Cyclic peptide tyrosine-tyrosine compound as modulation factor of nerve peptide y receptor

Abstract

To provide peptide tyrosine-tyrosine (PYY) analogs or derivatives thereof having improved metabolic stability and pharmacokinetic profiles.SOLUTION: A compound of the following formula I is provided. The invention also relates to pharmaceutical compositions and use methods thereof. The novel compounds are useful, in particular, for preventing, treating or ameliorating diseases and disorders including obesity, Type 2 diabetes, metabolic syndrome, insulin resistance, and dyslipidemia.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention generally relates to novel cyclic peptide tyrosine tyrosine (PYY) compounds that are regulators of the neuropeptide Y2 receptor. The present invention also relates to pharmaceutical compositions and methods of using the same. The novel compounds are useful, inter alia, for preventing, treating, or alleviating diseases and disorders such as obesity, type 2 diabetes, metabolic syndrome, insulin resistance, and dyslipidemia.

[0002] (Cross - Reference to Related Applications) This application claims priority based on U.S. Provisional Patent Application No. 62 / 413,613, filed on October 27, 2016, and U.S. Provisional Patent Application No. 62 / 413,586, filed on October 27, 2016. Each disclosure is incorporated herein by reference in its entirety.

[0003] (Reference to Electronically Submitted Sequence Listing) This application includes a sequence listing that was electronically submitted via EFS - Web as an ASCII - formatted sequence listing with the file name "PRD3411 Sequence Listing" and a creation date of October 23, 2017, having a size of 96 kb. The sequence listing submitted via EFS - Web is part of this specification and is incorporated herein by reference in its entirety. If there is any inconsistency in the structures of SEQ ID NOs: 1 - 111 between the information described in this specification and the sequence listing submitted electronically via EFS - Web with the file name "PRD3411 Sequence Listing", the information in this specification shall prevail.

Background Art

[0004] ​​​​​​​​​​​​​Neuropeptide Y (NPY) receptors are activated by a closely related group of peptide agonists called the "NPY family", which have different affinities for each receptor subtype. NPY, peptide tyrosine-tyrosine (PYY), and pancreatic polypeptide (PP), all 36 amino acids in length, are agonists of the NPY receptor family. NPY is a neurotransmitter that is synthesized, co-stored, and released together with norepinephrine and epinephrine. NPY is one of the most abundant and widely distributed peptides in the central nervous system (CNS) of humans and rodents, and is expressed in brain regions associated with feeding and stress. In the peripheral nervous system, NPY-containing neurons are mainly sympathetic. PYY is mainly synthesized and released by enteroendocrine cells. Cleavage of NPY and PYY by endopeptidase, dipeptidyl peptidase IV (DPP-IV), generates NPY and PYY, which are selective ligands for the Y2 and Y5 subtypes of the NPY receptor family. PP is found in pancreatic islet cells that are different from those that mainly store insulin, glucagon, or somatostatin. Five different NPY receptors have been identified to date, and four of them are understood to be relevant to human physiology. Receptors Y1, Y2, and Y5 preferentially bind NPY and PYY, while the Y4 receptor preferentially binds PP. The Y2 and Y5 receptors are also strongly activated by NPY3-36 and PYY3-36. In general, ligands of the NPY family have variable selectivity for each NPY receptor isoform. 3~36 3~36

[0005] ​​​​​​​​, PYY3-36 has been previously reported to have moderate to stable selectivity for the Y2 isoform. Each of these receptors is linked to the inhibition of adenylate cyclase via pertussis toxin-sensitive Gαi.

[0006] PYY is secreted from endocrine L-cells in response to food, especially after fat intake. 1~36 3~36 3~36 3~36 ​​​​​​​​​​​​​​​​​​​The acute effects on feeding are also shown to translate into dose-dependent effects on body weight in ob / ob mice, DIO mice, and Zucker fa / fa mice (Pittner RA et al. Int J Obes relat Metab Disord 2004 Aug;28(8):963 - 71). In addition, PYY 3~36 has also been shown to improve insulin-mediated glucose disposal and insulin sensitivity in rodents (Vrang N et al., Am J Physiol Regul Integr Comp Physiol Aug;291(2):R367 - 75) . Bariatric surgery results in an increase in circulating PYY immunoreactivity (le Roux CW e t al., Ann Surg 2006 Jan;243(1);108 - 14), and appears to play a role in postoperative weight loss . Considering its role in the control of appetite and food intake, and its anti-secretory and absorption-promoting effects in the mammalian gastrointestinal tract, PYY may be effective in the treatment of obesity and related conditions, as well as many gastrointestinal disorders. However, the therapeutic utility of PYY

[0007] itself is limited by its rapid metabolism and resulting short circulating half-life (Torang et al., Am.J.Physiol.Regul.Integ r.Comp.Physiol. 310:R866 - R874(2016)). 3~36 Therefore, it is desirable to obtain PYY analogs or derivatives thereof with improved metabolic stability and pharmacokinetic profiles for PYY3 - 36. The slow in vivo half-life 3~36 of itself limits its therapeutic potential. (Torang et al., Am.J.Physiol.Regul.Integ r.Comp.Physiol. 310:R866 - R874(2016)).

[0008] Thus, it is desirable to obtain PYY analogs or derivatives thereof with improved metabolic stability and pharmacokinetic profiles for PYY3 - 36. The slow in vivo half-life ​​ Such derivatives having ductility provide regulation of the Y2 receptor with a longer duration of action and would be suitable as therapeutic agents for subjects in need of such regulation.

[0009] The foregoing discussion is presented merely to provide a better understanding of the nature of the problems faced in the art and should not be construed as an admission of prior art, nor should the citation of any references herein be construed as an admission that such references constitute "prior art" of this application. SUMMARY OF THE INVENTION MEANS FOR SOLVING THE PROBLEM

[0010] A general aspect of the present invention is formula I:

[0011]

Chemical formula

[0012]

Chemical formula

[0013]

Chemical formula

[0014] The present invention also provides a method for preventing, treating, delaying the onset of, or alleviating a syndrome, disorder, or disease, or one or more symptoms of any of the foregoing syndrome, disorder, or disease, wherein the syndrome, disorder, or disease is selected from the group consisting of obesity, type 2 diabetes, metabolic syndrome (i.e., syndrome X), insulin resistance, impaired glucose tolerance (e.g., glucose tolerance), hyperglycemia, hyperinsulinemia, hypertriglyceridemia, dyslipidemia, atherosclerosis arteriosclerosis, diabetic nephropathy, and other cardiovascular risk factors such as hypertension and cardiovascular risk factors associated with unregulated cholesterol and / or lipid levels, osteoporosis, inflammation and eczema, and is effective for a subject in need thereof. a compound of formula I, a derivative thereof, or a pharmaceutically acceptable salt, or a form thereof, a composition administering any of the foregoing, or a drug, or a combination described herein

[0015] The present invention also contemplates preventing, treating, delaying the onset of, or remitting any of the diseases, disorders, syndromes, or symptoms described herein using combination therapy The combination therapy comprises administering to a subject in need thereof an effective amount of a compound of formula I, a derivative thereof, or a pharmaceutically acceptable salt, or a form thereof, a composition, or a drug, in combination with one or more of the following additional compounds: dipeptidyl peptidase -4 (DPP-4) inhibitors (e.g., sitagliptin, saxagliptin, linagliptin, alogliptin, etc.); GLP-1 receptor agonists (e.g., exenatide and liraglutide, etc. short-acting GLP-1 receptor agonists; intermediate-acting GLP-1 receptor agonists (e.g., liraglutide; long-acting GLP-1 receptor agonists such as extended-release exenatide, albiglutide, dulaglutide, etc.); sodium-glucose cotransporter-2 (SGLT-2) inhibitors (e.g., canagliflozin, dapagliflozin, empagliflozin, etc.); bile acid sequestrants (e.g., cholestyramine, etc.); and dopamine receptor agonists (e.g., bromocriptine immediate release). In some embodiments the dosage of the additional compound is reduced when administered in combination with a compound of formula I, a derivative thereof, or a pharmaceutically acceptable salt. In some embodiments, when used in combination with a compound of formula I the additional compound may be used at a lower dosage than when each is used alone receptor agonists (e.g., liraglutide; long-acting GLP-1 receptor agonists such as extended-release exenatide, albiglutide, dulaglutide, etc.); sodium-glucose cotransporter-2 (SGLT-2) inhibitors (e.g., canagliflozin, dapagliflozin, empagliflozin, etc.); bile acid sequestrants (e.g., cholestyramine, etc.); and dopamine receptor agonists (e.g., bromocriptine immediate release). In some embodiments the dosage of the additional compound is reduced when administered in combination with a compound of formula I, a derivative thereof, or a pharmaceutically acceptable salt. In some embodiments, when used in combination with a compound of formula I the additional compound may be used at a lower dosage than when each is used alone the dosage of the additional compound is reduced when administered in combination with a compound of formula I, a derivative thereof, or a pharmaceutically acceptable salt. In some embodiments, when used in combination with a compound of formula I the additional compound may be used at a lower dosage than when each is used alone the additional compound may be used at a lower dosage than when each is used alone when used in combination with a compound of formula I

[0016] The present invention contemplates preventing, treating, delaying the onset of, or remitting any of the diseases, disorders, syndromes, or symptoms described herein using combination therapy, and the combination therapy comprises administering to a subject in need thereof an effective amount of a compound of formula I, a derivative thereof, or a pharmaceutically acceptable salt, or a form, composition, or agent thereof, in combination with one or more of the following additional compounds: biguanide (e.g., metformin, etc.); insulin; oxyntomodulin; sulfonylurea (e.g., chlorpropamide, glimepiride, glipizide, glibide, glibenclamide, glibornuride, glysocamide, glyclopyramide, tolazamide, tolbutamide, acetohexamide, carbutamide, etc.); and thiazolidinedione (e.g., pioglitazone, rosiglitazone, lobeglitazone, ciglitazone, darglitazone, englitazone, netoglitazone, rivoglitazone, troglitazone, etc.). In some embodiments, when used in combination with a compound of formula I, a derivative thereof, or a pharmaceutically acceptable salt, the additional compound may be used at a lower dose than when each is used alone.

[0017] In still other embodiments, the present invention contemplates preventing, treating, delaying the onset of, or remitting any of the diseases, disorders, syndromes, or symptoms described herein using combination therapy, and the combination therapy comprises administering to a subject in need thereof an effective amount of a compound of formula I, a derivative thereof, or a pharmaceutically acceptable salt, or a form, composition, or agent thereof, in combination with bariatric surgery (e.g., gastric bypass surgery such as Roux-en-Y gastric bypass surgery; sleeve gastrectomy ​​​​​​​​​​​​​​​​ Resection; adjustable gastric banding; biliopancreatic diversion with duodenal switch; intragastric balloon; gastric plication, and combinations thereof) and the like in combination with surgical therapies.

[0018] Further aspects, features, and advantages of the present invention will be better understood by reading the following "Detailed Description of the Invention" and the " Claims".

[0019] In the background of the invention and throughout the specification, various publications, papers, and patents are cited or described. Each of these references is hereby incorporated by reference in its entirety into this specification. Considerations of documents, operations, materials, devices, articles, etc. included in this specification are for the purpose of providing the background of the present invention. Such considerations do not admit that any or all of these things

[0020] constitute a part of the prior art with respect to any of the inventions disclosed or claimed herein. Unless otherwise specified, all technical and scientific terms used in this specification

[0021] shall have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention pertains. If not, the specific terms used in this specification shall have the meanings set forth herein.

[0022] Unless otherwise specified, any numerical values such as concentrations or concentration ranges described in this specification shall be understood to be modified by the term "about" in all such cases. Therefore, numerical values generally include ±10% of the recited value. For example, a concentration of 1 mg / mL includes 0.9 mg / mL to 1.1 mg / mL. Similarly, a concentration range of 1% to 10% (w / v) includes 0.9% (w / v) to 11% (w / v). When used in this specification, the use of a numerical range, unless the context clearly indicates otherwise, expressly includes all possible sub-ranges, all individual numerical values within that range, including integers and fractions of values within that range.

[0023] Unless otherwise stated, the term "at least" preceding a series of elements should be understood to refer to all of those elements of the series. Those skilled in the art will recognize, or be able to confirm, many equivalents to the specific embodiments described herein using only routine experimentation. Such equivalents are intended to be encompassed by the present invention.

[0024] As used herein, the terms "comprises", "comprising", " includes", "including", "has", "having" ", "contains", or "containing", or any other variant thereof, are understood to include the recited integer or group of integers but not to imply the exclusion of any other integer or group of integers, and are intended to be inclusive or unrestricted. For example, a composition, mixture, process, method, article, or apparatus that includes a series of elements necessarily It is not necessarily limited to only those elements, and may include other elements that are not explicitly enumerated or that are not inherently present in such compositions, mixtures, processes, methods, articles, or apparatuses. Further, unless explicitly stated otherwise, "or" refers to an inclusive or and not an exclusive or. For example, the condition A or B is satisfied by any one of the following: when A is true (or present) and B is false (or absent), when A is false (or absent) and B is true (or present), and when both A and B are true (or present). It may include other elements that are not explicitly enumerated or that are not inherently present in such compositions, mixtures, processes, methods, articles, or apparatuses. Further, unless explicitly stated otherwise, "or" refers to an inclusive or and not an exclusive or. For example, the condition A or B is satisfied by any one of the following: when A is true (or present) and B is false (or absent), when A is false (or absent) and B is true (or present), and when both A and B are true (or present). It may include other elements that are not explicitly enumerated or that are not inherently present in such compositions, mixtures, processes, methods, articles, or apparatuses. Further, unless explicitly stated otherwise, "or" refers to an inclusive or and not an exclusive or. For example, the condition A or B is satisfied by any one of the following: when A is true (or present) and B is false (or absent), when A is false (or absent) and B is true (or present), and when both A and B are true (or present). It may include other elements that are not explicitly enumerated or that are not inherently present in such compositions, mixtures, processes, methods, articles, or apparatuses. Further, unless explicitly stated otherwise, "or" refers to an inclusive or and not an exclusive or. For example, the condition A or B is satisfied by any one of the following: when A is true (or present) and B is false (or absent), when A is false (or absent) and B is true (or present), and when both A and B are true (or present). It may include other elements that are not explicitly enumerated or that are not inherently present in such compositions, mixtures, processes, methods, articles, or apparatuses. Further, unless explicitly stated otherwise, "or" refers to an inclusive or and not an exclusive or. For example, the condition A or B is satisfied by any one of the following: when A is true (or present) and B is false (or absent), when A is false (or absent) and B is true (or present), and when both A and B are true (or present). It may include other elements that are not explicitly enumerated or that are not inherently present in such compositions, mixtures, processes, methods, articles, or apparatuses. Further, unless explicitly stated otherwise, "or" refers to an inclusive or and not an exclusive or. For example, the condition A or B is satisfied by any one of the following: when A is true (or present) and B is false (or absent), when A is false (or absent) and B is true (or present), and when both A and B are true (or present). It may include other elements that are not explicitly enumerated or that are not inherently present in such compositions, mixtures, processes, methods, articles, or apparatuses. Further, unless explicitly stated otherwise, "or" refers to an inclusive or and not an exclusive or. For example, the condition A or B is satisfied by any one of the following: when A is true (or present) and B is false (or absent), when A is false (or absent) and B is true (or present), and when both A and B are true (or present).

[0025] The terms "about," "approximately," "substantially," etc., when used herein to refer to dimensions or characteristics of components of a preferred invention, are understood by those skilled in the art to indicate that the recited dimensions / characteristics are not strict boundaries or parameters and that slight variations therefrom that are functionally the same or similar are not excluded. At a minimum, such references that include numerical parameters will include variations that, using the mathematical and industrial principles accepted in the art (e.g., rounding, measurement, or other systematic errors, manufacturing tolerances, etc.), will not change the least significant digit. The terms "about," "approximately," "substantially," etc., when used herein to refer to dimensions or characteristics of components of a preferred invention, are understood by those skilled in the art to indicate that the recited dimensions / characteristics are not strict boundaries or parameters and that slight variations therefrom that are functionally the same or similar are not excluded. At a minimum, such references that include numerical parameters will include variations that, using the mathematical and industrial principles accepted in the art (e.g., rounding, measurement, or other systematic errors, manufacturing tolerances, etc.), will not change the least significant digit. The terms "about," "approximately," "substantially," etc., when used herein to refer to dimensions or characteristics of components of a preferred invention, are understood by those skilled in the art to indicate that the recited dimensions / characteristics are not strict boundaries or parameters and that slight variations therefrom that are functionally the same or similar are not excluded. At a minimum, such references that include numerical parameters will include variations that, using the mathematical and industrial principles accepted in the art (e.g., rounding, measurement, or other systematic errors, manufacturing tolerances, etc.), will not change the least significant digit. The terms "about," "approximately," "substantially," etc., when used herein to refer to dimensions or characteristics of components of a preferred invention, are understood by those skilled in the art to indicate that the recited dimensions / characteristics are not strict boundaries or parameters and that slight variations therefrom that are functionally the same or similar are not excluded. At a minimum, such references that include numerical parameters will include variations that, using the mathematical and industrial principles accepted in the art (e.g., rounding, measurement, or other systematic errors, manufacturing tolerances, etc.), will not change the least significant digit. The terms "about," "approximately," "substantially," etc., when used herein to refer to dimensions or characteristics of components of a preferred invention, are understood by those skilled in the art to indicate that the recited dimensions / characteristics are not strict boundaries or parameters and that slight variations therefrom that are functionally the same or similar are not excluded. At a minimum, such references that include numerical parameters will include variations that, using the mathematical and industrial principles accepted in the art (e.g., rounding, measurement, or other systematic errors, manufacturing tolerances, etc.), will not change the least significant digit. The terms "about," "approximately," "substantially," etc., when used herein to refer to dimensions or characteristics of components of a preferred invention, are understood by those skilled in the art to indicate that the recited dimensions / characteristics are not strict boundaries or parameters and that slight variations therefrom that are functionally the same or similar are not excluded. At a minimum, such references that include numerical parameters will include variations that, using the mathematical and industrial principles accepted in the art (e.g., rounding, measurement, or other systematic errors, manufacturing tolerances, etc.), will not change the least significant digit. The terms "about," "approximately," "substantially," etc., when used herein to refer to dimensions or characteristics of components of a preferred invention, are understood by those skilled in the art to indicate that the recited dimensions / characteristics are not strict boundaries or parameters and that slight variations therefrom that are functionally the same or similar are not excluded. At a minimum, such references that include numerical parameters will include variations that, using the mathematical and industrial principles accepted in the art (e.g., rounding, measurement, or other systematic errors, manufacturing tolerances, etc.), will not change the least significant digit.

[0026] The term "identical" or "identity" percent, when in relation to two or more nucleic acid or polypeptide sequences (e.g., cyclic PYY polypeptide sequence), is compared for maximum match using one of the following sequence comparison algorithms or by visual inspection using methods known in the art in view of the present disclosure, and aligned The term "identical" or "identity" percent, when in relation to two or more nucleic acid or polypeptide sequences (e.g., cyclic PYY polypeptide sequence), is compared for maximum match using one of the following sequence comparison algorithms or by visual inspection using methods known in the art in view of the present disclosure, and aligned 3~36 The term "identical" or "identity" percent, when in relation to two or more nucleic acid or polypeptide sequences (e.g., cyclic PYY polypeptide sequence), is compared for maximum match using one of the following sequence comparison algorithms or by visual inspection using methods known in the art in view of the present disclosure, and aligned The term "identical" or "identity" percent, when in relation to two or more nucleic acid or polypeptide sequences (e.g., cyclic PYY polypeptide sequence), is compared for maximum match using one of the following sequence comparison algorithms or by visual inspection using methods known in the art in view of the present disclosure, and aligned The term "identical" or "identity" percent, when in relation to two or more nucleic acid or polypeptide sequences (e.g., cyclic PYY polypeptide sequence), is compared for maximum match using one of the following sequence comparison algorithms or by visual inspection using methods known in the art in view of the present disclosure, and aligned When present, it refers to two or more sequences or subsequences that are identical or have a specified percentage of identical amino acid residues or nucleotides. For sequence comparison, typically, one sequence functions as a reference sequence to which the test sequence is compared.

[0027] When using a sequence comparison algorithm, the test and reference sequences are input into a computer, and if necessary, subsequence coordinates are specified and sequence algorithm program parameters are specified. Then, the sequence comparison algorithm calculates the percentage of sequence identity of the test sequence(s) to the reference sequence based on the specified program parameters.

[0028] The optimal alignment of sequences for comparison can be, for example, the local homology algorithm of Smith & Waterman, Adv. Appl. Math. 2:482 (1981), the homology alignment algorithm of Needleman & Wunsch, J. Mol. Biol. 48:443 (1970), the similarity search method of Pearson & Lipman, Proc. Nat’l Acad. Sci. USA 85:2444 (1988), computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, WI), or visual inspection (generally, Current Protocols in Molecular Biology, F.M. Ausubel et al., eds., Current Protocols, a joint venture). ​​​​​​​​​​​​​re between Greene Publishing Associates, Inc. and John Wiley & Sons, Inc., (1995 Suppl ement)(see Ausubel) can be performed by.

[0029] Examples of algorithms suitable for determining percent sequence identity and sequence similarity are, respectively, Altschul et al. (1990) J. Mol. Biol. 215: 403-410 and Altschul et al. (1997) Nucleic Acids Res. 25: 33 89-3402, the BLAST and BLAST 2.0 algorithms described therein. Software for performing BLAST analysis is publicly available through the National C enter for Biotechnology Information.

[0030] A further indication that two nucleic acid sequences or polypeptides are substantially identical is that, as described below, the polypeptide encoded by the first nucleic acid is immunologically cross-reactive with the polypeptide encoded by the second nucleic acid. Thus, a polypeptide is typically substantially identical to a second polypeptide, for example, when the two polypeptides differ only by conservative substitutions. Another indication that two nucleic acid sequences are substantially identical is that, as described below, the two molecules hybridize to each other under stringent conditions. the polypeptide encoded by the first nucleic acid is immunologically cross-reactive with the polypeptide encoded by the second nucleic acid. Thus, a polypeptide is typically substantially identical to a second polypeptide, for example, when the two polypeptides differ only by conservative substitutions. Another indication that two nucleic acid sequences are substantially identical is that, as described below, the two molecules hybridize to each other under stringent conditions. the polypeptide encoded by the first nucleic acid is immunologically cross-reactive with the polypeptide encoded by the second nucleic acid. Thus, a polypeptide is typically substantially identical to a second polypeptide, for example, when the two polypeptides differ only by conservative substitutions. Another indication that two nucleic acid sequences are substantially identical is that, as described below, the two molecules hybridize to each other under stringent conditions. the polypeptide encoded by the first nucleic acid is immunologically cross-reactive with the polypeptide encoded by the second nucleic acid. Thus, a polypeptide is typically substantially identical to a second polypeptide, for example, when the two polypeptides differ only by conservative substitutions. Another indication that two nucleic acid sequences are substantially identical is that, as described below, the two molecules hybridize to each other under stringent conditions. Another indication that two nucleic acid sequences are substantially identical is that, as described below, the two molecules hybridize to each other under stringent conditions. hybridize to each other.

[0031] As used herein, "subject" means any animal, preferably a mammal, most preferably a human. As used herein, the term "mammal" refers to any includes mammals. Examples of mammals include, but are not limited to, cows , horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans and the like, and more preferably humans.

[0032] As used herein, the term "administering" optionally refers to a method for prophylactically, therapeutically or palliatively preventing, treating or alleviating a syndrome, disorder or disease described herein by using a compound of the present invention, a pharmaceutically acceptable salt thereof, or a form, composition or agent thereof, which is optionally conjugated to a half-life extending moiety. Such methods include administering an effective amount of the above compound, compound form, composition or agent at different times during the course of treatment or simultaneously in a combined form. The methods of the present invention are understood to encompass all known therapeutic treatment regimens. The term "effective amount" means the amount of an active compound or pharmaceutical agent that elicits a biological or medical response (including preventing, treating or alleviating the syndrome, disorder or disease being treated, or the symptoms of the syndrome, disorder or disease being treated) in a tissue system, animal or human being sought by a researcher, veterinarian, physician or other clinician. As used herein, the term "composition" includes a product containing specific components in specific amounts, as well as any product resulting directly or indirectly from the combination of specific amounts of specific components. In a general aspect, the present invention relates to Formula I:

[0033]

[0034]

[0035]

[0036] ​​​​​​​​​​​​ [Chemical formula] (wherein, p is 0 or 1, m is 0, 1, 2, 3, 4, or 5, n is 1, 2, 3, or 4, q is 0 or 1, provided that q is 1 only when Z 30 is absent, as a condition, BRIDGE is -Ph-CH2-S-, -triazolyl-, -NHC(O)CH2S -, -SCH2C(O)NH-, (OCH2CH2)2NHC(O)CH2S, -NHC (O)-, or -CH2S-, Z4 is K, A, E, S, or R, Z7 is A or K, Z9 is G or K, Z 11 is D or K, Z 22 is A or K, Z 23 is S or K, Z 26 is A or H, Z 30 is L, W, absent, or K (provided that Z 30 is absent only when q is 1. ) Z 34 is

[0037] [Chemical formula] or a derivative thereof, and the derivative is amidation, glycosylation, carbamylation, sulfur Z 35 is

[0038] [Chemical formula] or a derivative thereof, and the derivative is amidation, glycosylation, carbamylation, sulfur modified by one or more processes including acidification, phosphorylation, cyclization, lipidation, or PEGylation.) a compound, or a pharmaceutically acceptable salt thereof. is included.

[0039] In one embodiment, the present invention relates to the compound according to claim 1 or a derivative thereof (this derivative is a compound of formula I modified by one or more processes including amidation, lipidation, or PEGylation.).) or a pharmaceutically acceptable salt thereof. is included.

[0040] In another embodiment, the present invention relates to a compound of formula I or a derivative thereof (wherein, p is 0 or 1, m is 0, 1, 2, 3, 4, or 5, n is 1, 2, 3, or 4, q is 0 or 1, provided that q is 1 only when Z 30 is absent as a condition, BRIDGE is -Ph-CH2-S-, -triazolyl-, -NHC(O)CH2S -, -SCH2C(O)NH-, -(OCH2CH2)2NHC(O)CH2S, -NHC(O)-, or -CH2S- and, Z4 is K, A, E, S, or R, Z7 is A or K, and the amino side chain of said K is optionally

[0041]

Chemical formula

[0042]

Chemical formula

[0043]

Chemical formula

[0044]

Chemical formula

[0045]

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[0046]

Chemical formula

[0047]

Chemical formula

[0048]

Chemical formula

[0049]

Chemical formula

[0050]

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[0051]

Chemical formula

[0052]

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[0053] ​In another embodiment, the present invention provides a compound of formula I or a derivative thereof, wherein p is 0 or 1, m is 0, 1, 2, 3, or 5, n is 1, 2, or 4, q is 0 or 1, provided that q is 1 only when Z 30 is absent, and BRIDGE is -Ph-CH2-S-, -triazolyl-, -NHC(O)CH2S -, -(OCH2CH2)2NHC(O)CH2S, -NHC(O)-, or -CH2S -, Z4 is K, A, E, S, or R, Z7 is A or K, and the amino side chain of said K is

[0054]

Chemical formula

[0055]

Chemical formula

[0056]

Chemical formula

[0057]

Chemical formula

[0058]

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[0059]

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[0060]

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[0061]

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[0062]

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[0063]

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[0064] In another embodiment, the present invention provides a compound of formula I or a derivative thereof, wherein, p is 0 or 1, m is 0, 1, 2, 3, or 5, n is 1, 2, or 4, q is 0 or 1, provided that q is 1 only when Z 30 is absent, and BRIDGE is -Ph-CH2-S-, -triazolyl-, -NHC(O)CH2S -, -(OCH2CH2)2NHC(O)CH2S, -NHC(O)-, or -CH2S -, Z4 is K, A, E, S, or R, Z7 is A or K, and the amino side chain of said K is

[0065]

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[0066]

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[0067]

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[0068]

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[0069]

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[0070]

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[0071]

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[0072]

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[0073]

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[0074]

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[0075] Another embodiment of the present invention is a method for the preparation of a nucleic acid sequence of SEQ ID NO: 1 to SEQ ID NO: 110, or a pharma- ceutically acceptable derivative thereof. The compound of formula I or a derivative thereof is selected from the group consisting of a salt thereof

[0076] Another embodiment of the present invention is a method for the preparation of a nucleic acid sequence of SEQ ID NO: 2 to SEQ ID NO: 72, or a pharma- ceutically acceptable derivative thereof. The compound of formula I or a derivative thereof is selected from the group consisting of a salt thereof.

[0077] Another general aspect of the invention is a compound of formula I, a derivative thereof, or a pharma- ceutically acceptable salt thereof. As used herein, the present invention relates to a conjugate comprising a salt, and a half-life extending moiety conjugated thereto. In this case, the term "conjugated" refers to a compound that is covalently attached to a half-life extending moiety, either directly or via a linker. In this disclosure, the term "compound" refers to a compound of the present invention that is bonded or covalently connected. In the context of a compound of formula I, a derivative thereof, or a pharma- ceutically acceptable salt thereof, The phrase "a conjugate comprising a half-life extending moiety and a half-life extending moiety conjugated thereto" is intended to mean "a conjugate comprising a half-life extending moiety and a half-life extending moiety conjugated thereto." The term "combined compound" is used interchangeably with the term "combined compound."

[0078] As used herein, the term "linker" refers to a compound of the invention that is capable of binding to a half-life extension agent. Refers to a chemical module that contains a covalent bond or chain of atoms that connects a moiety to a phosphorus moiety through a covalent bond. Examples of the linker include a peptide linker, a hydrocarbon linker, and a polyethylene glycol linker. (PEG) linker, polypropylene glycol (PPG) linker, polysaccharide linker, A polyester linker, a hybrid linker consisting of PEG and an embedded heterocycle, and a hydrocarbon chain. is first covalently attached to a compound of the invention and then covalently attached to a half-life extending moiety. can be more connected.

[0079] As used herein, "half-life extension moiety" is used interchangeably with the term "half-life extending moiety". Exemplary half-life extension moieties include monoclonal antibodies or fragments thereof, albumin, al bumin variants, albumin-binding proteins and / or domains, transferrin, and fragments and analogs thereof, but are not limited thereto. For desired properties , additional half-life extension moieties that can be incorporated into the complexes of the present invention include, for example, PE G5000 or polyethylene glycol (PEG) molecules such as PEG20,000, α- tocopherolyl, fatty acids, and fatty acid esters of different chain lengths, such as laurate, my ristate, stearate, arachidate, behenate, oleate, arachidonate, octanedioic acid, tetradecanedioic acid, octadecanedioic acid, docosanedioic acid, etc., poly lysine, octane, carbohydrates (dextran, cellulose, oligosaccharides or polysaccharides). are mentioned.

[0080] The compounds of the present invention can be covalently linked to one or more of the half-life extension moieties using methods known in the art in view of the present disclosure. For example, as shown by the following examples , a half-life extension moiety such as a PEG moiety or a lipophilic moiety can be added to the peptide molecules of the present invention, for example, by incorporating cysteine or lysine residues into the molecule using known methods and attaching the half-life extension moiety to the cysteine or lysine. It is possible. Examples of the compounds of the present invention conjugated to monoclonal antibodies as half-life extension moieties are U.S. Provisional Patent Application No. 62 / 413,586, filed October 27, 2016, and "Antibody-coupled cyclic peptide tyrosine tyrosine com" filed on the same day as this application under Attorney Docket No. PRD3436 pounds as modulators of neuropeptide rec eptors", U.S. Patent Application No. ______, both of which are incorporated herein by reference in their entirety. According to an embodiment of the present invention, the electrophile reacts site-specifically with the sulfhydryl group of a Cys residue engineered within a half-life extension moiety such as a monoclonal antibody or a fragment thereof, thereby creating a covalent bond between the cyclic PYY peptide and the half-life extension moiety, and is introduced onto the side chain of the cyclic PYY of the present invention such as bromoacetamide or maleimide. The compounds of the present invention can be covalently linked to one or more of the half-life extension moieties directly or via a linker. Linkers useful in the present invention include, but are not limited to, peptide linkers, hydrocarbon linkers, polyethylene glycol (PEG) linkers, polypropylene glycol (PPG) linkers, polysaccharide linkers, polyester linkers, or hybrid linkers consisting of PEG and embedded heterocycles. In certain embodiments, the half-life extension moiety having a linker is prepared using methods known in the art, with amino acid residues 4, 7, 9, 10, 11, 13, 14, 15, 16, 17, 18 of PYY

[0081] , one or more amino acid positions of cyclic PYY such as 19, 20, 21, 22, 23, 24, 26, 30, or 31, can be complexed with the compounds of the present invention. In certain embodiments, the half-life extending moiety without a linker can be conjugated to the compounds of the present invention using methods known in the art at one or more amino acid positions of PYY such as 4, 7, 9, 10, 11, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 30, or 31. The numbering of the amino acid residues follows that of hPYY3. Any of the compounds of the present invention including but not limited to SEQ ID NOs: 1-110 can be conjugated directly or indirectly via a linker to a half-life extending moiety. According to an embodiment of the present invention, a compound selected from the group consisting of SEQ ID NOs: 74, 95, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, and 110, or a pharmaceutically acceptable salt thereof, can be covalently linked via a linker to a half-life extending moiety such as a monoclonal antibody or a fragment thereof. One or more amino acid positions of cyclic PYY such as 4, 7, 9, 10, 11, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 30, or 31 can be complexed with the compounds of the present invention. The numbering of the amino acid residues follows that of hPYY3. ~36 Any of the compounds of the present invention including but not limited to SEQ ID NOs: 1-110 can be conjugated directly or indirectly via a linker to a half-life extending moiety. According to an embodiment of the present invention, a compound selected from the group consisting of SEQ ID NOs: 74, 95, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, and 110, or a pharmaceutically acceptable salt thereof, can be covalently linked via a linker to a half-life extending moiety such as a monoclonal antibody or a fragment thereof. 101, 102, 103, 104, 105, 106, 107, 108, 109, and 110 can be conjugated directly or indirectly via a linker to a half-life extending moiety such as a monoclonal antibody or a fragment thereof. A complex comprising a peptide molecule of the present invention, or a peptide molecule covalently linked to one or more half-life extending moieties, can be assayed for functionality by assays known in the art in view of the present disclosure. For example, the biological or pharmacokinetic activity of the peptide molecule of the present invention can be assayed and compared using known in vitro or in vivo assays, either alone or in the complex according to the present invention. .

[0082] In one embodiment, the present invention provides Formula II:

[0083] In one embodiment, the present invention provides Formula II:

[0084] [Chemical formula] (wherein, p is 0 or 1, m is 0, 1, 2, 3, 4, or 5, n is 1, 2, 3, or 4, BRIDGE is -Ph-CH2-S-, -triazolyl-, or -NHC(O)CH 2S-, Z4 is K, A, E, or S, Z9 is G or K, and the amino side chain of said K is,

[0085] [Chemical formula] (wherein, t is 0, 1, or 2, u is 0 or 1, v is 14, 16, or 18.)

[0086] [Chemical formula] is substituted with, Z 11 is D or K, and the amino side chain of said K is,

[0087] [Chemical formula] (wherein, w is 0, 1, or 2, x is 0 or 1, y is 14, 16, or 18.)

[0088] [Chemical formula] is substituted with, Z 26 is A or H, Z 30 is L or K, and the amino side chain of said K is,

[0089] [Chemical formula] (wherein r is 0, 1, or 2, s is 0 or 1, q is 14, 16, or 18.), or

[0090] [Chemical formula] is substituted with Z 34 is

[0091] [Chemical formula] is Z 35 is

[0092] [Chemical formula] is.). A compound of or a pharmaceutically acceptable salt thereof.

[0093] In another embodiment, the present invention relates to formula II (wherein p is 0 or 1, m is 0, 2, 3, or 5, n is 1, 2, or 4, BRIDGE is -Ph-CH2-S-, -triazolyl-, or -NHC(O)CH 2S-, Z4 is K, A, E, or S, Z9 is G or K, and the amino side chain of said K is substituted with

[0094] [Chemical formula] Z 11 is D or K, and the amino side chain of said K is

[0095] [Chemical formula] is replaced by Z 26 is A or H, Z 30 is L or K, and the amino side chain of said K is

[0096] [Chemical formula] (wherein r is 0 or 2, s is 0 or 1, q is 14, 16, or 18.) is replaced by Z 34 is

[0097] [Chemical formula] and Z 35 is

[0098] [Chemical formula] a compound of) or a pharmaceutically acceptable salt thereof.

[0099] In another embodiment, the present invention provides a compound of formula II (wherein, p is 0 or 1, m is 0, 2, 3, or 5, n is 1, 2, or 4, BRIDGE is -Ph-CH2-S-, -triazolyl-, or -NHC(O)CH 2S-, Z4 is K, A, E, or S, Z9 is G or K, and the amino side chain of said K is

[0100] [Chemical formula] is replaced by Z 11is D or K, and the amino side chain of said K is

[0101]

Chemical formula

[0102]

Chemical formula

[0103]

Chemical formula

[0104]

Chemical formula

[0105]

Chemical formula

[0106]

Chemical formula

[0107] In another embodiment, the present invention provides a compound of formula II (wherein, p is 0 or 1, m is 0, 2, 3, or 5, n is 1, 2, or 4, BRIDGE is -Ph-CH2-S-, -triazolyl-, or -NHC(O)CH 2S-, Z4 is K, A, E, or S, Z9 is G or K, and the amino side chain of said K is

[0108]

Chemical formula

[0109]

Chemical formula

[0110]

Chemical formula

[0111]

Chemical formula

[0112]

Chemical formula

[0113]

Chemical formula

[0114] In another embodiment, the present invention provides a compound of formula II (wherein, p is 0 or 1, m is 0, 2, 3, or 5, n is 1, 2, or 4, BRIDGE is -Ph-CH2-S-, -triazolyl-, or -NHC(O)CH 2S-, Z4 is K, A, E, or S, Z9 is G or K, and the amino side chain of said K is

[0115]

Chemical formula

[0116]

Chemical formula

[0117]

Chemical formula

[0118]

Chemical formula

[0119]

Chemical formula

[0120] [Chemical formula] a compound of (), or a pharmaceutically acceptable salt thereof.

[0121] In another embodiment, the present invention provides a compound of formula II (wherein, p is 0 or 1, m is 0, 2, 3, or 5, n is 1, 2, or 4, BRIDGE is -Ph-CH2-S-, -triazolyl-, or -NHC(O)CH 2S-, Z4 is K, A, E, or S, Z9 is G, Z 11 is D, Z 26 is A or H, Z 30 is L or K, and the amino side chain of said K is

[0122] [Chemical formula] (wherein q is 14, 16, or 18).) substituted, Z 34 is

[0123] [Chemical formula] is Z 35 is

[0124] [Chemical formula] a compound of ().) or a pharmaceutically acceptable salt thereof.

[0125] In another embodiment, the present invention provides a formula selected from the group consisting of SEQ ID NO: 2 to SEQ ID NO: 46 It contains the compound of II.

[0126] Another embodiment of the present invention is an N-terminal to the PYY side chain cyclic analog that exhibits at least 70%, 75%, (3~36 ) 80%, 85%, 90%, 95%, or 99% sequence identity to hPYY. As an example of a method for determining sequence identity between two analogs, align two peptides (SEQ ID NO: 111). The sequence identity of the analog to hPYY( )

[0127]

Chemical formula

[0128] The cyclic PYY peptide PYY 3~36 acts as an agonist of the Y2 receptor to inhibit food intake and is an endogenous hormone secreted by L cells in the distal intestine. Considering its role in the regulation of appetite and food intake , as well as its antisecretory and absorption-promoting effects in the mammalian gastrointestinal tract, PYY 3~36 3~36 may be effective in the treatment of obesity and related conditions, as well as many gastrointestinal disorders. However, the therapeutic usefulness of PYY itself as a therapeutic agent is limited by its rapid 3~36 ​Limited by metabolism and short circulation half-life. Thus, the present invention, in a broad sense, relates to PY Y 3~36 modified PYY peptides that extend the half-life of the peptide and reduce peptide metabolism in vivo. 3~36 The present invention relates to complexes.

[0129] In certain embodiments of the present invention, the modified PYY 3~36 peptide is a cyclic PYY peptide. The terms "cyclic PYY peptide", "cyclic PYY analog", and "cyclic PY 3~36 Y Y 3~36 peptide analog" can be used interchangeably.

[0130] As used herein, the term "NTSC-PYY" is intended to describe an N-terminal to side chain cyclic analog of PYY.

[0131] The peptide sequences described herein are described according to normal convention, with the N-terminal region of the peptide on the left and the C-terminal region on the right. Although amino acid isomeric forms are known, unless otherwise explicitly indicated, the L-form amino acids are shown. For convenience in describing the molecules of the present invention, conventional and unconventional abbreviations (both single and three-letter codes) and functional moieties of various amino acids are used. These abbreviations are well known to those skilled in the art, but for clarity, they are listed below: A = Ala = alanine; R = Arg = arginine; N = Asn = asparagine; D = Asp = aspartic acid; βA = βAla = β-alanine; C = Cys = cysteine; hC = hCys = homocysteine; E = Glu = glutamic acid; Q = Gln = glutamine; G = Gly = glycine; H = His = histidine; I = Ile sn = asparagine; D = Asp = aspartic acid; βA = βAla = β-alanine; C = Cys = cysteine; hC = hCys = homocysteine; E = Glu = glutamic acid; Q = Gln = glutamine; G = Gly = glycine; H = His = histidine; I = Ile sn = asparagine; D = Asp = aspartic acid; βA = βAla = β-alanine; C sn = asparagine; D = Asp = aspartic acid; βA = βAla = β-alanine; C = Cys = cysteine; hC = hCys = homocysteine; E = Glu = glutamic acid; Q = Gln = glutamine; G = Gly = glycine; H = His = histidine; I = Ile =Isoleucine; L = Leu = Leucine; K = Lys = Lysine; Nle = Norleucine; F = Phe = Phenylalanine; P = Pro = Proline; S = Ser = Serine; T = Th r = Threonine; W = Trp = Tryptophan; Y = Tyr = Tyrosine, and V = Val = Valine.

[0132] For convenience, the numbering rule of amino acid residues used when naming the NTSC-PYY peptide of the present invention follows that of hPYY 3~36 . The specific amino acid substitutions introduced into the NTSC-PYY peptide for the natural residues at the corresponding positions of hPYY 3~36 are indicated by the appropriate amino acid code followed by the position of the substitution. Thus, "S4" within the NTSC-P YY peptide refers to the peptide in which the corresponding natural lys4 residue of hPYY is substituted with serine . Similarly, "hC31" within the NTSC-PYY peptide refers to the peptide in which the corresponding natural val31 residue of hPYY 3~36 is substituted with homocysteine . Further amino acid substitutions occurring within the NTSC-PYY peptide are described according to this rule and will be recognized as such by those skilled in the art. 3~36 and refers to the peptide in which the corresponding natural val31 residue of hPYY is substituted with homocysteine. Further amino acid substitutions occurring within the NTSC-PYY peptide are described according to this rule and will be recognized as such by those skilled in the art. and will be recognized as such by those skilled in the art.

[0133] Also for convenience, the naming rule used for the NTSC-PYY peptide of the present invention starts from the N-terminal residue involved in the cycle and proceeds in the left-to-right direction, incorporating the amino residues involved in the cycle together with the linking group(s) therebetween . In all cases, the N-terminal amino acid residue of the cycle is linked to the linking group via its α-amino functional group, which in turn connects to the side chain residue of the amino acid at position 31 of the NTSC-P YY peptide. Thus, "Cyclo-(I3 " is linked to the linking group via its α-amino functional group, which in turn connects to the side chain residue of the amino acid at position 31 of the NTSC-PYY peptide. Thus, "Cyclo-(I3 YY peptide. Thus, "Cyclo-(I3 "-m-COPhCH2-hC31)" is used to describe the cycle of NTSC-PYY peptides where the α-amino functionality of Ile3 is acylated with a meta-toluoyl acid residue, and its methyl group is further linked to the side chain of the hCys31 residue by a thioether bond . Similarly, "cyclo-(K4-CO(CH2)2NHCOCH2-hC31)" is used to describe the cycle of NTSC-PYY peptides where the native Ile3 residue is deleted and the α-amino functionality at the N-terminus of Lys4 is acylated with a 3 -acetamidopropanoyl group, and the acetamidomethylene carbon of which is connected to the side chain of the hCys31 residue by a thioether bond.

[0134] Lysine residues can be incorporated at various positions in the hP YY 3~36 sequence to provide a convenient functionality handle for further derivatization. Lysine residues can be modified to bind to monoclonal antibodies either directly or indirectly . In the case of indirect binding to monoclonal antibodies, the lysine residue can be modified to include a linker that allows the cyclic PYY peptide to bind to the monoclonal antibody . Those skilled in the art will recognize that related analogs can be used effectively in the same way and are contemplated herein .

[0135] The term "K(γ-Glu)" that appears in the peptide sequence represents a lysinyl residue where the ε-amino group of its side chain is acylated with the γ-carboxyl group of glutamic acid .

[0136] The term "K(γ-Glu-Pal(palmitoyl))" represents a lysinyl residue where the ε-amino group of its side chain ​​​is represented by a lysinyl residue acylated by the γ-carboxyl group of N-hexadecane-1-oil glutamate.

[0137] The term "K(γ-Glu-Stear(stearoyl))" refers to a lysinyl residue whose side-chain ε-amino group is acylated by the γ-carboxyl group of N-octadecane-1-oil glutamate.

[0138] The term "K(γ-Glu-Arach(arachidonyl))" refers to a lysinyl residue whose side-chain ε-amino group is acylated by the γ-carboxyl group of N-dodecane-1-oil glutamate.

[0139] The term "K(OEG)(8-amino-3,6-dioxaoctanoyl)" refers to a lysinyl residue whose side-chain ε-amino group is acylated by 8-amino-3,6-dioxaoctanoic acid.

[0140] The term "(OEG)2" refers to two OEG units linked together consecutively via an amide linkage (i.e., 17-amino-10-oxo -3,6,12,15-tetraoxa-9-azapentadecanoic acid).

[0141] The term "K(OEG)2" refers to a lysinyl residue whose side-chain ε-amino group is acylated by 17-amino-10-oxo -3,6,12,15-tetraoxa-9-azapentadecanoic acid.

[0142] The term "K((OEG)2-γ-Glu" refers to a lysinyl residue whose side-chain ε-amino group is (22S)-22-amino-10,19-dioxo-3,6,1 via its 1-carboxylic acid functional group Acylated with 2,15-tetraoxa-9,18-diazatricosandioic acid represents a lysinyl residue.

[0143] The term "K((OEG)2-γ-Glu-Stear)" refers to a lysinyl residue whose side-chain ε-amino group is acylated with (22S)-10,19-dioxo-22-stear ylamide-3,6,12,15-tetraoxa-9,18-diazatricosandioic acid via its 1-carboxylic acid functional group.

[0144] The term "K((OEG)2-γ-Glu-COC 16 CO2H)" refers to a lysinyl residue whose side-chain ε -amino group is acylated with (21S)-9,18,23-trioxo -2,5,11,14-tetraoxa-8,17,22-triazanonatriacontane -1,21,39-tricarboxylic acid via its 1-carboxylic acid functional group.

[0145] Similarly, the term "K((OEG)2-γ-Glu-COC 18 CO2H)" refers to a lysinyl residue whose side-chain ε-amino group is acylated with (21S)-9,18,23- trioxo-2,5,11,14-tetraoxa-8,17,22-triazapentacontane -1,21,41-tricarboxylic acid via its 1-carboxylic acid functional group.

[0146] The term "K((OEG)2-COC 16 CO2H)" refers to a lysinyl residue whose side-chain ε-amino group is acylated with 10,19-dioxo-3,6,12,15-tetra oxa-9,18-diazapentatriacontanedioic acid via its 1-carboxylic acid functional group. ​​represents the Leu residue.

[0147] The term "K(PEG24-AcBr)" refers to a lysinyl residue whose side-chain ε-amino group is acylated by N-bromoacetyl-75-amino-4,7,10,13,16, 19,22,25,28,31,34,37,40,43,46,49,52,55,5 8,61,64,67,70,73-tetraoxapentacontaheptanoic acid via its 1-carboxylic acid functional group.

[0148] The term "K(PEG12-AcBr)" refers to a lysinyl residue whose side-chain ε-amino group is acylated by N-bromoacetyl-39-amino-4,7,10,13,16, 19,22,25,28,31,34,37-dodecaoxanonatriacontanoic acid via its 1-carboxylic acid functional group.

[0149] The term "K(PEG6-AcBr)" refers to a lysinyl residue whose side-chain ε-amino group is acylated by N-bromoacetyl-3-[(17-amino-3,6,9,12,1 5-pentaoxaheptadec-1-yl)oxy]-propanoic acid via its 1-carboxylic acid functional group.

[0150] The term "K(PEG8-triazolyl-CH2CH2CO-PEG4-AcBr)" refers to a lysinyl residue whose side-chain ε-amino group is acylated by 27-[4-[2- 3-[2-[2-[3-(N-bromoacetylamino)propoxy]ethoxy]ethoxy propylaminocarbonyl]ethyl]tetrazol-1-yl]-4,7,10,13 ,16,19,22,25-octaoxaheptacosanic acid via its 1-carboxylic acid functional group. ​ Represents a lysyl residue.

[0151] The term "K(mPEG16)" refers to a lysyl residue in which the ε-amino group of its side chain is acylated by 4,7,10,13,16,19,22,25,28,31,34,37,4 0,43,46,49-hexadecaoxapentacontanoic acid through its 1-carboxylic acid functional group. Represents a lysyl residue.

[0152] The term "K(mPEG12)" refers to a lysyl residue in which the ε-amino group of its side chain is acylated by 4,7,10,13,16,19,22,25,28,31,34,37- dodecaoxaoctatriacontanoic acid through its 1-carboxylic acid functional group.

[0153] The term "VitE" refers to the α-tocopherolyl unit in the molecule.

[0154] The term "AcVitE" refers to an α-tocopherolyl unit having a methylenylcarboxy functional group in which its phenolic group is ether-linked.

[0155] The term "K-γ-Glu-AcVitE" refers to a lysyl residue in which the ε-amino group of its side chain is acylated by (2-(((2R)-2,5,7,8-tetramethyl-2-((4 R,8R)-4,8,12-trimethyltridecyl)chroman-6-yl)oxy)acetyl)-L-glutamic acid through its γ-carboxylic acid functional group.

[0156] Many of the compounds of the present invention incorporate a reduced amide bond between the C-terminal residue Y36 of the sequence and the adjacent residue R35. This reduced amide linkage is represented by the term "psi-(R35,Y36)". ​

[0157] Various amino acid residues containing the specific sequence of the present invention have a methylated α-amino group included. Thus, the terms "N-Me-Q34" or "N-Me-R35" each refer to α-N-methylated glutamine at position 34 of the sequence and α -N-methylated arginine at position 35 of the sequence, respectively.

[0158] In the description of the sequence, the term "N-Me-Q34, psi-(R35,Y36)" refers to a sequence containing both an α-methylglutamine residue at position 34 and a reduced amide bond between residues R35 and Y36.

[0159] Similarly, in the description of the sequence, the term "N-Me-R35, psi-(R35,Y36)" refers to a sequence containing both an α-methylarginine residue at position 35 and a reduced amide bond between this residue and Y36.

[0160] As used herein, the term "PEGylation" refers to a covalent complex of one or more polyethylene glycol (PEG) molecules and one or more NTSC-PYY peptides . The complex can contain, but is not limited to, 1 to 24 PEG molecules on one NTSC-P YY peptide. The complex may further include a suitable linker, including but not limited to, γ-glutamate, -NHC(O), C(O), and C alkyl (1~4) between the PEG molecule and the NTSC-PYY molecule. It may further include suitable linkers, including but not limited to, those mentioned above.

[0161] As used herein, the phrase "lipidation" refers to a covalent complex of an NTSC-PYY peptide and one or more lipophilic groups. Preferred lipophilic groups include long-chain hydrocarbons include a base. Other lipophilic groups include steroids, terpenes, fat-soluble vitamins, phytosterols, terpenoids, phospholipids, glycerol, and natural or synthetic fatty acids. Examples of lipophilic groups include, but are not limited to, α-tocopherolyl, stearic acid, palmitic acid, and arachidic acid. The complex may further include a suitable linker, such as, but not limited to, γ-glutamate, -NHC(O), C(O), and C ( 1~4) alkyl between the lipophilic molecule and the NTSC-PYY molecule.

[0162] The term "PYY" 3~36 shall refer to the following compound (SEQ ID NO: 111).

[0163]

Chemical formula

[0164] Pharmaceutical composition In another general aspect, the present invention relates to a pharmaceutical composition comprising the complex and compound of the present invention and a pharmaceutically acceptable carrier. As used herein, the term "pharmaceutical composition" means a product comprising the complex of the present invention together with a pharmaceutically acceptable carrier. The complex and compound of

[0165] the present invention and compositions containing them are also useful for the manufacture of medicaments for the therapeutic uses mentioned herein. ​​Refers to encapsulates, or other materials well-known in the art for use in pharmaceutical formulations. It should be understood that the properties of the carrier, excipient or diluent are determined by the route of administration for a particular use. As used herein, the term "pharmaceutically acceptable carrier" refers to a non-toxic material that does not interfere with the effects of the compositions according to the present invention or the biological activity of the compositions according to the present invention. For certain embodiments, any pharmaceutically acceptable carrier suitable for use in pharmaceutical compositions of antibodies can be used in the present invention in view of the present disclosure.

[0166] Pharmaceutically acceptable acidic / anionic salts for use in the present invention include acetate, benzenesulfonate, benzoate, bicarbonate, hydrogen tartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glycerceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, basic acetate, succinate, sulfate, tannate, tartrate, theoclate, tosylate, and triethiodide, but are not limited thereto. Also, organic acids or inorganic acids include hydroiodic acid, perchloric acid, sulfuric acid, phosphoric acid, propionic acid, glycolic acid, acids include, but are not limited to, those mentioned above. Methanesulfonic acid, hydroxyethanesulfonic acid, oxalic acid, 2-naphthalenesulfonic acid , p-toluenesulfonic acid, cyclohexanesulfamic acid, saccharinic acid or triflu oroacetic acid may be mentioned, but are not limited thereto.

[0167] Examples of pharmaceutically acceptable basic / cationic salts include aluminum, 2-amino- 2-hydroxymethyl-propan-1,3-diol (tris(hydroxymethyl)aminomethane, tromethane, or also known as "TRIS"), ammonia, benzathine , t-butylamine, calcium, chloroprocaine, choline, cyclohexylamine, , diethanolamine, ethylenediamine, lithium, L-lysine, magnesium, meglumine , N-methyl-D-glucamine, piperidine, potassium, procaine, quinine, sodium , triethanolamine, or zinc may be mentioned, but are not limited thereto.

[0168] In some embodiments of the present invention, pharmaceutical formulations containing the compounds of the present invention in an amount of about 0.001 mg / ml to about 100 mg / ml, about 0.01 mg / ml to about 50 mg / ml, or about 0.1 mg / ml to about 25 mg / ml are provided. The pharmaceutical formulation may have a pH of about 3.0 to about 10, for example , about 3 to about 7, or about 5 to about 9. The formulation may further contain at least one component selected from the group consisting of a buffer system, a preservative(s) optional), an isotonic agent(s)(optional), a chelating agent(s)(optional), a stabilizer, and a surfactant(s)(optional ).

[0169] Formulations of pharmaceutically active ingredients with pharmaceutically acceptable carriers are known in the art , for example, Remington: The Science and Prac Notice of Pharmacy (e.g., 21st edition (200 5), and any subsequent editions). Non-limiting examples of additional ingredients include buffers, diluents, solvents, tonicity regulators, preservatives, stabilizers, and chelating agents. One or more pharmaceutically acceptable carriers can be used when formulating the pharmaceutical composition of the present invention.

[0170] In one embodiment of the present invention, the pharmaceutical composition is a liquid formulation. Preferred examples of liquid formulations are aqueous formulations, i.e., formulations containing water. Liquid formulations can include solutions, suspensions, emulsions, microemulsions, gels, and the like. Aqueous formulations typically contain at least 50% w / w water, or at least 60%, 70%, 75%, 80%, 85%, 90%, or at least 95% w / w water.

[0171] In one embodiment, the pharmaceutical composition can be formulated as an injectable for injection via, for example, an injection device (e.g., a syringe or infusion pump). The injection can be delivered, for example, subcutaneously, intramuscularly, intraperitoneally, or intravenously.

[0172] In another embodiment, the pharmaceutical composition is a solid formulation, e.g., one that can be used as is or a lyophilized or spray-dried composition to which a solvent and / or diluent is added by a physician or patient prior to use. Solid dosage forms include tablets such as compressed tablets, and / or coated tablets, and capsules (e.g., hard or soft gelatin capsules). The pharmaceutical composition can also be in the form of, for example, sachets, dragees, powders, granules, lozenges, or powders for reconstitution.

[0173] ​​​​​The dosage form may be immediate release, in which case they contain a water-soluble or dispersible carrier or may be delayed release, sustained release, or modified release, in which case they may contain a water-insoluble polymer that regulates the dissolution rate of the dosage form in the gastrointestinal tract.

[0174] In other embodiments, the pharmaceutical composition may be delivered intranasally, orally, or sublingually.

[0175] The pH of the aqueous formulation can be from pH 3 to pH 10. In one embodiment of the invention, the pH of the formulation is from about 7.0 to about 9.5. In another embodiment of the invention, the pH of the formulation is from about 3.0 to about 7.0.

[0176] In another embodiment of the invention, the pharmaceutical composition contains a buffering agent. Non-limiting examples of buffering agents include arginine, aspartic acid, bicine, citrate, disodium hydrogen phosphate, fuma ric acid, glycine, glycylglycine, histidine, lysine, maleic acid, malic acid, sodium acetate sodium carbonate, sodium dihydrogen phosphate, sodium phosphate, succinate tartaric acid, tricine, and tris(hydroxymethyl)-aminomethane, and mixtures thereof. The buffering agent may be present individually or in aggregates at a concentration of about 0.01 mg / ml to about 50 m g / ml, for example about 0.1 mg / ml to about 20 mg / ml. Pharmaceutical compositions containing each one of these specific buffering agents constitute alternative embodiments of the invention.

[0177] In another embodiment of the invention, the pharmaceutical composition contains a preservative. Non-limiting examples of buffering agents include benzethonium chloride, benzoic acid, benzyl alcohol, bronopol, butyl 4-hi ​​Droxybenzoate, chlorobutanol, chlorocresol, chlorhexidine, chloro rufenesin, o-cresol, m-cresol, p-cresol, ethyl 4-hydroxy benzoate, imidurea, methyl 4-hydroxybenzoate, phenol, 2-f enoxyethanol, 2-phenylethanol, propyl 4-hydroxybenzoate, sodium dehydroacetate, thimerosal, and mixtures thereof. The preservative is present, individually or in combination, at a concentration of about 0.01 mg / ml to about 50 mg / ml, for example about 0.1 m g / ml to about 20 mg / ml. Pharmaceutical compositions containing each of these specific preservatives constitute alternative embodiments of the present invention.

[0178] In another embodiment of the present invention, the pharmaceutical composition contains an isotonic agent. Non-limiting examples of this embodiment include salts (such as sodium chloride), amino acids (such as glycine, histidine, arginine, lysine, isoleucine, aspartic acid, tryptophan, and threonine), alcohols such as glycerol, 1,2-propanediol (propylene glycol), 1, 3-propanediol, and 1,3-butanediol), polyethylene glycol ( for example, PEG400), and mixtures thereof. Another example of an isotonic agent is sugar. Non-limiting examples of sugars include, for example, fructose, glucose, mannose, sorbose, xylose, maltose, lactose, sucrose, trehalose, dextran, pullulan, dextrin, cyclodextrin, α- and β-HPCD, soluble starch, hydroxyethyl starch, and sodium carboxymethylcellulose, including single It may be a saccharide, disaccharide, polysaccharide, or water-soluble glucan. Another example of an isotonic agent is sugar alcohol and the term "sugar alcohol" is defined as a C(4-8) hydrocarbon having at least one -OH group . Non-limiting examples of sugar alcohols include mannitol , sorbitol, inositol, galactitol, dulcitol, xylitol, and arabitol. Pharmaceutical compositions containing each of the isotonic agents listed in this paragraph constitute alternative embodiments of the present invention . The isotonic agent may be present individually or in the aggregate at a concentration of about 0.01 mg / ml to about 50 mg / ml, for example about 0.1 mg / ml to about 20 mg / ml . Pharmaceutical compositions containing one of each of these specific isotonic agents constitute alternative embodiments of the present invention .

[0179] In another embodiment of the present invention, the pharmaceutical composition contains a chelating agent. Non-limiting examples of chelating agents include citric acid, aspartic acid, salts of ethylenediaminetetraacetic acid (EDTA), and mixtures thereof. The chelating agent may be present individually or in the aggregate at a concentration of about 0.01 mg / ml to about 50 mg / ml, for example about 0.1 mg / ml to about 20 mg / ml . Pharmaceutical compositions containing one of each of these specific chelating agents constitute alternative embodiments of the present invention .

[0180] In another embodiment of the present invention, the pharmaceutical composition contains a stabilizer. Non-limiting examples of stabilizers include one or more aggregation inhibitors, one or more oxidation inhibitors, one or more surfactants, and / or one or more protease inhibitors .

[0181] In another embodiment of the present invention, the pharmaceutical composition contains a stabilizer, and the stabilizer is carboxy Cellulose and its derivatives (HPC, HPC-SL, HPC-L, and HPMC, etc.), cyclodextrin, 2-methylthioethanol, polyethylene glycol (such as PEG 3350), polyvinyl alcohol (PVA), polyvinyl pyrrolidone, salts (such as sodium chloride), sulfur-containing substances, for example, monothioglycerol), or thioglycolic acid. The stabilizer may be present individually or in an aggregate at a concentration of about 0.01 mg / ml to about 50 mg / ml, for example, about 0.1 mg / ml to about 20 mg / ml. A pharmaceutical

[0182] composition containing one of each of these specific stabilizers constitutes an alternative embodiment of the present invention. In a further embodiment of the present invention, the pharmaceutical composition comprises one or more surfactants, preferably one surfactant, at least one surfactant, or two different surfactants. The term "surfactant" refers to any molecule or ion consisting of a water-soluble (hydrophilic) portion and a lipid-soluble (lipophilic) portion. Surfactants are selected from the group consisting of, for example, anionic surfactants, cationic surfactants, nonionic surfactants,

[0183] and / or zwitterionic surfactants. The surfactant may be present individually or in an aggregate at a concentration of about 0.1 mg / ml to about 20 mg / ml. A pharmaceutical composition containing one of each of these specific surfactants constitutes an alternative A pharmaceutical composition containing one of each of these specific protease inhibitors constitutes an alternative embodiment of the present invention.

[0184] The pharmaceutical composition of the present invention may contain an amount of amino acid base sufficient to reduce polypeptide aggregate formation during storage of the composition. The term "amino acid base" refers to one or more amino acids (methionine, histidine, imidazole, arginine, lysine, isoleucine, aspartic acid, tryptophan, threonine, etc.), or analogs thereof. Any amino acid may be present in either its free base form or its salt form. Any stereoisomer (i.e., L, D, or a mixture thereof) of the amino acid base may be present. The amino acid base may be present individually or in combination with other amino acid bases at a concentration of about 0.01 mg / ml to about 50 mg / m l, for example, at a concentration of about 0.1 mg / ml to about 20 mg / ml. A pharmaceutical composition containing one of each of these specific amino acid bases constitutes an alternative embodiment of the present invention. .

[0185] It is also obvious to those skilled in the art that the therapeutically effective amount of the compound or its pharmaceutical composition of the present invention varies depending on the desired effect. Therefore, the optimal dosage can be easily determined by those skilled in the art and varies depending on the specific compound used, the method of administration, the potency of the preparation, and the progression of the disease state. In addition, factors related to the specific subject being treated, including the age, weight, diet, and administration time of the subject, give rise to the need to adjust the dosage to an appropriate therapeutic concentration. .

[0186] For all indications, the compounds of the present invention are preferably administered in single or divided doses (e.g., The single dose can be divided into 2, 3, 4, 5, 6, 7, 8, 9, or 10 sub-doses and can be administered peripherally at a dose of about 1 μg to about 5 mg per day, or about 0 01 μg / kg to about 500 μg / kg, more preferably about 0.05 μg / kg to about 250 μg / kg, and most preferably less than about 50 μg / kg. The dosages within these ranges will of course vary depending on the potency of each agonist and can be readily determined by those skilled in the art . Thus, the above dosages are examples of average cases. Of course, there may be individual cases where dosages higher or lower than this are effective, and such cases are also within the scope of the present invention .

[0187] In certain embodiments, the compounds of the present invention are administered at a dose of about 1 μg to about 5 mg, or at a dose of about 0 .01 μg / kg to about 500 μg / kg, more preferably at a dose of about 0.05 μg / kg to about 250 μg / kg, most preferably at a dose less than about 50 μg / kg, at a dose of about 1 μ g to about 5 mg, or at a dose of about 0.01 μg / kg to about 500 μg / kg, more preferably at a dose of about 0.05 μg / kg to about 250 μg / kg, most preferably at a dose less than about 50 μg / kg, in combination with a dose of a second therapeutic agent (e.g., liraglutide).

[0188] Pharmaceutically acceptable salts of the compounds of the present invention include conventional non-toxic salts or quaternary ammonium salts formed from inorganic or organic acids or bases. Examples of such acid addition salts include acetate, adipate, benzoate, benzenesulfonate, citrate, camphorate, dodecyl sulfate, hydrochloride, hydrobromide, lactate, maleate, methanesulfonate , etc. ​Phosphates, nitrates, oxalates, pivalates, propionates, succinates, sulfates and tartrates are mentioned. As basic salts, ammonium salts, sodium salts and potassium salts such as alkali metal salts, calcium salts and magnesium salts such as alkaline earth metal salts, di salts with organic bases such as cyclohexylamino salts, and salts with amino acids such as arginine are mentioned. Further, the basic nitrogen-containing group may be quaternized, for example, by an alkyl halide .

[0189] The pharmaceutical composition of the present invention can be administered by any means that achieves its intended purpose . Examples include parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, intraoral or intraocular administration. It may also be administered by the oral route. Formulations suitable for parenteral administration include , for example, aqueous solutions of water-soluble salts, acidic solutions, alkaline solutions, dextrose aqueous solutions, isotonic carbohydrate solutions, and aqueous solutions of active complexes in water-soluble forms such as cyclodextrin inclusion complexes .

[0190] The present invention also encompasses a method for producing a pharmaceutical composition, which comprises mixing a pharmaceutically acceptable carrier with any of the compounds of the present invention . In addition, the present invention encompasses a pharmaceutical composition produced by mixing one or more pharmaceutically acceptable carriers with any of the compounds of the present invention .

[0191] Furthermore, the compounds of the present invention may have one or more crystalline polymorphs or amorphous crystalline forms, and accordingly , these forms are also intended to be included within the scope of the present invention. In addition, the compounds may form hydrates (i.e., hydrates) or solvates with water or common organic solvents, for example . As used herein In the present case, the term "solvate" refers to a physical combination of a compound of the present invention with one or more solvent molecules. This physical association can involve varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain cases, e.g., one or more solvent molecules are present in the crystal lattice of a crystalline solid. When incorporated into a solvent, the solvate becomes isolable. "Solvates" are intended to encompass both solution-phase and isolable solvates. Non-limiting examples of solvates include ethanolates, methanolates, and the like.

[0192] The present invention is intended to include within its scope polymorphs and solvates of the complexes of the invention. Therefore, the term "administration" in the treatment method of the present invention includes administration of the conjugate of the present invention. or polymorphs not specifically disclosed but which are clearly included within the scope of the present invention. or a solvate thereof to treat, ameliorate, or prevent the syndromes, disorders, or diseases described herein. This includes measures to prevent or cause

[0193] In another embodiment, the present invention relates to a compound of the present invention for use as a medicament.

[0194] The present invention includes within its scope prodrugs of the compounds of the present invention. A drug is a functional derivative of a compound that is readily convertible in vivo into the compound of interest. Thus, the term "administration" in the treatment methods of the present invention includes any of the above-mentioned methods described herein. Treatment of various disorders with compounds specifically disclosed or not specifically disclosed. Both include treatment with compounds that are converted to specific compounds in vivo after administration to a patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in is described in "Design of Prodrugs" (Ed. H. Bundgaard, Els evier, 1985).

[0195] Furthermore, within the scope of the present invention, when any element is referred to, particularly with respect to the compounds of the present invention , whether it is naturally occurring or synthetically produced, and whether it is in its natural abundance or in an isotopically enriched form, all isotopes and isotope mixtures of that element are intended to be included . For example, with respect to hydrogen, within its scope are included 1 H, 2 H (D), and 3 H( T). Similarly, with respect to carbon and oxygen, within their scope 12 C, 13 C and and 14 C, as well as 16 O and 18 O are each included. Such isotopes may be radioactive or non-radioactive. The radiolabeled compounds of the present invention are 3 H, 11 C, 18 F, 1 22 I, 123 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br, and 82 Br and may contain a radioisotope selected from the group of 3 H, 11 C, and 18 F.

[0196] Some compounds of the present invention may exist as atropisomers. Atropisomers is a stereoisomer resulting from the hindrance of rotation around a double bond, and the steric strain hindrance to rotation is high enough to allow isolation of the conformational isomers. All such conformational isomers and mixtures thereof should be understood to be included within the scope of the present invention.

[0197] If the compounds according to the present invention have at least one stereocenter, as a result they can exist as enantiomers or diastereomers. All such isomers and mixtures thereof should be understood to be included within the scope of the present invention.

[0198] If a mixture of stereoisomers results from the process for preparing the compounds according to the present invention, these isomers can be separated by conventional methods such as preparative chromatography. The compounds can be prepared in racemic form, or the individual enantiomers can also be prepared by either enantioselective synthesis or resolution. The compounds can form diastereomeric pairs by forming salts with optically active acids such as, for example, (-)-di-p-toluoyl-D-tartaric acid and / or (+)-di-p-toluoyl-L-tartaric acid, and then be resolved into their component enantiomers by standard methods such as fractional crystallization and regeneration of the free base. The compounds can also be resolved by forming esters or amides of the diastereomers and then performing chromatographic separation and removing the chiral auxiliary group. Alternatively, the compounds can be resolved using a chiral column via high performance liquid chromatography (HPLC) or SFC. In some cases, in the 1H NMR spectrum, observable by 1H NMR, which results in complex multiplets and peak integrations, ​​The compound may have rotational isomers.

[0199] In any of the processes for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups in any of the related molecules. This can be achieved by conventional protecting group means, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973, and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 (each of which is incorporated herein by reference in its entirety for all purposes). The protecting groups can then be removed using methods well known in the art at a convenient later stage. This can be achieved by conventional protecting group means, such as those described in Protective Groups in Organic Chemist ry, ed. J.F.W. McOmie, Plenum Press, 1973, and T .W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 (each of which is incorporated herein by reference in its entirety for all purposes). The protecting groups can then be removed using methods well known in the art at a convenient later stage. The protecting groups can then be removed using methods well known in the art at a convenient later stage. can be removed.

[0200] Method of Use The present invention is directed to a method for preventing, treating, or alleviating a Y2 receptor-mediated syndrome, disorder, or disease in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a compound of the present invention, a derivative thereof, or a pharmaceutically acceptable salt, optionally conjugated to a half-life extending moiety, or a pharmaceutical composition. The present invention is directed to a method for preventing, treating, or alleviating a Y2 receptor-mediated syndrome, disorder, or disease in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a compound of the present invention, a derivative thereof, or a pharmaceutically acceptable salt, optionally conjugated to a half-life extending moiety, or a pharmaceutical composition. The present invention is directed to a method for preventing, treating, or alleviating a Y2 receptor-mediated syndrome, disorder, or disease in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a compound of the present invention, a derivative thereof, or a pharmaceutically acceptable salt, optionally conjugated to a half-life extending moiety, or a pharmaceutical composition. The present invention also provides a method for preventing, treating, delaying the onset of, or alleviating a disorder, disease, or condition, or any one or more symptoms of the disorder, disease, or condition, in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of any

[0201] The present invention also provides a method for preventing, treating, delaying the onset of, or alleviating a disorder, disease, or condition, or any one or more symptoms of the disorder, disease, or condition, in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of any one or more of the compounds, derivatives, or pharmaceutically acceptable salts of the present invention. one or more of the compounds, derivatives, or pharmaceutically acceptable salts of the present invention. administering a compound of the invention, a derivative thereof, or a pharmaceutically acceptable salt, or a pharmaceutical composition, which is conjugated to a half-life extending moiety

[0202] According to certain embodiments, the disease disorder, or condition is obesity, type I or type II diabetes, metabolic syndrome (i.e., syndrome X), insulin resistance, glucose intolerance ( e.g., glucose tolerance), hyperglycemia, hyperinsulinemia, hypertriglyceridemia, congenital hyperinsulinism (CHI)-induced hypoglycemia, dyslipidemia, atherosclerosis, diabetic nephropathy , and hypertension and other cardiovascular risk factors, such as cholesterol and / or lipid levels that are not managed, osteoporosis, inflammation, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), kidney disease, and / or eczema, selected from the group consisting of

[0203] According to certain embodiments, a therapeutically effective amount refers to a therapeutic amount sufficient to achieve one, two, three, four , or more of the following effects: (i) reducing or alleviating the severity of the disease, disorder, or condition being treated, or symptoms associated therewith, (ii i) shortening the duration of the disease, disorder or condition being treated, or symptoms associated therewith , (iii) preventing the progression of the disease, disorder or condition being treated, or symptoms associated therewith , (iv) causing regression of the disease, disorder or condition being treated, or symptoms associated therewith , (v) preventing the progression or onset of the disease, disorder or condition being treated, or symptoms associated therewith , (vi) preventing recurrence of the disease, disorder or condition being treated, or symptoms associated therewith (vii) the disease, disorder, or condition being treated, or Reducing hospitalizations of a subject having a condition or a symptom associated therewith, (viii) treating shortening the hospitalization period of a subject having a disease, disorder or condition being treated, or a symptom associated therewith causing, (ix) increasing the survival rate of a subject having a disease, disorder or condition being treated, or a symptom associated therewith causing, (xi) inhibiting or alleviating a disease, disorder or condition of a subject being treated, or a symptom associated therewith, and / or (xii) enhancing or improving the prophylactic or therapeutic effect of another treatment. preventing or treating The therapeutically effective amount or dose can vary depending on various factors such as the disease, disorder or condition being treated, the means of administration, the target site, the physiological state of the subject (e.g., age, weight, health status, etc.), whether the subject is human or animal, other drugs being administered, and whether the treatment is prophylactic or therapeutic. The therapeutic dose is optimally titrated to optimize safety and efficacy.

[0204] When used herein, the terms "treat", "treating", and "treatment" all mean to refer to the improvement or reversal of at least one measurable physical parameter associated with a disease, disorder, or condition, which may not necessarily be recognized in the subject but may be recognizable in the subject. The terms "treat", "treating", and "treatment" may further refer to causing regression of a disease, disorder, or condition, preventing its progression, or at least slowing its progression. In certain embodiments, "treat" When used herein, the terms "treat", "treating", and "treatment" all mean to refer to the improvement or reversal of at least one measurable physical parameter associated with a disease, disorder, or condition, which may not necessarily be recognized in the subject but may be recognizable in the subject. The terms "treat", "treating", and "treatment" may further refer to causing regression of a disease, disorder, or condition, preventing its progression, or at least slowing its progression. In certain embodiments, "treat" When used herein, the terms "treat", "treating", and "treatment" all mean to refer to the improvement or reversal of at least one measurable physical parameter associated with a disease, disorder, or condition, which may not necessarily be recognized in the subject but may be recognizable in the subject. The terms "treat", "treating", and "treatment" may further refer to causing regression of a disease, disorder, or condition, preventing its progression, or at least slowing its progression. In certain embodiments, "treat" When used herein, the terms "treat", "treating", and "treatment" all mean to refer to the improvement or reversal of at least one measurable physical parameter associated with a disease, disorder, or condition, which may not necessarily be recognized in the subject but may be recognizable in the subject. The terms "treat", "treating", and "treatment" may further refer to causing regression of a disease, disorder, or condition, preventing its progression, or at least slowing its progression. In certain embodiments, "treat" When used herein, the terms "treat", "treating", and "treatment" all mean to refer to the improvement or reversal of at least one measurable physical parameter associated with a disease, disorder, or condition, which may not necessarily be recognized in the subject but may be recognizable in the subject. The terms "treat", "treating", and "treatment" may further refer to causing regression of a disease, disorder, or condition, preventing its progression, or at least slowing its progression. In certain embodiments, "treat"

[0205] As used herein, the terms "treat", "treating", and "treatment" all mean to refer to the improvement or reversal of at least one measurable physical parameter associated with a disease, disorder, or condition, which may not necessarily be recognized in the subject but may be recognizable in the subject. The terms "treat", "treating", and "treatment" may further refer to causing regression of a disease, disorder, or condition, preventing its progression, or at least slowing its progression. In certain embodiments, "treat" As used herein, the terms "treat", "treating", and "treatment" all mean to refer to the improvement or reversal of at least one measurable physical parameter associated with a disease, disorder, or condition, which may not necessarily be recognized in the subject but may be recognizable in the subject. The terms "treat", "treating", and "treatment" may further refer to causing regression of a disease, disorder, or condition, preventing its progression, or at least slowing its progression. In certain embodiments, "treat" As used herein, the terms "treat", "treating", and "treatment" all mean to refer to the improvement or reversal of at least one measurable physical parameter associated with a disease, disorder, or condition, which may not necessarily be recognized in the subject but may be recognizable in the subject. The terms "treat", "treating", and "treatment" may further refer to causing regression of a disease, disorder, or condition, preventing its progression, or at least slowing its progression. In certain embodiments, "treat" As used herein, the terms "treat", "treating", and "treatment" all mean to refer to the improvement or reversal of at least one measurable physical parameter associated with a disease, disorder, or condition, which may not necessarily be recognized in the subject but may be recognizable in the subject. The terms "treat", "treating", and "treatment" may further refer to causing regression of a disease, disorder, or condition, preventing its progression, or at least slowing its progression. In certain embodiments, "treat" As used herein, the terms "treat", "treating", and "treatment" all mean to refer to the improvement or reversal of at least one measurable physical parameter associated with a disease, disorder, or condition, which may not necessarily be recognized in the subject but may be recognizable in the subject. The terms "treat", "treating", and "treatment" may further refer to causing regression of a disease, disorder, or condition, preventing its progression, or at least slowing its progression. In certain embodiments, "treat" As used herein, the terms "treat", "treating", and "treatment" all mean to refer to the improvement or reversal of at least one measurable physical parameter associated with a disease, disorder, or condition, which may not necessarily be recognized in the subject but may be recognizable in the subject. The terms "treat", "treating", and "treatment" may further refer to causing regression of a disease, disorder, or condition, preventing its progression, or at least slowing its progression. In certain embodiments, "treat" As used herein, the terms "treat", "treating", and "treatment" all mean to refer to the improvement or reversal of at least one measurable physical parameter associated with a disease, disorder, or condition, which may not necessarily be recognized in the subject but may be recognizable in the subject. The terms "treat", "treating", and "treatment" may further refer to causing regression of a disease, disorder, or condition, preventing its progression, or at least slowing its progression. In certain embodiments, "treat" )」, "treating", and "treatment" refer to the alleviation of one or more symptoms associated with a disease, disorder, or condition, the prevention of the progression or onset thereof, or the shortening of its duration. In certain embodiments, "treat", "treating", and "treatment" refer to preventing the recurrence of a disease, disorder, or condition. In certain embodiments, "treat", "treating", and "treatment" refer to improving the survival rate of a subject having a disease, disorder, or condition. In certain embodiments, "treat", "treating", and "treatment" refer to the disappearance of a disease, disorder, or condition in a subject. In one embodiment, the present invention provides a method for preventing, treating, delaying the

[0206] onset, or alleviating obesity, or any one or more symptoms of obesity, in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a compound of the present invention, a derivative or pharmaceutically acceptable salt thereof, optionally conjugated to a half-life extending moiety, or a pharmaceutical composition. In some embodiments, the weight of the subject is, relative to the weight of the subject prior to administration of any of the complexes, compounds, pharmaceutical compositions, forms, or agents of the present invention described herein, or relative to a control subject that has not received any of the complexes, compositions, forms, agents, or combinations of the present invention described herein, e.g., from about 0.01% to about 0. 1%, from about 0.1% to about 0.5%, from about 0.5% to about 1%, from about 1% to about Reduced by about 25% to about 30%, about 30% to about 35%, about 35% to about 40%, about 40% to about 45%, or about 45% to about 50%.

[0207] In some embodiments, the weight loss is, for example, about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months , about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 1.5 years, about 2 years, about 2.5 years, about 3 years, about 3.5 years, about 4 years, about 4.5 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, about 15 years, or about 20 years and is maintained.

[0208] The present invention provides a method of performing it on a subject in need of preventing, treating, delaying the onset of, or remitting a syndrome, disorder, or disease, or any one or more symptoms thereof, wherein the syndrome, disorder, or disease is obesity, type I or type II diabetes, metabolic syndrome (i.e., syndrome X), insulin resistance, impaired glucose tolerance (e.g., glucose tolerance), hyperglycemia, hyperinsulinemia , hypertriglyceridemia, hypoglycemia due to congenital hyperinsulinism (CHI), dyslipidemia, atherosclerosis, diabetic nephropathy, and other cardiovascular risk factors such as hypertension and cardiovascular risk factors associated with unregulated cholesterol and / or or lipid levels, osteoporosis, inflammation, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (N ASH), kidney disease, and eczema, and administering to a subject in need thereof an effective amount of a compound of the present invention, optionally conjugated to a half-life extending moiety, a derivative thereof comprising administering a compound, its derivative, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

[0209] As used herein, metabolic syndrome refers to a subject having any one or more of hyperglycemia (e.g., fasting hyperglycemia), hypertension, abnormal cholesterol levels (e.g., low HDL levels), abnormal triglyceride levels (e.g., high triglycerides), a large waist circumference (i.e., waist circumference), increased fat in the abdominal area, insulin resistance, glucose tolerance, high C-reactive protein levels (i.e., a pre-inflammatory state), and plasma plasminogen activator inhibitor-1 and fibrinogen levels (i.e., a thrombotic state).

[0210] The present invention provides a method for reducing food intake in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a compound of the present invention, optionally conjugated to a half-life extending moiety, a derivative thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition. In some embodiments, the food intake of the subject is reduced by, for example, about 0.01% to about 0.1%, about 0.1% to about 0.5%, about 0.5% to about 1%, about 1% to about 5%, about 2% to about 3%, about 5% to about 10%, about 10% to about 15%, about 15% to about 20%, about 20% to about 25%, about 25% to about 30%, about 30% to about 35%, about 35% to about 40%, about 40% to about 45%, or about 45% to about 50% compared to the food intake of the subject before administration of any of the conjugates, compounds, compositions, forms, agents, or combinations of the present invention described herein, or compared to a control subject that has not received any of the conjugates, compounds, compositions, forms, agents, or combinations of the present invention described herein. The present invention provides a method for reducing food intake in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a compound of the present invention, optionally conjugated to a half-life extending moiety, a derivative thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition. The present invention provides a method for reducing food intake in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a compound of the present invention, optionally conjugated to a half-life extending moiety, a derivative thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition. In some embodiments, the food intake of the subject is reduced by, for example, about 0.01% to about 0.1%, about 0.1% to about 0.5%, about 0.5% to about 1%, about 1% to about 5%, about 2% to about 3%, about 5% to about 10%, about 10% to about 15%, about 15% to about 20%, about 20% to about 25%, about 25% to about 30%, about 30% to about 35%, about 35% to about 40%, about 40% to about 45%, or about 45% to about 50% compared to the food intake of the subject before administration of any of the conjugates, compounds, compositions, forms, agents, or combinations of the present invention described herein, or compared to a control subject that has not received any of the conjugates, compounds, compositions, forms, agents, or combinations of the present invention described herein. In some embodiments, the food intake of the subject is reduced by, for example, about 0.01% to about 0.1%, about 0.1% to about 0.5%, about 0.5% to about 1%, about 1% to about 5%, about 2% to about 3%, about 5% to about 10%, about 10% to about 15%, about 15% to about 20%, about 20% to about 25%, about 25% to about 30%, about 30% to about 35%, about 35% to about 40%, about 40% to about 45%, or about 45% to about 50% compared to the food intake of the subject before administration of any of the conjugates, compounds, compositions, forms, agents, or combinations of the present invention described herein, or compared to a control subject that has not received any of the conjugates, compounds, compositions, forms, agents, or combinations of the present invention described herein. In some embodiments, the food intake of the subject is reduced by, for example, about 0.01% to about 0.1%, about 0.1% to about 0.5%, about 0.5% to about 1%, about 1% to about 5%, about 2% to about 3%, about 5% to about 10%, about 10% to about 15%, about 15% to about 20%, about 20% to about 25%, about 25% to about 30%, about 30% to about 35%, about 35% to about 40%, about 40% to about 45%, or about 45% to about 50% compared to the food intake of the subject before administration of any of the conjugates, compounds, compositions, forms, agents, or combinations of the present invention described herein, or compared to a control subject that has not received any of the conjugates, compounds, compositions, forms, agents, or combinations of the present invention described herein. In some embodiments, the food intake of the subject is reduced by, for example, about 0.01% to about 0.1%, about 0.1% to about 0.5%, about 0.5% to about 1%, about 1% to about 5%, about 2% to about 3%, about 5% to about 10%, about 10% to about 15%, about 15% to about 20%, about 20% to about 25%, about 25% to about 30%, about 30% to about 35%, about 35% to about 40%, about 40% to about 45%, or about 45% to about 50% compared to the food intake of the subject before administration of any of the conjugates, compounds, compositions, forms, agents, or combinations of the present invention described herein, or compared to a control subject that has not received any of the conjugates, compounds, compositions, forms, agents, or combinations of the present invention described herein. In some embodiments, the food intake of the subject is reduced by, for example, about 0.01% to about 0.1%, about 0.1% to about 0.5%, about 0.5% to about 1%, about 1% to about 5%, about 2% to about 3%, about 5% to about 10%, about 10% to about 15%, about 15% to about 20%, about 20% to about 25%, about 25% to about 30%, about 30% to about 35%, about 35% to about 40%, about 40% to about 45%, or about 45% to about 50% compared to the food intake of the subject before administration of any of the conjugates, compounds, compositions, forms, agents, or combinations of the present invention described herein, or compared to a control subject that has not received any of the conjugates, compounds, compositions, forms, agents, or combinations of the present invention described herein. In some embodiments, the food intake of the subject is reduced by, for example, about 0.01% to about 0.1%, about 0.1% to about 0.5%, about 0.5% to about 1%, about 1% to about 5%, about 2% to about 3%, about 5% to about 10%, about 10% to about 15%, about 15% to about 20%, about 20% to about 25%, about 25% to about 30%, about 30% to about 35%, about 35% to about 40%, about 40% to about 45%, or about 45% to about 50% compared to the food intake of the subject before administration of any of the conjugates, compounds, compositions, forms, agents, or combinations of the present invention described herein, or compared to a control subject that has not received any of the conjugates, compounds, compositions, forms, agents, or combinations of the present invention described herein. In some embodiments, the food intake of the subject is reduced by, for example, about 0.01% to about 0.1%, about 0.1% to about 0.5%, about 0.5% to about 1%, about 1% to about 5%, about 2% to about 3%, about 5% to about 10%, about 10% to about 15%, about 15% to about 20%, about 20% to about 25%, about 25% to about 30%, about 30% to about 35%, about 35% to about 40%, about 40% to about 45%, or about 45% to about 50% compared to the food intake of the subject before administration of any of the conjugates, compounds, compositions, forms, agents, or combinations of the present invention described herein, or compared to a control subject that has not received any of the conjugates, compounds, compositions, forms, agents, or combinations of the present invention described herein. In some embodiments, the food intake of the subject is reduced by, for example, about 0.01% to about 0.1%, about 0.1% to about 0.5%, about 0.5% to about 1%, about 1% to about 5%, about 2% to about 3%, about 5% to about 10%, about 10% to about 15%, about 15% to about 20%, about 20% to about 25%, about 25% to about 30%, about 30% to about 35%, about 35% to about 40%, about 40% to about 45%, or about 45% to about 50% compared to the food intake of the subject before administration of any of the conjugates, compounds, compositions, forms, agents, or combinations of the present invention described herein, or compared to a control subject that has not received any of the conjugates, compounds, compositions, forms, agents, or combinations of the present invention described herein.

[0211] In some embodiments, the reduction in food intake is, for example, about 1 week, about 2 weeks, about 3 weeks , about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 1.5 years , about 2 years, about 2.5 years, about 3 years, about 3.5 years, about 4 years, about 4.5 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, about 15 years, or about 20 years.

[0212] The present invention provides a method for reducing glycated hemoglobin (A1C) in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a compound of the present invention optionally conjugated to a half-life extending moiety, a derivative or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition. In some embodiments, the subject's A1C is, relative to the subject's A1C prior to administration of any of the complexes, compounds, compositions, forms, agents, or combinations of the present invention described herein, or compared to a control subject not receiving any of the complexes, compounds, compositions, forms, agents, or combinations of the present invention described herein, for example, reduced by about 0 .001% to about 0.01%, about 0.01% to about 0.1%, about 0.1% to about 0.2%, about 0 .2% to about 0.3%, about 0.3% to about 0.4%, about 0.4% to about 0.5%, about 0.5% to about 1%, about 1% to about 1.5%, about 1.5% to about 2%, about 2% to about 2.5%, about 2.5% to about 3%, about 3% to about 4%, about 4% to about 5%, about 5% to about 6%, about 6% to about 7%, about 7% to about 8%, about 8% to about 9%, or about 9% to about 10%.

[0213] In other embodiments, the method is for a subject in need of reducing fasting blood glucose levels,​​​​​​ providing it, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention, a derivative or pharmaceutically acceptable salt thereof, or a pharmaceutical composition, optionally conjugated to a half-life extending moiety The fasting blood glucose level is reduced to less than about 140 - about 150 mg / dL, less than about 140 - about 130 mg / dL, less than about 130 - about 120 mg / dL, less than about 120 - about 110 mg / dL, less than about 110 - about 100 mg / dL, less than about 100 - about 90 mg / dL, or less than about 90 - about 80 mg / dL, relative to the fasting blood glucose level of the subject prior to administration of any of the complexes, compounds, compositions, forms, agents, or combinations of the invention described herein, or as compared to a control subject not receiving any of the complexes, compounds, compositions, forms, agents, or combinations of the invention described herein.

[0214] The invention provides a method of modulating Y2 receptor activity in a subject in need thereof, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention, a derivative or pharmaceutically acceptable salt thereof, or a pharmaceutical composition, optionally conjugated to a half-life extending moiety As used herein, "modulating" refers to increasing or decreasing receptor activity.

[0215] In some embodiments, the effective amount of a compound of the invention, a derivative or pharmaceutically acceptable salt thereof, or a pharmaceutical composition, optionally conjugated to a half-life extending moiety, is administered to a subject in need thereof once, twice, three times, four times, five times, six times, seven times, or eight times a day. In some embodiments, the effective amount of a compound of the invention, a derivative or pharmaceutically acceptable salt thereof, or a pharmaceutical composition, optionally conjugated to a half-life extending moiety, is administered to a subject in need thereof ​​​​​​​​The compound, derivative or pharmaceutically acceptable salt thereof, or pharmaceutical composition of the present invention is administered to a subject in need thereof once every two days, once a week, twice a week, three times a week, four times a week, five times a week, six times a week, twice a month, three times a month, or four times a month.

[0216] Another embodiment of the present invention includes a method for preventing, treating, delaying the onset of, or remitting one or more symptoms of a disease, disorder, or syndrome, or any one of the diseases, disorders, or syndromes in a subject in need thereof, the method comprising administering to a subject in need thereof, in combination therapy, an effective amount of the compound, derivative or pharmaceutically acceptable salt thereof, or pharmaceutical composition of the present invention, optionally conjugated to a half-life extending moiety. In certain embodiments, the combination therapy is a second therapeutic agent. In certain embodiments, the combination therapy is a surgical therapy.

[0217] As used herein, the term "combined" refers to the use of multiple therapies in connection with the administration of two or more therapeutic agents to a subject.

[0218] As used herein, combination therapy refers to administering to a subject in need thereof, an effective amount of a compound, derivative or pharmaceutically acceptable salt thereof, or pharmaceutical composition, optionally conjugated to a half-life extending moiety, simultaneously with one or more additional therapeutic agents, or one or more surgical therapies. In some embodiments, the one or more additional therapeutic agents or surgical therapies can be administered on the same day as an effective amount of the compound, derivative or pharmaceutically acceptable salt thereof, or pharmaceutical composition of the present invention, Surgical therapy may be administered in the same week or the same month as an effective amount of a compound of the invention, optionally conjugated to a half-life extending moiety, a derivative thereof or a pharmaceutically acceptable salt, or a pharmaceutical composition.

[0219] In certain embodiments, the disease or disorder is selected from the group consisting of obesity, type II diabetes, metabolic syndrome insulin resistance, and dyslipidemia, and the second therapeutic agent may be an anti- diabetic agent. In certain embodiments, the anti-diabetic agent may be a glucagon-like peptide- 1 (GLP-1) receptor modulator.

[0220] The invention also contemplates using combination therapy to prevent, treat, delay the onset of, or remit any of the diseases, disorders, syndromes, or symptoms described herein in a subject in need thereof, and the combination therapy comprises administering to a subject in need thereof an effective amount of a compound of the invention, optionally conjugated to a half-life extending moiety, a derivative thereof or a pharmaceutically acceptable salt, or a pharmaceutical composition, in combination with one or more of the following therapeutic agents: dipeptidyl peptidase-4 (DPP-4) inhibitors (e.g., sitagliptin, saxagliptin, linagliptin, alogliptin, etc.); GLP- 1 receptor agonists (e.g., short-acting GLP-1 receptor agonists such as exenatide and lixisenatide; intermediate-acting GLP-1 receptor agonists (e.g., liraglutide); long-acting GLP-1 receptor agonists such as extended-release exenatide, albiglutide, dulaglutide, etc.); sodium-glucose cotransporter-2 (SGLT-2) inhibitors (e.g., canagliflozin, dapagliflozin, empagliflozin, etc.); bile acids (e.g., citagliptin, saxagliptin, linagliptin, alogliptin, etc.); GLP- 1 receptor agonists (e.g., short-acting GLP-1 receptor agonists such as exenatide and lixisenatide; intermediate-acting GLP-1 receptor agonists (e.g., liraglutide); long-acting GLP-1 receptor agonists such as extended-release exenatide, albiglutide, dulaglutide, etc.); sodium-glucose cotransporter-2 (SGLT-2) inhibitors (e.g., canagliflozin, dapagliflozin, empagliflozin, etc.); bile acids (e.g., liraglutide); long-acting GLP-1 receptor agonists such as extended-release exenatide, albiglutide, dulaglutide, etc.); sodium-glucose cotransporter-2 (SGLT-2) inhibitors (e.g., canagliflozin, dapagliflozin, empagliflozin, etc.); bile acids (e.g., canagliflozin, dapagliflozin, empagliflozin, etc.); bile Acid blockers (e.g., colesevelam, etc.); dopamine receptor agonists (e.g., bromo criptine rapid release); biguanides (e.g., metformin, etc.); insulin; oxy ntomodulin; sulfonylureas (e.g., chlorpropamide, glimepiride, glipiz ide, glibide, glibenclamide, glibornuride, glysocipide, glyclopyrami de, tolazamide, tolbutamide, acetohexamide, carbutamide, etc.); and thiazoli dinediones (e.g., pioglitazone, rosiglitazone, lobeglitazone, ciglitazone daluglitazone, englitazone, netoglitazone, riboglitazone, troglitazone etc.). In some embodiments, the dose of the additional therapeutic agent(s) is optionally reduced when combined with the compound, its derivative or its pharmaceutically acceptable salt of the present invention incorporated into the half-life extension portion, or a pharmaceutical composition. In some embodiments, when used in combination with the complex or compound of the present invention, the additional therapeutic agent(s) can be used at a lower dose than when each is used alone. The disease or disorder is obesity, type I or type II diabetes, metabolic syndrome (i.e., syndrome X), insulin resistance, impaired glucose tolerance (e.g., glucose tolerance), hyperglycemia, hyper insulinemia, hypertriglyceridemia, congenital hyperinsulinism (CHI)-induced hypoglycemia

[0221] hypoglycemia, dyslipidemia, atherosclerosis, diabetic nephropathy, and other cardiovascular risk factors such as hypertension and cardiovascular risk factors associated with unregulated cholesterol and / or lipid levels, osteoporosis, inflammation, non-alcoholic fatty liver disease (NAFLD), non-alcoholic cirrhosis, and other metabolic disorders. cholesterol and / or lipid levels, osteoporosis, inflammation, non-alcoholic fatty liver disease (NAFLD), non-alcoholic cirrhosis, and other metabolic disorders. vascular risk factors, osteoporosis, inflammation, non-alcoholic fatty liver disease (NAFLD), non-alcoholic From the group consisting of non-alcoholic steatohepatitis (NASH), kidney disease, and eczema, a specific In an embodiment, the second therapeutic agent can be liraglutide.

[0222] The present invention contemplates using a combination therapy to prevent, treat, delay the onset of, or remit any of the diseases, disorders, syndromes, or symptoms described herein in a subject in need thereof, and the combination therapy comprises administering to a subject in need thereof an effective amount of the compound of the present invention, its derivative or a pharmaceutically acceptable salt, optionally conjugated to a half-life extending moiety, or a pharmaceutical composition, in combination with a surgical therapy. In certain embodiments, the surgical treatment can be a bariatric surgery (e.g., a gastric bypass surgery such as a Roux-en-Y gastric bypass surgery; a sleeve gastrectomy; an adjustable gastric band surgery; a biliopancreatic diversion with duodenal switch; an intragastric balloon; a gastric plication, and combinations thereof). In embodiments where one or more additional therapeutic agents or surgical therapies are administered on the same day as an effective amount of the complex or compound of the present invention, the complex or compound of the present invention can be administered before, after, or simultaneously with the additional therapeutic agent or surgical therapy. The use of the term "combined" does not limit the order in which the treatments are administered to the subject. For example, a first treatment (e.g., a composition described herein) can be administered to a subject before (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 16 hours, 24 hours, 48 hours, 72 hours, 96 hours , 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), simultaneously

[0223] with, or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours) of the administration of a second treatment to the subject. The use of the term "combined" does not limit the order in which the treatments are administered to the subject. For example, a first treatment (e.g., a composition described herein) can be administered to a subject before (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 16 hours, 24 hours, 48 hours, 72 hours, 96 hours hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), simultaneously with, or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours) of the administration of a second treatment to the subject. Time, 12 hours, 16 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks , and can be administered after 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks .

[0224] Abbreviations Throughout this specification and the present application, the following abbreviations may be used. Abu: 4-aminobutyric acid; A c2O: acetic anhydride; aq: aqueous; alloc: allyloxycarbonyl; arach: arachidonyl; Boc: tert-butoxycarbonyl; BSA: bovine serum albumin; CDI: 1,1’-carbonyldiimidazole; DCM:: dichloromethane; Dde: 1 -(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl; DIB AL-H: diisobutylaluminum hydride; DIC: diisopropylcarbodiimide; DIEA: diisopropylethylamine; DMA: N,N-dimethylacetamide; DM F: N,N-dimethylformamide; DMSO: methyl sulfoxide; DODT: 2,2 ’-(ethylenedioxy)diethanethiol; EDC: N-(3-dimethylaminopropyl )-N’-ethylcarbodiimide; EDCI: 1-(3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride; Et: ethyl; EtOAc: ethyl acetate; EtOH: ethyl alcohol; FBS: fetal bovine serum; Fmoc: 9-fluorenylmethyloxyca rbony; g: gram; h: hour; HATU: 2-(1H-7-azabenzotriazol -1-yl)-1,1,3,3-tetramethylaminium hexafluorophosphate; HBSS: Hank's balanced salt solution; HBTU 2-(1H-benzotriazol-1-yl )-1,1,3,3-tetramethyluronium hexafluorophosphate); HCTU : 2-(6-Chloro-1H-benzotriazol-1-yl)-1,1,3,3-tetra methylaminium hexafluorophosphate; HCl: Hydrochloric acid; HEPES: 4-(2- hydroxyethyl)-1-piperazineethanesulfonic acid; HOBT: 1-hydroxybenz zotriazole; HPLC: High performance liquid chromatography; ivDde: 1-(4,4- dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl; LAH : Lithium aluminum hydride; LCMS: High pressure liquid chromato graphy with mass spectrometer; Me: Methyl; MeCN: Acetonitrile; MeOH: Methyl alcohol; mg : Milligram; min: Minute; Mmt: 4-Methoxytrityl; mpm: mL / min; Mtt : 4-Methyltrityl; NHS: N-Hydroxysuccinimide; NMP: 1-Methyl- 2-pyrrolidone; OEG: 8-Amino-3,6-dioxaoctanoyl; Oxyma: Ethyl cyano(hydroxyimino)acetate; Pal: Palmitoyl; Pbf: 2,2, 4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl; Pd(PPh3)4 : Tetrakis(triphenylphosphine)palladium(0); PhSiH3: Phenylsi lane; psi: Reduced amide bond (between adjacent amino acids); PyBroP: Bromo-t ris-pyrrolidino-phosphonium hexafluorophosphate; Pyoxim: 1-cyano -2-ethoxy-2-oxoethylideneaminooxy-tris-pyrrolidino-phosphoni um hexafluorophosphate; rt: Room temperature; RT: Retention time; satd.: Saturated; S PPS: Solid phase peptide synthesis; Stear: Stearoyl; t-Bu: tert-Butyl; TBTU: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl ammonium tetrafluoroborate; TFA: trifluoroacetic acid; THF: tetrahydro furan; THP: tetrahydropyranyl; TIPS: triisopropylsilane; Tri s: tris(hydroxymethyl)aminomethane; Trt: triphenylmethyl

[0225] Synthesis The compounds of formula I in the present invention can be synthesized according to general synthetic methods known to those skilled in the art. The following description of the synthesis is for illustrative purposes only and is in no way intended to limit the present invention.

[0226] The NTSC cyclic PYY (NTSC-PYY) analogs or derivatives of the present invention can be synthesized by various known conventional procedures for forming successive peptide linkages between amino acids, using an automated peptide synthesizer, conventional bench synthesis, or a combination of both approaches, preferably by solid-phase peptide synthesis (SPPS) as generally described by Merrifield (J. Am. Chem. Soc., 1963, 85, 2 149 - 2154). Conventional procedures for peptide synthesis involve the condensation between the free amino group of one amino acid residue (with other reactive functional groups suitably protected) and the free carboxyl yl group of another amino acid (with its reactive functional groups also suitably protected). Examples of condensing agents commonly used for peptide bond formation include diisopropylcarbodiimide (DIC) with or without 1-hydroxybenzotriazole (HOBt) or ethyl cyano(hydroxyimino)acetate (Oxyma Pure), 2-(1H-benzotriazol yl)-1,1,3,3-tetramethylammonium tetrafluoroborate (TBTU), etc. Examples of condensing agents commonly used for peptide bond formation include 1-hydroxybenzotriazole (HOBt) or ethyl cyano(hydroxyimino)acetate (Oxyma Pure) with or without diisopropylcarbodiimide (DIC), 2-(1H-benzotriazol yl)-1,1,3,3-tetramethylammonium tetrafluoroborate (TBTU), etc. ​O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethylaminium hexafluorophosphate (HBTU), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3, 3-tetramethylaminium hexafluorophosphate (HATU), 2-(6-chloro -1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium hexafluorophosphate (HCTU), 1-cyano-2-ethoxy-2-oxoethyl idenaminooxy-tris-pyrrolidino-phosphonium hexafluorophosphate( PyOxim), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tet ramethylaminium tetrafluoroborate (TBTU) bromo-tris-pyrrolidino- phosphonium hexafluorophosphate (PyBroP), etc. can be mentioned.

[0227] The automated peptide synthesis methodology is described by Yu (J. Org. Chem., 1992, 57, 478 1~4784) and has been recently improved by Palasek (J. Pept. Sci., 2007, 13, 143~148). Preferably, by applying microwave heating it can be carried out at room temperature or high temperature.

[0228] The compound (C-terminal amide) of the present invention can be conveniently prepared using the N-α-Fmoc protected amino acid methodology in which the carboxy terminus of a suitably protected N-α-Fmoc protected amino acid is coupled onto a conventional solid phase resin using a suitable coupling agent. Suitable conventional commercially available solid phase resins include Rink amide MBHA resin, Rink amide AM resin, Tentagel S RAM Resin, Fmoc-PAL-PEG PS resin ​​​, SpheriTide Rink amide resin, ChemMatrix Rink resin, Sieber amide resin, TG Sieber resin, and the like. Subsequently, the resin-bound Fmoc-amino acid may be deprotected by exposure to 20% piperidine in either DMF or NMP, and this treatment serves to selectively remove the Fmoc protecting group. Subsequently, additional Fmoc-protected amino acids are successively coupled and deprotected, thereby generating the desired resin-bound, protected peptide. In certain cases, it may be necessary to utilize an orthogonal reactive protecting group for another amine in the peptide sequence that will withstand the Fmoc deprotection conditions. Protecting groups such as 4-methyltrityl (Mtt) or 4- methoxytrityl (Mmt) are both removable by 1% TFA / DCM treatment or, preferably, allyloxycarbonyl (alloc; removable by Pd(PPh 3)4 / PhSiH3 treatment), 1-(4,4-dimethyl-2,6-dioxo cyclohex-1-ylidene)ethyl (Dde; removable by treatment with 2-3% hydrazine / DMF), and 1-(4,4-dimethyl-2,6-dioxocyclohex -1-ylidene)-3-methylbutyl (ivDde; removable by treatment with 2-3% hydrazine / DMF) can be effectively used in such cases.

[0229] In conventional peptide synthesis methodologies, the reactive side chains of α-amino acids are generally protected through synthesis with suitable protecting groups to render them inert to the coupling and deprotection protocols. Multiple protecting groups for amino acid side chains are known in the art, but this specification ​In the present specification, the following protecting groups are most preferred: serine, threonine, glutamic acid, asparagine, tert-Butyl (t-Bu) for glycine, tyrosine, and asparagine, glutamine, and cysteine. Trityl (Trt) for tryptophan, homocysteine, and histidine; and lysine ε-amino group is tert-butyloxycarbonyl (Boc); Ginine is 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl ( These protecting groups can be deprotected by treatment with strong acids such as concentrated trifluoroacetic acid (TFA). are removed.

[0230] Upon completion of SPPS, the resin-bound, side-chain protected peptide was deprotected and triisopropylated. Propylsilane (TIPS), water, phenol, and carbocations such as anisole Using a cleavage cocktail consisting primarily of (TFA) along with various combinations of scavengers The peptide / cocktail filtrate is then precipitated with cold ether. The crude solid peptide is isolated by cleavage of the Sieber resin-bound protected peptide. In the particular case of tides, cleavage of the protected peptide from the resin leads to side-chain deprotection. Repeated treatment with 1-2% TFA in DCM without further oxidization can be advantageously used to isolate the product. Once complete, further manipulation of the protected peptide can be carried out in solution phase reactions. Finally, the protected peptide was globally deprotected using a separate treatment with a cleavage cocktail. The crude peptide thus obtained can then be reacted with 1,000 sucrose to obtain a 1,000 sucrose ester, which can be protected and precipitated as described above. Low concentrations (approximately 100%) of acetonitrile or ethanol in a predominantly aqueous solvent system containing organic cosolvents <4mg / mL). If the pH of the solution is raised to >5, the peptide then dissolves intramolecularly. Through a cyclization reaction, the corresponding crude NTSC PYY analog of the present invention is formed. In this way, the formed NTSC PYY analog can be purified using purification techniques generally known in the art. A preferred method of peptide purification used herein is reverse-phase high-performance liquid chromatography (HPLC). The purified peptide is then characterized by liquid chromatography / mass spectrometry (LC / MS).

[0231] General Scheme A general synthetic procedure for the synthesis of C-terminal amide NTSC-PYY peptides where BRIDGE is -Ph-CH2-S- is shown in Scheme 1.

[0232]

Chemical Structure

[0233] Scheme 1: Synthesis of Toloylthioether-Linked NTSC-PYY Peptide: C-Terminal Amide. A) Synthesis of Resin-Bound C-Terminal Amide Peptide The protected peptidyl resin can be synthesized on a 0.1 mmol scale using the above-described Fmoc strategy as shown in Scheme 1 using a CEM Liberty Blue Microwave Peptide Synthesizer with low loading Rink amide resin, preferably Fmoc-PAL-PEG PS resin (about 0.16 - 0.2 meq / g, supplied by Applied Biosystems). Standard Fmoc-protected amino acids (supplied by Novabiochem (EMD Millipore), Bachem, Peptides International, or Chem-Impex) are used as coupling agents with For resin filling using DIC / Oxyma and a reaction temperature of approximately 90 °C for 4 minutes can be coupled 5-fold in excess. Fmoc-Arg(Pbf)-OH is double-bonded at 90 °C for 4 minutes each and Fmoc-His(Trt)-OH can be coupled using a two-step protocol of 4 minutes at room temperature followed by 8 minutes at 50 °C. Single Fmoc deprotection can be carried out at 90 °C for 1.5 minutes using 20% piperidine in DM F (deprotection solution). .

[0234] B) Coupling procedure for halomethylbenzoic acid The Fmoc-deprotected peptide resin (0.1 mmol) is treated in a microwave reactor with a solution of either chloro- or bromomethylbenzoic acid (20 equivalents), the desired isomer (meta or para), and DIC (10 equivalents) in DMF (4 mL) at 7 5 °C for 15 minutes. The reaction completeness can be determined by the Kaiser ninhydrin test (Kaiser, et al ., Anal. Biochem., 1970, 34, 595 - 598). If the coupling is determined to be incomplete, the coupling can be repeated with fresh reagents . .

[0235] C) Peptide cleavage procedure from resin Once SPPS is complete, the resin can be thoroughly washed with DMF and then DCM and dried . The resin is then treated with a cleavage cocktail (10 mL / 0.1 mmol scale) consisting of either TFA / water / TIPS (95:2.5:2.5) (Cle avage Cocktail A), or more preferably TFA / water / phenol / T IPS (88:5:5:2) (Cleavage Cocktail B) in a microwave reactor . ​​​It can be filtered after heating at 38 °C for 40 minutes. The resin is washed with TFA, and the combined filtrate can be concentrated to a volume of about 2.5 mL under a nitrogen stream, and then the peptide can be precipitated by adding cold diethyl ether (40 mL). The peptide / ether suspension was centrifuged well and the ether layer was decanted. The peptide pellet was resuspended in ether, centrifuged, decanted well, and this process can be repeated 3 times. Then, the crude peptide thus obtained can be dried under a gentle nitrogen stream.

[0236] D) Peptide cyclization (thioether formation) procedure The crude cysteine- or homocysteine-containing peptide can be dissolved in deoxygenated MeCN / water (50 - 60% MeCN) or EtOH / water (60% EtOH) at a concentration of <4 mg / mL. Then, the pH of the peptide solution can be raised to about 7 - 9 by adding any of solid NaHCO3, saturated aqueous NaHCO3, or 1M aqueous Tris buffer (pH 7.5), and the resulting solution can be stirred at room temperature for 3 - 16 hours. Typically, cyclization is completed within 3 - 4 hours as determined by analytical LC / MS.

[0237] E) Peptide purification procedure The cyclization reaction mixture may be acidified to pH 1.5 - 3 by the addition of TFA, and the solution can be concentrated to remove most of the organic co-solvent (MeCN or EtOH) until a slight turbidity occurs. A minimal amount of co-solvent may be added back if necessary to homogenize the mixture, and then the resulting solution can be directly purified by preparative HPLC ​It may be carried out. Purification is performed using a reverse-phase C18 or C8 column selected from the following, with an Agilent PrepStar HPLC system or a Gilson HPLC 2020 Personal Purification System: Varian Pursuit XR C18 (21×250 mm, 100 Å, 5 μm); Varian Pursuit XR diphenyl (30×100 mm, 100 Å, 5 μm); Zorbax 300 SB-C8 (21×250 mm, 300 Å, 5 μm); Waters Atlantis T3 C18 (19×250 mm, 100 Å, 5 μm); Agilent Polaris 5 C18-A (30×250 mm, 180 Å, 5 μm). The mobile phase consists of buffer A (0.1% TFA in water) and a gradient elution of buffer B (0.1% TFA in MeCN) ranging from an initial concentration of 10 - 20% B to a final concentration of 40 - 90% B, and the running time can range from 36 to 80 minutes. UV detection can be monitored at 220 and 254 nm. The product-containing fractions can be analyzed by analytical HPLC using an Agilent 1100 HPLC system with an appropriate column type (4.6×250 mm, 5 μm) from the above. The pure fractions can be combined, concentrated to remove most of the organic phase, and then lyophilized. TFA / HCl salt exchange can be performed later by three freeze-drying steps from 2 mM HCl according to the procedure described by Andrushchenko et al. (J. Pept. Sci., 2006, 13, 37 - 43). A general synthetic procedure for the synthesis of the C-terminal amide NTSC-PYY peptide where BRIDGE is -NHC(O)CH2S- is shown in Scheme 2. lent PrepStar HPLC system or Gilson HPLC 2020 Personal Purification System can be carried out : Varian Pursuit XR C18 (21×250 mm, 100 Å, 5 μ m); Varian Pursuit XR diphenyl (30×100 mm, 100 Å, 5 μm); Zorbax 300 SB-C8 (21×250 mm, 300 Å, 5 μm) ; Waters Atlantis T3 C18 (19×250 mm, 100 Å, 5 μ m); Agilent Polaris 5 C18-A (30×250 mm, 180 Å 、5 μm). The mobile phase consists of buffer A (0.1% TFA in water), and a gradient elution of buffer B (0.1% TFA in MeCN) ranging from an initial concentration of 10 - 20% B to a final concentration of 40 - 90% B from which the running time can range from 36 to 80 minutes. UV detection can be monitored at 220 and 254 nm. The product-containing fractions can be analyzed by analytical HPLC using an Agilent 1100 HPLC system with an appropriate column type (4. 6×250 mm, 5 μm) from the above. The pure fractions can be combined, concentrated to remove most of the organic phase, and then lyophilized. TFA / HCl salt exchange can be performed later by three freeze-drying steps from 2 mM HCl according to the procedure described by Andrushch enko et al. (J. Pept. Sci., 2006, 13, 37 - 43). The pure fractions are combined, concentrated to remove most of the organic phase, and then may be lyophilized. After that, it may be lyophilized. TFA / HCl salt exchange can be performed later by three freeze-drying steps from 2 mM HCl according to the procedure described by Andrushch enko et al. (J. Pept. Sci., 2006, 13, 37 - 43). It can be carried out later by three freeze-drying steps from 2 mM HCl according to the procedure described by Andrushchenko et al. (J. Pept. Sci., 2006, 13, 37 - 43).

[0238] A general synthetic procedure for the synthesis of the C-terminal amide NTSC-PYY peptide where BRIDGE is -NHC(O)CH2S- is shown in Scheme 2. A general synthetic procedure for the synthesis of the C-terminal amide NTSC-PYY peptide where BRIDGE is -NHC(O)CH2S- is shown in Scheme 2.

[0239]

Chem.

[0240] Scheme 2: Synthesis of Acetamidyldithioether - Linked NTSC - PYY Peptide: C Terminal amide Steps A, C, D, and purification (E) are essentially the same as those described in Scheme 1 However, as described below, an alternative BRIDGE may be introduced in Step B if desired.

[0241] The Fmoc - deprotected peptide resin (0.1 mmol) can be treated with a solution of bromoacetic anhydride (6 - 20 equivalents) in DMF (5 mL) in a microwave reactor at 50 °C for 5 minutes and by that time, the reaction can generally be judged to be complete by the Kaiser ninhydrin test If the coupling is determined to be incomplete, the coupling may be repeated with fresh reagents if necessary.

[0242] Z 35 A general synthetic procedure for the synthesis of the C - terminal amide NTSC - PYY peptide where Z is either or is shown in Scheme 3

[0243]

Chem.

[0244]

Chem.

[0245] Scheme 3: Loading of the psi-(R35,Y36) moiety onto Sieber resin A) HATU - mediated coupling: ​​In a fritted microwave reactor (supplied by CEM Corporation) the NovaSyn TG Sieber resin (supplied by Novabiochem) ( 0.1 mmol) may be treated with a deprotection solution (5 mL) and heated at 50 °C for 2.5 minutes. The reaction product is discharged, washed with DMF, and treated again with the deprotection solution at 50 °C for 5 minutes. The resin is discharged washed with DMF, and then subjected to a third deprotection treatment at 50 °C for 5 minutes. The resin is discharged and washed thoroughly with DMF and then with DCM. The resin is then treated with Fmoc-Arg(Pbf)-psi-(N-Boc)Tyr(tBu) -OH (3 - 5 equivalents) from the syringe 14 in DMF (4 mL), HATU (2.75 - 4.5 equivalents), and DIEA (6 - 10 equivalents) and the solution is mixed at room temperature for 24 hours. The mixture is discharged and the resin is washed thoroughly with DMF . Then, under microwave conditions, the resin is end-capped by treatment with 20% Ac2O in DMF (5 mL) at 50 °C for 5 minutes. The reaction product is discharged and the resin is washed thoroughly with DMF and then with DCM.

[0246] A) (Alternative) DIC / Oxyma-mediated coupling: In a fritted microwave reactor, the NovaSyn TG Sieber resin 0.1 mmol) is deprotected as described in step A above and then treated with a solution of moc-Arg(Pbf)-psi-(N-Boc)Tyr(tBu)-OH (2 .75 equivalents), DIC (2.75 equivalents), Oxyma (2.75 equivalents), and DIEA ( 0.275 equivalents) in MeCN (4 mL) and mixed at room temperature for 24 hours. The reaction product is discharged and the resin is washed thoroughly with DMF and then with DCM and can be used directly without end-capping.

[0247] ​​​ B) Reduction amide (psi-R35,Y36) peptide on pre-packed Sieber resin Purification of peptide Further amino acid extension onto the pre-packed (psi-R35,Y36)-Sieber resin can be carried out on a CEM Liberty Blue Microwave peptide synthesizer. Standard Fmoc-protected amino acids are coupled 5-fold in excess relative to the initial resin loading using HBTU / DIEA as the coupling agent and a reaction temperature of about 50 °C for 15 minutes. Fmoc-Arg(Pbf)-OH may be double-coupled using a two-step protocol of 25 minutes at room temperature followed by 15 minutes at 5 0 °C for each coupling, and Fmoc-His(T rt)-OH may be double-coupled using a two-step protocol of 4 minutes at room temperature followed by 8 minutes at 50 °C for each coupling. Fmoc deprotection can be carried out in two steps of 1) 2.5 minutes at 50 °C and 2) 5 minutes at 50 °C using fresh deprotection solution for each step and, optionally, double-coupling can be advantageously used throughout to improve the quality of the isolated crude peptide. The placement of the thioether BRIDGE moiety can proceed at a reaction temperature of 50 °C by either of the bromomethylbenzoic acid linkages shown in step B of Scheme 1. Alternatively, the thioether BRIDGE moiety may be introduced using the bromoacetylation linkage shown in step B of Scheme 2 Once SPPS is complete, the resin is washed thoroughly with DMF and then DCM and dried. The cleavage of the protected peptide from the Sieber resin is then carried out with DCM (10 mL / 0. and then DCM and dried. The cleavage of the protected peptide from the Sieber resin is then carried out with DCM (10 mL / 0. and then DCM and dried. The cleavage of the protected peptide from the Sieber resin is then carried out with DCM (10 mL / 0. and then DCM and dried. The cleavage of the protected peptide from the Sieber resin is then carried out with DCM (10 mL / 0.

[0248] The placement of the thioether BRIDGE moiety can proceed at a reaction temperature of 50 °C by either of the bromomethylbenzoic acid linkages shown in step B of Scheme 1. Alternatively, the thioether BRIDGE moiety may be introduced using the bromoacetylation linkage shown in step B of Scheme 2 and then DCM and dried. The cleavage of the protected peptide from the Sieber resin is then carried out with DCM (10 mL / 0. The thioether BRIDGE moiety may be introduced using the bromoacetylation linkage shown in step B of Scheme 2 Once SPPS is complete, the resin is washed thoroughly with DMF and then DCM and dried. The cleavage of the protected peptide from the Sieber resin is then carried out with DCM (10 mL / 0.

[0249] Once SPPS is complete, the resin is washed thoroughly with DMF and then DCM and dried. The cleavage of the protected peptide from the Sieber resin is then carried out with DCM (10 mL / 0. Once SPPS is complete, the resin is washed thoroughly with DMF and then DCM and dried. The cleavage of the protected peptide from the Sieber resin is then carried out with DCM (10 mL / 0. Achieved in a solution of 1 - 2% TFA in 1 mmol scale, mixed for about 10 minutes, and then can be filtered. This treatment can be repeated 9 more times, using a new cocktail for each treatment. Next, the combined filtrate is concentrated to obtain the protected crude peptide as a yellow syrup / solid, which can be used directly for subsequent overall deprotection. The protected peptide obtained above is treated with Cleavage Cocktail B (10 mL) at room temperature for 2.5 hours and then concentrated to a volume of about 2.5 mL under a nitrogen stream. The crude peptide can be precipitated by adding cold diethyl ether (40 mL). The peptide / ether suspension is centrifuged well and the ether layer is decanted. The peptide pellet is resuspended in ether, centrifuged, and decanted well, and this process can be repeated 3 times. The crude peptide thus obtained can be dried under a gentle nitrogen stream. Cyclization and purification of the reduced amide (psi - R35, Y36) peptide can be achieved according to the procedures described in Steps D and E of Scheme 1.

[0250] Synthesis of the lipidated c - terminal amide NTSC - PYY peptide can be achieved according to Scheme 4.

[0251]

Chemical Structure

[0252] Scheme 4: Procedure for introducing lipidated lysine residues into the peptide sequence synthesized on PAL - PEG PS Rink amide resin A) Procedure for introducing derivatized lysine residues into the peptide sequence constructed on a standard Rink amide resin residue Purified up to a point prior to the desired derivatization time point and prepared as described in Scheme 1, Step A to the resin-bound C-terminal amide peptide, add either Dde-Lys(Fmoc)- OH or ivDde-Lys(Fmoc)-OH, then Fmoc-Glu- OtBu (all supplied by Novabiochem), and sequentially couple and purify under microwave conditions (manually or using a Liberty Blue Peptide Synthesizer) as described in Scheme 1, Step A This can be done. After Fmoc deprotection, the resin is treated with a solution of a lipophilic acid [palmitic acid or α-tocopheryl oxyacetic acid (AcVitE)] ( 5 - 10 equivalents), DIC (5 - 10 equivalents), and either HOBT or Oxyma (5 - 10 equivalents ) in DMF at 90 °C for 10 minutes under microwave conditions. Then, the reaction mixture is drained and the resin is washed with DMF.

[0253] B) Procedure for Deprotecting Dde- or ivDde-Protected Lysinyl Peptides The derivatized lysinyl peptide resin can be treated with a solution of 3% hydrazine in DMF (6 mL / 0.1 mmol resin) at 90 °C for 3.5 minutes under microwave conditions. The reaction mixture is drained and this procedure can be repeated two more times. The reaction mixture is drained and the resin is washed thoroughly with DMF, then with DCM.

[0254] C) Procedure for Direct Incorporation of the Fmoc-Lys(Pal-Glu-OtBu)-OH Residue When the palmitoylated-γ-Glu-lysyl residue is incorporated into the sequence, Fmoc-L ​​​​​​​ys(Pal-Glu-OtBu)-OH(Peptides Internation al or ActivePeptide) is depicted in Scheme 1, Step A. It can be used directly in the procedure.

[0255] Compounds of the invention having lipidated lysine residues can be prepared according to Scheme 1, Steps B, C, D, and E. This can be completed by following the steps in E.

[0256] Lipidated reduced amide (psi-R35,Y36), C-terminal amide, NTSC-PYY Synthesis of the peptide can be accomplished according to Scheme 5.

[0257] [ka]

[0258] Scheme 5: (psi-R35,Y36) Synthesis on preloaded Sieber resin A procedure for introducing derivatized lysine residues into selected peptide sequences. A) (psi-R35,Y36) Peptide constructed on pre-loaded Sieber resin A procedure for introducing derivatized lysine residues into tide sequences. Partially purified reduced amide (C) ... psi-R35,Y36) peptide was incubated at 50°C for 15 min with HATU / DIEA or HB Alloc-Lys(Fmoc)-OH was synthesized using either the TU / DIEA coupling method. (available from Chem-Impex or AAPPTec, LLC), followed by Fmoc- Glu-OtBu and then palmitic acid (5 equivalents each) can be sequentially coupled. The lipophilic acids that can be bound are stearic acid, arachidic acid, octadecanedioic acid, mono- tert-Butyl ester (available from AstaTech, Inc.), or 20-( tert-Butoxy)-20-oxoicosanoic acid (available from Key Organics, Inc. ), NMP can be used as a solvent for reasons of improved reagent solubilization , and the coupling reaction can be mediated by HATU / DIEA at 50 °C for 30 minutes. Alternatively , for arachidonic acid, the coupling uses the DIC / Oxym a-mediated procedure described in Scheme 1, Step A, but is carried out using 5 equivalents of the reagent and THF as the reaction solvent .

[0259] B) Alloc Deprotection Procedure The above resin (0.1 mmol) is washed with deoxygenated DCM and then treated with PhSiH3 (12.5 equivalents) in deoxygenated DCM (5 mL). After 2 minutes, a solution of Pd(PPh3)4 (0.25 equivalent) in deoxygenated DCM (5 mL ) is added and mixed well, and the reaction mixture is mixed under a nitrogen atmosphere for 0.5 hour. The reaction mixture is drained, and the resin is washed once with deoxygenated DCM. The resin is treated again with PhSiH3 (12.5 equivalents) and Pd(PPh3)4 (0.25 equivalent) as described above and reacted for an additional 0.5 hour. The reaction mixture is drained, and the resin is washed thoroughly successively with DCM, DMF, and again with DCM.

[0260] Further purification and completion of the peptide can be carried out starting from Step B of Scheme 3 and proceeding as described above in this specification.

[0261] The synthesis of C-terminal amide NTSC-PYY analogs where BRIDGE is triazolyl is shown in Scheme 6 .

[0262]

Chemical Structure

[0263] Scheme 6: Synthesis of Triazolol-Linked NTSC-PYY Analogs: C-Terminal Amide Peptides A) Synthesis of Resin-Bound C-Terminal Amide Peptides Containing Azide and Alkynyl A protected peptide containing resin-bound ε-azidonorleucine with its N-terminus protected by 4-pentynoic acid can be prepared according to Scheme 1, Step A. A double-bond protocol can be used for the incorporation of 4-pentynoic acid.

[0264] B) Procedure for Introducing Derivatized Lysine Residues into Resin-Bound C-Terminal Amide Peptides Containing Azide and Alkynyl According to the procedure described in Scheme 1, Step A, Fmoc-Lys(Dde)-OH can be incorporated into SPPS at the sequence position to be derivatized. Once the linear sequence is completed (after the incorporation of 4-pentynoic acid), the resin is treated with 3% hydrazine in DMF (8 mL / 0.1 mmol scale) at room temperature for 5 minutes, and then the mixture is drained. This procedure can be repeated approximately 6 times. Then, the resin is washed thoroughly with DMF and then with DCM. Then, according to the procedure described in Example 6A, Fmoc-Glu-OtBu and lipophilic acids are sequentially coupled onto the Dde-deprotected resin.

[0265] C) Procedure for Cleaving Azide- and Alkynyl-Containing Peptides from the Resin Once SPPS is completed, the resin can be washed thoroughly with DMF and then with DCM and dried. Then, the resin is treated with a cleavage cocktail consisting of TFA / water / DODT / TIPS (92.5:2.5:2.5:2.5) (Cleavage Cocktail C) (10 mL / 0.1 mmol scale). Treat with kale), heat in a microwave reactor at 38 °C for 40 minutes, and then filter. The resin is washed with TFA, and the combined filtrate is concentrated to a volume of about 2.5 mL under a nitrogen stream, and the peptide can be , precipitated by adding cold diethyl ether (40 mL). The pe ptide / ether suspension is centrifuged well and the ether layer is decanted. The peptide pellet can be resuspended in ether, centrifuged, and decanted, and this process can be repeated 3 times . The crude peptide thus obtained can be dried under a gentle nitrogen stream .

[0266] D) Peptide cyclization (triazole formation) procedure

[0267] The following solutions can be prepared using deoxygenated water. 1) CuSO4 (7 mg in 2 mL of water) 2) 30 mg of TBTA in 5.4 mL of EtOH and 0.6 mL of MeCN 3) Premix solution 1 (943 μL) and solution 2 (4.8 mL) 4) Sodium ascorbate (30 mg in 3 mL of water)

[0268] To a solution of the crude peptide from step C (0.021 mmol) in either deoxygenated water or HEPES buffer (pH 7.4) (20 mL), add solution 3, followed by solution 4 (2.4 mL ), and warm the resulting milky solution to 35 - 40 °C until cyclization is determined to be complete by LCMS analysis (about 1 - 5 hours) . Dilute the reaction solution to 40 mL with either water (0.1% TFA) or 60% MeCN / water (0.1% TFA), filter, and directly purify by preparative HPLC using multiple injections as described in step E

[0269]

[0269] ​ Scheme for the synthesis of C-terminal amide NTSC-PYY analogs where the BRIDGE is a lactam is shown in Scheme 7.

[0270]

Chemical Structure

[0271] Scheme 7: Synthesis of lactam-bridged cyclic peptides. A) Synthesis of resin-bound C-terminal amide peptides The protected peptidyl resin can be synthesized using the Fmoc strategy on a Protein Technologies Symphony X peptide synthesizer. The coupling is performed using HATU and NMM in DMF for 10 minutes at room temperature, either on Rink amide resin or Sieber resin. The Fmoc amino acids are used in 6-fold excess and can be double-coupled. For peptides containing the psi-(R35,Y36) modification Fmoc-Arg(Pbf)Ψ[CH2N(Boc)]Tyr(t-Bu)-OH is coupled in 3-fold excess using HATU and NMM in DMF for 1 hour at room temperature. The α-amino of the terminal residue of the linear sequence may be Boc-protected and the γ-carboxyl group of the glutamate residue forming the lactam bridge may be allyl-protected. Lysine(s) in the peptide may be orthogonally Dde-protected. at room temperature. The α-amino of the terminal residue of the linear sequence may be Boc-protected, and the γ-carboxyl group of the glutamate residue forming the lactam bridge may be allyl-protected. Lysine(s) in the peptide (plural optional) may be orthogonally Dde-protected. optional) may be orthogonally Dde-protected. optional) may be orthogonally Dde-protected.

[0272] B) Synthesis of γ-glutamate-N-hydroxysuccinimide ester After completion of the linear sequence, the allyl protecting group of the glutamate side chain can be removed using Pd(PPh3)4 and PhSiH3 in DCM. Then, N-hydroxysuccinimide imide (NHS) ester is prepared using HATU and DIEA in NHS for 10 minutes at room temperature. imide (NHS) ester is prepared using HATU and DIEA in NHS for 10 minutes at room temperature. It can be synthesized by double bonding.

[0273] C) Lactam cyclization procedure The peptide is treated with TFA / TIPS / water (95:2.5:2.5) at room temperature for 2 hours to cleave it from the resin, deprotect it globally, then precipitate it in ether, collect it by centrifugation and dry it. The crude product may be dissolved in DMSO. TEA (10 equivalents) is added and the cyclization is allowed to proceed at room temperature for 1 hour. The crude product is diluted with water and can be purified by preparative RP-H PLC. The peptide is dissolved in 2% hydrazine / DMF (concentration 5 mM) and stirred at room temperature for 1 hour to deprotect the orthogonally dde-protected lysine . The reaction mixture is diluted with water, 10% TFA / water is added to adjust the pH to 2, and the solution can be directly purified by preparative RP-HPLC as described in Scheme 1, step E . The solution-phase synthesis of the lipidated C-terminal amide NTSC -PYY analog in which BRIDGE is a lactam is shown in Scheme 8. The solution-phase synthesis of the lipidated C-terminal amide NTSC-PYY analog in which BRIDGE is a lactam is shown in Scheme 8.

[0274] The solution-phase synthesis of the lipidated C-terminal amide NTSC-PYY analog in which BRIDGE is a lactam is shown in Scheme 8.

[0275]

Chemical formula

[0276] Scheme 8: Z 11 Solution-phase lipidation of the lactam-bridged C-terminal amide cyclic peptide shown for lysine. Z4, Z7, Z9, Z 11 , Z 22 , Z 23 , or Z 30Only one of them is lysine The peptide obtained in Scheme 7 above, which may be, is dissolved in DMF (at a concentration of 5 mM), TEA (5 equivalents) is added, followed by the protected lipid N-hydroxy ester (2 equivalents). The reaction is allowed to proceed overnight at room temperature and can then be purified by preparative HPLC. The t-butyl ester is deprotected at room temperature for 30 minutes in TFA / TIPS / water (95:2.5:2.5 ), the reaction is concentrated, and purified by preparative RP -HPLC as described in Scheme 1, Step E.

[0277] General procedure for synthesizing bromoacetylated cyclic thioether peptides Schemes 9, 10, and 11 all show various routes to the bromoacetylated cyclic thioether pep tides of the present invention. In Scheme 9, the thioether bridge is formed by the reaction of a thiol-containing amino acid side chain in the peptide sequence with the bromoacetyl group at the amino terminus of the peptide. Scheme 10 illustrates a similar approach to Scheme 9, but with a separate PEG spacer inserted between the lysine side chain and the bromoacetyl group. Scheme 11 illustrates another class of bromoacetylated cyclic thioether peptides in which the bridge is formed by the reaction of a thiol nucleophile at the amino terminus of the peptide with a bromoacetyl group covalently attached to the lysine side chain within the peptide sequence.

[0278] A. Synthesis of resin-bound C-terminal amide peptides The protected peptide on the resin can be synthesized on Sieber amide or R ink amide resin using the FMOC strategy. Standard FMOC-protected amino acids (Novab iochem (supplied by EMD Millipore), Bachem, Peptides International, or Chem-Impex) can be coupled at room temperature or elevated temperature with a 3- to 6-fold excess relative to the resin loading using DIC / Oxyma, HBTU / DIPEA, or HATU / NMM as coupling agents. Double couplings can be performed for high purity and especially for amino acids attached to α-N-alkylated amino acids. For peptides containing the psi-(R35,Y36) modification, Fmoc-Arg(Pbf) Ψ[CH2N(Boc)]Tyr(t-Bu)-OH can be coupled at 3-fold excess using HATU and NMM in DMF for 1 hour at room temperature.

[0279] B. Bromoacetylation Procedure for Resin-Bound Peptides The lysine to be bromoacetylated can be orthogonally protected with any of the alloc, ivDDE, or DDE protecting groups. After completion of the linear sequence on the resin, the orthogonally protected lysine may be deprotected (for alloc, Pd(Ph3)4 and phenylsilane in DCM ; for DDE or ivDDE, 2% hydrazine in DMF), and the amino group can be bromoacetylated under various conditions such as 1) reacting with a large excess of bromoacetic anhydride in DMF in a microwave reactor at 50 °C for 5 minutes (by which point the reaction can generally be determined to be complete by the Kaiser ninhydrin test), 2) reacting with a large excess of bromoacetic anhydride in DMF or DCM in the presence of a base such as TEA or DIPEA at room temperature, or 3) coupling with bromoacetic acid using DIC or DIC / Oxyma.

[0280] ​​​​​​​​​​​C. Peptide Cleavage Procedure from Resin Once SPPS is completed, the resin is washed thoroughly with DMF and then with DCM and dried can be. Using the Sieber amide resin - bound peptide, the dried resin is treated with a 1 - 2% TFA solution in DCM (10 mL) for 5 - 10 minutes and then filtered. This treatment can be repeated several more times, using a fresh cocktail for each treatment. Then, the filtrates are combined and concentrated to obtain the protected crude peptide as a yellow foam. Next, this foam is treated with cleavage cocktail TFA / phenol / H2O / TIPS (88 / 5 / 5 / 2) or TFA / water / TIPS (95:2.5:2.5), or TFA / phenol / H2 O / TIPS / DTT (84 / 10 / 2.5 / 2.5 / 1) and heated in a microwave reactor at 38 °C for 30 - 45 minutes or at room temperature for 2 - 3.5 hours. The crude peptide can be precipitated in cold diethyl ether. The peptide / ether suspension can be centrifuged and the ether layer decanted. The peptide pellet can be resuspended in ether, centrifuged, and decanted, and this process can be repeated 3 times. The crude peptide thus obtained can be dried under a gentle nitrogen stream. Alternatively, the Sieber amide or Rink amide resin - bound peptide can be treated with the cleavage cocktail as described above without pretreatment with 1 - 2% TFA in DCM to obtain a fully

[0281] deprotected peptide. deprotected peptide.

[0282] D. Peptide Cyclization (Thioether Formation) Procedure The crude free thiol - and bromoacetamide - containing peptides are optionally added with EDTA and ​It may be dissolved in deoxygenated MeCN / water or EtOH / water at a concentration of 4 to 10 mg / mL. . Then, the pH of the peptide solution can be raised to about 7 to 9 by adding any base such as NaHCO3, NaOH, DIPEA, or TEA, and the resulting solution is stirred at room temperature for 0.25 to 2.5 hours.

[0283] Alternatively, the crude peptide can be purified by HPLC, the peptide fractions can be combined, basified to about pH 7 to 9, and optionally stirred at room temperature for 0.25 to 2.5 hours in the presence of EDTA. After acidification, the reaction solution can be concentrated at room temperature to remove the organic solvent, and then subjected to HPLC purification.

[0284] E. Peptide purification procedure The cyclization reaction mixture is acidified with TFA, the solution is concentrated to remove most of the organic co-solvent (MeCN or EtO H), and then the resulting solution can be directly purified by preparative HPLC on a reverse-phase column. The mobile phase consists of buffer A (0.1% TFA in water) and buffer B (0.1% TFA in MeCN) with an initial concentration of 0 to 20% B to a final concentration of 40 to 90% B, and the elution is a gradient elution, and the run time can be in the range of 20 to 60 minutes. UV detection can be monitored at 220 and 254 nm. The product-containing fractions can be analyzed by HPLC using a Waters T3 Atl antis C18 column (4.6 × 250 mm, 5 μm) on an Agilent 1100 HPLC system. The pure fractions can be combined, concentrated to remove most of the organic phase, and then lyophilized.

[0285]

Chemical formula

[0286] Scheme 9. Synthesis of bromoacetylated cyclic thioether C-terminal amide peptides in which the thioether bridge is formed by the reaction of a thiol-containing amino acid side chain in the peptide sequence with a bromoacetyl group at the amino terminus of the peptide. In this scheme, the lysine side chain is protected with the dde protecting group and removed by treatment with 2% hydrazine in DMF.

[0287]

Chemical Structure

[0288] Scheme 10. Synthesis of bromoacetylated cyclic thioether peptides in which the thioether bridge is formed by the reaction of a thiol-containing amino acid side chain in the peptide sequence with a bromoacetyl group at the amino terminus of the peptide, and a separate PEG spacer is introduced between the bromoacetyl group and the lysine side chain. In this scheme, the lysine side chain is protected with the alloc protecting group and removed by treatment with Pd(PPh3)4 and phenylsilane.

[0289]

Chemical Structure

[0290] Scheme 11. Synthesis of bromoacetylated cyclic thioether peptides in which the thioether bridge is formed by the reaction of a thiol group at the amino terminus of the peptide with a bromoacetylated lysine side chain in the peptide sequence, and a separate PEG spacer is introduced between the bromoacetyl group and another lysine side chain.

[0291] General Procedure for the Synthesis of Bromoacetylated Cyclic Lactam Peptides ​​​​​​​​​​Cyclic lactam peptides can be synthesized according to the procedure shown in Scheme 12. They are. Cyclic lactam peptides are first prepared with Z4, Z7, Z9, Z 11 , Z 22 , Z 23 , or Z 30 Only one of them is synthesized according to Scheme 7 where only one of them is lysine. Next, the lysine is bromoacetylated at room temperature for 20 minutes using bromoacetic acid N-hydroxysuccinimide ester (3 - 7 equivalents) in 10% ACN / water at pH 10. The final bromoacetylated peptide can be purified by RP-HPLC as outlined for cyclic thioether peptides.

[0292]

Chemical formula

[0293] Scheme 12. Synthesis of bromoacetylated cyclic lactam C-terminal amide peptides

[0294] General procedure for the synthesis of bromoacetylated cyclic triazole-linked peptides Bromoacetylated cyclic triazole-linked peptides can be synthesized according to the procedure shown in Scheme 13. The linear protected peptide on the resin can be synthesized in a similar manner as described for cyclic thioether peptides in Scheme 10, except that L-azido-lysine may be incorporated into the triazole formation and the N-terminal residue may be 4-pentynoic acid. The Fmoc is removed with 20% piperidine in DMF and then reacted with bromoacetic anhydride. The linear sequence may be fully deprotected (TFA / TIPS / water: 95% / 2.5% / 2.5%) and the crude peptide is precipitated in cold ether. , may be recovered by centrifugation and purified by preparative RP-HPLC. Purified linear peptides are cyclized in the presence of CuSO4 / TBTA and NaASrb in a buffer solution (such as HEPES, MOPS) to obtain cyclic triazole-linked peptides, which can be purified by preparative RP-HPLC as described in Scheme 1, Step E. This can be done.

[0295] One of ordinary skill in the art will recognize that alternative classes of cyclic triazole-linked peptides beginning with a linear sequence where the N-terminal residue is an azidocarboxylic acid (e.g., 5-azidopentanoic acid) and the residue at position 30 or 31 is an alkynyl amino acid (e.g., 2-amino-7-octynoic acid) can be synthesized in a manner similar to that described above. This can be done.

[0296]

Chemical Structure

[0297] Scheme 13. Synthesis of bromoacetyl-cyclic triazole-linked C-terminal amide peptides.

[0298] Peptide Analysis and Characterization The purified peptides were analyzed by LC / MS on a Hewlett Packard Series 1100 MSD system configured with an HP1100 series HPLC using a WATERS Atlantis T3 C18 (4.6 × 25 0 mm, 300 Å, 5 μm) column. Depending on the polar / nonpolar nature of the peptide, one of three gradients was used: Method 1) 15 - 60% B over 22 minutes, Method 2) 30 - 60% B over 22 minutes, or Method 3) 40 - 90% B over 22 minutes at a flow rate of 1 mL / min and a column temperature of 3 5 °C. ​​​(The above buffering agents A and B). By electrospray analysis (ES-API, positive ion scan), mass spectrometry of each peptide was provided. In all cases, multiple charged species were observed, and 1 / 3[M+3] + and 1 / 4[M+4] + ions were the most prominently observed ions characteristic of. All products had the expected multiple charged ions within acceptable limits. The results of the peptide mass spectral analysis and the observed LC retention times (RT) are shown in Table 1.

[0299]

Table 1-1

[0300]

Table 1-2

[0301]

Table 1-3

[0302] Intermediate The following examples and embodiments described herein are for illustrative purposes only, and various modifications or changes considered thereof will be presented to those skilled in the art, and it is understood that they are included within the spirit and scope of this application and the appended patent claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes .

[0303] Intermediate 1 Synthesis of α-tocopheryl oxyacetic acid (AcVitE) (8) A) Tert-butyl α-tocopheryl oxyacetate (7):

[0304]

Chem.

[0305] α-Tocopherol (1.14 g, 2.65 mmol) in acetone (10 mL), t ert-butyl bromoacetate (470 μL, 3.18 mmol), and K2CO3( 1.1 g, 7.94 mmol) was stirred at room temperature for 2 - 3 days. Then, the mixture was filtered through a small plug of K2CO3, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography eluting with EtOAc / heptane (0 - 5%) to give tert-butyl α-tocopheryloxyacetate (7) as a colorless oil. 1 1H NMR (CDCl3) δ 4.17 (s, 2H), 2.56 (t, J = 6. 57 Hz, 2H), 2.18 (s, 3H), 2.14 (s, 3H), 2.07 (s, 3H ), 1.65 - 1.86 (m, 2H), 1.52 (s, 9H), 0.98 - 1.46 (m , 22H), 0.80 - 0.90 (m, 14H).

[0306] B) α-Tocopheryloxyacetic acid (AcVitE) (8)

[0307]

Chem.

[0308] To a solution of tert-butyl α-tocopheryloxyacetate (7) ( 1.4 g, 2.57 mmol) in DCM (12 mL) was added TFA (6 mL), and the resulting solution was stirred at room temperature. After 2 h, the solution was concentrated under reduced pressure, and the resulting dark oil was taken up in MeOH / DC ​​Purified by silica gel chromatography eluting with M (0 to 2.5% containing 0.5% HOAc) to obtain α-tocopheryl oxyacetic acid (AcVitE) (8) as an amber syrup and this was slowly solidified under vacuum. H NMR (CDCl3) δ 4.34 ( 1 s, 2H), 2.57 (t, J = 6.82 Hz, 2H), 2.16 (s, 3H), 2.1 2 (s, 3H), 2.08 (s, 3H), 1.79 (qt, J = 6.76, 13.01 H z, 2H), 1.48 - 1.59 (m, 3H), 1.18 - 1.48 (m, 12H), 1 .01 - 1.17 (m, 7H), 0.77 - 0.93 (m, 14H). LC / MS: C3 1H O4 calculated mass: 488.75; measured value: 489.5 [M + H] 52 + .

[0309] Intermediate 2 1. Synthesis of (S)-22-(tert-butoxycarbonyl)-43,43-dimethyl-10 ,19,24,41-tetraoxo-3,6,12,15,42-pentaoxa-9,1 8,23-triazatetratetracontan-1-oic acid (16) A) Benzyl 2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecane-13-oate (9)

[0310]

Chemical formula

[0311] In a 100 mL round-bottom flask, 2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecane-13-oic acid (18 g, 68.366 mmol), benzyl bromide (23.386 g, 136.732 mmol), potassium carbonate (28.346 g, 205 (mmol) were added.​​ .099 mmol), and DMF (200 mL) were added. The resulting solution was stirred overnight at room temperature and diluted with EtOAc (500 mL). The mixture was washed with water (300 mL) and brine (1 50 mL × 2). The organic phase was evaporated and purified by silica gel column (EtOAc / propylene ether, 1:5) to obtain benzyl 2,2-dimethyl-4-oxo-3,8,1 1-trioxa-5-azatridecane-13-oate as a colorless oil (9). LC / MS: C H . LC / MS: Calculated mass for C 18 H 27 NO6: 353.2, Found: 354.05 [M + H] + .

[0312] B) Benzyl 2-(2-(2-aminoethoxy)ethoxy)acetate (10)

[0313]

Chemical formula

[0314] Into a 500 mL round-bottom flask, benzyl 2,2-dimethyl-4-oxo-3,8,11 -trioxa-5-azatridecane-13-oate (12 g, 33.955 mmol) , TFA (19.358 g, 169.774 mmol), and DCM (150 mL) were added . The resulting solution was stirred overnight at room temperature. The mixture was evaporated and dried to obtain benzyl 2 -(2-(2-aminoethoxy)ethoxy)acetate as a pale yellow oil (10). LC / MS: Calculated mass for C H 13 H 19 NO4: 253.13, Found: 254. 05 [M + H] + .

[0315] C). Benzyl 2,2-dimethyl-4,13-dioxo-3,8,11,17,20- pentaoxa-5,14-diazadocosane-22-oate (11)

[0316]

Chemical formula

[0317] Into a 250 mL round-bottom flask, 2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecane-13-carboxylic acid (8.835 g, 33.558 mmol), benzyl 2-(2-(2-aminoethoxy)ethoxy)acetate (8.5 g, 33.558 mmol), HATU (15.312 g, 40.270 mmol), DIEA (8.674 g, 67.116 mmol), and DMF (100 mL) were added. The resulting solution was stirred overnight at room temperature and diluted with EtOAc (500 mL). The organic layer was washed with water (200 mL) and brine (100 mL × 2). The organic phase was evaporated and purified by silica gel column (DCM / MeOH, 10:1) to obtain benzyl 2,2-dimethyl-4,13-dioxo-3,8,11,17,20-pentaoxa-5,14-diazadocosane-22-oate as a pale yellow oil (11). LC / MS: C H N2O9 mass calculated value: 498.26, measured value: 499.50 [M+H] . 24 H 38 +

[0318] D) Benzyl 17-amino-10-oxo-3,6,12,15-tetraoxa-9- azaheptadecan-1-oate (12)

[0319]

Chemical formula

[0320] In a 500 mL round-bottom flask, benzyl 2,2-dimethyl-4,13-dioxo-3, 8,11,17,20-pentaoxa-5,14-diazadocosane-22-oate (1 5 g, 30.086 mmol), TFA (17.153 g, 150.431 mmol), and DCM (200 mL) were added. The resulting solution was stirred overnight at room temperature. The mixture was evaporated and dried to obtain benzyl 17-amino-10-oxo-3,6,12,15-tetra oxa-9-azapentadecan-1-oate as a pale yellow oil (12). L C / MS: C 19 H 30 Calculated mass of C H + N2O7: 398.21, found: 399.2 [M

[0321] E)(S)-1-Benzyl 23-tert-butyl 22-(((9H-fluoren-9 -yl)methoxy)carbonylamino)-10,19-dioxo-3,6,12,15- tetraoxa-9,18-diazatricosane-1,23-dioate (13)

[0322]

Chemical formula

[0323] In a 250 mL round-bottom flask, benzyl 17-amino-10-oxo-3,6,12, 15-tetraoxa-9-azapentadecan-1-oate (11 g, 27.607 mm ol), (S)-4-(((9H-fluoren-9-yl)methoxy)carbonylamino )-5-tert-butoxy-5-oxopentanoic acid (11.746 g, 27.607 m (mol), HATU (12.596 g, 33.128 mmol), DIEA (7.136 g, 55.214 mmol), and DMF (100 mL) were added. The resulting solution was stirred overnight at room temperature and diluted with EtOAc (500 mL). The organic layer was washed with water (200 mL × 2) and brine (200 mL). The organic phase was evaporated and purified by silica gel chromatography (DCM / MeOH, 10:1) to obtain (S)-1-benzyl 23-ter t-butyl 22-(((9H-fluoren-9-yl)methoxy)carbonylamino)- 10,19-dioxo-3,6,12,15-tetraoxa-9,18-diazatricos 43 C H5 12 as a pale yellow oil (13). LC / MS: C + .

[0324] F) (S)-1-benzyl 23-tert-butyl 22-amino-10,19-diox o-3,6,12,15-tetraoxa-9,18-diazatricosane-1,23-dio ate (14)

[0325]

Chemical formula

[0326] In a 250 mL round-bottom flask, (S)-1-benzyl 23-tert-butyl 22-(((9H-fluoren-9-yl)methoxy)carbonyl amino)-10,19-dioxo-3,6,12,15-tetraoxa-9,18-di azatricosane-1,23-dioate (10 g, 12.408 mmol) in DCM (3%, 100 mL), and DBU was added. The resulting solution was stirred overnight at room temperature and then washed with water (200 mL × 2). The organic phase was concentrated. The residue was dissolved in water (200 mL) and extracted with ether (200 mL × 2). The aqueous phase was extracted with DCM (200 mL). The organic phase was evaporated and dried to give (S)- -1-benzyl 23-tert-butyl 22-amino-10,19-dioxo-3,6, 12,15-tetraoxa-9,18-diazatriacosan-1,23-dioate as a pale yellow oil (14). LC / MS: C 28 H 45 N3O 10 mass calculated value: 5 83.31, found: 584.65 [M+H] + .

[0327] G) (S)-1-benzyl 21,39-di-tert-butyl 9,18,23-trio kiso-2,5,11,14-tetraoxa-8,17,22-triazanonaconta ne-1,21,39-tricarboxylate (15)

[0328]

Chemical formula

[0329] To a 50 mL round-bottom flask were added (S)-1-benzyl 23-tert-butyl 22-am ino-10,19-dioxo-3,6,12,15-tetraoxa-9,18-diazatri acosan-1,23-dioate (1.575 g, 2.699 mmol), 18-tert -butoxy-18-oxooctadecanoic acid (1 g, 2.699 mmol), HATU (1 .231 g, 3.239 mmol), DIEA (697.654 mg, 5.398 mmo l, 2 equiv), and DMF (15 mL). The resulting solution was stirred overnight at room temperature and E It was diluted with tOAc (200 mL). The organic layer was washed with water (100 mL × 2) and brine (10 0 mL). The organic phase was concentrated and purified by silica gel chromatography (DCM / MeO H, 10:1) to obtain (S)-1-benzyl 21,39-di-tert-butyl 9,18,23-trioxo-2,5,11,14-tetraoxa-8,17,22- triazanonatriacontane-1,21,39-tricarboxylate as a pale yellow oil (15). LC / MS: C 50 H 85 N3O 13 Mass calculated value: 935.61 , found value: 936.6 [M + H] + .

[0330] H)(S)-22-(tert-butoxycarbonyl)-43,43-dimethyl-10 ,19,24,41-tetraoxo-3,6,12,15,42-pentaoxa-9,1 8,23-triazatetratetracontane-1-acid (16)

[0331]

Chemical formula

[0332] To a 100 mL round-bottom flask, (S)-1-benzyl 21,39-di-tert-butyl 9,18,23-trioxo-2,5,11,14-tetraoxa-8,17,22- triazanonatriacontane-1,21,39-tricarboxylate (2.5 g, 3. 041 mmol), Pd / C (10 wt%, 500 mg), and MeOH (50 mL) were added. The resulting solution was stirred at room temperature overnight under H2 (3.5 atm). The residue was filtered, concentrated, and purified by reverse-phase silica gel chromatography (NH4HCO3 / H2O, 0.05%) Purified to give (S)-22-(tert-butoxycarbonyl)-43,43-dimethyl -10,19,24,41-tetraoxo-3,6,12,15,42-pentaoxa -9,18,23-triazatetratetracontan-1-oic acid as a pale yellow semi-solid (16) and obtained. LC / MS: C 43 H 79 N3O 13 Calculated mass value: 845.56, measured value: 846.55 [M+H] + . 1 1H NMR (300 MHz, CD3OD) δ: 4.24~ 4.29 (m, 1H), 4.07 (s, 2H), 4.03 (s, 2H), 3.69~3. 72 (m, 8H), 3.57~3.67 (m, 4H), 3.45~3.49 (m, 2H) , 3.34~3.42 (m, 2H), 2.23~2.35 (m, 6H), 2.12~2. 21 (m, 1H), 1.93~1.96 (m, 1H), 1.52~1.70 (m, 4H) , 1.45~1.51 (m, 18H), 1.33 (s, 24H).

Example

[0333] The compounds of the present invention can be prepared by methods known to those skilled in the art. The following examples are , merely representative examples of the present invention and do not limit the present invention in any way.

[0334] Example 1: Synthesis of cyclic PYY analog SEQ ID NO: 1

[0335]

Chemical formula

[0336] Scheme 14. Synthesis of Fmoc-psi-[Arg(Pbf)-(N-Boc)Tyr(tB u)]-OH 1.Fmoc-psi-[Arg(Pbf)-(N-Boc)Tyr(tBu)]-O Synthesis of H A. Synthesis of H2N-Tyr(tBu)-OAll To a solution of Fmoc-Tyr(tBu)-O (69 g, 150 .15 mmol) and K2CO3 (62 g, 445.36 mmol) in ice-cold DMF (500 mL) was added allyl bromide (72 g, 595.16 mmol), and the resulting mixture was stirred for 3 h. Next, ice / water (1 L) was added and the mixture was extracted with EtOAc. The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to afford Fmoc-Tyr(t Bu)-OAll as a yellow oil. To a solution of Fmoc-Tyr(tBu )-OAll (70 g, 140.1 mmol) in ice-cold DMF (600 mL) was added piperidine (150 mL) dropwise over 2 0 min. After 3 h, the reaction solution was poured into water / ice (1 L) and extracted with EtOAc (2 × 2 L). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography and eluted with EtOAc / petroleum ether (10:1) to afford 34 g of H2N- Tyr(tBu)-OAll as a yellow oil. (2×2L) and extracted. The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography and eluted with EtOAc / petroleum ether (10:1) to afford 34 g of H2N- Tyr(tBu)-OAll as a yellow oil. tOAc / petroleum ether (10:1) to give 34 g of H2N- Tyr(tBu)-OAll as a yellow oil.

[0337] B. Synthesis of Fmoc Arg(Pbf)-N(Me)OMe(2) To a mixture of Fmoc Arg(Pbf)-OH (1) (64. 8 g, 99.88 mmol), N,O-dimethylhydroxylamine hydrochloride (20 g, 2 06.2 mmol), and HATU (57 g, 149.91 mmol) in ice-cold DCM (500 mL) was added DIEA (52 g, 402.2 mmol) dropwise over 10 min, and the resulting mixture was stirred for 1 h. Next, ice / water (1 L) was added and the mixture was extracted with EtOAc. The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography and eluted with EtOAc / petroleum ether (10:1) to afford Fmoc Arg(Pbf)-N(Me)OMe(2) as a yellow oil. It was stirred overnight at room temperature. Then, the reaction mixture was poured into water / ice (1 L) and extracted with DCM (1 L). The organic extract was dried (Na2SO4) and concentrated under reduced pressure to give 70 g of crude Fmoc-Arg(Pbf)-N(Me)OMe (2) as a yellow solid, which was used without further purification.

[0338] C. Synthesis of Fmoc-Arg(Pbf)-CHO (3) Under an inert atmosphere of nitrogen, a solution of LAH (1 M, 107 mL, 0.107 mmol) in cooled (-78 °C) THF was added dropwise over 1 h via cannula to a solution of Fmoc-Arg(Pbf)-N(Me)OMe (2) (50 g, 72.3 mmol) in cooled (-50 °C) THF (100 mL). After stirring at -78 °C for 5 h, the mixture was poured into 1 N HCl solution (300 mL), and additional 1 N HCl was added if necessary to adjust the pH to 4, and then extracted with EtOAc (2 × 2 L). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to give 45 g of crude Fmoc-Arg(Pbf)-CHO (3) as a yellow solid, which was used without further purification.

[0339] D. Synthesis of Fmoc-psi-[Arg(Pbf)-Tyr(tBu)]-OAll (4) To a solution of Fmoc-Arg(Pbf)-CHO (3) (45 g, 71.12 mmol) from Step C, H2N-Tyr(tBu)-OAll (32 g, 115.37 mmol) from Step A, MeOH (200 mL), and HOAc (15 mL) in ice-cooled THF (200 mL), sodium cyanoborohydride (18.0 g, 286.4 mmol) was added portionwise over 30 min. ​​​​​​​​​​​Add separately in small portions and stir the resulting solution overnight at room temperature. Add saturated aqueous NaHCO3( 500 mL) solution to quench the reaction and extract the mixture with EtOAc (2 × 2 L). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with E tOAc / petroleum ether (10:1) to give 40 g of Fmoc-psi-[Arg(Pbf)-Tyr( tBu)]-OAll (4) as a yellow solid.

[0340] E. Synthesis of Fmoc-psi-[Arg(Pbf)-N(Boc)Tyr(tBu)]-OA ll (5) To a solution of Fmoc-psi-[Arg(Pbf)-Tyr(tBu )-OAll] (4) (53 g, 59.28 mmol) in MeCN (240 mL) was added di-tert-butyl dicarbonate (20 g, 91.3 mmol) and the resulting solution was stirred overnight at 50 °C. The mixture was then concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether (1:1 ) to give 32 g of Fmoc psi-[Arg(Pbf)-N(Boc)Tyr(tBu)]-OAll (5) as a yellow solid.

[0341] F. Synthesis of Fmoc-psi-[Arg(Pbf)-N(Boc)Tyr(tBu)]-OH (6) Under an inert atmosphere of nitrogen, to a cooled (-30 °C) solution of Fmoc- psi-[Arg(Pbf)-N(Boc)Tyr(tBu)]-OAll (5) (32 g, 32 mmol) in DCM (600 mL) was added Pd(PPh3)4 (3.0 g, 4.33 mmol). ​Subsequently, N-methylaniline (10 g, 93 mmol) was added dropwise over 30 minutes. The resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOA c / petroleum ether (1:1) to give 26.8 g of Fmoc-psi-[Arg(Pbf)-N(B oc)Tyr(tBu)]-OH (6) as a yellowish solid. 1 H NMR (300 MHz, CD3O D) δ 7.75~7.77 (2H, m), 7.59~7.60 (2H, m), 7.32~ 7.33 (4H, m), 7.09~7.11 (2H, m), 6.87~7.00 (2H, m), 4.27~4.50 (3H, m), 3.30~3.50 (4H, m), 3.02~ 3.23 (3H, m), 2.75 - 2.98 (3H, m), 2.57 (3H, s), 2. 48 (3H, s), 2.00 (3H, s), 1.31~1.41 (28H, m). LC / MS (ES, m / z): C 52 H 67 N5O 10 S calculated mass: 953.46, found : 954.55 [M + H] +

[0342] 2. Loading of the dipeptide Fmoc-psi-(R35-N(Boc)-Y36) onto the Sieber resin In a fritted microwave reactor (supplied by CEM Corporation), NovaSyn TG Sieber resin (supplied by Novabiochem) ( 0.2 mmol) was treated with 20% piperidine in DMF (10 mL) and heated in a CEM microwave reactor at 50 °C for 2.5 minutes. The reaction mixture was discharged, the resin was washed with DMF, and C In an EM microwave reactor, it was treated again with 20% piperidine in DMF at 50 °C for 5 minutes. . After discharging and washing with DMF, the deprotection process was repeated once more. Then, the resin was treated with Fmoc-psi-[Arg(Pbf)-(N-Boc )Tyr(tBu)]-OH (3 - 5 equivalents), HATU (2.75 - 4.8 equivalents), and DIEA (6 - 10 equivalents) in a solution of DMF (4 mL) obtained from the above, and mixed at room temperature for 6 - 24 hours. The mixture was discharged , and after thoroughly washing the resin with DMF, it was end-protected by treating with 20% Ac2O in DMF ( 5 mL) under microwave conditions at 50 °C for 5 minutes. The reaction product was discharged, and the resin was thoroughly washed with DMF and DCM.

[0343] 3. Synthesis of Fmoc-βA-IKPEAPGEK(Alloc)ASPEELNRYYASL RHYLNL(hC)TRQ(psi-R35Y36)-Sieber resin Amino acid elongation onto pre-packed (psi-R35,Y36)-Sieber resin (0.2 mmol) was performed on a CEM Liberty Blue Microwave Peptide Synthesis device. Standard α-Fmoc protected amino acids were double-coupled at 50 °C for 15 minutes with HBTU / DIEA as the coupling agent, at a 3.8-fold excess relative to the initial resin loading. Fmoc-Arg(Pbf)-OH was double-coupled using a two-step protocol of 25 minutes at room temperature followed by 15 minutes at 50 °C, and Fmoc-His(Trt)-OH was double-coupled using a two-step protocol of 4 minutes at room temperature followed by 8 minutes at 50 °C.

[0344] 4. Fmoc-βA-IKPEAPGEK(NH2)ASPEELNRYYASLRH Synthesis of YLNL(hC)TRQ(psi-R35Y36)-Sieber resin: Allo c deprotection The resin obtained above was treated with a solution of phenylsilane (25 equivalents ) in deoxygenated DCM (10 mL). After stirring for about 2 minutes, a solution of Pd(PPh3)4 (0.5 equivalent) in DCM (10 mL) was added, and the resin mixture was stirred under argon for 30 minutes. The reaction mixture was discharged, and the resin was washed with deoxygenated DCM. Deprotection was repeated with fresh reagents, and then the reaction mixture was discharged, and the resin was thoroughly washed with DCM and DMF.

[0345] 5. Fmoc-βA-IKPEAPGEK(NH-dPEG 12 -NHFmoc)AS PEELNRYY ASLRHYLNL(hC)TRQ(psi-R35Y36)-Si eber resin synthesis: N-Fmoc dPEG 12 Coupling of carboxylic acid to 11K The above Alloc-deprotected peptide-Sieber resin was treated in a CEM microwave reactor at 50 °C for 15 minutes with a solution of N-Fmoc-dPEG12-carboxylic acid (5 equivalents), HBTU (4.8 equivalents), and DIEA (10 equivalents) in DMF (7 mL), and by that point, the reaction showed a negative Kaiser test. The reaction mixture was discharged, and the resin was washed thoroughly with DMF and DCM.

[0346] 6. BrCH2COHN-βA-IKPEAPGEK(NH-dPEG 12 -NHCO CH2Br)ASPEEL NRYYASLRHYLNL(hC)TRQ(psi-R3 5Y36)-Sieber resin synthesis: Bis-bromoacetylation of βA and dPEG 12 in ​​The above resin was subjected to Fmoc deprotection using 20 % piperidine in fresh DMF in a CEM microwave reactor at 50 °C for 5 minutes. The deprotection was repeated twice. The Fmoc-deprotected peptide resin thus obtained was treated in a CEM microwave reactor with a solution of bromoacetic anhydride (20 equivalents) in DMF (5 mL) at 5 0 °C for 10 minutes. By that point, the reaction showed a negative Kaiser test. The reaction mixture was drained, and the resin was washed thoroughly with DMF and DCM and then dried.

[0347] 7. Synthesis of BrCH2COHN-βA-IKPEAPGEK(NH-dPEG 12 -NHCO CH2Br)ASPEEL NRYYASLRHYLNL(hC)TRQ(psi-R3 5Y36)-CONH2: Cleavage from the resin and overall deprotection The dried resin was treated with a solution of 1.5% TFA in DCM (10 mL), mixed for 5 - 10 minutes, and then filtered. This treatment was repeated 9 more times using a fresh cocktail for each treatment. The combined filtrates were then combined and concentrated to give the protected crude peptide as a yellow foam. This foam was treated with 20 mL of cleavage cocktail (TFA / phenol / H2O / TIPS = 88 / 5 / 5 / 2) at room temperature for 2.5 hours and then concentrated to a volume of approximately 2. 5 mL under a nitrogen stream. Then, cold ether (40 mL) was added to precipitate the peptide. The mixture was centrifuged (5 minutes, 5000 rpm) and decanted. This process was repeated 2 more times to give the crude peptide as an off-white powder. Alternatively, the resin was treated with the cleavage cocktail without prior treatment with 1 - 2% TFA in DCM to obtain the fully deprotected peptide.

[0348] ​

[0349] 8. Cyclic PYY Analogue SEQ ID NO:1: Cyclization Procedure A and Purification The above crude peptide was dissolved in deoxygenated 50% MeCN / H2O (5 - 10 mg / mL), and E DTA (1 mM) was optionally added. Then, 7.5 w / v% NaHCO3 solution was added to raise the pH of the reaction solution to about 8. The resulting solution was stirred at room temperature for 0.5 - 2.5 hours and then acidified to pH < 1 by adding TFA. Then, under reduced pressure at room temperature the solution was concentrated to about half of its original volume (about 24 mL). The resulting solution was purified by reverse - phase preparative HPLC using a Varian Pursuit XR C18 column (30×250 mm, 100 Å, 5 μm) on a Gilson HPLC 2020 Personal Purification System. The mobile phase consisted of buffer A (0.1% TFA in water ), and a gradient elution of buffer B (0.1% TFA in MeCN) ranging from an initial concentration of 20% B to a final concentration of 50% B over 36 minutes . UV detection was monitored at 220 and 254 nm. The product - containing fractions were analyzed by HPLC using the same column type (4.6×250 mm, 5 μm) on an Agilent 1100 HPLC system. The pure fractions were combined and then lyophilized to obtain the product as a fluffy solid . For the peak of the product at 12.27 minutes (LC: Atlantis T3 C18 column, 5 μm, 4.6×250 mm, 1.0 mL / min, 15 - 60% gradient) LCMS: 1225.5 (M + 4H) / 4, 1633.4 (M + 3H) / 3 and 2450 .0 (M + 2H) / 2.

[0350] Example 2: Synthesis of Cyclic PYY Analogue SEQ ID NO:2​​ 1. H2N-IKPEAPGEDASPEELNRYYASLRHYLNL(hC)T Synthesis of RQRY-PAL-PEG resin The protected peptidyl resin was synthesized using the above-described Fmoc strategy on a 0.1 mmol scale using low loading Rink amide resin, preferably Fmoc-PAL-PEG PS resin (about 0.16 - 0.2 meq / g, supplied by Applied Biosystems), on a CEM Liberty Blue Micro wave peptide synthesizer. Standard Fmoc-protected amino acids were coupled 5-fold in excess relative to resin loading using DIC / Oxyma as coupling agent and a reaction temperature of about 90 °C for 4 minutes. Fmoc-Arg(Pbf)-OH was double-coupled at 90 °C for 4 minutes each, and Fmoc-His(Trt)-OH was coupled using a two-step protocol of 4 minutes at room temperature followed by 8 minutes at 50 °C. One Fmoc deprotection was performed using 20% piperidine in DMF (deprotection solution) at 90 °C for 1.5 minutes. PAL-PEG PS resin (about 0.16~0.2 meq / g, supplied by Applied Biosystems) was used and synthesized on a CEM Liberty Blue Micro wave peptide synthesizer. Standard Fmoc-protected amino acids were coupled 5-fold in excess relative to resin loading using DIC / Oxyma as coupling agent and a reaction temperature of about 90 °C for 4 minutes. Fmoc-Arg(Pbf)-OH was double-coupled at 90 °C for 4 minutes each, and Fmoc-His(Trt)-OH was coupled using a two-step protocol of 4 minutes at room temperature followed by 8 minutes at 50 °C. One Fmoc deprotection was performed using 20% piperidine in DMF (deprotection solution) at 90 °C for 1.5 minutes. wave peptide synthesizer. Standard Fmoc-protected amino acids were coupled 5-fold in excess relative to resin loading using DIC / Oxyma as coupling agent and a reaction temperature of about 90 °C for 4 minutes. Fmoc-Arg(Pbf)-OH was double-coupled at 90 °C for 4 minutes each, and Fmoc-His(Trt)-OH was coupled using a two-step protocol of 4 minutes at room temperature followed by 8 minutes at 50 °C. One Fmoc deprotection was performed using 20% piperidine in DMF (deprotection solution) at 90 °C for 1.5 minutes. The protected peptidyl resin was synthesized using the above-described Fmoc strategy on a 0.1 mmol scale using low loading Rink amide resin, preferably Fmoc-PAL-PEG PS resin (about 0.16 - 0.2 meq / g, supplied by Applied Biosystems), on a CEM Liberty Blue Micro wave peptide synthesizer. Standard Fmoc-protected amino acids were coupled 5-fold in excess relative to resin loading using DIC / Oxyma as coupling agent and a reaction temperature of about 90 °C for 4 minutes. Fmoc-Arg(Pbf)-OH was double-coupled at 90 °C for 4 minutes each, and Fmoc-His(Trt)-OH was coupled using a two-step protocol of 4 minutes at room temperature followed by 8 minutes at 50 °C. One Fmoc deprotection was performed using 20% piperidine in DMF (deprotection solution) at 90 °C for 1.5 minutes. The protected peptidyl resin was synthesized using the above-described Fmoc strategy on a 0.1 mmol scale using low loading Rink amide resin, preferably Fmoc-PAL-PEG PS resin (about 0.16 - 0.2 meq / g, supplied by Applied Biosystems), on a CEM Liberty Blue Micro wave peptide synthesizer. Standard Fmoc-protected amino acids were coupled 5-fold in excess relative to resin loading using DIC / Oxyma as coupling agent and a reaction temperature of about 90 °C for 4 minutes. Fmoc-Arg(Pbf)-OH was double-coupled at 90 °C for 4 minutes each, and Fmoc-His(Trt)-OH was coupled using a two-step protocol of 4 minutes at room temperature followed by 8 minutes at 50 °C. One Fmoc deprotection was performed using 20% piperidine in DMF (deprotection solution) at 90 °C for 1.5 minutes. The protected peptidyl resin was synthesized using the above-described Fmoc strategy on a 0.1 mmol scale using low loading Rink amide resin, preferably Fmoc-PAL-PEG PS resin (about 0.16 - 0.2 meq / g, supplied by Applied Biosystems), on a CEM Liberty Blue Micro

[0351] 2. m-BrCH2PhCOHN-IKPEAPGEDASPEELNRYYASLR Synthesis of HYLNL(hC)TRQRY-PAL-PEG resin The above-described Fmoc-deprotected peptide-resin (0.1 mmol) was treated in a microwave reactor at 75 °C for 15 minutes with a solution of m-bromomethylbenzoic acid (20 equivalents) and DIC (10 equivalents) in DMF (4 mL), at which point the reaction was generally determined to be complete by Kaiser ninhydrin test (Kaiser, et al., Anal. Biochem., 1970, 34, 595~598). If the coupling was determined to be incomplete The above-described Fmoc-deprotected peptide-resin (0.1 mmol) was treated in a microwave reactor at 75 °C for 15 minutes with a solution of m-bromomethylbenzoic acid (20 equivalents) and DIC (10 equivalents) in DMF (4 mL), at which point the reaction was generally determined to be complete by Kaiser ninhydrin test (Kaiser, et al., Anal. Biochem., 1970, 34, 595~598). If the coupling was determined to be incomplete The above-described Fmoc-deprotected peptide-resin (0.1 mmol) was treated in a microwave reactor at 75 °C for 15 minutes with a solution of m-bromomethylbenzoic acid (20 equivalents) and DIC (10 equivalents) in DMF (4 mL), at which point the reaction was generally determined to be complete by Kaiser ninhydrin test (Kaiser, et al., Anal. Biochem., 1970, 34, 595~598). If the coupling was determined to be incomplete The above-described Fmoc-deprotected peptide-resin (0.1 mmol) was treated in a microwave reactor at 75 °C for 15 minutes with a solution of m-bromomethylbenzoic acid (20 equivalents) and DIC (10 equivalents) in DMF (4 mL), at which point the reaction was generally determined to be complete by Kaiser ninhydrin test (Kaiser, et al., Anal. Biochem., 1970, 34, 595~598). If the coupling was determined to be incomplete The above-described Fmoc-deprotected peptide-resin (0.1 mmol) was treated in a microwave reactor at 75 °C for 15 minutes with a solution of m-bromomethylbenzoic acid (20 equivalents) and DIC (10 equivalents) in DMF (4 mL), at which point the reaction was generally determined to be complete by Kaiser ninhydrin test (Kaiser, et al., Anal. Biochem., 1970, 34, 595~598). If the coupling was determined to be incomplete When determined, the coupling was repeated with fresh reagent. The reactants were discharged and the resin was washed thoroughly with DMF and D CM.

[0352] 3. m-BrCH2PhCOHN-IKPEAPGEDASPEELNRYYASLR Synthesis of HYLNL(hC)TRQRY-CONH2: Deprotection and cleavage from resin The above resin was then treated with a cleavage cocktail consisting of TFA / water / phenol / TIPS (88:5:5:2) (10 mL / 0.1 mmol scale) in a microwave reactor and heated at 38 °C for 40 minutes, then filtered. The resin was washed with TFA and the combined filtrate was concentrated under a nitrogen stream to a volume of approximately 2.5 mL, and the peptide was precipitated by adding cold diethyl ether (40 mL). The peptide / ether suspension was centrifuged and the ether layer was decanted. The peptide pellet was resuspended in ether, centrifuged, decanted, and this process was repeated 3 times. The crude peptide thus obtained was dried under a gentle nitrogen stream.

[0353] 4. Cyclic PYY analog SEQ ID NO: 2: Cyclization procedure A and purification The above crude peptide was dissolved in deoxygenated MeCN / water (60% MeC N) at a concentration of ≤4 mg / mL. The pH of the peptide solution was then raised to approximately 7 - 9 by adding aqueous NH4OAc (200 mM, pH 8.4), and the resulting solution was stirred at room temperature until cyclization was complete (typically 3 - 4 hours) as determined by LCMS. The cyclization reaction mixture was acidified to pH 1.5 - 3 by adding TF A, and the solution was concentrated to remove most of the organic co-solvent until a slight turbidity occurred. The mixture was made homogeneous by adding a minimum amount of organic co-solvent as necessary. An aliquot of MeCN was added back, and the resulting solution was purified directly by preparative HPLC with multiple injections using a C18 Varian Pu rsuit XR C18 (21×250 mm, 100 Å, 5 μm) column. The mobile phase consisted of buffer A (0.1% TFA in water) and buffer B (0.1% TFA in MeCN) with a gradient elution ranging from an initial concentration of 20% B to a final concentration of 40% B over 45 minutes. UV detection was monitored at 220 and 254 nm. The product-containing fractions were analyzed by analytical HPLC on an Agil ent 1100 HPLC system using the appropriate columns listed in Table 1. The pure fractions were combined, concentrated to remove most of the organic phase, and then lyophilized. Example 3: Synthesis of Cyclic PYY Analogue SEQ ID NO: 3 1. Synthesis of (H2N)-IKPEAPGEDASPEELNRYYASLRHYLNL-(azido-norLeu)-TRQRYPAL-PEG Resin Using Fmoc-azido norLeu-OH instead of Fmoc-hCys(trt)-OH at position 31, the resin-bound peptide was prepared on a 0.1 mmol scale according to the method described in Example 2, Step 1.

[0354]

[0355]

[0356] SLRHYLNL-(azido-norLeu)-TRQRYPAL-PEG resin was synthesized by binding 4-pentynoic acid onto the above resin under microwave conditions using the DIC / HOBT protocol (75 °C, 10 minutes). The reaction mixture was drained, and the resin was washed with DMF and DCM for ten minutes.

[0356]

[0356] 3. (HCCH(CH2)2CONH)-IKPEAPGEDASPEELNRYYA Synthesis of SLRHYLNL-(azido-norLeu)-TRQRYPAL-CONH2 The above resin was treated with a 10 mL cleavage cocktail consisting of TFA / DODT / H2 O / TIS (92.5:2.5:2.5:2.5) under microwave conditions (38 °C, 40 minutes). The reaction product was discharged and the resin was washed with TFA (10 mL). Then, the combined filtrate was concentrated to a volume of approximately 2.5 mL under a nitrogen stream. Next, cold ether (40 mL) was added to precipitate the peptide, and the mixture was centrifuged (5 minutes, 5000 rpm) and decanted. This process was repeated two more times to obtain the crude peptide as an off-white powder. .

[0357] 4. Cyclic PYY analog SEQ ID NO: 3 Prepare 7 mg of CuSO4 in 2 mL of deoxygenated H2O. Prepare 30 mg of TBTA in 5.4 mL of EtOH and 0.6 mL of MeCN. Pre-mix 0.94 mL of the CuSO4 solution and 4.8 mL of the TBTA solution. Prepare 30 m g of sodium ascorbate in 3 mL of deoxygenated H2O.

[0358] To a solution of the crude azide-containing peptide (100 mg) from step 3 in 20 mL of deoxygenated water, add the pre-mixed CuSO4 / TBTA solution, followed by the addition of 2.4 mL of the sodium ascorbate solution (the solution immediately turned milky white). The mixture was heated to 40 °C and stirred for 1.5 hours At this point, LCMS analysis showed a complete reaction. The mixture was diluted with water to approximately 40 mL (0.1% TFA), the mixture was centrifuged, and the supernatant was purified by reverse phase preparative HPLC. Purification was performed at 35 °C using a Varian Pursuit XR C18 column (21×250 mm, 1 00 Å, 5 μm). The mobile phase consisted of buffer A (0.1% TFA in water ), and buffer B (0.1% TFA in MeCN) with an initial concentration of 10% B to an intermediate concentration of 18% B (21 mpm), and then to a final concentration of 33% B (10.5 mpm) over 35 minutes in a gradient elution. UV detection was monitored at 220 and 254 nm. The product-containing fractions were analyzed by analytical HPLC using the same column type as above (4.6×250 mm, 5 μm) on an Agilen t 1100 HPLC system. The pure fractions were combined and then lyophilized to obtain the product as a cotton-like solid . Example 4: Synthesis of Cyclic PYY Analogue SEQ ID NO: 4

[0359] 1. (Dde)K(NH2)ASPEELNRYYASLRHYLNL(hC)TRQ Synthesis of RY-PAL-PEG Resin Using the method described in Step 1 of Example 2, a resin-bound peptide was prepared .

[0360] 2. (Dde)K(NH-Glu-(OtBu)NH2)ASPEELNRYYASL Synthesis of RHYLNL(hC)TRQRY-PAL-PEG Resin Fmoc-Glu-OtBu (5 eq) was coupled onto the above resin using a microwave condition DIC / Oxyma coupling method (90 °C, 6 minutes, dc). The resin was drained and washed with DMF. Then, Fmoc deprotection was carried out using a three-step protocol (0.5 minutes at 75 °C , 3 minutes at 75 °C, 3 minutes at 75 °C) (with DMF washing at each step) using 20% piperidine in DMF .

[0361] 3. (Dde)K(NH-Glu-(OtBu)NH-Pal)ASPEELNRYY Synthesis of ASLRHYLNL(hC)TRQRY-PAL-PEG resin Palmitic acid (5 equivalents) was coupled onto the above resin using the DIC / Oxyma coupling method (90 °C, 5 minutes) under microwave conditions. The resin was drained and washed thoroughly with DMF and DCM.

[0362] 4. (H2N)K(NH-Glu-(OtBu)NH-Pal)ASPEELNRYY Synthesis of ASLRHYLNL(hC)TRQRY-PAL-PEG resin After washing the above resin with DMF, it was treated with a 2% hydrazine solution in DMF (6 mL / 0.1 mmol resin) at room temperature for 5 minutes, then drained and washed with DMF. The treatment was repeated 5 times.

[0363] 5. (H2N)IKPEAPGEK(NH-Glu-(OtBu)NH-Pal)AS Synthesis of PEELNRYYASLRHYLNL(hC)TRQRY-PAL-PEG resin The remaining amino acid couplings were carried out using the method described in Example 2, Step 1.

[0364] 6. Cyclic PYY analog SEQ ID NO: 4 The remaining synthesis was carried out using the method described in Example 2, Steps 2 - 4. Purification of the product was performed at room temperature using a Varian Pursuit XRS C18 column (21×250 mm, 100 Å, 5 μm). The mobile phase consisted of buffer A (0.1% TFA in water) and a gradient elution of buffer B (0.1% TFA in MeCN) from 23% B to an intermediate concentration of 33% B (21 mpm) over 5 minutes, and then to a final concentration of 48% B (10.5 mpm) over 55 minutes.

[0365] ​​ Example 5: Synthesis of Cyclic PYY Analogue SEQ ID NO: 5 In step 3, instead of palmitic acid, α-tocopheryl oxyacetic acid (AcVitE) (8) was used, and the title compound was prepared according to the procedure described in Example 4. Purification of the product was performed at room temperature using an Agilent 300SB C8 column (21×250 mm, 100 Å, 5 μm ) with a mobile phase consisting of buffer A (0.1% TFA in water) and a gradient elution of buffer B (0.1% TFA in MeCN) starting at an initial concentration of 35% B for 5 minutes to an intermediate concentration of 45% B (21 mpm), and then to a final concentration of 60% B (10.5 mpm) over 60 minutes.

[0366] Example 6: Synthesis of Cyclic PYY Analogue SEQ ID NO: 6 1. (HCCH(CH2)2CONH)-IKPEAPGEDASPEELNRYYA SLRHYLNK(Dde)-(azido-norLeu)-TRQRY-PAL-PEG Synthesis of Resin The resin-bound peptide was prepared using Fmoc-Lys(Dde)-OH instead of Fmoc-Leu-OH at position 30 as described in step 1 of Example 3, and incorporating 4-pentynoic acid (double bond) at position 2 after Fmoc-Ile-OH at position 3 in this step.

[0367] 2. (HCCH(CH2)2CONH)-IKPEAPGEDASPEELNRYYA SLRHYLNK(NH2)-(azido-norLeu)-TRQRY-PAL-PEG Synthesis of Resin The above resin was treated with 3% hydrazine in DMF (8 mL / 0.1 mmol scale) at room temperature for 5 minutes, then the mixture was drained and washed with DMF. This procedure was repeated about 5 times. ​​​​​​​, Subsequently, the resin was washed thoroughly with DMF and then with DCM.

[0368] 3. (HCCH(CH2)2CONH)-IKPEAPGEDASPEELNRYYA SLRHYLNK(NH-γ-Glu-AcVitE)-(azido-norLeu)-T Synthesis of RQRY-PAL-PEG resin Using the coupling procedure described in Example 2, Step 1, with a coupling time of 5 minutes, Fmoc-Glu -OtBu was coupled onto the above resin. The resin was treated with 20% piperidine in DMF using a three-step microwave protocol (0.5 minutes at 75 °C, 3 minutes at 75 °C, 3 minutes at 75 °C) for deprotection, and then the resin was washed thoroughly with DMF and DCM. Next, α-tocopheryl oxyacetic acid (AcVitE) (8) was coupled onto the resin using the same procedure as used for the coupling of Fmoc-Glu-OtBu.

[0369] 4. (HCCH(CH2)2CONH)-IKPEAPGEDASPEELNRYYA SLRHYLNK(NH-γ-Glu-AcVitE)-(azido-norLeu)-T Synthesis of RQRY-CONH2 Cleavage and precipitation of the peptide from the above resin were carried out using the procedure described in Example 3, Step 3.

[0370] 5. Cyclic PYY analog SEQ ID NO: 6 Using the procedure described in Example 3, Step 4, the title compound was prepared. Purification of the product was carried out on a Varian Pursuit XR C8 column (21×250 mm, 100 Å, 5 μm ) at 35 °C. The mobile phase was buffer A (0.1% TFA in water), and starting from an initial concentration of 35% B, increasing to an intermediate concentration of 48% B over 5 minutes (21 mpm), and then to a final concentration of 63% over 40 minutes. Gradient elution of buffer B (0.1% TFA in MeCN) in the range of %B (10.5 mpm) from was obtained.

[0371] Example 7: Synthesis of cyclic PYY analog SEQ ID NO: 7 Using the K(NH-γ-Glu-Pal) residue placed at the 9th position instead of the 11th position, the title compound was prepared according to the procedure described in Example 4. Purification of the product was carried out at room temperature using an Agilent 300SB C8 column (21×250 mm, 100 Å, 5 μm). The mobile phase was buffer A (0.1% TFA in water) and buffer B (0.1% TFA in MeCN) with a gradient elution starting from an initial concentration of 23% B to an intermediate concentration of 43% B (21 mpm) and then to a final concentration of 43% B (10.5 mpm) over 40 minutes. Fractions containing impure products were re-purified at room temperature on a Waters T3 C 18 column (250×19 mm, 100 Å, 5 μm) using a gradient from an initial concentration of 25% B to an intermediate concentration of 35% B (21 mpm) and then to a final concentration of 45% B (10.5 mpm) over 80 minutes.

[0372] Example 8: Synthesis of cyclic PYY analog SEQ ID NO: 8 Using the K(NH-γ-Glu-Pal) residue placed at the 30th position instead of the 11th position, the title compound was prepared according to the procedure described in Example 4. Purification of the product was carried out at 35 ℃ using an Agilent 300SB C8 column (21×250 mm, 100 Å, 5 μm). The mobile phase was buffer A (0.1% TFA in water) and buffer B (0.1% TFA in MeCN) with a gradient elution starting from an initial concentration of 21% B to an intermediate concentration of 31% B (21 mpm) and then to a final concentration of 41% B (10.5 mpm ) over 40 minutes. Fractions containing impure products The fractionation was carried out at room temperature on a Waters T3 C18 column (250×19 mm, 100 Å, 5 μm) using a gradient from an initial concentration of 21% B to an intermediate concentration of 31% B (21 mpm) and then to a final concentration of 40% B (10.5 mpm) over 80 minutes. and then to a final concentration of 40% B (10.5 mpm) over 80 minutes. It was then repurified on a Waters T3 C18 column (250×19 mm, 100 Å, 5 μm) at room temperature using a gradient from an initial concentration of 21% B to an intermediate concentration of 31% B (21 mpm) and then to a final concentration of 40% B (10.5 mpm) over 80 minutes.

[0373] Example 9: Synthesis of Cyclic PYY Analogue SEQ ID NO: 9 1. H2N-IKPEAPGEDASPEELNRYYASLRHYLNL(hC)T Synthesis of RQ(psi-R35Y36)-Sieber Resin The amino acid elongation onto the pre-packed (psi-R35,Y36)-Sieber resin (0.1 mmol) from Example 1, Step 2 was carried out using a 5-fold excess of the protected amino acids with the modifications added as described in Example 1, Step 3. The amino acid elongation onto the pre-packed (psi-R35,Y36)-Sieber resin (0.1 mmol) from Example 1, Step 2 was carried out using a 5-fold excess of the protected amino acids with the modifications added as described in Example 1, Step 3. The amino acid elongation onto the pre-packed (psi-R35,Y36)-Sieber resin (0.1 mmol) from Example 1, Step 2 was carried out using a 5-fold excess of the protected amino acids with the modifications added as described in Example 1, Step 3.

[0374] 2. m-BrCH2PhCOHN-IKPEAPGEDASPEELNRYYASLRHYLNL(hC)TRQ(psi-R35Y36)-Sieber Resin Synthesis m-BrCH2PhCOHN-IKPEAPGEDASPEELNRYYASLRHYLNL(hC)TRQ(psi-R35Y36)-Sieber resin synthesis was carried out according to the procedure described in Example 1, Step with the modification that the coupling was carried out at 50 °C instead of 75 °C, and m-bromomethylbenzoic acid was coupled onto the above resin. m-BrCH2PhCOHN-IKPEAPGEDASPEELNRYYASLRHYLNL(hC)TRQ(psi-R35Y36)-Sieber resin synthesis was carried out according to the procedure described in Example 1, Step with the modification that the coupling was carried out at 50 °C instead of 75 °C, and m-bromomethylbenzoic acid was coupled onto the above resin. m-BrCH2PhCOHN-IKPEAPGEDASPEELNRYYASLRHYLNL(hC)TRQ(psi-R35Y36)-Sieber resin synthesis was carried out according to the procedure described in Example 1, Step with the modification that the coupling was carried out at 50 °C instead of 75 °C, and m-bromomethylbenzoic acid was coupled onto the above resin.

[0375] 3. Cyclic PYY Analogue SEQ ID NO: 9 The title compound was prepared from the above resin according to the procedure described in Example 1, Steps 7 and 8. The purification of the product was carried out at 35 °C using a Varian Pursuit XR C18 column (21×250 mm, 100 Å, 5 μm). The mobile phase was buffer A (0.1% TFA in water), and buffer B (MeCN) with a gradient from an initial concentration of 10% B to an intermediate concentration of 18% B (21 mpm) over 10 minutes and then to a final concentration of 33% B (10.5 mpm) over 35 minutes. The title compound was prepared from the above resin according to the procedure described in Example 1, Steps 7 and 8. The purification of the product was carried out at 35 °C using a Varian Pursuit XR C18 column (21×250 mm, 100 Å, 5 μm). The mobile phase was buffer A (0.1% TFA in water), and buffer B (MeCN) with a gradient from an initial concentration of 10% B to an intermediate concentration of 18% B (21 mpm) over 10 minutes and then to a final concentration of 33% B (10.5 mpm) over 35 minutes. The title compound was prepared from the above resin according to the procedure described in Example 1, Steps 7 and 8. The purification of the product was carried out at 35 °C using a Varian Pursuit XR C18 column (21×250 mm, 100 Å, 5 μm). The mobile phase was buffer A (0.1% TFA in water), and buffer B (MeCN) with a gradient from an initial concentration of 10% B to an intermediate concentration of 18% B (21 mpm) over 10 minutes and then to a final concentration of 33% B (10.5 mpm) over 35 minutes. The title compound was prepared from the above resin according to the procedure described in Example 1, Steps 7 and 8. The purification of the product was carried out at 35 °C using a Varian Pursuit XR C18 column (21×250 mm, 100 Å, 5 μm). The mobile phase was buffer A (0.1% TFA in water), and buffer B (MeCN) with a gradient from an initial concentration of 10% B to an intermediate concentration of 18% B (21 mpm) over 10 minutes and then to a final concentration of 33% B (10.5 mpm) over 35 minutes. The title compound was prepared from the above resin according to the procedure described in Example 1, Steps 7 and 8. The purification of the product was carried out at 35 °C using a Varian Pursuit XR C18 column (21×250 mm, 100 Å, 5 μm). The mobile phase was buffer A (0.1% TFA in water), and buffer B (MeCN) with a gradient from an initial concentration of 10% B to an intermediate concentration of 18% B (21 mpm) over 10 minutes and then to a final concentration of 33% B (10.5 mpm) over 35 minutes. It consisted of gradient elution with 0.1% TFA in water.

[0376] Example 10: Synthesis of cyclic PYY analog SEQ ID NO: 10 Use Dde-Lys(Fmoc)-OH instead of Fmoc-Leu-OH at position 30 and in step 3, use α-tocopheryl oxyacetic acid (AcVitE )(8) instead of palmitic acid and prepare the title compound according to the procedure described in Example 4. Purification of the product was performed at room temperature using an Agilent 300SB C8 column (21×250 mm, 100 Å, 5 μ m). The mobile phase was buffer A (0.1% TFA in water) and 10 gradually from an initial concentration of 30% B to an intermediate concentration of 40% B (21 mpm), and then over 35 minutes to a final concentration of 55% B (21 mpm) gradient elution of buffer B (0.1% TFA in MeCN) in the range of It consisted of. Fractions containing impure product were adjusted from an initial concentration of 35% B to an intermediate concentration of 43 % B (21 mpm) over 5 minutes, and then to a final concentration of 58% B (10.5 mpm) over 40 minutes with a modified gradient and re-purified.

[0377] Example 11: Synthesis of cyclic PYY analog SEQ ID NO: 11 1. Synthesis of (Alloc)K(NH2)-(hC)-TRQ(psi-R35Y36)-Sieber resin Use Alloc-Lys(Fmoc)-OH instead of Fmoc-Leu-OH at position 30 and prepare the above resin according to the procedure described in Example 9, step 1.

[0378] 2. Synthesis of (Alloc)K(NH-γ-Glu-AcVitE)-(hC)-TRQ(ps i-R35Y36)-Sieber resin Fmoc-Glu-OtBu and α-tocopheryl oxyacetic acid (AcVitE)(8) (5 equivalents each) were sequentially coupled onto the above resin at 50 °C for 15 - 20 minutes under microwave conditions using HBTU / DI EA mediated coupling.

[0379] 3. H2N - K(NH - γ - Glu - AcVitE)-(hC)-TRQ(psi - R 35Y36)-Sieber resin synthesis According to the procedure described in Example 1, Step 4, the alloc protecting group was removed.

[0380] 4. Cyclic PYY analog SEQ ID NO: 11 Using 1M TRIS / HCl buffer (pH 7.5) instead of NH4OAc buffer and making modifications to cause cyclization, according to the procedure described in Example 9, Steps 1 - 3, the title compound was prepared from the above resin. Purification of the product was carried out at 35 °C using a Varian Pursuit XR C18 column (21×250 mm, 100 Å, 5 μm). The mobile phase consisted of buffer A (0.1% TFA in water) and a gradient elution of buffer B (0.1% TFA in MeCN) from an initial concentration of 10% B to an intermediate concentration of 18% B (21 mpm) over 10 minutes, and then to a final concentration of 33% B (10.5 mpm ) over 35 minutes.

[0381] Example 12: Synthesis of cyclic PYY analog SEQ ID NO: 12 In Step 1, using Fmoc - N - Me - Arg(pbf)-OH instead of Fmoc - Arg(pbf)-OH at position 35, and using 1M NaHC O3 buffer instead of NH4OAc buffer and making modifications to cause cyclization, according to the procedure described in Example 2, the title compound was prepared. Purification of the product was carried out at room temperature using a Varian Pursuit XR C18 column (30×250 mm, 100 Å, 5 μm). The mobile phase was Buffer A (0.1% TFA in water), and gradient elution with Buffer B (0.1% TFA in MeCN) in the range of 10 - 60% B (30 mpm) over 36 minutes. consisted of.

[0382] Example 13: Synthesis of cyclic PYY analog SEQ ID NO: 13 In Step 2, palmitic acid was used instead of α-tocopheryl oxyacetic acid (AcVitE) (8), and 60% EtOH / H2O was used as the solvent instead of MeCN / H2O, and saturated aqueous NaHCO3 was used instead of NH4OAc buffer to cause cyclization. With modifications, the title compound was prepared according to the procedure described in Example 11. Purification of the product was performed at room temperature using a Waters XBridge C18 OBD column (50×250 mm, 5 μm ). The mobile phase was Buffer A (10 mM NH4OH in water, pH about 9), and gradient elution with Buffer B (MeCN) in the range of an initial concentration of 15% B to an intermediate concentration of 20% B (100 mpm) over 5 minutes, and then to a final concentration of 35% B (100 mpm) over 40 minutes. consisted of.

[0383] Example 14: Synthesis of cyclic PYY analog SEQ ID NO: 14 In Step 1, a Lys(NH-γ-Glu-P al) residue located at position 30 instead of position 11 was used, and Fmoc-N-Me-Arg(pbf)-OH was used instead of Fmoc-Arg(pbf)-OH at position 35 in Step 1. In Step 6, 1M NaHCO3 buffer was used instead of NH4OAc buffer to cause cyclization. With these modifications, the title compound was prepared according to the procedure described in Example 4. Purification of the product was performed using a Varian Pursuit XR C18 column (30×250 mm, 100 Å, 5 μm) Then, room temperature was carried out. The mobile phase consisted of buffer A (0.1% TFA in water) and a gradient elution of buffer B (0.1% TFA in MeCN) in the range of 20 ~70% B (30 mpm) over 36 minutes. Impure fractions were collected using a gradient of 30 - 50% B (30 mpm) over 25 minutes and re - purified at room temperature on a Varian Pursuit XR diphenyl column (30×100 mm, 100 Å, 5 μm).

[0384] Example 15: Synthesis of Cyclic PYY Analogue SEQ ID NO: 15 Using a Lys(NH - γ - Glu - Pal) residue placed at position 30 instead of position 11, using Fmoc - βAla - OH instead of the Fmoc - Ile - OH bond at position 3, and causing cyclization using 1M NaHCO3 buffer instead of NH4OAc buffer, and the coupling with bromoacetic anhydride was carried out in step 6 (step 2 of Example 2) with a modification where it was used instead of m - bromomethylbenzoic acid, and the title compound was prepared according to the procedure described in Example 4: The Fmoc - deprotected peptide resin (0.1 mmol) was treated at 50 °C for 5 - 10 minutes in a microwave reactor with a solution of bromoacetic anhydride (10 equivalents) in DMF (5 mL) (by this point, the reaction was generally determined to be complete by the Kaiser ninhydrin test). If the coupling was determined to be incomplete, the coupling was repeated with fresh reagent. Purification of the product was carried out at room temperature using a Varian Pursuit t XR C18 column (30×250 mm, 100 Å, 5 μm). The mobile phase consisted of buffer A (0.1% TFA in water) and a gradient elution of buffer B (0.1% TFA in MeCN) in the range of 20 - 60% B (30 mpm) over 36 minutes. Impurities were removed using a gradient of 30 - 50% B (30 mpm) over 25 minutes. (30 mpm). The pure fraction was re-purified at room temperature over a Varian Pursuit XR diphenyl column (30×100 mm, 100 Å, 5 μm) using a gradient of 30 - 50% B (30 mpm) over 25 minutes. arian Pursuit XR diphenyl column (30×100 mm, 100 Å, 5 μm).

[0385] Example 16: Synthesis of cyclic PYY analog SEQ ID NO: 16 Using a Lys(NH-γ-Glu-Pal) residue placed at position 30 instead of position 11, omitting the Fmoc-Ile-OH bond at position 3, and in step 6 (step 2 of Example 2), using p-bromomethylbenzoic acid instead of m-bromomethylbenzoic acid, the title compound was prepared according to the procedure described in Example 4. Additionally, 1M NaHCO3 buffer was used instead of NH4OAc buffer to cause cyclization. The purification of the product was performed at room temperature using a Varian Pursuit XR C18 column (30×250 mm, 100 Å, 5 μm). The mobile phase consisted of buffer A (0.1% TFA in water) and a gradient elution of buffer B (0.1% TFA in MeCN) from 20 - 70% B (30 mpm) over 36 minutes. The impure fractions were re-purified at room temperature over a Varian Pursuit XR diphenyl column (30×100 mm, 100 Å, 5 μm) using a gradient of 30 - 50% B (30 mpm) over 25 minutes. using p-bromomethylbenzoic acid instead of m-bromomethylbenzoic acid, the title compound was prepared according to the procedure described in Example 4. Additionally, 1M NaHCO3 buffer was used instead of NH 4OAc buffer to cause cyclization. The purification of the product was performed at room temperature using a Varian Pursuit XR C18 column (30×250 mm, 100 Å, 5 μm). The mobile phase consisted of buffer A (0.1% TFA in water) and a gradient elution of buffer B (0.1% TFA in MeCN) from 20 - 70% B (30 mpm) over 36 minutes. The impure fractions were re-purified at room temperature over a Varian Pursuit XR diphenyl column (30×100 m using a Varian Pursuit XR C18 column (30×250 mm, 100 Å, 5 μm). The mobile phase consisted of buffer A (0.1% TFA in water) and a gradient elution of buffer B (0.1% TFA in MeCN) from 20 - 70% B (30 mpm) over 36 minutes. The impure fractions were re-purified at room temperature over a Varian Pursuit XR diphenyl column (30×100 m using a Varian Pursuit XR C18 column (30×250 mm, 100 Å, 5 μm). The mobile phase consisted of buffer A (0.1% TFA in water) and a gradient elution of buffer B (0.1% TFA in MeCN) from 20 - 70% B (30 mpm) over 36 minutes. The impure fractions were re-purified at room temperature over a Varian Pursuit XR diphenyl column (30×100 m The mobile phase consisted of buffer A (0.1% TFA in water) and a gradient elution of buffer B (0.1% TFA in MeCN) from 20 - 70% B (30 mpm) over 36 minutes. The impure fractions were re-purified at room temperature over a Varian Pursuit XR diphenyl column (30×100 m from 20 - 70% B (30 mpm) over 36 minutes. The impure fractions were re-purified at room temperature over a Varian Pursuit XR diphenyl column (30×100 m from 20 - 70% B (30 mpm) over 36 minutes. The impure fractions were re-purified at room temperature over a Varian Pursuit XR diphenyl column (30×100 m using a gradient of 30 - 50% B (30 mpm) over 25 minutes at room temperature over a Varian Pursuit XR diphenyl column (30×100 m m, 100 Å, 5 μm).

[0386] Example 17: Synthesis of cyclic PYY analog SEQ ID NO: 17 Using a Lys(NH-γ-Glu-Pal) residue placed at position 30 instead of position 11, using Fmoc-Ala-OH instead of Fmoc-Lys(Boc)-OH at position 4 in step 1, the title compound was prepared according to the procedure described in Example 4. In step 6 using Fmoc-Ala-OH instead of Fmoc-Lys(Boc)-OH at position 4 in step 1, the title compound was prepared according to the procedure described in Example 4. In step 6 Subsequently, TRIS / HCl buffer (1 M, pH 7.5) was used instead of NH4OAc buffer to cause cyclization. The purification of the product was carried out at room temperature using an Agilent Polaris C1 8-A column (30×250 mm, 100 Å, 5 μm). The mobile phase consisted of buffer A (0.1% TFA in water) and a gradient elution of buffer B (0.1% TFA in MeCN) with an initial concentration of 20% B for 5 minutes to an intermediate concentration of 35% B (40 mpm) and then to a final concentration of 45% B (40 mpm) over 40 minutes.

[0387] Example 18: Synthesis of Cyclic PYY Analogue SEQ ID NO: 18 Using the Lys(NH-γ-Glu-Pal) residue placed at position 30 instead of position 11, in step 1, Fmoc-Glu (OtBu)-OH was used instead of Fmoc-Lys(Boc)-OH at position 4, and the title compound was prepared according to the procedure described in Example 4. In step 6, TRIS / HCl buffer (1 M, pH 7.5) was used instead of NH4OAc buffer to cause cyclization. The purification of the product was carried out at room temperature using an Agilent Pola ris C18-A column (30×250 mm, 100 Å, 5 μm). The mobile phase consisted of buffer A (0.1% TFA in water) and a gradient elution of buffer B (0.1% TFA in MeCN) with an initial concentration of 20% B to an intermediate concentration of 35% B (40 mpm) and then to a final concentration of 45% B (40 mp m) over 40 minutes.

[0388] Example 19: Synthesis of Cyclic PYY Analogue SEQ ID NO: 19 The Lys(NH-γ-Glu-Pal) residue placed at position 30 instead of position 11, in step 1, Fmoc-N-Me was used instead of Fmoc-Arg(pbf)-OH at position 35 -Arg(pbf)-OH and Fmoc-hCys(trt)-OH were replaced with Fmoc- Cys(trt)-OH, and in step 6 (step 2 of Example 2), p-bromomethyl benzoic acid was used instead of m-bromomethyl benzoic acid, and the title compound was prepared according to the procedure described in Example 4.

[0389] The following modifications were made to step 6 (Examples 2, steps 3 and 4): The crude peptide obtained before cyclization was purified at room temperature using a Varian Pursuit XR C18 column (30×250 mm, 100 Å, 5 μm). The mobile phase consisted of buffer A (0.1% T FA in water), and a gradient elution of buffer B (0.1% TFA in MeCN) in the range of 20 - 70% B (30 mpm) over 36 minutes. The product-containing fractions were combined and treated with solid NaHCO3 to raise the pH to about 7 - 8. The resulting solution was stirred at room temperature for 4 hours and then acidified to pH 4 with TFA. The solution was concentrated to a volume of 5 - 10 mL, MeCN was added to dissolve any precipitate. The purification of the product was carried out as above with a gradient of 20 - 60% B (30 mpm ) over 36 minutes.

[0390] ) over 36 minutes. Example 20: Synthesis of Cyclic PYY Analogue SEQ ID NO: 20 A Lys(NH-γ-Glu-Pal) residue placed at position 30 instead of position 11, in step 1, Fmoc-N-Me- Arg(pbf)-OH was used instead of Fmoc-Arg(pbf)-OH at position 35, and Fmoc -Cys(trt)-OH was used instead of Fmoc-hCys(trt)-OH, and the title compound was prepared according to the procedure described in Example 4. The crude linear peptide was purified and cyclized according to the modification described in Example 19. The final product ​Purification of the product was carried out using a gradient of 20 - 60% B (30 mpm) over 36 minutes.

[0391] Example 21: Synthesis of cyclic PYY analog SEQ ID NO: 21 Using a Lys(NH-γ-Glu-Pal) residue placed at position 30 instead of at position 11 and using Fmoc-Ala-OH instead of Fmoc-His(trt)-OH at position 26 and using Fmoc-Ala-OH instead of Fmoc-Lys(Boc)-OH at position 4 in step 1, the title compound was prepared according to the procedure described in Example 4. In step 6 TRIS / HCl buffer (1 M, pH 7.5) was used instead of NH4OAc buffer to cause cyclization. Purification of the product was carried out at room temperature using an Agilent Polaris C 18-A column (30×250 mm, 100 Å, 5 μm). The mobile phase consisted of buffer A (0.1% TFA in water), and a gradient elution of buffer B (0.1% TFA in MeCN) with an initial concentration of 20% B increased to an intermediate concentration of 35% B over 5 minutes (40 mpm), and then to a final concentration of 45% B over 40 minutes (40 mpm). 18-A column (30×250 mm, 100 Å, 5 μm) was used and carried out at room temperature. The mobile phase was buffer A (0.1% TFA in water), and a gradient from an initial concentration of 20% B to an intermediate concentration of 35% B over 5 minutes (40 mpm), and then to a final concentration of 45% B over 40 minutes (40 mpm) of buffer B (0.1% TFA in MeCN).

[0392] Example 22: Synthesis of cyclic PYY analog SEQ ID NO: 22 Using a Lys(NH-γ-Glu-Pal) residue placed at position 30 instead of at position 11 and using Fmoc-Ala-OH instead of Fmoc-His(trt)-OH at position 26 and using Fmoc-Glu(OtBu)-OH instead of Fmoc-Lys(Boc)-OH at position 4 in step 1, the title compound was prepared according to the procedure described in Example 4. In step 6 TRIS / HCl buffer (1 M, pH 7.5) was used instead of NH4OAc buffer to cause cyclization. Purification of the product was carried out using an Agilent Pol ​ Performed at room temperature using an Aris C18-A column (30×250 mm, 100 Å, 5 μm). The mobile phase consisted of buffer A (0.1% TFA in water) and a gradient elution of buffer B (0.1% TFA in MeCN) from an initial concentration of 20% B to an intermediate concentration of 33% B (40 mpm) over 5 minutes and then to a final concentration of 43% B (40 mpm) over 40 minutes.

[0393] Example 23: Synthesis of Cyclic PYY Analogue SEQ ID NO: 23 Instead of α-tocopheryl oxyacetic acid (AcVitE) (8), monooctadecane diacid mono-tert-butyl ester (available from AstaTech, Inc.) was used, and NMP was used as the solvent instead of HATU / DIEA and DMF at 50 °C for 30 minutes in Step 2. In Step 2, two units of Fmoc-OEG-OH were coupled in series before coupling Fmoc-Glu-OtBu, and the title compound was prepared according to the procedure described in Example 11. The crude linear peptide was purified and cyclized according to the modification described in Example 19 using a gradient of 20 - 60% B. The final product was purified using a gradient of 20 - 70% B (30 mpm) over 36 minutes.

[0394] Example 24: Synthesis of Cyclic PYY Analogue SEQ ID NO: 24 Instead of monooctadecane diacid mono-tert-butyl ester, 20-(tert-butoxy)-20-oxoicosanoic acid (available from Key Organics, Inc.) was used, and the title compound was prepared according to the procedure described in Example 23. The crude linear peptide was purified and cyclized according to the modification described in Example 19 using a gradient of 20 - 60% B. ​​​​​​​​​​​​It was carried out using a gradient of 20 - 60% B (30 mpm) over 36 minutes. It was carried out.

[0395] Example 25: Synthesis of cyclic PYY analog SEQ ID NO: 25 Using stearic acid instead of α - tocopheryl oxyacetic acid (AcVitE) (8), and using NMP as the solvent instead of HATU / DIEA and DMF at 50 °C for 30 minutes in step 2, The title compound was prepared according to the procedure described in Example 11 using the coupling protocol. The crude linear peptide was purified and cyclized according to the modification described in Example 19 using a gradient of 20 - 80% B. The purification of the final product was carried out using a gradient of 20 - 80% B (30 mpm) over 36 minutes. (30 mpm).

[0396] Example 26: Synthesis of cyclic PYY analog SEQ ID NO: 26 Using arachidic acid instead of α - tocopheryl oxyacetic acid (AcVitE) (8), and using NMP as the solvent instead of HATU / DIEA and DMF at 50 °C for 30 minutes in step 2, The title compound was prepared according to the procedure described in Example 11 using the coupling protocol. The crude linear peptide was purified and cyclized according to the modification described in Example 19 using a gradient of 20 - 90% B. The purification of the final product was carried out using a gradient of 20 - 90% B (30 mpm) over 36 minutes. (30 mpm).

[0397] Example 27: Synthesis of cyclic PYY analog SEQ ID NO: 27 Following the procedure described in Example 23, but omitting the coupling of Fmoc - Glu - OtBu after the tandem Fmoc - OEG - OH coupling, the title compound was prepared. The crude linear peptide was purified and cyclized according to the modification described in Example 19 using a gradient of 20 - 60% B. The final product Purification of the product was carried out using a gradient of 20 - 60% B (30 mpm) over 36 minutes.

[0398] Example 28: Synthesis of cyclic PYY analog SEQ ID NO: 28 Palmitic acid was used instead of α - tocopheryl oxyacetic acid (AcVitE) (8), the coupling of Fmoc - Ile - OH at the 3 - position was omitted, and in step 4 (Example 9, step 2) p - bromomethylbenzoic acid was used instead of m - bromomethylbenzoic acid, and the title compound was prepared according to the procedure described in Example 11. The crude linear peptide was purified and cyclized according to the modification described in Example 19 using a gradient of 20 - 60 % B. Purification of the final product was carried out using a gradient of 20 - 60% B (30 mpm) over 36 minutes. % B. Purification of the final product was carried out using a gradient of 20 - 60% B (30 mpm) over 36 minutes.

[0399] Example 29: Synthesis of cyclic PYY analog SEQ ID NO: 29 Palmitic acid was used instead of α - tocopheryl oxyacetic acid (AcVitE) (8), Fmoc - βAla - OH was used instead of Fmoc - Ile - OH at the 3 - position, and using the modification described in Example 15, in step 4 (Example 9, step 2) bromoacetic anhydride was coupled instead of m - bromomethylbenzoic acid, and the title compound was prepared according to the procedure described in Example 11. The crude linear peptide was purified and cyclized according to the modification described in Example 19 using a gradient of 20 - 60% B. Purification of the final product was carried out using a gradient of 20 - 60 % B over 36 minutes using a gradient of 20 - 60% B (30 mpm). % B. Purification of the final product was carried out using a gradient of 20 - 60% B (30 mpm) over 36 minutes. % B (30 mpm).

[0400] Example 30: Synthesis of cyclic PYY analog SEQ ID NO: 30 Palmitic acid was used instead of α - tocopheryl oxyacetic acid (AcVitE) (8), , use Fmoc-β-OH instead of 3-position Fmoc-Ile-OH, and in Example 15 described modifications were used, and in Step 4 (Example 9, Step 2), m-bromomethylbenzoic acid was replaced by bromoacetic anhydride for coupling, and according to the procedure described in Example 11, the title compound was prepared. The crude linear peptide was purified and cyclized according to the modification described in Example 19 using a gradient of 20 - 60%B . The purification of the final product was carried out using a gradient of 20 - 60%B ( 30 mpm) over 36 minutes.

[0401] Example 31: Synthesis of Cyclic PYY Analogue SEQ ID NO: 31 Using stearic acid instead of octadecanedioic acid mono-tert-butyl ester , according to the procedure described in Example 23, the title compound was prepared. The crude linear peptide was purified and cyclized according to the modification described in Example 19 using a gradient of 20 - 60%B. The purification of the final product was carried out using a gradient of 20 - 60%B (30 mpm) over 36 minutes.

[0402] Example 32: Synthesis of Cyclic PYY Analogue SEQ ID NO: 32 In Step 2, palmitic acid was used instead of α-tocopheryloxyacetic acid (AcVitE)(8), and Fmoc-Al a-OH was used instead of Fmoc-His(trt)-OH at position 26, and in Step 4 (Example 9, Step 1), Fmoc-Ala-OH was used instead of Fmoc-Lys(B oc)-OH at position 4, and according to the procedure described in Example 11, the title compound was prepared. In Step 6, TRIS / HCl buffer (1M, pH 7.5) was used instead of NH4OAc buffer to cause cyclization. The purification of the product was carried out on an Agilent Polaris C18-A column (30×250 mm, 100 Å , 100 Å , 5 μm) was used and carried out at room temperature. The mobile phase was buffer A (0.1% TFA in water), and over 5 minutes from an initial concentration of 20% B to an intermediate concentration of 35% B (40 mpm), and then over 40 minutes to a final concentration of 45% B (40 mpm) gradient elution of buffer B (0.1% TFA in MeCN) consisted of.

[0403] Example 33: Synthesis of cyclic PYY analog SEQ ID NO: 33 In step 2, palmitic acid was used instead of α-tocopheryl oxyacetic acid (AcVitE) (8), and in step 4 (Example 9, step 1), instead of Fmoc-Gln(trt)-OH at position 34 Fmoc-N(Me)-Gln(trt)-OH was used, and according to the procedure described in Example 11, the title compound was prepared. In this case, the coupling was carried out at room temperature using NMP as the solvent and the HATU / DIEA protocol (1 hour, single bond). Fmoc-N(Me)-Gln(trt)-OH and Fmoc-Arg(pbf )-OH were double-bonded. A two-step Fmoc deprotection protocol was used throughout ([[]] 20% piperidine in DMF; room temperature; 10 minutes, 15 minutes). The crude linear peptide was purified and cyclized according to the modification described in Example 19 using a gradient of 20-70 % B. The final product was purified using a gradient of 20-70% B (30 mpm) over 36 minutes.

[0404] Example 34: Synthesis of cyclic PYY analog SEQ ID NO: 34 Palmitic acid was used instead of α-tocopheryl oxyacetic acid (AcVitE) (8), instead of Fmoc-hCys(trt)-OH at position 31 Fmoc-Cys(trt) -OH was used, and instead of Fmoc-Ile-OH at position 3, 6-Fmoc-aminohexane ​​​​Using phosphoric acid and the modifications described in Example 15, in Step 4 (Example 9, Step 2), Bromoacetic anhydride was coupled instead of m-bromomethylbenzoic acid, and the title compound was prepared according to the procedure described in Example 11. Aqueous NaHCO3 (2N) was used instead of the NH4OAc buffer to cause cyclization. Purification of the product was carried out at room temperature using a Varian Pursu it XR C18 column (30×250 mm, 100 Å, 5 μm). The mobile phase consisted of Buffer A (0.1% TFA in water) and a gradient elution of Buffer B (0.1% TFA in MeCN) from 20 to 70% B over 36 minutes (30 mpm). Example 35: Synthesis of Cyclic PYY Analogue SEQ ID NO: 35 The title compound was prepared according to the procedure described in Example 9 with the following modifications: To prepare the packed Sieber resin used in this specification, according to the procedure described in Example 1, Step 1,

[0405] Fmoc-psi-[N-Me-Arg(Pbf)-N(Boc)Tyr(tBu)]-OH prepared from Fmoc-N-Me-Arg(pbf)-OH was used instead of Fmoc-Arg(Pbf)-N (Boc)Tyr(tBu)]-OH (6), Fmoc-Lys(Pal-Glu-OtBu)-OH (from Active Peptide) was used instead of Leu at position 30, m-chloromethylbenzoic acid was used instead of m-bromomethylbenzoic acid in Step 2, coupling was carried out at room temperature using NMP as the solvent, and the HATU / DIEA protocol (1 hour, single bond) was used, Fmoc-Arg(pb ​​​​​​​​​f) -OH was double-bonded. A two-step Fmoc deprotection protocol was used throughout (20% piperidine in DMF; room temperature; 10 minutes, 15 minutes). The crude linear peptide was purified and cyclized according to the modifications described in Example 19 using a gradient of 20- 70% B. The final product was purified using a gradient of 20-70% B (30 mpm) over 36 minutes.

[0406] Example 36: Synthesis of Cyclic PYY Analogue SEQ ID NO: 36 Using Fmoc-βAla-OH instead of Fmoc-Ile-OH at the 3-position and following the modifications described in Example 15, bromoacetic anhydride was coupled instead of m-bromomethylbenzoic acid in Step 4 (Example 9, Step 2), and the title compound was prepared according to the procedure described in Example 35. The modified workup of Example 19 was omitted. Fmoc-βAl a-OH was coupled at 50 °C for 20 minutes under microwave conditions. Saturated aqueous NaHCO3 was used instead of NH 4OAc buffer to cause cyclization. The product was purified at room temperature using a Varia n Pursuit XR C18 column (30 × 250 mm, 100 Å, 5 μm). The mobile phase consisted of buffer A (0.1% TFA in water) and a gradient elution of buffer B (0.1% TFA in MeCN) in the range of 20- 70% B (30 mpm) over 36 minutes.

[0407] Example 37: Synthesis of Cyclic PYY Analogue SEQ ID NO: 37 Using Fmoc-Cys(trt)-OH instead of Fmoc-hCys(trt)-OH at the 31-position and Fmoc-Lys(Pal -Glu-OtBu)-OH (from Active Peptide) instead of Fmoc-Leu-OH at the 30-position, Example The title compound was prepared according to the procedure described in 9. In addition, Fmoc-Abu-OH was added at the 2-position sequence in Step 1, and the coupling with bromoacetic anhydride was used instead of m-bromomethylbenzoic acid in Step 2 using the modification described in Example 15. Saturated aqueous NaHCO3 was used instead of the NH4OAc buffer in Step 3 to cause cyclization. Purification of the product was performed at room temperature using a Varian Pursuit XR C18 column (30×250 mm, 100 Å, 5 μm). The mobile phase consisted of buffer A (0.1% TFA in water), and a gradient elution of buffer B (0.1% TFA in MeCN) in the range of 20 - 70% B (30 mpm) over 36 minutes. (0.1% TFA in water), and a gradient elution of buffer B (0.1% TFA in MeCN) in the range of 20 - 70% B (30 mpm) over 36 minutes. (0.1% TFA in MeCN) over 36 minutes.

[0408] Example 38: Synthesis of Cyclic PYY Analogue SEQ ID NO: 38 The title compound was prepared according to the procedure described in Example 35 with the following modifications: Fm oc-βAla-OH was added at the 2-position sequence according to Step 1 using microwave conditions at 50 °C for 20 minutes, and the coupling with bromoacetic anhydride was used instead of m-bromomethylbenzoic acid in Step 2 using the modification described in Example 15. Saturated aqueous NaHCO 3 was used instead of the NH4OAc buffer to cause cyclization. Purification of the product was performed at room temperature using a Varian Pursuit XR C18 column (30×250 mm, 100 Å, 5 μ m). The mobile phase consisted of buffer A (0.1% TFA in water), and a gradient elution of buffer B (0.1% TFA in MeCN) in the range of 20 - 80% B (30 mpm) over 36 minutes. arian Pursuit XR C18 column (30×250 mm, 100 Å, 5 μ m) at room temperature. The mobile phase consisted of buffer A (0.1% TFA in water), and a gradient elution of buffer B (0.1% TFA in MeCN) in the range of 20 - 80% B (30 mpm) over 36 minutes. consisted of a gradient elution of buffer B (0.1% TFA in MeCN) in the range of 20 - 80% B (30 mpm) over 36 minutes.

[0409] Example 39: Synthesis of Cyclic PYY Analogue SEQ ID NO: 39 ​In Step 2, arachidonic acid was used instead of α-tocopheryl oxyacetic acid (AcVitE) (8), and the title compound was prepared according to the procedure described in Example 11. Fmo c-Ser(tBu)-OH was used instead of Fmoc-Lys(Boc)-OH at the 4-position in Step 4 (Example 9, Step 1), and m-chloromethylbenzoic acid was used instead of m-bromomethylbenzoic acid in Step 4 ( Example 9, Step 2). 60% EtOH / H2O was used as the solvent instead of MeCN / H2O, and saturated aqueous NaHCO 3 was used instead of the NH4OAc buffer in Step 4 to cause cyclization. The purification of the product was carried out at room temperature using a Waters XBridge C18 OBD column (50×250 mm , 5 μm). The mobile phase consisted of buffer A (10 mM NH4OH in water , pH about 9), and buffer B (MeCN) with a gradient elution ranging from an initial concentration of 20% B to an intermediate concentration of 25% B (100 mpm) over 5 minutes , and then to a final concentration of 40% B (100 mpm) over 40 minutes.

[0410] Example 40: Synthesis of Cyclic PYY Analogue SEQ ID NO: 40 1. (HCCH(CH2)2CONH)-IKPEAPGEDASPEELNRYYA SLRHYLNK(Dde)-(azido-norLeu)-TRQ(psi-R35Y3 6)-Sieber Resin Synthesis Amino acid extension onto the pre-packed (psi-R35,Y36)-Sieber resin (0.1 mmol) from Example 1, Step 2 was carried out at room temperature using NMP as the solvent, a 5-fold excess of protected amino acids, and the HATU / DIEA protocol (1 hour, single bond). Fmoc-Arg(pbf)-OH and Fmoc-His(trt)-OH were ​ Double bonds were formed. A two-step Fmoc deprotection protocol was used throughout (20% piperidine in DMF; room temperature; 10 min, 15 min).

[0411] 2. (HCCH(CH2)2CONH)-IKPEAPGEDASPEELNRYYA SLRHYLNK(NH2)-(azido-norLeu)-TRQ(psi-R35Y3 6)-Synthesis of Sieber resin The above resin was treated with 2% hydrazine in DMF (12 mL / 0.2 mmol scale) at room temperature for 2 minutes, and then the mixture was drained. This procedure was repeated about 4 times, and then the resin was washed thoroughly with DMF and then with DCM.

[0412] 3. (HCCH(CH2)2CONH)-IKPEAPGEDASPEELNRYYA SLRHYLNK((OEG)2-γ-Glu-Pal)-(azido-norLeu)- TRQ(psi-R35Y36)-Synthesis of Sieber resin The above resin was coupled with (S)-10,19-dioxo-22-palmitamido-3,6,12,15-tetraoxa-9,18-diazatricosandioic acid (5 equivalents) using an HBTU / DIEA protocol at room temperature for 1.5 hours [prepared according to the procedure described for the synthesis of Intermediate 3 by using palmitic acid instead of 18-tert-butoxy-18-oxooctadecanoic acid]. The resin was drained and washed thoroughly with DMF and DCM. 10,19-dioxo-22-palmitamido-3,6,12,15-tetraoxa-9 ,18-diazatricosandioic acid

[0413] 4. (HCCH(CH2)2CONH)-IKPEAPGEDASPEELNRYYA SLRHYLNK((OEG)2-γ-Glu-Pal)-(azido-norLeu)- ​​​​​​Synthesis of TRQ(psi-R35Y36)-CONH2 The dried resin was treated with a 2% TFA solution in DCM (20 mL) and mixed for 20 minutes and then filtered. This treatment was repeated two more times using a fresh cocktail for each treatment. The combined filtrates were then combined and concentrated to give the protected crude peptide as a yellow foam This foam was treated with 20 mL of cleavage cocktail (TFA / H2O / TIPS = 95 / 2.5 / 2.5) for 2.5 hours at room temperature and then concentrated to a volume of approximately 2.5 mL under a nitrogen stream Cold ether (40 mL) was then added to precipitate the peptide and the mixture was centrifuged separated (5 minutes, 5000 rpm) and decanted. This process was repeated two more times to give the crude peptide as an off-white powder.

[0414] Alternatively, the resin was treated with the cleavage cocktail without pretreatment with 1 - 2% TFA in DCM to directly obtain the fully deprotected peptide The crude peptide was purified by reverse-phase preparative HPLC using a Varian Pursuit XR C18 column (30×250 m

[0415] m, 100 Å, 5 μm). The mobile phase consisted of buffer A (0.1% TFA in water), and a gradient elution of buffer B (0.1% TFA in MeC N) from 20 - 70% over 36 minutes. UV detection was monitored at 220 and 254 nm The product-containing fractions were analyzed by analytical HPLC using an Agilent 1100 HPLC system with the same column type as above (4.6×250 mm, 5 μm) The pure fractions were combined and then lyophilized to give the product as a cotton-like solid. 1 6.87 minutes (LC: Atlantis T3 C18 column, 5 μm, 4.6×250 m ​​ LCMS: 121 with respect to the peak of the product at m, 1.0 mL / min, 30 - 60% gradient 1.8 (M + 4H) / 4, 1615.4 (M + 3H) / 3 and 2422.9 (M + 2H) / 2 / 2

[0416] 5. Cyclic PYY analog SEQ ID NO: 40 Prepare 5.1 mg of CuSO4 in 1 mL of H2O. Prepare 10.4 m g of TBTA in 3 mL of EtOH. Pre - mix 400 μL of the CuSO4 solution and 3 mL of the TBTA solution Prepare 13 mg of sodium ascorbate in 2 mL of H2O

[0417] To a solution of the azide - containing peptide (37 mg) purified in step 4 in 4 mL of HEPES (0.1 M, pH 7.4), add 1.7 mL of the pre - mixed CuSO4 / TBTA solution and then add 1 mL of the sodium ascorbate solution. Adjust the EtOH / H2O ratio until the reaction solution becomes clear. Stir the mixture at room temperature for 3 hours and monitor by HPLC After 30 minutes, the reaction is complete. Adjust the mixture to pH 4 and purify by reverse - phase preparative HPLC The purification is carried out using a Varian Pursuit XR C18 column (30×250 mm, 1 00 Å, 5 μm). The mobile phase consists of buffer A (0.1% TFA in water) and a gradient elution of buffer B (0.1% TFA in MeCN) in the range of 20 - 60% B over 36 minutes The UV detection is monitored at 220 and 254 nm. The product - containing fractions are analyzed by analytical HPLC using the same column type (4.6×250 mm, 5 μm) as above on an Agilent 11 00 HPLC system. Combine the pure fractions and then lyophilize to obtain the product as a cotton - like solid from the gradient elution consisting of buffer A (0.1% TFA in water) and a gradient elution of buffer B (0.1% TFA in MeCN) in the range of 20 - 60% B over 36 minutes. The UV detection is monitored at 220 and 254 nm. The product - containing fractions are analyzed by analytical HPLC using the same column type (4.6×250 mm, 5 μm) as above on an Agilent 11 00 HPLC system. Combine the pure fractions and then lyophilize to obtain the product as a cotton - like solid lyophilize to obtain the product as a cotton - like solid

[0418] Example 41: Synthesis of Cyclic PYY Analogue SEQ ID NO: 41 In step 3, instead of (S)-10,19-dioxo-22-palmitamido-3,6,1 2,15-tetraoxa-9,18-diazatriacosanedioic acid, L-glutamic acid, N-(1-oxohexadecyl)-, 1-(1,1-dimethylethyl) ester was used and the title compound was prepared according to the procedure described in Example 40.

[0419] Example 42: Synthesis of Cyclic PYY Analogue SEQ ID NO: 42 In step 3, instead of (S)-10,19-dioxo-22-palmitamido-3,6,1 2,15-tetraoxa-9,18-diazatriacosanedioic acid, (S)-22- (tert-butoxycarbonyl)-43,43-dimethyl-10,19,24,41- tetraoxo-3,6,12,15,42-pentaoxa-9,18,23-triazatet ratetracontane-1-acid (16) (Intermediate 2) was used and the title compound was prepared according to the procedure described in Example 40.

[0420] Example 43 Synthesis of Cyclic PYY Analogue SEQ ID NO: 43 1. (Alloc)Lys((OEG)2-γ-Glu-NH2)-(hC)-TRQ Synthesis of (psi-R35Y36)-Sieber Resin Amino acid elongation onto pre-packed (psi-R35,Y36)-Sieber resin (0.1 mmol) from Example 1, step 2 was carried out at room temperature using NMP as the solvent, 5-fold excess of protected amino acids, and the HATU / DIEA protocol (1 hour, single bond). Fmoc-Arg(pbf)-OH was double-bonded. Two-step Fmoc deprotection was used. was performed. The protocol was used throughout (20% piperidine in DMF; room temperature; 10 min, 15 min).

[0421] 2. (Alloc)Lys((OEG)2-γ-Glu-Pal)-(hC)-TRQ (psi-R35Y36)-Sieber resin synthesis Using microwave conditions with HATU / DIEA and NMP as solvents at 50 °C for 20 - 30 minutes, palmitic acid was coupled onto the resin from step 1.

[0422] 3. (H2N)Lys((OEG)2--γ-Glu-Pal)-(hC)-TRQ( (psi-R35Y36)-Sieber resin synthesis The alloc protecting group of the above resin was removed according to the procedure described in Example 1, step 4.

[0423] 4. Cyclic PYY analog SEQ ID NO: 43 Using m-chloromethylbenzoic acid instead of m-bromomethylbenzoic acid in step 2, the title compound was prepared from the above resin according to the procedure described in Example 9, steps 1 - 3. The crude linear peptide was purified and cyclized according to the modification described in Example 19 using a gradient of 20 - 60% B. The final product was purified using a gradient of 20 - 60% B (30 mp m) over 36 minutes.

[0424] Example 44 Synthesis of cyclic PYY analog SEQ ID NO: 44 The title compound was prepared according to the procedure described in Example 43, modified such that the tandem Fmoc-OEG-OH units and Fmoc-Glu-OtBu units were incorporated in step 2 instead of step 1. Octadecanedioic acid mono-tert-butyl ester (AstaT ech, Inc.) was used in step 2 instead of palmitic acid, and the linker lipid ​​​​ The column was placed at position 11 instead of position 30. The crude linear peptide was purified and cyclized according to the modification described in Example 19 using a gradient of 20 - 70% B. The purification of the final product was carried out using a gradient of 20 - 70% B (30 mpm) over 36 minutes.

[0425] Example 45 Synthesis of Cyclic PYY Analogue SEQ ID NO: 45 Fmoc-dPEG24 - carboxylic acid was used instead of the Fmoc - OEG - OH units in series and modified to be incorporated into step 2 together with palmitic acid. The title compound was prepared according to the procedure described in Example 43. The linker - lipid sequence was placed at position 11 instead of position 30. The crude linear peptide was purified and cyclized according to the modification described in Example 19 using a gradient of 20 - 90% B. The purification of the final product was carried out using a gradient of 20 - 90% B (30 mpm) over 36 minutes. Example 46 Synthesis of Cyclic PYY Analogue SEQ ID NO: 46 Fmoc - Lys(Pal - Glu - OtBu) - OH (from Active Peptide) was used instead of Leu at position 30, and the title compound was prepared according to the procedure described in Example 9. Additionally, Fmoc - βAla - OH was added onto the sequence at position 2 according to step 1 using microwave conditions at 50 °C for 20 minutes, and the coupling with bromoacetic anhydride was carried out using the modification described in Example 15 in step 2 instead of m - bromomethylbenzoic acid. The solid crude linear peptide was purified and cyclized according to the modification described in Example 19 using a gradient of 20 - 70% B. The purification of the final product was carried out using a gradient of 20 - 70% B (30 mpm) over 36 minutes.

[0426]

[0427] Example 47 Synthesis of Cyclic PYY Analogue SEQ ID NO: 47 A linker-lipid sequence was placed at the 7-position instead of the 11-position, and the title compound was prepared according to the procedure described in Example 44. Purification of the product was carried out at room temperature using a Varian Pursuit XR C18 column (30×250 mm, 100 Å, 5 μm). The crude linear peptide was purified and cyclized according to the modification described in Example 19 using a gradient of 20 - 60% B. Purification of the final product was carried out using a gradient of 20 - 60% B (30 mpm) over 36 minutes.

[0428] Example 48 Synthesis of Cyclic PYY Analogue SEQ ID NO: 48 In step 2, mono-tert-butyl ester of octadecanedioic acid (AstaTech, Inc.) was used instead of palmitic acid, and a linker-lipid sequence was placed at the 22-position instead of the 30-position with a coupling time of 30 minutes. The title compound was prepared according to the procedure described in Example 43. The crude linear peptide was purified and cyclized according to the modification described in Example 19 using a gradient of 20 - 70% B. Purification of the final product was carried out using a gradient of 20 - 70% B (30 mpm) over 36 minutes.

[0429] Example 49 Synthesis of Cyclic PYY Analogue SEQ ID NO: 49 In step 2, 16-tetrahydropyran-2-yloxy palmitic acid was used instead of α-tocopheryl oxyacetic acid (AcVitE) (8), and in step 4 (Example 9, step 2 ), m-chloromethyl benzoic acid was used instead of m-bromomethyl benzoic acid. The title compound was prepared according to the procedure described in Example 11. 60% EtOH / H2O was used as the solvent instead of MeCN / H2O, and saturated aqueous NaHCO3 was used in step 4 instead of N ​​​​​​​ It was used in place of the H4OAc buffer to cause cyclization. The purification of the product was carried out using a Waters XBridge C18 OBD column (50×250 mm, 5 μm) at room temperature. The mobile phase consisted of buffer A (10 mM NH4OH in water, pH about 9) and a gradient elution of buffer B (MeCN) ranging from an initial concentration of 20%B to an intermediate concentration of 10%B (100 mpm) over 5 minutes and then to a final concentration of 30%B (100 mpm) over 40 minutes. using a Waters XBridge C18 OBD column (50×250 mm, 5 μm) at room temperature. The mobile phase consisted of buffer A (10 mM NH4OH in water, pH about 9) and a gradient elution of buffer B (MeCN) ranging from an initial concentration of 20%B to an intermediate concentration of 10%B (100 mpm) over 5 minutes and then to a final concentration of 30%B (100 mpm) over 40 minutes. consisted of a gradient elution of buffer B (MeCN) ranging from an initial concentration of 20%B to an intermediate concentration of 10%B (100 mpm) over 5 minutes and then to a final concentration of 30%B (100 mpm) over 40 minutes. .

[0430] Example 50 Synthesis of Cyclic PYY Analogue SEQ ID NO: 50 Following the procedure described in Example 48, a linker-lipid sequence was placed at position 23 instead of position 30 to prepare the title compound.

[0431] Example 51 Synthesis of Cyclic PYY Analogue SEQ ID NO: 51 Using Fmoc-Lys(Pal-Glu-OtBu)-OH (from Active Peptide) instead of Fmoc-Leu-OH at position 30 and Fmoc-Ser(tBu)-OH instead of Fmoc-Lys(Boc)-OH at position 4 in Step 1, following the procedure described in Example 9, the title compound was prepared. 60% EtOH / H2O was used as the solvent instead of MeCN / H2O, and saturated aqueous NaHCO3 was used in Step 4 instead of the NH4OAc buffer to cause cyclization. The purification of the product was carried out using a Waters XBridge C18 OBD column (50×250 mm, 5 μm) at room temperature. The mobile phase consisted of buffer A (10 mM NH4OH in water, pH about 9) and a gradient elution of buffer B (MeCN) ranging from an initial concentration of 10%B to an intermediate concentration of 20%B (100 mpm) over 5 minutes and then to a final concentration of 30%B (100 mpm) over 40 minutes. using Fmoc-Lys(Pal-Glu-OtBu)-OH (from Active Peptide) instead of Fmoc-Leu-OH at position 30 and Fmoc-Ser(tBu)-OH instead of Fmoc-Lys(Boc)-OH at position 4 in Step 1 to prepare the title compound following the procedure described in Example 9. 60% EtOH / H2O was used as the solvent instead of MeCN / H2O, and saturated aqueous NaHCO3 was used in Step 4 instead of the NH4OAc buffer to cause cyclization. The purification of the product was carried out using a Waters XBridge C18 OBD column (50×250 mm, 5 μm) at room temperature. The mobile phase consisted of buffer A (10 mM NH4OH in water, pH about 9) and a gradient elution of buffer B (MeCN) ranging from an initial concentration of 10%B to an intermediate concentration of 20%B (100 mpm) over 5 minutes and then to a final concentration of 30%B (100 mpm) over 40 minutes. as the solvent instead of MeCN / H2O, and saturated aqueous NaHCO3 was used in Step 4 instead of the NH4OAc buffer to cause cyclization. The purification of the product was carried out using a Waters XBridge C18 OBD column (50×250 mm, 5 μm) at room temperature. The mobile phase consisted of buffer A (10 mM NH4OH in water, pH about 9) and a gradient elution of buffer B (MeCN) ranging from an initial concentration of 10%B to an intermediate concentration of 20%B (100 mpm) over 5 minutes and then to a final concentration of 30%B (100 mpm) over 40 minutes. using a Waters XBridge C18 OBD column (50×250 mm, 5 μm) at room temperature. The mobile phase consisted of buffer A (10 mM NH4OH in water, pH about 9) and a gradient elution of buffer B (MeCN) ranging from an initial concentration of 10%B to an intermediate concentration of 20%B (100 mpm) over 5 minutes and then to a final concentration of 30%B (100 mpm) over 40 minutes. It consisted of gradient elution of buffer B (MeCN) in the range of a final concentration of 30% B (100 mpm). The impure fraction was re-chromatographed using a gradient consisting of an initial concentration of 10% B to an intermediate concentration of 20% B (100 mpm) over 5 minutes and then a final concentration of 30% B (100 mpm) over 60 minutes.

[0432] Example 52 Synthesis of cyclic PYY analog SEQ ID NO: 52 Fmoc-dPEG12-carboxylic acid was used instead of the Fmoc-OEG-OH units in series, and it was incorporated with Fmoc-Glu-OtBu and palmitic acid in step 2 and the title compound was prepared according to the procedure described in Example 43. The linker-lipid sequence was placed at position 11 instead of position 30. The crude linear peptide was purified and cyclized according to the modification described in Example 19 using a gradient of 20 - 70% B. Purification of the final product was carried out using a gradient of 20 - 70% B (30 mpm) over 36 minutes.

[0433] Example 53 Synthesis of cyclic PYY analog SEQ ID NO: 53 Instead of Fmoc-dPEG12-carboxylic acid, 4 units of Fmoc-OEG-OH in series were used and the title compound was prepared according to the procedure described in Example 52.

[0434] Example 54 Synthesis of cyclic PYY analog SEQ ID NO: 54 Instead of two units, 2 units of Fmoc-OEG-OH in series were placed and the title compound was prepared according to the procedure described in Example 53.

[0435] Example 55 Synthesis of cyclic PYY analog SEQ ID NO: 55 The linker-lipid sequence was placed at position 23 instead of position 30 and the procedure described in Example 43 was followed ​​​Therefore, the title compound was prepared. The crude linear peptide was purified and cyclized according to the modification described in Example 19 using a gradient of 20 - 70% B. and eluted over 36 minutes using a gradient of 20 - 70% B (30 mpm).

[0436] Example 56: Synthesis of Cyclic PYY Analogue SEQ ID NO: 56 In Step 2, (4'-chlorobiphenyl-4-yl)acetic acid was used instead of α-tocopheryloxyacetic acid (AcVitE) (8), and in Step 4 (Example 9, Step 2), m-chloromethylbenzoic acid was used instead of m-bromomethylbenzoic acid. According to the procedure described in Example 11, the title compound was prepared. 60% EtOH / H₂O was used as the solvent instead of MeCN / H₂O, and saturated aqueous NaHCO₃ was used instead of NH₄OAc buffer in Step 4 to cause cyclization. The product was purified at room temperature using a Waters XBridge C18 OBD column (50×250 mm, 5 µm). The mobile phase consisted of Buffer A (10 mM NH₄OH in water, pH about 9) and a gradient elution of Buffer B (MeCN) in the range of 10 - 28% B (100 mpm) over 40 minutes. The mobile phase consisted of Buffer A (10 mM NH₄OH in water, pH about 9) and a gradient elution of Buffer B (MeCN) in the range of 10 - 28% B (100 mpm) over 40 minutes.

[0437] Example 57: Synthesis of Cyclic PYY Analogue SEQ ID NO: 57 In Step 2, 3-[(2,4-dichlorophenoxy)phenyl]-4-yl]propionic acid was used instead of α-tocopheryloxyacetic acid (AcVitE) (8), and in Step 4 (Example 9, Step 2), m-chloromethylbenzoic acid was used instead of m-bromomethylbenzoic acid. According to the procedure described in Example 11, the title compound was prepared. 60% EtOH / H₂O was used as the solvent instead of MeCN / H₂O, and saturated aqueous NaHCO₃ was used in the process ​ In Step 4, it was used instead of the NH4OAc buffer to cause cyclization. The purification of the product was carried out at room temperature using a Waters XBridge C18 OBD column (50×250 mm, 5 μ m). The mobile phase consisted of buffer A (10 mM NH4OH in water, pH about 9), and a gradient elution of buffer B (MeCN) in the range of 10 - 30% B (80 mpm) over 40 minutes . The product-containing fractions were combined, acidified with TFA, concentrated, and re-chromatographed on an Agilent Polaris C18-A column (30×250 mm, 100 Å, 5 μm) at room temperature. The mobile phase consisted of buffer A (0.1% TFA in water), and a gradient elution of buffer B (0.1% TFA in MeCN) in the range of an initial concentration of 20% B to an intermediate concentration of 15% B (40 mpm) and then a final concentration of 45 % B (40 mpm) over 45 minutes .

[0438] Example 58: Synthesis of Cyclic PYY Analogue SEQ ID NO: 58 In Step 2, 11-(4-fluorophenyl)undecanoic acid was used instead of α-tocopheryloxyacetic acid (AcVitE) (8), and in Step 4 (Example 9, Step 2), m-chloromethylbenzoic acid was used instead of m-bromomethylbenzoic acid, and the title compound was prepared according to the procedure described in Example 11 . 60% EtOH / H2O was used as the solvent instead of MeCN / H 2O, and saturated aqueous NaHCO3 was used instead of the NH4OAc buffer in Step 4 to cause cyclization. The purification of the product was carried out at room temperature using a Waters XB ridge C18 OBD column (50×250 mm, 5 μm) . The mobile phase consisted of buffer A (10 mM NH4OH in water, pH about 9), and over 40 minutes It consisted of gradient elution of buffer B (MeCN) in the range of 15~35%B (100 mpm).

[0439] Example 59: Synthesis of cyclic PYY analog SEQ ID NO: 59 Omit step 2 and incorporate the palmitic acid bond in step 1, following the procedure described in Example 43 Thus, the title compound was prepared. The linker-lipid sequence was placed at the 22nd position instead of the 11th position The crude linear peptide was purified and cyclized following the modification described in Example 19 using a gradient of 20~70%B Thus. The final product was purified using a gradient of 20~70%B (30 mpm) over 36 minutes

[0440] Example 60: Synthesis of cyclic PYY analog SEQ ID NO: 60 Instead of four, two tandem FMOC-OEG-OH units were incorporated, and the linker-lipid sequence was placed at the 7th position instead of the 11th position Following the procedure described in Example 53, the title compound was prepared The crude linear peptide was purified and cyclized following the modification described in Example 19 using a gradient of 20~80%B The final product was purified using a gradient of 20~80%B (30 mpm) over 36 minutes

[0441] Example 61: Synthesis of cyclic PYY analog SEQ ID NO: 61 In step 2, 11-[(4-trifluoromethyl)phenyl]undecanoic acid was used instead of α-tocopheryloxyacetic acid (AcVitE) (8), and in step 4 (Example 9, step 2) m-chloromethylbenzoic acid was used instead of m-bromomethylbenzoic acid Following the procedure described in Example 11, the title compound was prepared. 60% EtOH / H2O was used as the solvent instead of MeCN / H2O, and saturated aqueous NaHCO3 was used in step 4 ​​​It was used instead of the NH4OAc buffer to cause cyclization. Purification of the product was performed using a Waters XBridge C18 OBD column (50×250 mm, 5 μm) at room temperature. The mobile phase consisted of buffer A (10 mM NH4OH in water, pH ~9), and a gradient elution of buffer B (MeCN) from 15 - 35% B (100 mpm) over 40 minutes.

[0442] Example 62: Synthesis of cyclic PYY analog SEQ ID NO: 62 In step 2, 11,11,11-trifluoroundecanoic acid was used instead of α-tocopheryloxyacetic acid (AcVitE) (8), and in step 4 (Example 9, step 2) m-chloromethylbenzoic acid was used instead of m-bromomethylbenzoic acid. The title compound was prepared according to the procedure described in Example 11. 60% EtOH / H2O was used as the solvent instead of MeCN / H2O, and saturated aqueous NaHCO3 was used instead of the NH4OAc buffer in step 4 to cause cyclization. Purification of the product was performed at room temperature using a Waters XB ridge C18 OBD column (50×250 mm, 5 μm). The mobile phase consisted of buffer A (10 mM NH4OH in water, pH ~9), and a gradient elution of buffer B (MeCN) from 10 - 28% B (100 mpm) over 40 minutes. It was used instead of the NH4OAc buffer to cause cyclization. Purification of the product was performed using a Waters XB ridge C18 OBD column (50×250 mm, 5 μm) at room temperature. The mobile phase consisted of buffer A (10 mM NH4OH in water, pH ~9), and a gradient elution of buffer B (MeCN) from 10 - 28% B (100 mpm) over 40 minutes.

[0443] Example 63: Synthesis of cyclic PYY analog SEQ ID NO: 63 In step 2, 15,15,15-trifluoropentadecanoic acid was used instead of α-tocopheryloxyacetic acid (AcVitE) (8), and in step 4 (Example 9, step 2) m-chloromethylbenzoic acid was used instead of m-bromomethylbenzoic acid. The title compound was prepared according to the procedure described in Example 1. ​​​The title compound was prepared according to the procedure described in 1. 60% EtOH / H2O was used as the solvent instead of MeCN / H2O, and saturated aqueous NaHCO3 was used instead of NH4OAc buffer in step 4 to cause cyclization. The purification of the product was carried out at room temperature using a Waters XBridge C18 OBD column (50×250 mm, 5 μm). The mobile phase consisted of buffer A (10 mM NH4OH in water, pH about 9) and a gradient elution of buffer B (MeCN) in the range of 15 - 30% B (100 mpm) over 40 minutes. H2O, and saturated aqueous NaHCO3 was used instead of NH4OAc buffer in step 4 to cause cyclization. The purification of the product was carried out using a Waters XBridge C18 OBD column (50×250 mm, 5 μm) at room temperature. The mobile phase consisted of buffer A (10 mM NH4OH in water, pH about 9) and a gradient elution of buffer B (MeCN) in the range of 15 - 30% B (100 mpm) over 40 minutes.

[0444] Example 64: Synthesis of Cyclic PYY Analogue SEQ ID NO: 64 In step 2, 16-ethoxypalmitic acid was used instead of α-tocopheryloxyacetic acid (AcVitE) (8), and in step 4 (Example 9, step 2), m-chloromethylbenzoic acid was used instead of m-bromomethylbenzoic acid. The title compound was prepared according to the procedure described in Example 11. 60% EtOH / H2O was used as the solvent instead of MeCN / H2O, and saturated aqueous NaHCO3 was used instead of NH4OAc buffer in step 4 to cause cyclization. The purification of the product was carried out using a Waters XBridge C18 OBD column (50×250 mm, 5 μm) at room temperature. The mobile phase consisted of buffer A (10 mM NH4OH in water, pH about 9) and a gradient elution of buffer B (MeCN) in the range of 15 - 30% B (100 mpm) over 40 minutes. The purification of the product was carried out at room temperature using a Waters XBridge C18 OBD column (50×250 mm, 5 μm). The mobile phase consisted of buffer A (10 mM NH4OH in water, pH about 9) and a gradient elution of buffer B (MeCN) in the range of 15 - 30% B (100 mpm) over 40 minutes.

[0445] Example 65: Synthesis of Cyclic PYY Analogue SEQ ID NO: 65 In step 2, 13, ​​​​​​​​​​13,14,14,15,15,16,16,16-D9-Palmitic acid (Cambridge Isotopes) was used, and m-chloromethylbenzoic acid was used instead of m-bromomethylbenzoic acid in Step 4 (Example 9, Step 2), and the title compound was prepared according to the procedure described in Example 11. 60% EtOH / H2O was used as the solvent instead of MeCN / H2O, and saturated aqueous NaHCO3 was used instead of the NH4OAc buffer in Step 4 to cause cyclization. The purification of the product was carried out at room temperature using a Waters XBridge C18 OBD column (50×250 mm, 5 μm). The mobile phase consisted of buffer A (10 mM NH4OH in water, pH about 9), and a gradient elution of buffer B (MeCN) from 15 - 20% B (100 mpm) over 5 minutes and then to 35% B (100 mpm) over 40 minutes. and in Step 4 (Example 9, Step 2), m-chloromethylbenzoic acid was used instead of m-bromomethylbenzoic acid, and the title compound was prepared according to the procedure described in Example 11. and the title compound was prepared according to the procedure described in Example 11. in turn. 60% EtOH / H2O was used as the solvent instead of MeCN / H2O, and saturated aqueous NaHCO3 was used instead of the NH4OAc buffer in Step 4 to cause cyclization. The purification of the product was carried out at room temperature using a Waters XBridge C18 OBD column (50×250 mm, 5 μm). The mobile phase consisted of buffer A (10 mM NH4OH in water, pH about 9), and a gradient elution of buffer B (MeCN) from 15 - 20% B (100 mpm) over 5 minutes and then to 35% B (100 mpm) over 40 minutes. (50×250 mm, 5 μm). The mobile phase consisted of buffer A (10 mM NH4OH in water, pH about 9), and a gradient elution of buffer B (MeCN) from 15 - 20% B (100 mpm) over 5 minutes and then to 35% B (100 mpm) over 40 minutes. from 15 - 20% B (100 mpm) over 5 minutes and then to 35% B (100 mpm) over 40 minutes. The purification of the product was carried out at room temperature using a Waters XBridge C18 OBD column (50×250 mm, 5 μm). The mobile phase consisted of buffer A (10 mM NH4OH in water, pH about 9), and a gradient elution of buffer B (MeCN) from 15 - 20% B (100 mpm) over 5 minutes and then to 35% B (100 mpm) over 40 minutes.

[0446] Example 66: Synthesis of Cyclic PYY Analogue SEQ ID NO: 66 In Step 2, 11-[(2,4-bis(trifluoromethyl)phenyl]undecanoic acid was used instead of α-tocopheryloxyacetic acid (AcVitE) (8), and in Step 4 (Example 9, Step 2), m-chloromethylbenzoic acid was used instead of m-bromomethylbenzoic acid, and the title compound was prepared according to the procedure described in Example 11. 60% EtOH / H2O was used as the solvent instead of MeCN / H2O, and saturated aqueous NaHCO3 was used instead of the NH4OAc buffer in Step 4 to cause cyclization. The purification of the product was carried out at room temperature using a Waters XBridge C18 OBD column (50×250 mm, 5 μm). The mobile phase consisted of buffer A (10 mM NH4OH in water, pH about 9), and a gradient elution of buffer B (MeCN) from 15 - 20% B (100 mpm) over 5 minutes and then to 35% B (100 mpm) over 40 minutes. and the title compound was prepared according to the procedure described in Example 11. 60% EtOH / H2O was used as the solvent instead of MeCN / H2O, and saturated aqueous NaHCO3 was used instead of the NH4OAc buffer in Step 4 to cause cyclization. The purification of the product was carried out at room temperature using a Waters XBridge C18 OBD column (50×250 mm, 5 μm). The mobile phase consisted of buffer A (10 mM NH4OH in water, pH about 9), and a gradient elution of buffer B (MeCN) from 15 - 20% B (100 mpm) over 5 minutes and then to 35% B (100 mpm) over 40 minutes. The purification of the product was carried out at room temperature using a Waters XBridge C18 OBD column (50×250 mm, 5 μ m). The mobile phase consisted of buffer A (10 mM NH4OH in water, pH Approximately 9), and a gradient elution of buffer B (MeCN) in the range of 15 - 35% B (100 mpm) over 40 minutes ) consisted of.

[0447] Example 67: Synthesis of cyclic PYY analog SEQ ID NO: 67 In step 2, instead of α - tocopheryl oxyacetic acid (AcVitE) (8), 11 - [(3,5 - bis(trifluoromethyl)phenyl]undecanoic acid was used, and in step 4 (Example 9, step 2), instead of m - bromomethylbenzoic acid, m - chloromethylbenzoic acid was used. The title compound was prepared according to the procedure described in Example 11. 60% EtO H / H2O was used as the solvent instead of MeCN / H2O, and saturated aqueous NaHCO3 was used instead of NH4OAc buffer in step 4 to cause cyclization. Purification of the product was carried out at room temperature using a Waters XBridge C18 OBD column (50×250 mm, 5 μ m). The mobile phase consisted of buffer A (10 mM NH4OH in water, pH approximately 9), and a gradient elution of buffer B (MeCN ) in the range of 15 - 35% B (100 mpm) over 40 minutes. The mobile phase consisted of buffer A (10 mM NH4OH in water, pH approximately 9), and a gradient elution of buffer B (MeCN ) in the range of 15 - 35% B (100 mpm) over 40 minutes.

[0448] Example 68: Synthesis of cyclic PYY analog SEQ ID NO: 68 1. (Fmoc)-βA - IKPEAPGEK(Alloc)ASPEELNRYYA Synthesis of SLRHYLNCVTRQ(psi - R35Y36)-Sieber resin Amino acid extension onto the pre - loaded (psi - R35,Y36)-Sieber resin (0.1 mmol) from Example 1, step 2 was carried out at room temperature using DMF as the solvent, a 6 - fold excess of protected amino acids, and the HATU / DIEA protocol (10 minutes, double bond). amino acids, and the HATU / DIEA protocol (10 minutes, double bond) using DMF as the solvent at room temperature It was carried out. The two-step Fmoc deprotection protocol was used throughout (20 % piperidine in DMF; room temperature; 10 min, 15 min).

[0449] 2. Synthesis of (Fmoc)-βA-IKPEAPGEK((OEG)2-γ-Glu-NHCO (CH2) 16 CO2tBu)-ASPEELNRYYASLRHYLNCVTRQ(p si-R35Y36)-Sieber resin For each treatment, using a modified reaction time of 10 minutes, according to the method described in Example 1, Step 4, the above resin was deprotected. Then, using HATU / DIEA protocol (1 hour, room temperature) in DMF, the resin was coupled with intermediate 2(15) (5 equivalents).

[0450] 3. Synthesis of (BrAc)-βA-IKPEAPGEK((OEG)2-γ-Glu-NHCO (CH2) 16 CO2tBu)-ASPEELNRYYASLRHYLNCVTRQ(p si-R35Y36)-Sieber resin After Fmoc deprotection (20% piperidine / DMF), the above resin was treated with bromoacetic anhydride (1 0 equivalents, room temperature, 30 minutes) to obtain bromoacetyl resin.

[0451] 4. Synthesis of (BrAc)-βA-IKPEAPGEK((OEG)2-γ-Glu-NHCO (CH2) 16 CO2tBu)-ASPEELNRYYASLRHYLNCVTRQ(p si-R35Y36)-CONH2 The above resin was treated with a cleavage cocktail consisting of TFA / H2O / TIPS (95:2.5:2.5 ) at room temperature for 1.5 hours. According to the procedure described in Example 1, Step 7, the crude peptide was precipitated with ether.

[0452] 5. Cyclic PYY analog SEQ ID NO: 68 The crude peptide obtained above was dissolved at a concentration of 10 mg / mL in 10% MeCN / H2O and TEA was added to raise the solution pH to 8 - 9. After stirring at room temperature for about 20 minutes, T FA was added to lower the pH to 2, and the solution was directly purified by preparative HPLC on a Kinetics C18 Evo column (3 0×100 mm, 100 Å, 5 μm). The mobile phase consisted of buffer A (0.1% TFA in water), and a gradient elution of buffer B ( 0.1% TFA in MeCN) from 20 - 60% over 22 minutes. UV detection was monitored at 220 and 254 nm The pure fractions were combined and then lyophilized to obtain the product as a fluffy solid obtained.

[0453] Example 69: Synthesis of cyclic PYY analog SEQ ID NO: 69 1. (Boc)-G-ISPEAPGEK(dde)ASPEELNRYYASLRH Synthesis of YLNLE(OAllyl)TRQ(psi-R35Y36)-Sieber resin Amino acid elongation onto the pre-loaded (psi-R35,Y36)-Sieber resin (0.1 mmol) from Example 1, step 2 was carried out at room temperature using DMF as the solvent, 6-fold excess of protected amino acids, and the HATU / NMM protocol (10 minutes, double bond). A two-step Fmoc deprotection protocol was used throughout (20% piperidine in DMF; room temperature; 10 minutes, 15 minutes).

[0454] 2. (Boc)-G-ISPEAPGEK(dde)ASPEELNRYYASLRH Synthesis of YLNLE(NHS)TRQ(psi-R35Y36)-Sieber resin For each process, using the corrected reaction time of 10 minutes, the method described in Example 1, Step 4 was followed to perform Alloc deprotection of the above resin. Then, in DMF, HATU / D Using the IEA protocol (1 hour, room temperature, double bond), the resin was reacted with NHS (10 equivalents) and bonded.

[0455] 3. (NH2)-G-ISPEAPGEK(dde)ASPEELNRYYASLRH Synthesis of YLNLE(NHS)TRQ(psi-R35Y36) The above resin was treated with a cleavage cocktail consisting of TFA / H2O / TIPS (95:2.5:2.5 ) at room temperature for 1.5 hours. According to the procedure described in Example 1, Step 7, the crude peptide was precipitated with ether.

[0456] 4. Cyclic PYY analog SEQ ID NO: 69 The crude peptide obtained above was dissolved at a concentration of 80 mg / mL in DMSO, and TEA (2 5 equivalents) was added to cause lactamization. After stirring at room temperature for about 30 minutes, the reaction was diluted 10-fold with 10% MeCN / water, the pH was adjusted to 2, and the crude peptide was separated by preparative HPLC on a Kineti cs C18 Evo column (30×100 mm, 100 Å, 5 μm). The mobile phase consisted of buffer A (0.1% TFA in water) and a gradient of buffer B (0.1% TFA in MeCN) from 1 0 to 60% B over 22 minutes. UV detection was monitored at 220 and 254 nm. The pure fractions were combined and then lyophilized to obtain the K(Dde)-protected peptide. The Dde protecting group was removed using 2% hydrazine / DMF ( 10 mg peptide / ml) at room temperature for 30 minutes. The reaction was diluted 10-fold with 10% MeC N / water, the pH was adjusted to 2 with TFA, and the crude peptide solution was purified as described above and a product was obtained as a cotton-like solid.

[0457] Example 70: Synthesis of Cyclic PYY Analogue SEQ ID NO: 70 Using Fmoc-E(OAll)-OH instead of Fmoc-Leu-OH at position 30 and using Fmoc-Val-OH instead of Fmoc-E(OAll)-OH at position 31 the title compound was prepared according to the procedure of Example 69.

[0458] Example 71: Synthesis of Cyclic PYY Analogue SEQ ID NO: 71 1. (Boc)-G-ISPEAPGEK(dde)ASPEELNRYYASLRH YLN E(OAllyl)VTRQ(N-Me-R)Y - NovaSyn TGR resin Synthesis Using the procedure described in Example 69, Step 1, amino acid elongation onto NovaSyn TGR resin (0.1 m mol) was performed.

[0459] 2. Cyclic PYY analogue SEQ ID NO: 71 The title compound was prepared from the above resin according to the procedures described in Example 69, Steps 2 - 4 .

[0460] Example 72: Synthesis of Cyclic PYY Analogue SEQ ID NO: 72 1. (S)-22-(tert-Butoxycarbonyl)-43,43-dimethyl-10 ,19,24,41-tetraoxo-3,6,12,15,42-pentaoxa-9,1 8,23-triazatetratetracontane-1-oic N-hydroxysuccinimide ester Synthesis In 1.0 mL of DMF, (S)-22-(tert-butoxycarbonyl)-43,4 3-dimethyl-10,19,24,41-tetraoxo-3,6,12,15,42-penta N-taoxa-9,18,23-triazatetratetracontan-1-oic acid (Intermediate 2(16 )) (54.0 mg, 0.063 mmol), N-hydroxysuccinimide (14.6 mg, 0.127 mmol), and HATU (24.1 mg, 0.063 mmol) in a solution were added DIEA (0.022 mL, 0.127 mmol), and the mixture was stirred at room temperature for 30 minutes and used directly in the next step without further purification.

[0461] 2. Synthesis of cyclic PYY analog SEQ ID NO: 72 To a solution of [cyclo-(G2-E30),S4,K11,psi-(R 35,Y36)]-PYY2~36 (prepared in Example 70) (4 mg, 0.96 μmol) in DMF (0.2 mL) were added 24 μL of the N-hydroxyester solution (prepared in Step 1) and TEA (0.6 6 μL; 5 equivalents), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted 10-fold with 10% MeCN / water , the pH was adjusted to 2 with TFA, and the crude peptide was purified directly by preparative HPLC on a Kinetics C18 Evo column (30×100 mm, 100 Å, 5 μm). The mobile phase consisted of buffer A (0.1% TFA in water), and a gradient elution of buffer B (0.1% TFA in MeCN) from 10 to 60% B over 22 minutes . UV detection was monitored at 2 20 and 254 nm. The pure fractions were combined and then lyophilized to obtain the t-butyl ester-protected peptide. The t-butyl ester protecting group was removed using a mixture of TFA / H2O / TIPS (95:2.5:2.5) at room temperature for 1.5 hours . The mixture was concentrated and the peptide was purified as described above to obtain the product as a fluffy solid. The mixture was concentrated, and the peptide was purified as above to obtain the product as a fluffy solid.

[0462] Example 73: Synthesis of cyclic PYY analog SEQ ID NO: 73 In Step 5, instead of N-Fmoc-dPEG12-carboxylic acid, N-Fmoc-d PEG6-carboxylic acid was used to prepare the title compound according to the procedure described in Example 1. done.

[0463] Example 74: Synthesis of Cyclic PYY Analogue SEQ ID NO: 74 Following the procedure described in Example 1, but omitting Step 5 of the PEG linker coupling, the title compound was prepared.

[0464] Example 75: Synthesis of Cyclic PYY Analogue SEQ ID NO: 75 Instead of Fmoc-hCys(trt)-OH at position 31, Fmoc-Cys(trt)- OH was used, and the Fmoc-βAla-OH coupling step in Step 3 was omitted. According to the procedure described in Example 1 the title compound was prepared.

[0465] Example 76: Synthesis of Cyclic PYY Analogue SEQ ID NO: 76 Modifications were made to Steps 3 and 4, and the title compound was prepared according to the procedure described in Example 1. In Step 3, Fmoc-Lys(Alloc)-OH and Fmoc-Lys( dde)-OH were used at positions 30 and 11, respectively. After deprotecting the Alloc at position 30 with Pd( PPh3)4-phenylsilane, mPEG16-carboxylic acid was coupled with HATU and DIPEA. In Step 4, the dde at position 11 was removed using 2% hydrazine in DMF. removed.

[0466] Example 77: Synthesis of Cyclic PYY Analogue SEQ ID NO: 77 In Step 3, mPEG12-carboxylic acid was used instead of mPEG16-carboxylic acid, and in Step 5, the Fmoc-dPEG12-carboxylic acid coupling step was omitted. In Example 7 the procedure was followed. The title compound was prepared according to the procedure described in 6.

[0467] Example 78: Synthesis of Cyclic PYY Analogue SEQ ID NO: 78 In Step 3, instead of Fmoc-Gln(trt)-OH, Fmoc-N-Me-G ln(trt)-OH was used and the title compound was prepared according to the procedure described in Example 1. done.

[0468] Example 79: Synthesis of Cyclic PYY Analogue SEQ ID NO: 79 In Step 1B, instead of Fmoc-Arg(pbf)-OH, Fmoc-N-Me- Arg(pbf)-OH was used and the title compound was prepared according to the procedure described in Example 1. done.

[0469] Example 80: Synthesis of Cyclic PYY Analogue SEQ ID NO: 80 Instead of Fmoc-Lys(Boc)-OH at the 4-position, Fmoc-Arg(pbf)-O H was used, and instead of Fmoc-Leu-OH at the 30-position in Step 3, Fmoc-Tr p(Boc)-OH was used and the title compound was prepared according to the procedure described in Example 79. done.

[0470] Example 81: Synthesis of Cyclic PYY Analogue SEQ ID NO: 81 Instead of Fmoc-hCys(trt)-OH at the 31-position, Fmoc-Cys(trt) -OH was used, and instead of Fmoc-βAla-OH in Step 3, Fmoc-γ- aminobutyric acid was used and the title compound was prepared according to the procedure described in Example 80.

[0471] Example 82: Synthesis of Cyclic PYY Analogue SEQ ID NO: 82 Instead of Fmoc-βAla-OH, Fmoc-PEG2-carboxylic acid was used, and 31 Use Fmoc-Cys(trt)-OH instead of Fmoc-hCys(trt)-OH at position and omit the coupling of Fmoc-Ile-OH in step 3, and prepare the title compound according to the procedure described in Example 1.

[0472] Example 83: Synthesis of Cyclic PYY Analogue SEQ ID NO: 83 Use Fmoc-Lys(N3)- OH instead of Fmoc-hCys(trt)-OH at position 31, and use pent-4-enoic acid instead of Fmoc-βAla-OH in step 3, and prepare the title compound according to the procedure described in Example 1 according to the following cyclization procedure B.

[0473] Cyclization Procedure B: To a solution of the peptide completely deprotected with AcBr (38 mg, 0.0067 mmol) at position 11 in 2 mL of HEPES (pH 7.4), add 1.7 mL of a pre-mixed CuSO4 / TBTA solution (the solution was prepared by mixing a solution of 2.2 mg of CuSO4 in water (0.4 m L) and a solution of 11 mg of TBTA in EtOH), followed by addition of 7 mg of sodium ascorbate in water (1 mL). Keep the clear reaction solution mixed at room temperature and monitor by HPLC. After 30 minutes, the reaction was complete, adjust the reaction mixture to pH 4 with TFA, and perform HPLC purification (Pursuit XRS 5 250×30 mm C18 column, run at a flow rate of 30 mpm, monitor at 214 nM wavelength, and use a gradient ranging from 20 - 60% MeCN-water / water (both with 0.1% TFA) over 36 minutes). Collect the desired fractions and lyophilize.

[0474] Example 84: Synthesis of Cyclic PYY Analogue SEQ ID NO: 84 Omit the Fmoc-βAla-OH coupling step and use Fmoc-dPEG12 -carboxylic acid in step 5, and use N3-PEG8 carboxylic acid instead of bromoacetic acid in step 3. Use the 3-(bromomethyl)benzoic acid coupling with DIC instead of anhydride acylation, and prepare the title compound according to the procedure

[0475] described in Example 1 according to the following cyclization procedure C. Cyclization procedure C: To a solution of the fully deprotected peptide (20 mg, 0.0035 mmol) in 5 mL of degassed water, add an aqueous NaHCO3 solution to adjust the reaction mixture to pH 6.4 or higher. After 20 minutes, LCMS indicated that the reaction was complete. Adjust the reaction mixture to pH 4 using TFA, and perform HPLC purification (Pursuit XRS 5 250×30 mm C18 column, run at a flow rate of 30 mpm, monitor at a wavelength of 214 nM,

[0476] and use a gradient in the range of 10-60% MeCN-water / water (both with 0.1% TFA) over 36 minutes). Collect the desired fractions and lyophilize. After cyclization, the cyclization intermediate was subjected to linker elongation by click chemistry according to cyclization procedure B using N-(1-bromo-2-oxo-7,10,13-trioxa-3-azapentadec-16-yl)penta-4-ynamide, which was prepared by coupling N-Boc-PEG4-NH2 with penta-4-ynoic acid

[0477] using HATU-DIPEA, followed by deprotection of Boc with TFA and Using a PEG12-AcBr linker placed at the 23rd position instead of the 11th position, the title compound was prepared according to the procedure described in Example 1.

[0478] Example 86: Synthesis of Cyclic PYY Analogue SEQ ID NO: 86 Using a PEG12-AcBr linker placed at the 22nd position instead of the 11th position, the title compound was prepared according to the procedure described in Example 1.

[0479] Example 87: Synthesis of Cyclic PYY Analogue SEQ ID NO: 87 Using a PEG12-AcBr linker placed at the 7th position instead of the 11th position, the title compound was prepared according to the procedure described in Example 1

[0480] Example 88: Synthesis of Cyclic PYY Analogue SEQ ID NO: 88 Using Fmoc-V-OH instead of Fmoc-hCys(trt)-OH at the 31st position and using Fmoc-Cys(trt)-OH instead of Fmoc-Leu-OH at the 30th position and using Fmoc-Gly-OH instead of Fmoc-βAla-OH in Step 3 the title compound was prepared according to the procedure described in Example 1.

[0481] Example 89: Synthesis of Cyclic PYY Analogue SEQ ID NO: 89 Step 1 was omitted to prepare a reduced dipeptide, and in Step 2, using Fmoc-(N-Me)Arg-OH instead of Fmoc-psi-(R3 5-N(Boc)-Y36)-OH packing and using Fmoc-Tyr(tBu)-OH packing followed by coupling with the title compound was prepared according to the procedure described in Example 88.

[0482] Example 90: Synthesis of Cyclic PYY Analogue SEQ ID NO: 90 Using Fmoc-βAla-OH instead of Fmoc-Gly-OH in Step 3​ Then, according to the procedure described in Example 89, the title compound was prepared.

[0483] Example 91: Synthesis of Cyclic PYY Analogue SEQ ID NO: 91 In step 3, instead of Fmoc-Cys(trt)-OH at position 30, Fmoc-hC ys(trt)-OH was used, and according to the procedure described in Example 89, the title compound was prepared thereof.

[0484] Example 92: Synthesis of Cyclic PYY Analogue SEQ ID NO: 92 Instead of Fmoc-Val-OH at position 31, Fmoc-hCys(trt)-OH was used and, instead of Fmoc-Cys(trt)-OH at position 30 in step 3, Fmoc- Leu-OH was used, and according to the procedure described in Example 90, the title compound was prepared.

[0485] Example 93: Synthesis of Cyclic PYY Analogue SEQ ID NO: 93 Instead of Fmoc-hCys(trt)-OH at position 31, Fmoc-Val-OH was used and, instead of Fmoc-Leu-OH at position 30, Fmoc-Cys(trt)-OH was used. Instead of Fmoc-βAla-OH at the N-terminus in step 3, Fmoc-Gly -OH was used, and according to the procedure described in Example 1, the title compound was prepared.

[0486] Example 94: Synthesis of Cyclic PYY Analogue SEQ ID NO: 94 Instead of Fmoc-hCys(trt)-OH at position 31, Fmoc-Val-OH was used and, instead of Fmoc-Leu-OH at position 30 in step 3, Fmoc-Cys(t rt)-OH was used, and according to the procedure described in Example 1, the title compound was prepared.

[0487] Example 95: Synthesis of Cyclic PYY Analogue SEQ ID NO: 95 Use Fmoc-Val-OH instead of 31 - bit Fmoc-hCys(trt)-OH and use Fmoc-Glu(OAlloc)-OH instead of 30 - bit Fmoc-Leu-OH and use Fmoc-Lys(Dde)-OH instead of 11 - bit Fmoc-Lys(Alloc)-OH and use Fmoc-Ser(tBu)-OH instead of 4 - bit Fmoc-Lys(Boc)-OH and use Boc-Gly-OH instead of N - terminal Fmoc-βAla-OH in step 3, and prepare the title compound (0.05 mmol scale) according to the procedure described in Example 1

[0488] To the resin obtained above, add a solution of deoxygenated DCM (10 mL), phenylsilane (10 equivalents) , and Pd(PPh3)4 (0.2 equivalent) in DCM (1 mL), and stir the mixture for 10 minutes. Drain the reaction product, wash the resin with deoxygenated DCM, and repeat the deprotection once

[0489] To the resin obtained above, add DMF (10 mL), HATU (5 equivalents), and DIEA (10 equivalents), stir the mixture for 5 minutes, then add a solution of N - hydroxysuccinimide (10 equivalents) in DMF , and stir for another 20 minutes. Filter the resin and repeat the procedure once

[0490] Deprotect the above resin in TFA / TIPS / water (95 / 2.5 / 2.5) (10 mL) at room temperature for 2 hours. Concentrate the cleavage cocktail to about 1 mL, then add it to 40 mL of ether . Collect the resulting precipitate by centrifugation and dry it under N2

[0491] Dissolve the material obtained above in 9 mL of DMSO with 10 equivalents of TEA added, and react​​​​ The reaction was allowed to proceed at room temperature for 3 hours. The resulting solution was diluted to 30 mL with water and the pH was adjusted to 2 and eluted with a linear gradient of 20 - 40% MeCN in water (0.1% TFA) over 30 minutes on a 30 mm×250 mm C18 column by RP-HPLC. The fractions containing the product were lyophilized.

[0492] Next, the material obtained above was treated with 1 - 2% hydrazine / DMF (1 mL) to remove Dde from lysine. The resulting mixture was diluted to 10 mL with water and the pH was adjusted to 2 before purification by RP-HPLC as described above.

[0493] Next, the resulting product was dissolved in 10% MeCN / water, the pH was adjusted to 10, and a solution of N-hydroxysuccinimide bromoacetate (3 equivalents of a 0.1 M / DMF solution) was added and the reaction was allowed to proceed at room temperature for 10 minutes. The resulting mixture was diluted to 10 mL with water and the pH was adjusted to 2 before purification by RP-HPLC as described above to obtain the title product.

[0494] Example 96: Synthesis of Cyclic PYY Analogue SEQ ID NO: 96 In Step 5, N-Fmoc-dPEG24-carboxylic acid was used instead of N-Fmoc-dPEG12-carboxylic acid and the title compound was prepared according to the procedure described in Example 1 .

[0495] Example 97: Synthesis of Cyclic PYY Analogue SEQ ID NO: 97 In Step 3, Fmoc-Gly-OH was used instead of Fmoc-βAla-OH and the title compound was prepared according to the procedure described in Example 1 .

[0496] Example 98: Synthesis of Cyclic PYY Analogue SEQ ID NO: 98 ​​​​Follow the procedure described in Example 89, but in step 5, omit the Fmoc-dPEG12-carboxylic acid coupling step to prepare the title compound.

[0497] Example 99: Synthesis of cyclic PYY analog SEQ ID NO: 99 Follow the procedure described in Example 90, but in step 5, omit the Fmoc-dPEG12-carboxylic acid coupling step to prepare the title compound.

[0498] Example 100: Synthesis of cyclic PYY analog SEQ ID NO: 100 Follow the procedure described in Example 94, but in step 5, omit the Fmoc-dPEG12-carboxylic acid coupling step to prepare the title compound.

[0499] All of the following sequences are considered to be examples of the present invention.

[0500] Sequence Listing SEQ ID NO: 1 Name: [Cyclo-(βA2-COCH2-hC31),K(PEG12-AcBr)1 1,psi-(35R,36Y)]-PYY2-36 Structure:

[0501]

Chem.

[0502] SEQ ID NO: 2 Name: [Cyclo-(I3-m-COPhCH2-hC31)]-PYY3-36 Structure:

[0503]

Chem.

[0504] SEQ ID NO: 3 Name: [Cyclo-(I3-CO(CH2)2triazolyl-Nle31)]-PYY3 -36 Structure:

[0505]

Chem.

[0506] Accession number 4 Name: [Cyclo-(I3-m-COPhCH2-hC31),K(γ-Glu-Pal )11]-PYY3-36 Structure:

[0507]

Chem.

[0508] Accession number 5 Name: [Cyclo-(I3-m-COPhCH2-hC31),K(γ-Glu-AcV itE)11]-PYY3-36 Structure:

[0509]

Chem.

[0510] Accession number 6 Name: [Cyclo-(I3-CO(CH2)2triazolyl-Nle31),K(γ-G lu-AcVitE)11]-PYY3-36 Structure:

[0511]

Chem.

[0512] Accession number 7 Name: [Cyclo-(I3-m-COPhCH2-hC31),K(γ-Glu-Pal )9]-PYY3-36 Structure:

[0513] [Chemical]

[0514] Accession number 8 Name: [Cyclo-(I3-m-COPhCH2-hC31),K(γ-Glu-Pal )30]-PYY3-36 Structure:

[0515] [Chemical]

[0516] Accession number 9 Name: [Cyclo-(I3-m-COPhCH2-hC31),psi-(R35Y36 )]-PYY3-36 Structure:

[0517] [Chemical]

[0518] Accession number 10 Name: [Cyclo-(I3-m-COPhCH2-hC31),K(γ-Glu-AcV itE)30]-PYY3-36 Structure:

[0519] [Chemical]

[0520] Accession number 11 Name: [Cyclo-(I3-m-COPhCH2-hC31),K(γ-Glu-AcV itE)30,psi-(R35,Y36)]-PYY3-36 Structure:

[0521] [Chemical]

[0522] Sequence number 12 Name: [Cyclo-(I3-m-COPhCH2-hC31),(N-Me-R35)] -PYY3-36 Structure:

[0523]

Chem.

[0524] Sequence number 13 Name: [Cyclo-(I3-m-COPhCH2-hC31),K(γ-Glu-Pal )30,psi-(R35,Y36)]-PYY3-36 Structure:

[0525]

Chem.

[0526] Sequence number 14 Name: [Cyclo-(I3-m-COPhCH2-hC31),K(γ-Glu-Pal )30,(N-Me-R35)]-PYY3-36 Structure:

[0527]

Chem.

Claims

1. Formula I: 【Chemical 1】 (wherein, p is 0 or 1, m is 0, 1, 2, 3, 4, or 5, n is 1, 2, 3, or 4, q is either 0 or 1, provided that q is 1 only if Z ３０ is absent and BRIDGE is -Ph-CH ２ -S-, -triazolyl-, -NHC(O)CH ２ S -、-SCH ２ C(O)NH-、 -(OCH ２ CH ２ ) ２ NH C(O)CH ２ S, -NH C(O)-, or -CH ２ S- and Z ４ is K, A, E, S, or R, Z ７ is A or K, Z ９ is G or K, Z １１ is D or K, Z ２２ is A or K, Z ２３ is S or K, Z ２６ is A or H, Z ３０ is L, W, absent, or K (provided that Z ３０ is absent only when q is 1 exists.) Z ３４ is 【Chemical 2】 and Z ３５ is 【Chemical 3】 or a derivative thereof, wherein the derivative is modified by one or more processes including amidation, glycosylation, carbamylation, sulfation, phosphorylation, cyclization, lipidation, or PEGylation .) A compound of, or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein the compound is a compound of Formula I, or a compound of Formula I modified by one or more processes including amidation, lipidation, or PEGylation, or a pharmaceutically acceptable salt thereof.

3. (wherein, i is an integer from 0 to 24, and X = Br, I, or Cl.), (wherein, t is 0, 1, or 2, BRIDGE is -Ph-CH ２ -S-, -triazolyl-, -NHC(O)CH ２ S -、-SCH ２ C(O)NH-、-(OCH ２ CH ２ ) ２ NHCOCH ２ S、-NH C(O)-, or -CH ２ S-, and Z ７ is A or K, and the amino side chain of said K is optionally [Chemical 4] u is 0 or 1, -C(O)CH ２ Br, -C(O)CH ２ I, or -C(O)CH ２ substituted with Cl, Z ９ is G or K, and the amino side chain of the K is optionally 【Chemical Formula 5】 v is 14, 16, or 18.), (wherein, i is an integer from 0 to 24, and X = Br, I, or Cl.), (wherein, w is 0, 1, 2, or 4, 【Chemical Formula 6】 x is 0 or 1, -C(O)CH ２ Br, -C(O)CH ２ I, or -C(O)CH ２ substituted with Cl, Z １１ is D or K, and the amino side chain of said K is optionally 【Chemical Formula 7】 y is 14, 16, or 18.), (wherein, i is an integer from 0 to 24, and X = Br, I, or Cl.), (wherein, i is an integer from 0 to 24, and X = Br, I, or Cl.), 【Chemical 8】 (wherein, i is an integer from 0 to 24, and X = Br, I, or Cl.), 【Chemical Formula 9】 -C(O)CH ２ Br, -C(O)CH ２ I, or -C(O)CH ２ substituted with Cl, Z ２２ is A or K, and the amino side chain of said K is optionally 【Chemical 10】 exists.), the amino side chain of said K is optionally, -C(O)CH ２ Br, -C(O)CH ２ I, or -C(O)CH ２ substituted with Cl, Z ２３ is S or K, and the amino side chain of said K is optionally 【Chemical 11】 (wherein, r is 0, 1, or 2, -C(O)CH ２ Br, -C(O)CH ２ I, or -C(O)CH ２ substituted with Cl, Z ３０ is L, W, absent, or K (provided that Z ３０ is non- only when q is 1 s is 0 or 1, 【Chemical 12】 q is 14, 16, or 18.), or is substituted with, The compound according to claim 2, or a pharmaceutically acceptable salt thereof. 【Chemical 13】

4. m is 0, 1, 2, 3, or 5, n is 1, 2, or 4, is substituted with, (wherein, t is 0, Z ７ is A or K, and the amino side chain of said K is 【Chemical Formula 14】 u is 1, Z ９ is G or K, and the amino side chain of said K is 【Chemical Formula 15】 v is 14.), is substituted with, (wherein, w is 0 or 4, x is 1, Z １１ is D or K, and the amino side chain of the K is optionally 【Chemical 16】 y is 14.), is substituted with, is substituted with, 【Chemical 17】 is substituted with, Z ２２ is A or K, and the amino side chain of said K is 【Chemical 18】 exists.), the amino side chain of said K is, Z ２３ is S or K, and the amino side chain of said K is 【Chemical Formula 19】 (wherein, r is 0 or 2, Z ３０ is L, W, absent, or K (provided that Z ３０ is only invalid when q is 1 s is 1, 【Chemical 20】 q is 14, 16, or 18.), or is substituted with, The compound according to claim 3, or a pharmaceutically acceptable salt thereof. 【Chemical 21】

5. The compound according to claim 1, selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 110, or a pharmaceutically acceptable salt thereof.

6. ​ ​ ​ A compound according to any one of claims 1 to 5, and a half-life extending moiety complexed therewith A complex comprising the same.

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 or the complex according to claim 6, and a pharmaceutically acceptable carrier.

8. A method for preventing, treating, or alleviating obesity, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 5, the complex according to claim 6, or a form, composition, or agent thereof The method described above.

9. A method for preventing, treating, or alleviating a syndrome, disorder, or disease, wherein the syndrome, disorder, or disease is selected from the group consisting of obesity, type 2 diabetes, metabolic syndrome, insulin resistance, and dyslipidemia, and administering to a subject in need of prevention, treatment, or alleviation an effective amount of a compound according to any one of claims 1 to 5, the complex according to claim 6, or a form, composition, or agent thereof The method described above.

10. The method according to claim 9, wherein the syndrome, disorder, or disease is type 2 diabetes.

11. A method for reducing food intake, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 5, the complex according to claim 6, or a form, composition, or agent thereof The method described above.

12. A method for modulating Y2 receptor activity, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 5, the complex according to claim 6, or a form, composition, or agent thereof The method described above.

13. A method for treating a disease, disorder, or syndrome selected from the group consisting of obesity, type 2 diabetes, metabolic syndrome, insulin resistance, and dyslipidemia, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 5, the complex according to claim 6, or a form, composition, or agent thereof in combination with at least one antidiabetic drug The method described above.

14. The method according to claim 13, wherein the antidiabetic drug is a glucagon-like peptide-1 receptor modulator.

15. A method for preparing a pharmaceutical composition, comprising a compound according to any one of claims 1 to 5 or ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ A method comprising combining the complex according to claim 6 with a pharmaceutically acceptable carrier. Method.

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