.69 mmol) was added. The reaction mixture was stirred overnight and then concentrated to dryness to obtain a green oil, which was purified by flash column chromatography (10% CH 3 OH-CH 2 Cl 2) and purify it by Cyclic G-2 Allyl Pp (20 mg, 37%) was prepared as an off-white solid. mp 106-109°C; [α] D -102.7 (CH 2 Cl 2 In c 0.95); nmax (CH 2 Cl 2 ) / cm-1 3456, 3226, 2920, 1666, 1454, 1325, 1306, 1299, 1210, 1133, 1109, 1028, 1010, 949, 928, 882, 793, 761 and 733; δH (400 MHz, CDCl 3 ) 1.92-2.01 (2H, m, Proγ-H 2 ), 2.09-2.16 (2H, m, Proβ-H 2 ), 2.39-2.56 (2H, m, C H 2 CH 2 =CH 2 ), 3.46-3.53 (1H, m, Proδ- H A H B ), 3.78-3.87 (2H, m, Proδ-H A H B and Glyα- H A H B ), 4.09 (1H, d, J 17.2, Glya-H A H B ), 5.16-5.20 (2H, m, CH=C H 2), 5.73-5.84 (1H, m, C H =CH2) and 7.17 (1H, br s, NH); δC (100 MHz, CDCl 3 ) 20.1 (CH 2 , Proγ-C), 34.1 (CH 2 , Proβ-C), 41.7 (CH 2 , C H 2 CH 2=CH 2 ), 44.9 (CH 2 , Proδ-C), 46.4 (CH 2 , Glyα-C), 67.2 (quat., Proα-C), 120.9 (CH 2 , CH= C H 2 ), 131.0 (CH, C H=CH 2 ), 163.4 (quat., NCO) and 171.7 (quat., CONH); m / z (EI+) 195.1132 (M + .C 10 H 15 N 2 O 2 requires 5 195.1134).

[0149] Example 4: (8aS)-Methyl-spiro[cyclopentane-1,3(4H)-tetrahydropyrrolo[1,2-a]pyrazine]-1,4(2H)-dione (cyclic cyclopentyl-G-2-MeP) Synthesis of Formula III [ka] Scheme 4: Reagents, conditions, and yields: (i) Et3N, HOAt, CIP, 1,2-dichloroethane, 83 °C, N2, 19 h (23%); (ii) 10% Pd / C, CH3OH, rt, 17 h (65%). N-Benzyloxycarbonyl-1-aminocyclopentane-1-carboxylic acid (twenty one) At 0° C., a solution of 1-aminocyclopentanecarboxylic acid (Fluka) (0.20 g, 1.54 mmol) and sodium carbonate (0.49 g, 4.64 mmol) in water (5 cm 3 ) in a 2.5 cm 3 ) solution was added dropwise. Stirring was continued at room temperature overnight, and the reaction mixture was washed with diethyl ether. The aqueous layer was acidified with 2M hydrochloric acid, extracted with ethyl acetate, and dried (Na 2 SO 4 ), filtered and the solvent removed. Urethane 21 (0.253 g, 62%) was obtained as an oil that solidified on standing. 1H NMR analysis showed that urethane 21 was a 70:30 mixture of conformers (the ratio was estimated from the resonance integrals assigned to the NH protons of the minor and major conformers at δ 5.31 and 7.29-7.40, respectively). mp 70-80 °C (lit.1 82-86 °C, ethyl acetate, petroleum ether); δH (400 MHz; CDCl 3 Me 4 Si) 1.83 (4H, br s, 2 x cyclopentyl-H 2 ), 2.04 (2H, br s, cyclopentyl-H 2 ), 2.20-2.40 (2H, m, cyclopentyl-H 2 ), 5.13 (2H, br s, OC H 2 Ph), 5.31 (0.7H, br s, NH) and 7.29-7.40 (5.3H, m, Ph and NH*); δC (100 MHz; CDCl 3 ) 24.6 (CH 2 , cyclopentyl-C), 37.5 (CH 2 , cyclopentyl-C), 66.0 (quat., cyclopentyl-C), 66.8 (CH 2 , O C H 2 Ph), 128.0 (CH, Ph), 128.1 (CH, Ph), 128.4 (CH, Ph), 136.1 (quat, Ph), 155.8 (quat., NCO 2 ) and 179.5 (quat., CO 2 H). N-Benzyloxycarbonylmethylcyclopentyl-glycyl-L-2-methylproline (twenty two) A solution of the hydrochloride salt 10 (78 mg, 0.43 mmol), the carboxylic acid 21 (0.15 g, 0.56 mmol) and 1-hydroxy-7-azabenzotriazole (Acros) (15 mg, 0.11 mmol) in dry 1,2-dichloroethane (24 cm 3 , 1.4 mmol) was added to a solution of dry triethylamine (0.19 cm 3, 1.4 mmol) was added dropwise at room temperature under a nitrogen atmosphere and the reaction mixture was stirred for 10 min. 2-Chloro-1,3-dimethylimidazolidine hexafluorophosphate (CIP) (Aldrich) (0.12 g, 0.43 mmol) was added and the resulting solution was heated under reflux for 19 h, after which 10% aqueous hydrochloric acid (30 cm 3 ), saturated sodium bicarbonate solution (30 cm 3 ), dried (MgSO 4 ), filtered and evaporated to dryness in vacuo. The resulting residue was purified by flash column chromatography (60% ethyl acetate-hexanes) to give Amide Obtained 22 (39 mg, 23%) as a white solid. 13 C NMR analysis revealed that amide 22 is a 3:1 mixture of urethane conformers. Trans:cis It was shown to be a mixture (the ratio was estimated from the relative intensities of the resonances assigned to the urethane carbonyl-C atom of the major and minor conformers at δ 154.1 and 155.7). mp 200-203 °C; [α] D -54.5 (CH 2 Cl 2 In c 1.52); nmax (film) / cm -1 3432, 3239, 5 3042, 2953, 1736, 1712, 1627, 1540, 1455, 1417, 1439, 1374, 1282, 1256, 1216, 1194, 1171, 1156, 1136, 1100, 1081, 1042, 1020, 107, 953, 917, 876, 756 and 701; δH (400 MHz, CDCl 3 ) 1.33-1.53 ​​(3H, br m, Proα-CH 3 ), 1.62-2.20 (11H, m, Proβ-H 2 , Proγ-H 2 and 7 x cyclopentyl-H), 2.59-2.71 (1H, br m, 1 x cyclopentyl-H), 3.31-3.42 (1H, br m, Prod- H A H B), 3.58-3.79 (4H, br m, OCH 3 and Proδ-H A H B ), 4.92-5.17 (3H, m, NH and OC H 2 Ph) and 7.27-7.42 (5H, s, Ph); δC (100 MHz, CDCl 3 ) 21.7 (CH 3 , Proα-CH 3 ), 24.1* (CH 2 , cyclopentyl-C), 24.2 (CH 2 , cyclopentyl-C), 24.4 (CH 2 , Proγ-C), 24.5 (CH 2 , cyclopentyl-C), 36.4 (CH 2 , cyclopentyl-C), 37.1 (CH 2 , cyclopentyl-C), 37.2* (CH 2 , cyclopentyl-C), 37.7 (CH 2 , Proβ-C), 38.2* (CH 2 , cyclopentyl-C), 48.5 (CH 2 , Proδ-C), 52.1 (CH 3 , OCH 3 ), 66.6 (CH 2 , O C H 2 Ph), 66.9 (quat., Proα-C), 67.2 (quat., Glyα-C), 127.8 (CH, Ph), 128.2 (CH, Ph), 128.4 (CH, Ph), 136.6 (quat., Ph), 154.1 (quat., NCO 2 ), 155.7* (quat., NCO 2 ), 170.5 (quat., Gly-CO) and 174.7 (quat., C O 2 CH 3 ); m / z (EI+) 388.1991 (M + .CC21 H 28 N 2 O 5 requires 388.1998). (8aS)-Methyl-spiro[cyclopentane-1,3(4H)-tetrahydropyrrolo[1,2-a]pyrazine]-1,4(2H)-dione (cyclic cyclopentyl-G-2MeP) Formula III To a solution of amide 22 (54 mg, 0.14 mmol) in methanol (4.6 cm3) was added 10% Pd on activated carbon (2.2 mg, 0.021 mmol) and the vessel was flushed with hydrogen gas. The resulting suspension was stirred vigorously under a hydrogen atmosphere for 17 h and then filtered through a mat of diatomaceous earth (Celite®) with methanol (15 cm3). The filtrate was concentrated to dryness under reduced pressure to give a yellow semi-solid which was purified by reverse-phase C18 flash column chromatography (0-10% CH3CN / H2; gradient elution) to give the cyclic cyclopentyl-G-2MeP (20 mg, 65%) as a yellow solid. mp 160-163°C; [α]D -97.9 (c 1.61 in CH2Cl2); nmax (film) / cm-1 3429, 2956, 2928, 2856, 1667, 1643, 1463, 1432, 1373, 1339, 1254, 1224, 1175, 1086, 1048, 976, 835, 774 and 730; δH (300 MHz, CDCl3) 1.47 (3H, br s, 8a-CH3), 1.56-2.19 (11H, m, 8-H2, 7-H2 and 7 x cyclopentyl), 2.58-2.67 (1H, br m, 1 x cyclopentyl), 3.48-3.56 (1H, m, 6-HAHB), 3.72-3.82 (1H, m, 6-HAHB) and 6.56 (1H, br s, NH); δC (75 MHz, CDCl3) 19.9 (CH2, 7-C), 24.6 (CH2, cyclopentyl), 24.92 (CH3, 8a-CH3), 24.93 (CH2, cyclopentyl), 36.0 (CH2, 8-C), 38.7 (CH2, cyclopentyl), 41.9 (CH2, cyclopentyl), 44.8 (CH2, 6-C), 64.3 (quat., 8a-C), 66.8 (quat., 3-C), 168.3 (quat., 4-C) and 172.2 (quat., 1-C); m / z (EI+) 222.1369 (M+. C12H18N2O2 should be 222.1368). Animal models and clinical studies The pharmacological studies described below have demonstrated that cyclic G-2 allele P is effective in reducing symptoms of Prader-Willi syndrome (PWS). These are not limiting, and other compositions and methods of the invention can be developed without undue experimentation. All of these compositions and methods are considered to be part of this disclosure. All of the following experiments were performed using protocols prepared under guidelines approved by the Animal Ethics Committee of the University of Chile or an equivalent regulatory authority.

[0150] Example 5: Delivery of cG2-Allyl P to the Brain Following Oral Administration In an in vivo study, male Sprague Dawley rats (14 weeks old) were given a single oral gavage dose of cG-2-allylP (100mg / kg or 200mg / kg). Cerebrospinal fluid (CSF) and whole blood were collected at 1.5 and 4 hours post-dose, and brain tissue was collected at 4 hours post-dose to assess cG-2-allylP exposure. Table 1 below shows blood, CSF and brain cG-2-allylP in CSF and blood 1.5 hours post-dose. [Table 1] After a single oral dose, the cG-2-allyl P concentrations in blood and cerebrospinal fluid increased approximately proportionally to those in blood, cerebrospinal fluid, and brain at 1.5 hours and 4 hours, respectively. The cG-2-allyl P concentrations in blood and brain tissue at 4 hours were approximately equal.

[0151] Example 6: Effects of cG-2-Allyl P in Prader-Willi syndrome model mice A. Mouse model C57BL / 6-Magel2tm1Stw / J Jackson Stock number: 009062 Mouse locus 7qB4 / B5 (identical to the Prader-Willi region at human chromosome 15q11-q13) is a paternally-identified imprinted gene. Magel2 , Ndn, Mkrn3 and Peg12 clusters. Magel2 Silencing allele, so inherited from the paternal side Magel2Only the allele is expressed. To maintain lineage, heterozygous females were mated with wild-type males (or C57BL / 6J inbred males), as the resulting offspring would not have the abnormal phenotype. Magel2 -Null" descendants (maternal and paternal Magel2 Wild-type females were mated with heterozygous males to obtain the imprinted / silenced wild-type alleles (both of which are functional). Magel2 -lacZ (null) allele is allowed from the father. Magel2 -null mice not only showed disruption of circadian rhythms and metabolism, total activity, food intake, preweaning body weight, and male and female reproductive ability, but also showed increased obesity and behavioral changes after weaning. Magel2 Magel2 null mice recapitulated Prader-Willi syndrome. Because the genetic mutation in Magel2 null animals is the same as that in humans, studies in Magel2 null mice can reasonably predict the effects of compounds on humans. B. Experimental Design In vivo experiments were performed in P60-aged C57BL / 6-Magel2tm1Stw / J (Magel2-null) mice and wild-type littermates during the light phase (Magel2 wild-type littermates were used as controls). In studies 1 and 2, 10 mice were used per treatment group, and in study 3, 6 mice per group. Study 1: C57BL / 6-Magel2tm1Stw / J (Magel2-null) mice were evaluated by behavioral assays. In study 2, we tested the efficacy of cG-2-Allyl P in treating obesity and insulin levels in Magel2-null mice. In study 3, we tested IGF-1 levels in Magel2-null mice. Since humans also have similar genetic abnormalities, studies with Magel2-null mice can reasonably predict the effects of compounds of formulas I, II, III, and IV in humans with Prader-Willi syndrome. Experiments were carried out in accordance with the requirements of the UK Animals (Scientific Procedures) Act 1986. Mice were housed in plastic cages (35 × 30 × 12 cm) in groups of five and were acclimated to the animal facility for at least 1 week before the start of the study. Room temperature (21°C ± 2°C), relative humidity (55% ± 5%), a 12-h light / dark cycle (lights on from 7 am to 7 pm), and air exchange (16 times per hour) were automatically controlled. Animals had free access to commercial food pellets and water. The tests were performed during the light phase of the circadian cycle, and the order of tests was determined based on the principle of performing the most demanding test last. Magel2 -Designed to replicate and extend the native behavioral characteristics of null mice. Magel2 Null wild-type control mice were dosed once daily for 6 weeks prior to testing and then tested 30 min after cG-2-allylP (NNZ2591) administration. The study groups and treatment matrix are listed in Table 2 below. [Table 2] TransnetXY automated genotyping (www.transnetyx.com / ). TRANSNETYX, INC., 8110 Cordova Rd. Suite 119, Cordova, TN 38016, USA was used for genotyping. All experiments were performed with subjects blinded to genotype or drug treatment. Separate investigators prepared and coded dosing solutions, assigned mice to study treatment groups, dosed animals, and collected behavioral data.

[0152] Example 6a: Hypoactivity in the open field To evaluate whether cG-2-allyleP is effective in treating hypoactivity in PWS, we performed an open-field study. Magel2-null mice were less active in the open field than their WT littermates, reflecting impaired motor ability. The experimental results, measuring distance traveled and activity time, are shown in Figures 2 and 3, respectively. Relative distance traveled or time spent actively is shown on the vertical axis, and the average for each treatment group is shown on the horizontal axis. Wild-type (WT) mice treated with vehicle only (left column) were considered to be 100% mobile or have 100% activity. Magel2 -Null mice treated with vehicle only (second column from the left) showed significantly lower distance traveled and activity time. All groups treated with cG-2-allylP at 100 mg / kg or 200 mg / kg were no different from the wild-type group treated with vehicle, and 100 mg / kg or 200 mg / kg Magel2 They showed that it normalized mild to moderate hypoactivity in null mice and had no effect on wild-type mice. Open field (hypoactivity) - Distance traveled ANOVA = analysis of variance, ns = not significant, WT = wild-type littermate control; ****=p<0.0001 Overview of ANOVA [Table 3] Sidak's multiple comparison test Summary P-value [Table 4] Open Field (Hypoactivity)-Motility Overview of ANOVA [Table 5] Sidak's multiple comparison test Summary P-value [Table 6]

[0153] Example 6b: Nest building For small rodents, nests are important for insulation, reproduction, and protection. Nest building is a necessary activity for mice to raise their young and is an indicator of social adaptation and daily living activities. Changes in nest building behavior, such as failure to build nests, usually indicate changes in health and welfare. Nest building behavior is sensitive to genetic mutations in many pathological disease states. Nest-building behavior was impaired in Magel2-null mice. Therefore, a series of studies were performed to determine whether cG-2-allele P could restore nest-building quality. The results are shown in Figure 4. The vertical axis shows nest-building quality on a scale of 1 to 5, and the horizontal axis shows the average value for each treatment group. Wild-type mice treated with vehicle showed a nest mass of approximately 5 (left panel). In contrast, mice treated with vehicle alone Magel2 -null mice (second row from the left) constructed significantly lower quality nests. All groups treated with 100 mg / kg and 200 mg / kg cG-2-allylP did not differ from the wild-type group. Magel2 It was shown that the abnormal nest architecture in null mice was normalized, while wild-type mice were unaffected. Nest building ANOVA = analysis of variance, ns = not significant, WT = wild-type littermate control; ****=p<0.00001. Overview of ANOVA [Table 7] Sidak's multiple comparison test Summary P-value [Table 8]

[0154] Example 6c: Social preferences and social interactions Individuals with Prader-Willi syndrome exhibited deficits in social behavior compared to individuals without Prader-Willi syndrome. Two tests were performed to evaluate the social behavior deficits in Magel2-null mice. The social preference split test measured preference for the object versus the familiar mouse. The test results are shown in Figure 5. Magel2 -Null mice treated with vehicle alone (left column 2) showed significantly greater preference for the subject than wild-type (WT) mice treated with vehicle alone (left column). All groups treated with 100 mg / kg or 200 mg / kg of cG-2-allylP did not differ from the wild-type group treated with vehicle; Magel2 They showed that this normalized the social behavioral deficits in null mice and had no effect on wild-type mice. social preferences ANOVA = analysis of variance, ns = not significant, WT = wild-type littermate control; ****=p<0.0001 Overview of ANOVA [Table 9] Sidak's multiple comparison test Summary P-value [Table 10] The social interaction sniffing test measured the number of sniffing events. The test results are shown in Figure 6. Magel2 -Null mice treated with vehicle alone (left column 2) showed significantly fewer sniffing events than wild-type (WT) mice treated with vehicle alone (left column). All groups treated with cG-2-allylP at 100 mg / kg or 200 mg / kg were no different from the wild-type group treated with vehicle; Magel2 They showed that this normalized the social behavioral deficits in null mice and had no effect on wild-type mice. social interaction ANOVA = analysis of variance, ns = not significant, WT = wild-type littermate control; ****=p<0.0001 Overview of ANOVA [Table 11] Sidak's multiple comparison test Summary P-value [Table 12]

[0155] Example 6d: Novel Object Search (NOR) The NOR test was used to evaluate cognitive abilities and is based on the tendency of mice to spend more time exploring novel objects than familiar objects. Magel2-null mice showed a deficit in the ability to discriminate between familiar and novel objects. The results of the NOR test are shown in Figure 7. Magel2-null mice treated with vehicle only (left column 2) spent significantly less time with the novel opponent compared to wild-type (WT) mice treated with vehicle only (left column). All groups treated with 100 mg / kg or 200 mg / kg cG-2-allylP did not differ from the vehicle-treated WT group, indicating that 100 mg / kg or 200 mg / kg normalized this cognitive deficit in Magel2-null mice and had no effect on WT mice. Novel Object Exploration ANOVA = analysis of variance, ns = not significant, WT = wild-type littermate control; ****=p<0.0001 Overview of ANOVA [Table 13] Sidak's multiple comparison test Summary P-value [Table 14]

[0156] Example 6e: Elevated Plus Maze The elevated plus maze test is used to evaluate anxiety-related behavior. Normal mice showed a preference to close their arms tightly rather than open them. The open arm time of each group is shown in Figure 8. Magel2 Null mice (left column 2, Figure 8) showed significantly more open arm time than wild-type (WT) mice treated with vehicle only (left column). All groups treated with 100 mg / kg or 200 mg / kg of cG-2-allylP were no different from the vehicle-treated wild-type group; Magel2 We showed that it normalized these defects in null mice and was unaffected in wild-type mice. Elevated Plus Maze (Open Arm Time) ANOVA = analysis of variance, ns = not significant, WT = wild-type littermate control; ****=p<0.0001 Overview of ANOVA [Table 15] Sidak's multiple comparison test Summary P-value [Table 16]

[0157] Example 6f: Efficacy of cG-2-AllylP in treating obesity and hormonal abnormalities in Magel2-null mice Prader-Willi syndrome is associated with metabolic and hormonal abnormalities in humans. Magel2-null mice recapitulate some of the metabolic and hormonal aspects of patients with Prader-Willi syndrome. Experiments were performed to determine whether cG-2-allylP has metabolic and hormonal normalizing effects. Male Magel2-null mice showed similar weight gain curves compared to littermate wild-type controls from 6 to 18 weeks of age, whereas female Magel2-null mice showed significant weight gain over time. In this study, female Magel2-null mice were used because they showed significant weight gain compared to littermate wild-type controls. A. Effect of the cG-2 allele on fat mass in Magel2-null mice The mean fat mass for each treatment group was measured and is shown in FIG. Magel2 - Null mice treated with vehicle alone (left column 2) had significantly higher fat mass than wild-type mice treated with vehicle alone (left column). Magel2 -null mice were no different from WT mice, and this dose Magel2 It was shown to normalize fat mass in cG-2-null mice, but had no effect on WT mice treated with cG-2-AriP. Effect on fat mass ANOVA = analysis of variance, ns = not significant, WT = wild-type littermate control; ****=p<0.0001 Overview of ANOVA [Table 17] Sidak's multiple comparison test Summary P-value [Table 18] B. Effect of the cG-2-allele on insulin levels in Magel2-null mice Insulin was measured for each group. The results are shown in Table 3 below ([Table 19]). Magel2-null mice treated with vehicle alone showed significantly higher insulin levels than WT mice treated with vehicle alone. Magel2-null mice treated with cG-2-allylP (200 mg / kg) did not differ from the WT group, indicating that this dose normalizes insulin levels in Magel2-null mice. WT mice treated with cG-2-allylP had no effect. Table 3 [Table 19] ns = not significant, WT = wild-type littermate control

[0158] Example 6g: IGF-1 levels in Magel2-null mice Prader-Willi syndrome may be associated with altered human IGF-1 levels. Circulating IGF-1 levels in each group were measured as shown in Figure 10. Magel2-null mice treated with vehicle alone (left column 2) showed significantly lower circulating IGF-1 than wild-type mice treated with vehicle alone (left column). Magel2-null mice treated with cG-2-allylP (200 mg / kg) did not differ from the WT group, indicating that this dose normalizes circulating IGF-1 levels in Magel2-null mice. WT mice treated with cG-2-allylP had no effect. IGF-1 levels ANOVA = analysis of variance, ns = not significant, WT = wild-type littermate control; ****=p<0.0001 Overview of ANOVA [Table 20] Sidak's multiple comparison test Summary P-value [Table 21]

[0159] Example 7: Effects of Cyclo-L-glycyl-L-2-allylproline on people with Prader-Willi syndrome method Thirty Prader-Willi syndrome subjects were recruited for the proposed study. The subjects were females and males aged between 4 and 20 years (mean = 12.1 SD = 4.4). All subjects had confirmed loss of function in the 15q11-q13 region on the paternal copy of chromosome 15 and also met the diagnostic criteria for Prader-Willi syndrome based on the assessment of behavioral and somatic symptoms. The majority of subjects (72%) were receiving rhGH treatment at the time of screening. Subjects were instructed to ensure that their concomitant medications were stable for at least 6 weeks prior to the study. The study was a randomized, double-blind, placebo-controlled, parallel study in which subjects were randomized 1:1:1 to placebo and received 6 mg / kg or 12 mg / kg cyclo-L-glycyl-L-2-allylproline oral liquid twice daily for 84 days. Subjects completed the clinical trial questionnaire (HQ-CT), Clinical Global Severity Index (CGI-S), Caregiver Global Impression of Change (CaGI-I), Aberrant Behavior Checklist (ABC) and ABC subscales, Interpersonal Responsiveness Scale, Repetitive Behavior Scale-Revised (RBS-R), PWS Anxiety and Distress Questionnaire (PADQ), and Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) at baseline. Also completed body fat assessment (BFA), fasting glucose, blood lipids (HDL, LDL, VLDL, triglycerides), serum IGF-1 (total binding IGF-1 binding protein-3 [IGFBP-3]), fasting insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) at baseline. The effect of cyclo-L-glycyl-L-2-allylproline treatment was analyzed by repeated measures analysis of covariance (ANCOVA) of the change in baseline score for each measure plus the Clinical Global Impression of Change (CGI-I).Safety was assessed using caregiver reports of adverse events, a panel of standard laboratory tests, and electrocardiograms (ECGs). Suggestive results

[0160] There were no differences in the incidence of treatment-emergent adverse events between placebo and either dose, and no treatment-related abnormal patterns in clinical laboratory tests or electrocardiogram measurements. All adverse events were short in duration and mild in severity. No serious adverse events were reported. All subjects completed the study. The results of the efficacy analysis are as follows: -CGI-I measurements showed dose-dependent, statistically significant differences in improvement between the treatment and placebo groups. The Prader-Willi Distress Questionnaire (PADQ) showed dose-related and statistically significant differences from baseline between the treatment and placebo groups. The change from baseline in CY-BOCS was statistically significant between the active and placebo groups. For free IGF-1, the change from baseline between the treatment and placebo groups was dose-dependent and statistically significant. -There was a trend towards a decrease in fasting blood glucose and BFA between the active drug and placebo groups.

Claims

1. A composition for treating or preventing Prader-Willi syndrome, comprising a compound of formula I or a pharma- ceutically acceptable salt, hydrate, stereoisomer or prodrug thereof. 【Chemistry 1】 (In the formula, X １ is selected from the group consisting of NR′, O and S; X ２ is CH ２ , NR′, O and S; R １ , R ２ , R ３ , R ４ , and R ５ are independently hydrogen, halogen, -OR', -SR', -NR'R', -NO ２ , -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', alkyl, heteroalkyl, alkenyl, alkynyl, 3- to 10-membered carbocycle, and 3- to 10-membered heterocycle; wherein alkyl, heteroalkyl, alkenyl, alkynyl, 3- to 10-membered carbocyclic ring and 3- to 10-membered heterocyclic ring are each unsubstituted or halogen, -OR', -SR', -NR'R', -NO ２ , -CN, -C(O)R', -C(O)OR', -C(O)NR'R', -C(NR')NR'R', alkyl, heteroalkyl, alkenyl, and alkynyl; wherein each R' is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, a 3- to 10-membered carbocycle, and a 3- to 10-membered heterocycle; Or R ４ and R ５ Together, -CH ２ - (CH ２ ) ｎ -CH ２ -, n is an integer from 0 to 6, Or R ２ and R ３ Together, -CH ２ - (CH ２ ) ｎ -CH ２ -, n is an integer from 0 to 6, However, R １ CH ３ and R ２ is hydrogen, R ３ is hydrogen, R ４ is hydrogen, R ５ is not benzyl, but R １ is hydrogen, R ２ and R ３ At least one of them is not hydrogen.)

2. The R １ is hydrogen, -CH ３ and -CH ２ CHCH ２ The composition for treating or preventing Prader-Willi syndrome according to claim 1, selected from the group consisting of:

3. The R ２ is hydrogen and -CH ３ The composition for treating or preventing Prader-Willi syndrome according to claim 1 or 2, selected from the group consisting of:

4. The R ３ is hydrogen and -CH ３ The composition for treating or preventing Prader-Willi syndrome according to any one of claims 1 to 3, selected from the group consisting of:

5. The X １ The composition for treating or preventing Prader-Willi syndrome according to any one of claims 1 to 4, wherein

6. The X ２ is CH ２ The composition for treating or preventing Prader-Willi syndrome according to any one of claims 1 to 5, wherein the composition is selected from the group consisting of S.

7. The R ４ and R ５ are each hydrogen or together are -CH ２ - (CH ２ ) ３ -CH ２ - and -CH ２ - (CH ２ ) ２ -CH ２ The composition for treating or preventing Prader-Willi syndrome according to any one of claims 1 to 6, wherein the composition is selected from the group consisting of:

8. The composition for treating or preventing Prader-Willi syndrome according to any one of claims 1 to 7, wherein the compound of formula I is selected from the group consisting of: 【Chemistry 2】 【Chemistry 3】 【Chemistry 4】

9. The composition for treating or preventing Prader-Willi syndrome according to any one of claims 1 to 8, wherein the compound of formula I is: 【Chemistry 5】

10. A composition for treating or preventing Prader-Willi syndrome according to any one of claims 1 to 9, which prevents or reduces the likelihood or severity of one or more symptoms of Prader-Willi syndrome.

11. The composition for treating or preventing Prader-Willi syndrome according to any one of claims 1 to 10, wherein the Prader-Willi syndrome is evaluated using one or more clinical tests selected from the group consisting of genetic testing, IGF-1 in serum, total IGF-1, free IGF-1, IGF-1 (bound to IGFBPs), IGF-1 in cerebrospinal fluid (CSF), total IGF-1, free IGF-1, IGFBPs in serum, IGFBP-1, -2, -3, -4, -5, -6 in serum, IGFBPs, IGFBP-1, -2, -3, -4, -5, -6 in CSF, blood glucose level, blood lipids (HDL, LDL, VLDL, triglycerides), homeostasis model assessment of insulin resistance (HOMA-IR), body mass index (BMI), and body fat assessment (BFA).

12. The composition for treating or preventing Prader-Willi syndrome according to claim 10 or 11, wherein the severity of the symptoms is evaluated using one or more clinical tests selected from the group consisting of the Binge Eating Questionnaire (HQ-CT), Clinical Global Severity Index (CGI-S), Clinical Global Impression of Change (CGI-I), Caregiver Global Impression of Change (CaGI-I), Aberrant Behavior Checklist (ABC) and ABC subscales, Interpersonal Responsiveness Scale, Repetitive Behavior Scale-Revised (RBS-R), PWS Anxiety and Distress Questionnaire (PADQ), gut microbiota composition (16S or other sequencing method), Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS), and Montefiore-Einstein Rigidity Scale-Revised PWS (MERS-R-PWS).

13. The composition for treating or preventing Prader-Willi syndrome according to any one of claims 10 to 12, wherein the symptoms or findings associated with Prader-Willi syndrome are selected from the group consisting of early growth deficiency, excessive appetite (bulimia), obesity, type 2 diabetes, elevated blood insulin, metabolic syndrome, multiple endocrine disorders, hypotonia, hypogonadism, sleep disorders, sleep apnea, speech disorders, decreased pain sensitivity, impaired bone health, strabismus, hypopigmentation, gastrointestinal hypomotility, scoliosis, adrenal insufficiency, seizures, hypothyroidism, hypoglycemia, hypogonadotropic syndrome, characteristic facial features, mild to moderate intellectual disability and learning disabilities, cognitive impairment, neurobehavioral disorders, intellectual disability, cognitive rigidity, increased anxiety, severe tantrums, obsessive-compulsive behavior, self-injury, psychiatric disorders, symptoms of autism, and growth hormone deficiency (GHD).

14. A composition for treating or preventing Prader-Willi syndrome described in any one of claims 1 to 13, administered in combination with a further therapeutic agent.

15. The additional therapeutic agent may be recombinant human growth hormone (rhGH), human growth hormone, recombinant human IGF-1 (rhIGF-1), IGF-1, IGF-2, any IGF binding protein (IGFBP), IGFBP-3, insulin, any statin, any appetite suppressant, transforming growth factor-β1, activin, nerve growth factor, growth hormone binding protein, basic fibroblast growth factor, acidic fibroblast growth factor, hst / Kf gk gene product, FGF-3, FGF-4, FGF-6, keratinocyte growth factor and rhinogen-induced growth factor, int-2, fibroblast growth factor homologous factor-1 (FHF-1), FHF-2, FHF-3, FHF-4, keratinocyte growth factor 2, glial activating factor, FGF-10, FGF-16, ciliary neurotrophic factor, brain-derived nerve growth factor, neurotrophin 3, neurotrophin 4, bone morphogenetic protein 2 (BMP-2), glial cell Cell line-derived neurotrophic factor, activity-dependent neurotrophic factor, cytokine leukemia inhibitory factor, oncostatin M, interleukin, a-interferon, beta-interferon, gamma-interferon, consensus interferon, TNF-a, clomethiazole; kynurenic acid, Semax, tacrolimus, L-threo-1-phenyl-2-decanoylamino-3,3-morpholino-1-propanol, corticotropin-(4-9) analog (4 15. The composition for treating or preventing Prader-Willi syndrome according to claim 14, wherein the compound is selected from the group consisting of 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX), LY303070, LY300164, and anti-MAdCAM-1 antibody MECA-367.

16. The composition for treating or preventing Prader-Willi syndrome according to claim 15, wherein the additional therapeutic agent is recombinant human growth hormone (rhGH).

17. A composition for treating or preventing Prader-Willi syndrome described in any one of claims 1 to 16, which is administered orally.

18. The composition for treating or preventing Prader-Willi syndrome according to any one of claims 1 to 17, wherein the compound of formula I is administered at a dose of about 0.001 mg / kg to about 600 mg / kg.

19. A composition for treating or preventing Prader-Willi syndrome described in any one of claims 1 to 18, which is used in mammals.

20. The composition for treating or preventing Prader-Willi syndrome according to any one of claims 1 to 19, which is used for humans.

21. A composition for treating or preventing Prader-Willi syndrome described in any one of claims 1 to 20, further comprising a pharma-ceutically acceptable excipient.

22. 22. The composition for treating or preventing Prader-Willi syndrome according to claim 21, wherein the pharma- ceutically acceptable excipient is selected from the group consisting of binders, carriers, additives, adjuvants, microemulsions, coarse emulsions, and liquid crystals.

23. A composition for treating or preventing Prader-Willi syndrome as described in claim 21 or 22, formulated as an oral solution, oral suspension, or a powder for preparing an oral solution or oral suspension.

24. 23. The composition for treating or preventing Prader-Willi syndrome according to claim 21 or 22, formulated as a tablet or capsule.

25. A composition for treating or preventing Prader-Willi syndrome described in any one of claims 1 to 24, wherein the compound is cG-2-allylP (formula II), cyclic cyclopentyl-G-2-MeP (formula III), or cyclic cyclohexyl-G-2-MeP (formula IV).

26. A composition for treating or preventing Prader-Willi syndrome as described in claim 25, wherein the compound is formulated in an aqueous solution.

27. ​​A composition for treating or preventing Prader-Willi syndrome described in any one of claims 1 to 24, wherein the dose of the compound is about 0.01 mg / kg body weight (mg / kg) to about 1000 mg / kg, about 0.1 mg / kg to about 500 mg / kg, about 0.1 mg / kg to about 200 mg / kg, about 0.01, 0.1, 1, 10, 20, 50, 75, 100, 500, 1000, or 5000 mg / kg.

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