Triple agonists of GLP1 / GIP / NPY2 receptor

Abstract

The present invention relates to triple agonists of the GLP1 / GIP / NPY2 receptor. Disclosed are hybrid polypeptides that agonize GIP, GLP-1 and neuropeptide Y2 (NPY2) receptors and their medical use in the treatment of a variety of diseases, conditions or conditions, such as obesity, diabetes and / or NASH. The polypeptides have the general structure Z1-Z2-Z3 wherein Z1 is a hybrid polypeptide that provides GIPR and GLP1R agonism, Z2 is a linker, and Z3 is a polypeptide that provides hY2R agonism.

Description

This application is a divisional application of the invention application filed on December 20, 2023, with Chinese application number 202380082085.X and invention title "Triple Agonist of GLP1 / GIP / NPY2 Receptors". Technical Field

[0001] This invention relates to hybrid polypeptides that agonize GIP, GLP-1 and neuropeptide Y2 (NPY2) receptors and their medical use in the treatment of various diseases, symptoms or conditions, such as obesity, diabetes and / or NASH. Background Technology

[0002] Overweight and obesity are defined as abnormal or excessive fat accumulation that poses a health risk. A body mass index (BMI) exceeding 27 kg / m² is considered obesity. 2 Considered overweight, with a BMI exceeding 30 kg / m². 2 Obesity is considered a serious condition. BMI is calculated based on weight and height. Obesity has reached pandemic levels over the past 50 years. Since 1975, the global obesity rate has almost tripled. In 2016, more than 1.9 billion adults and more than 340 million children and adolescents were overweight or obese. Overweight and obesity are major risk factors for many chronic diseases, including type 2 diabetes, cardiovascular disease, and cancer, which are leading causes of morbidity and death in the United States. Therefore, obesity is a serious condition associated with poor mental health, reduced quality of life, and decreased life expectancy (Abdelaal 2017). According to the WHO, overweight and obesity are no longer considered a problem unique to high-income countries and are rising sharply in low- and middle-income countries. The WHO Global Health Observatory indicated that in 2016, 39% of women and men aged 18 and over were overweight, and 11% of men and 15% of women were obese.

[0003] Peptide YY (PYY) is a 36-amino acid peptide with the sequence YPIKPEAPREDASPEELNRYYA SLRHYLNLVTRQRY (SEQ ID NO:308), found in the mucosa of the gastrointestinal tract, particularly in endocrine L cells of the ileum and colon. PYY, along with neuropeptide Y (NPY) and pancreatic polypeptide (PP), belongs to the pancreatic polypeptide (PP) family. This peptide family acts on NPY receptors named NPY1R (Y1), NPY2R (Y2), NPY4R (Y4), and NPY5R (Y5). This receptor family belongs to a class of G protein-coupled receptors (GPCRs) expressed in the CNS, particularly in the hypothalamus region. Receptors NPY1R-NPY5R exhibit anorexia (NPY2R, NPY4R) and appetite-stimulating effects (NPY5R, NPY1R). Peptide YY exists primarily in two forms, PYY. 1-36 and PYY3-36 PYY 1-36 Released from intestinal L cells in proportion to energy intake after meals and partially truncated into PYY. 3-36 The PYY 3-36 It is the main circulating form of PYY and a relatively selective Y2 receptor agonist. PYY 1-36 and PYY 3-36 It inhibits gastric acid secretion, gastrointestinal transit, and food intake. It suppresses food intake through stimulation of Y2 receptors on vagal afferent neurons and interaction with Y2 receptors in the hypothalamus, consistent with the ability of PYY to enter the brain via periventricular organs (e.g., the last ventricular area and subfornical organs). Furthermore, it is known that blood PYY concentrations are lower in obese individuals than in healthy individuals. Therefore, NPY2R and / or NPY4R agonists may hold potential for treating obesity.

[0004] Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) belong to the incretin family. GLP-1 (7-37) is a 31-amino acid peptide with the sequence HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG (SEQ ID NO:309), and GIP is a 42-amino acid peptide with the sequence YAEGTFISDYSIAMDKIHQQDFVNWLLAQKGKKNDWKHNITQ (SEQ ID NO:310). GLP-1 and GIP are secreted by L cells and K cells in the small intestine, respectively. GLP-1 acts via the GLP-1 receptor and is known to have glucose-dependent insulinotropic effects (i.e., stimulation of insulin release) and appetite-suppressing effects. GIP acts via the GIP receptor and is also known to have glucose-dependent insulinotropic effects, but its effect on appetite is unclear. GLP-1 receptor / GIP receptor co-agonist peptides have been reported to exhibit stronger hypoglycemic and weight-reduction effects than GLP-1 receptor agonists alone. Therefore, studies have been conducted based on the structures of natural glucagon, GIP, or GLP-1 to develop GLP-1 / GIP receptor co-agonists for the treatment of obesity and / or diabetes.

[0005] The most notable effect of GLP-1 agonists is their ability to promote insulin secretion in a glucose-dependent manner by binding to GLP-1 receptors expressed on pancreatic β-cells. Almost equally important, GLP-1 agonists have been shown to inhibit glucagon secretion at glucose levels above fasting levels. Decisively, this does not affect glucagon's response to hypoglycemia, making GLP-1 agonists a safe antidiabetic drug with a very low incidence of hypoglycemia compared to insulin. In June 2021, semaglutide (a GLP-1 agonist) was approved by the FDA for long-term weight management in obese or overweight adults with at least one weight-related symptom (such as hypertension, type 2 diabetes, or high cholesterol). As an anti-obesity drug, GLP-1 agonists work by binding to GLP-1 receptors in the hypothalamus, thereby suppressing appetite. Furthermore, GLP-1 agonists bind to GLP-1 receptors in the stomach, inhibiting gastric emptying, gastric acid secretion, and peristalsis, thus collectively promoting satiety. Therefore, individuals with diabetes treated with GLP-1 receptor agonists often experience beneficial weight loss in addition to controlling their blood sugar levels.

[0006] However, despite long-term efforts, the number of overweight and obese patients continues to rise. First-line treatments for overweight and obese patients include diet and exercise, but these are often not sufficiently effective. Second-line treatment options include surgery and drug therapy for obesity. Existing drug treatments appear to lack efficacy and / or safety, and only a limited number of approved therapies exist in the US and Europe, such as semaglutide. Therefore, there remains a high medical need for more effective and safer treatment options. Given the biological effects of PYY, GIP, or GLP-1, future obesity treatments could benefit from simultaneously targeting GLP1-R, GIPR, and NPY2R. In fact, recent research in the field of obesity has aimed to develop hybrid peptides that act as triple agonists of these receptors (see, for example, EP3467106 A1). Hybrid peptides are highly desirable compared to combination therapies using individual peptides for several reasons. First, hybrid peptides are easier to formulate into a single dosing unit compared to mixtures of different peptides. This is primarily because different peptides can have different physiological and chemical properties at a given pH, such as isoelectric point, solubility, or chemical stability. This means that a formulation developed for one peptide may not be ideal or compatible with another peptide. Therefore, combination therapies using individual peptides may require individual dosing units. Secondly, compared to individual peptides, hybrid peptides are cheaper to manufacture and also reduce the burden of regulatory approval.

[0007] The present invention aims to provide a hybrid polypeptide that activates all receptors GLP1-R, GIPR and NPY2R in order to provide improved treatment for, for example, obesity, diabetes and / or metabolic syndrome.

[0008] In addition, an objective of the present invention is to provide a triple agonist that is soluble at or about physiological pH (e.g., pH 7).

[0009] Another objective of the present invention is to provide a triple agonist having a long duration of action in vivo, i.e., a long in vivo half-life.

[0010] Another objective of this invention is to provide a triple agonist that activates all receptors GLP1-R, GIPR, and NPY2R and is soluble at or near physiological pH (e.g., pH 7).

[0011] Another objective of this invention is to provide a triple agonist that activates all receptors GLP1-R, GIPR, and NPY2R, is soluble at or near physiological pH (e.g., pH 7), and has a long duration of action in vivo.

[0012] Another objective of this invention is to provide a triple agonist that exhibits good selectivity for GLP-1, GIP, and NPY2 receptors relative to other incretin or related receptors. For example, the agonist of this invention may not activate other receptors from the NPY receptor family, such as NPY1, NPY4, or NPY5 receptors, and / or may not activate GLP-2 or glucagon receptors. Summary of the Invention

[0013] In a first aspect, the present invention provides a polypeptide of a general structure according to formula (I) or a pharmaceutically acceptable salt thereof. Z1-Z2-Z3 (I), in, Z1 is a hybrid polypeptide that provides GIPR and GLP1R agonist activity, and it contains the following amino acid sequence. Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK (SEQ IDNO: 306), Or its derivatives having one, two or three substitutions; Z2 is the linker; Z3 is a polypeptide that provides hY2R agonist activity and contains the following amino acid sequence. ASLRHYYNWLTRQRY (SEQ ID NO:307) or its derivatives having 1, 2, 3, 4 or 5 substitutions.

[0014] In a second aspect, the present invention provides a polypeptide comprising a general structure of formula (I) or a pharmaceutically acceptable salt thereof. Z1-Z2-Z3 (SEQ ID NO:647) (I), in, Z1 is a GIP / GLP1 hybrid polypeptide containing the following amino acid sequence. Y-Aib-X3-GTFTSDX 10 -SIX 13 -LX 15 -X 16 -X 17 -AX 19 -X 20 -X 21 -FX 23 -X 24 -X 25 -LX 27 -K(SEQ ID NO:646), X3 was selected as either E or D; X 10 Selected as Y or L; X 13 Selected as Aib or L; X 15 The answer is E, D, or A; X 16 The options are K, E, D, Aib, G, LysAc, A, L, S, Q, or R; X 17 The answer is Q, E, K, or A; X 19 The answer is Q or E; X 20 Selected as Aib, D-Asp, or D-Arg; X 21 The answer is A, E, or K; X 23 V or I; X 24 The answer is E or Q; X 25 The choice is W or Y; X 27 For I or L; Z2 is composed of the amino acid sequence GGX. 31 -X 32 -X 33 -X 34 The connecting base is composed of Where X 31 Selected as P, G, or Q; X 32 Selected as S, E, or R; X 33 The choice is S, E, Y, or T; X 34 The choice is G, P, Y, or A; Z3 is a polypeptide containing the following amino acid sequence. X 35 -X 36 -X 37 -X 38 -X 39 -YX41 -X 42 -X 43 -X 44 -TX 46 -X 47 -X 48 -X 49 , Where X 35 The answer is A, Q, I, V, E, or L; X 36 Selected as S, E, T, D, or L; X 37 The options are L, Aib, V, D-Leu, I, or Tle; X 38 Selected as R, L, or Aib; X 39 Selected as H, Aib, D-His, or Tle; X 41 The options are L, Y, Aib, I, or Tle; X 42 Selected as N or Aib; X 43 The options are W, H, L, R, or Aib; X 44 Selected as L, Aib, D-Arg, D-Asp, or Tle; X 46 Selected as R, hArg, or D-Arg; X 47 Selected as Q, bh-Gln, or NMeQ; X 48 Selected as R or NMeR; X 49 The selected values ​​are Y, Tle, Chg, D-Tyr, and Phg.

[0015] In a third aspect, the present invention relates to polypeptides according to the first or second aspect, which are used as pharmaceutical agents.

[0016] In a fourth aspect, the present invention relates to a method for treating diseases, conditions and / or symptoms selected from a list of: overweight, obesity, type 1 and type 2 diabetes, eating disorders, hyperlipidemia, metabolic syndrome, NAFLD / NASH and / or cardiovascular disease, the method comprising administering to an individual in need a therapeutically effective amount of a polypeptide or a pharmaceutically acceptable salt thereof according to the first or second aspect. Terms, definitions and conventions

[0017] Terms not specifically defined herein shall be given the meaning that would be given to them by those skilled in the art in light of the disclosure and context. However, unless otherwise stated, as used in this specification, the following terms shall have designated meanings and shall follow the conventions described below. amino acids

[0018] According to the present invention, unless otherwise stated, all amino acids are L-amino acids (L-stereoisomers, natural amino acids). In this document, substitutions in analogs / derivatives may be substitutions of natural amino acids and non-natural amino acids (including L-stereoisomers and D-stereoisomers). Substitutions in derivatives may be conservative substitutions using conserved amino acids. The groups of conserved amino acids may be defined as: G, A, V, L, I, P (aliphatic or cyclic), S, C, T, M (containing hydroxyl or sulfur) F, Y, W (Fang ethnic group) H, K, R (alkaline) D, E, N, Q (acidic or amide)

[0019] Common non-natural amino acids include NMeG, which represents the amino acid methylglycine (also known as N-methylglycine, NMeGly, MeGly, or sarcosine); NMeP, which represents the amino acid methyl-L-proline (also known as N-methyl-L-proline, NMePro, or (S)-1-methylpyrrolidine-2-carboxylic acid); Dpr, which represents the amino acid (S)-2,3-diaminopropionic acid (also known as L-2,3-diaminopropionic acid); Aib, which represents the amino acid 2-amino-2-methylpropionic acid (also known as 2-aminoisobutyric acid); NMeQ, which represents the amino acid N-methyl-L-glutamine (also known as N-methylglutamine, NMeGln, or MeGln); and NMeAla, which represents the amino acid N-methyl-L-alanine (also known as N-methylalanine, NMeA, or MeAla). Cha represents the amino acid (S)-2-amino-3-cyclohexylpropionic acid (also known as L-cyclohexylalanine); Tle represents the amino acid (S)-2-amino-3,3-dimethylbutyric acid (also known as L-2-(tert-butyl)glycine); 1-Nal represents the amino acid (S)-2-amino-3-(naphthyl-1-yl)propionic acid (also known as 3-(1-naphthyl)-L-alanine); Pip represents the amino acid (S)-piperidine-2-carboxylic acid (also known as L-2-piperidinecarboxylic acid); Nip represents the amino acid (S)-piperidine-3-carboxylic acid (also known as L-piperidinecarboxylic acid); Nle represents the amino acid (2S)-2-aminohexanoic acid (also known as L-leucine); Phe(4F) represents the amino acid (S)-2-amino-3-(4-fluorophenyl)propionic acid (also known as 4-fluoro-L-phenylalanine). Salts and pharmaceutically acceptable salts

[0020] According to the present invention, the polypeptide or its derivative may be in the form of a salt.

[0021] According to the present invention, polypeptides or their derivatives may be in the form of pharmaceutically acceptable salts. Therefore, pharmaceutically acceptable salts are intended to include any salt commonly used in formulations of peptides. Such salts include acid addition salts and basic salts, and examples can be found, for example, in Remington's Pharmaceutical Sciences, 17th edition. Similarly, polypeptides or pharmaceutically acceptable salts may be in the form of solvates (e.g., hydrates). Nomenclature of compounds:

[0022] Compounds are represented using Boehringer Ingelheim Line Notation (BILN), which describes complex peptides in a human-readable format (Fox et al., J. Chem. Inf. Model. 2022, 62, 17, 3942-3947). In BILN, chains are composed of monomers, such as A for alanine and Aib for isobutyric acid, with the two monomers connected by a hyphen “-”. Different chains are separated by a dot “.”, and the connection between chains is explicitly defined in parentheses after the monomer, including the linking ID number and the R-group number, for example, K(1,3) represents a lysine residue that is linked to another monomer with the same linking ID “1” via its R “3”-group (ε-amino). As an example, Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYLNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2) (SEQ ID NO:412), wherein C20DA represents 19-carboxynodecanoyl, gGlu([γE]) represents L-γ-glutamyl, which is linked to C20DA via its amino group and then to the amino group of the next gGlu via its γ-carboxyl group. This is repeated 4 times, resulting in a total of 6 gGlu residues. The gGlu residues are then linked to the ε-amino group of lysine (eLys) via the final γ-carboxyl group, and then to the ε-amino group of lysine (K) in the peptide backbone via the carboxyl group, thus fully defining the following structure:

[0023] Structure disclosed SEQ ID NO:412 Lipidification

[0024] In this paper, lipidation refers to the optional permeation through linker / spacer (-(Y-)). 1-8A lipid (L), such as C18DA (octadecanoic acid), C20DA (eicosanoic acid), or other half-life-extending moieties, is covalently linked to the hybrid polypeptide according to the invention. The linker / spacer may consist of one or more covalently linked monomers commonly used in the art, such as [γE], [OEG], or [AHX] as described below.

[0025] Lipidification can occur at lysine residues (i.e., at the ε(epsilon) amino group) or at the N-terminus of the polypeptide, preferably at lysine residues as illustrated herein. Without wishing to be bound by any theory, it is thought that such lipophilic substituents bind to albumin and other plasma components in the bloodstream, thereby protecting the compounds of the present invention from renal filtration and enzymatic degradation. Therefore, lipification is typically performed to improve the pharmacokinetic profile of the polypeptide by, for example, improving metabolic stability, reducing enzymatic degradation, and decreasing secretion and metabolism, all of which can improve the in vivo half-life (t... 1 / 2 The peptide according to the invention can be esterified or non-esterified depending on the desired half-life. If a linker / spacer is present, the lipid (L) is covalently linked at one end to the linker / spacer (-(Y-)). 1-8 The polypeptide is covalently linked at the other end to a linker / spacer (-(Y-)). 1-8 (That is, lipid-linker-peptide). Alternatively, when no linker / spacer is present, the lipid (L) is directly covalently linked to the polypeptide (i.e., lipid-peptide). The linker / spacer can consist of 1 to 8 monomers, including 8 covalently linked monomers (i.e., -Y). 1 -;-Y 1 -Y 2 -;-Y 1 -Y 2 -Y 3 -;-Y 1 -Y 2 -Y 3 -Y 4 -;-Y 1 -Y 2 -Y 3 -Y 4 -Y 5 -;-Y 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 -;-Y 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 -Y7 -; or -Y 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 -Y 7 -Y 8 The polypeptide is composed of, for example, [γE], [OEG], or [AHX], or selected from, for example, [γE], [E], [OEG], [eLys], or [AHX]. Most preferably, the polypeptide is in the form of the general formula LY. 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 -Y 7 -Y 8 - structural lipidation, where L is a lipid selected from C18DA or C20DA, and further wherein Y 1 -Y 8 Each of them is independently selected from non-existent, [γE], [OEG], [eLys] or [AHX], or selected from non-existent, [γE], [E], [OEG], [eLys] or [AHX].

[0026] Lipids (L) can be linked to a linker / spacer (-(Y-)) via esters, ethers, sulfonyl esters, thioesters, amides, amines, triazoles, or sulfonamides, preferably via amides or esters. 1-8 Therefore, it should be understood that lipids (L) preferably include acyl, sulfonyl, alkyne, azido, N, O, or S atoms, forming part of esters, sulfonyl esters, thioesters, triazoles, amides, amines, or sulfonamides. Preferably, the acyl or O or N atom in the lipophilic substituent (L) is connected to the linking group / spacer (-(Y-)). 1-8 It forms part of an amide or ester.

[0027] Similarly, the connecting base / spacer (-(Y-)) 1-8 (If present) linked to amino acid residues of the hybrid polypeptide according to the invention via an ester, sulfonyl ester, thioester, amide, amine, or sulfonamide. Therefore, it should be understood that the linker / spacer (if present) preferably comprises an acyl group, sulfonyl group, N atom, O atom, or S atom, forming part of an ester, sulfonyl ester, thioester, amide, amine, or sulfonamide. Preferably, the linker (-(Y-)) 1-8 The acyl group or O or N atom in ) forms part of an amide or ester with an amino acid residue.

[0028] The lipophilic substituent (L) may comprise a hydrocarbon chain having 10 to 24 carbon atoms, for example 14 to 22 carbon atoms, or for example 16 to 20 carbon atoms. Preferably, it has at least 14 carbon atoms, and more preferably 20 carbon atoms or less. For example, the hydrocarbon chain may contain 14, 15, 16, 17, 18, 19, or 20 carbon atoms. The hydrocarbon chain may be straight or branched, and may be saturated or unsaturated. Furthermore, the hydrocarbon chain may include terminal functional groups, such as carboxylic acid groups, sulfonic acid groups, or tetrazolium groups. Based on the foregoing discussion, it should also be understood that the hydrocarbon chain is preferably partially substituted, the portion forming with the amino acid residues of the hybrid polypeptide according to the invention or with the linker group (-(Y-)). 1-8(e.g., acyl, sulfonyl, N, O, or S atom) as part of a linker. Most preferably, the hydrocarbon chain is acyl-substituted (for attachment to the linker / spacer), and thus the hydrocarbon chain can be part of an alkanoyl group (e.g., dodecyl, 2-butyloctanoyl, tetradecyl, hexadecyl, heptadecanyl, octadecyl, nonadecanyl, or eicosyl). These hydrocarbon chains, acyl-substituted at one end, can be further functionalized at the other end with a carboxylic acid group. Examples of functionalized hydrocarbon chains (e.g., lipophilic substituents L) are 15-carboxy-pentadecanyl (abbreviated C16DA), 17-carboxy-heptadecanyl (abbreviated C18DA), and 19-carboxy-nonadecanyl (abbreviated C20DA). Preferred lipids or lipids / linkers in the present invention are C18DA, C18DA[E][E][E][E]-(SEQ ID NO: 640), C18DA[E][E][E][E][E]-(SEQ ID NO: 636), C18DA[E][E][E][E][E][E]-(SEQ ID NO: 637), C18DA[γE]-, C18DA[γE][γE]-, C18DA[γE][γE][γE]-, C18DA[γE][γE][γE][γE]-, C18DA[γE][γE][γE][ γE][γE]-, C18DA[γE][γE][γE][γE][γE][γE]-, C18DA[γE][γE][γE][γE][γE][γE][γE]-, C20DA, C20DA[γE]-, C20 DA[γE][γE]-, C20DA[γE][γE][γE]-, C20DA[γE][γE][γE][γE]-, C20DA[γE][γE][γE][γE][γE]-, C20DA[γE][γE][ γE][γE][γE][γE]-, C20DA[γE][γE][γE][γE][γE][γE][γE]-, C18DA[eLys], C18DA[E][E][E][E][E][eLys]-(SEQ ID NO:635), C18DA[E][E][E][E][E][E][eLys]-(SEQ IDNO:643), C18DA[γE][eLys]-, C18DA[γE][γE][eLys]-, C18DA[γE][γE][γE][eLys]-, C18DA[γE][γE][γE][γ E][eLys]-, C18DA[γE][γE][γE][γE][γE][eLys]-, C18DA[γE][γE][γE][γE][γE][γE][eLys]-, C20DA[eLys],C20DA[E][E][E][E][E][eLys]-(SEQ ID NO:639)、C20DA[γE][eLys]-、C20DA[γE][γE][eLys]-、C20DA[γE][γE][γE][eLys]-、C20DA[γE][ γE][γE][γE][eLys]-、C20DA[γE][γE][γE][γE][γE][eLys]-、C20DA[γE][γE][γE][γE][γE][γE] [eLys]-、C20DA[γE][γE][γE][γE][γE][γE][γE][eLys]-、C20DA[γE][γE][γE][γE][γE][eLys][ eLys]-、C18DA[OEG][OEG]-、C18DA[E][E][E][OEG][OEG]-、C18DA[E][E][E][E][OEG][OEG]-(SEQ ID NO:634)、C18DA[γE][OEG][OEG]-、C18DA[γE][γE][OEG][OEG]-、C18DA[γE][γE][γE][OEG][OEG]-、C18DA[γE][γE][γE][γE][OEG][OEG]-、C18DA[γE][γE][γE][γE][OEG][OEG]-、C20DA[OEG][OEG]-、C20DA[E][E][E][E][OEG][OEG]-(SEQ IDNO:638)、C20DA[γE][OEG][OEG]-、C20DA[γE][γE][OEG][OEG]-、C20DA[γE][γE][γE][OEG][OEG]-、C20DA[γE][γE][γE][γE ][OEG][OEG]-、C20DA[γE][γE][γE][γE][γE][OEG][OEG]-、C18DA[OEG]-、C18DA[γE][OEG]-、C18DA[γE][γE][OEG]-、C18DA[γE ][γE][γE][OEG]-、C18DA[γE][γE][γE][γE][OEG]-、C18DA[γE][γE][γE][γE][γE][OEG]-、C18DA[γE][γE][γE][γE][γE][γE][ OEG]-、C20DA[OEG]-、C20DA[γE][OEG]-、C20DA[γE][γE][OEG]-、C20DA[γE][γE][γE][OEG]-、C20DA[γE][γE][γE][γE][OEG]-、C20DA[γE][γE][γE][γE][γE][OEG]-、C20DA[γE][γE][γE][γE][γE][γE][OEG]-、C18DA[OEG][eLys]-、C18DA[γE][OEG][eLys]-、C18DA[γE][γE][ OEG][eLys]-、C18DA[γE][γE][γE][OEG][eLys]-、C18DA[γE][γE][γE][γE][OEG][eLys]-、C18DA[γE][γE][γE][γE][γE][OEG][eLys]-、C20DA[OEG ][eLys]-、C20DA[γE][OEG][eLys]-、C20DA[γE][γE][OEG][eLys]-、C20DA[γE][γE][γE][OEG][eLys]-、C20DA[γE][γE][γE][γE][OEG][eLys]-、C 20DA[γE][γE][γE][γE][γE][OEG][eLys]-、C18DA[OEG][OEG][eLys]-、C18DA[γE][OEG][OEG][eLys]-、C18DA[γE][γE][OEG][OEG][eLys]-、C18DA [γE][γE][γE][OEG][OEG][eLys]-、C18DA[γE][γE][γE][γE][OEG][OEG][eLys]-、C20DA[OEG][OEG][eLys]-、C20DA[γE][OEG][OEG][eLys]-、C20 DA[γE][γE][OEG][OEG][eLys]-、C20DA[γE][γE][γE][OEG][OEG][eLys]-、C20DA[γE][γE][γE][γE][OEG][OEG][eLys]-、C18DA[AHX]、C18DA[γE][ AHX]-、C18DA[γE][γE][AHX]-、C18DA[γE][γE][γE][AHX]-、C18DA[γE][γE][γE][γE][AHX]-、C18DA[γE][γE][γE][γE][γE][AHX]-、C18DA[γE][γE][γE][γE][γE][AHX]-、C18DA[γE][γE][γE][γE][γE][γE][AHX]-、C20DA[AHX]、C20DA[γE][γE][AHX]-C20DA[γE][γE][γE][γE][γE][AHX]- or C20DA[γE][γE][γE][γE][γE][γE][AHX]-. Preferably, the polypeptide is located at amino acid position X. 28 Lipidification occurs at the lysine (K) residue in the protein. N-end and C-end

[0029] In this document, peptides are typically amidated at the C-terminus (-CONH2), as with natural peptides. However, the peptides of the present invention may also have a free carboxylic acid (-COOH) or another post-translational modification, such as a methyl ester (-COOMe). In a highly preferred embodiment of the invention, the peptide is amidated at the C-terminus. The peptides according to the invention may have a free amine (-NH2), be N-acylated (-NHCOR), N-methylated (-NHCH3 or -N(CH3)2), deamined at the N-terminus, or N-esterified. Pharmaceutical Composition

[0030] In this document, it should be understood that the polypeptides or pharmaceutically acceptable salts thereof according to the invention may be in the form of pharmaceutical compositions. Pharmaceutical compositions may comprise pharmaceutically acceptable carriers and / or one or more excipients. Pharmaceutical compositions (i.e., formulations) include (but are not limited to) tablets, pills, capsules, emulsions, suspensions, sustained-release formulations, solutions, or lyophilized powders intended to be dissolved prior to administration. In some embodiments, the formulation may be a reservoir-type formulation providing slow release. It should be understood that different routes of administration may be used depending on the choice of formulation and the chemical and / or metabolic stability of the polypeptide. Such routes of administration may include (but are not limited to) oral administration, non-enteric administration (intravenous (IV), subcutaneous (SC), intradermal (ID), and intramuscular (IM)) or inhalation. In a preferred embodiment of the invention, the route of administration is non-enteric administration. In one, and even more preferred, the route of administration is subcutaneous.

[0031] Peptide therapeutic agents are typically provided as pharmaceutical liquid formulations in pre-filled, ready-to-use injection devices. These peptide formulations intended for subcutaneous administration have a limited application volume. Therefore, good solubility of the peptides at or near physiological pH (e.g., pH 7) is a requirement for application in ready-to-use injection devices. Invention Details

[0032] In a first aspect, the present invention provides a polypeptide of a general structure according to formula (I) or a salt thereof or a pharmaceutically acceptable salt thereof. Z1-Z2-Z3 (I), in, Z1 is a GIP / GLP1 hybrid polypeptide containing or composed of the following amino acid sequences. Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK (SEQ IDNO: 306), Or its derivatives having one, two or three amino acid substitutions; Z2 is the linker; Z3 is a polypeptide containing or composed of the following amino acid sequences. ASLRHYYNWLTRQRY (SEQ ID NO:307) or its derivatives having 1, 2, 3, 4 or 5 amino acid substitutions.

[0033] The compounds of the present invention bind to and / or activate GLP-1, GIP and hY2 (NPY2) receptors. Connector base Z2

[0034] Peptide fragments Z1 and Z3 are linked via linker Z2. It should be understood that Z1 and Z3 can be linked using various linkers commonly used in technologies such as fusion proteins. Preferably, the linker comprises or consists of a short peptide of 1 to 10 amino acid residues, for example, 2 to 9 amino acids, preferably 3 to 8 amino acids, more preferably 4 to 7 amino acids, even more preferably 5 to 7 amino acids, and most preferably 6 amino acid residues. Therefore, in a preferred embodiment, linker Z2 is a short peptide of 6 amino acid residues (i.e., amino acid X). 29 -X 34 In a more preferred embodiment, Z2 has or contains the amino acid sequence GGPSEG (SEQ ID NO: 311, i.e., amino acid X). 29 -X 34 This could be a derivative thereof having 1, 2, 3, or 4 amino acid substitutions. Preferably, the 1, 2, 3, or 4 amino acid substitutions in Z2 are present at position X. 31 X 32 X 33 or X 34 Any position within (i.e., within the amino acid sequence PSEG (SEQ ID NO: 644)). Therefore, the Z2 derivative is a Z2 peptide analog of SEQ ID NO: 311 with one or more amino acid substitutions compared to SEQ ID NO: 311.

[0035] In a highly preferred embodiment (Z2-Emb1), Z2 (i.e., amino acid X) 29 -X 34 It has or contains the amino acid sequence GGX 31 X 32 X 33 X34 , where X 31 Selected as P, G, or Q; X 32 Selected as S, E, or R; X 33 Selected as S, E, or Y, or preferably selected as S, E, Y, or T; X 34 It is selected as G, P, Y or A; or as a derivative having one amino acid substitution.

[0036] In other highly preferred embodiments, Z2 has an amino acid sequence of any of the Z2 embodiments disclosed in the second aspect of the invention (e.g., Z2-Emb2, Z2-Emb3). hybrid polypeptide Z1

[0037] Z1 (i.e., amino acid X1-X) 28 The product is a GIP / GLP1 hybrid polypeptide comprising or consisting of the amino acid sequence Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK (SEQ ID NO:306), or a derivative thereof having one, two, or three amino acid substitutions. The sequence Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK (SEQ ID NO:306) (i.e., Z1 in SEQ ID NO:286) was selected as a reference sequence. Table 1 summarizes (see page 21ff) the number of substitutions in Z1, one or more positions of the substituted Z1, and exemplary amino acids in the substitutions compared to the reference sequence (i.e., SEQ ID NO:286). As shown in Table 1, amino acid positions X3, X... 10 X 13 X 15 X 16 X 17 X 19 X 20 X 21 X 23 X 24 X 25 or X 27 Tolerance to substitution. Therefore, in a preferred embodiment, one, two, or three substitutions in the Z1 derivative are present at amino acid positions X3, X4. 10 X 13 X 15 X 16 X 17 X 19 X 20 X 21 X 23 X24 X 25 or X 27 Any position within the Z1 sequence. Preferably, the Z1 derivative has one or two substitutions. Most preferably, the Z1 derivative has one substitution. Therefore, the Z1 derivative is a Z1 peptide analog of the amino acid sequence SEQ ID NO:306 (i.e., Z1 in SEQ ID NO:286) having one or more amino acid substitutions compared to SEQ ID NO:306.

[0038] In a highly preferred embodiment, one or more substitutions in the derivatives of Z1 are selected as follows: X3 is selected as D; X 10 L and X were selected. 13 L and X were selected. 15 The answer is D or A; X 16 The options selected are E, D, Aib, G, LysAc, A, L, S, Q, or R; X 17 The answer is E, K, or A; X 19 E and X were selected. 20 Selected as D-Asp or D-Arg; X 21 E is selected, or preferably E or K; X 23 I; X were selected. 24 Q and X were selected. 25 Y was selected as the answer; X was selected as the answer. 27 L was selected.

[0039] Z1 may be composed of or contain the amino acid sequence Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK (SEQ ID NO:306), or may be a derivative thereof, wherein the derivative is located at amino acid positions X3 and X4. 10 X 13 X 15 X 16 X 17 X 19 X 21 X 23 X 24 X 25 or X 27 Any position has 1, 2, or 3 amino acid substitutions, wherein one or more substitutions are selected as follows: X3 is selected as D; X 10 L and X were selected. 13 L and X were selected. 15 The answer is D; X 16 The answer is E, D, G, A, S, Q, or R; X 17 The answer is either E or A; X19 E and X were selected. 21 E or K were chosen; X 23 I; X were selected. 24 Q and X were selected. 25 Y was selected as the answer; X was selected as the answer. 27 L was selected.

[0040] Z1 may be composed of or contain the amino acid sequence Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK (SEQ ID NO:306), or may be a derivative thereof, wherein the derivative is located at amino acid positions X3 and X4. 10 X 13 X 15 X 16 X 17 X 21 X 23 X 24 or X 25 Any position has 1, 2, or 3 amino acid substitutions, wherein the substitutions are selected as follows: X3 is selected as D; X 10 L and X were selected. 13 L and X were selected. 15 The answer is D; X 16 The answer is E, D, G, A, S, Q, or R; X 17 The answer is either E or A; X 21 E and X were selected. 23 I; X were selected. 24 Q and X were selected. 25 Y was selected.

[0041] Z1 may be composed of or contain the amino acid sequence Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK (SEQ ID NO:306), or may be a derivative thereof, wherein the derivative is located at amino acid position X. 21 or X 24 Any position may have one or two, preferably one, amino acid substitutions, wherein one or more substitutions are selected as follows: X 21 The answer is A or E; X 24 The answer is either E or Q. Polypeptide Z3

[0042] Z3 (i.e., amino acid X) 35 -X 49This is a polypeptide that provides hY2R agonist activity, comprising or consisting of the amino acid sequence ASLRHYYNWLTRQRY (SEQ ID NO:307), or a derivative thereof having 1, 2, 3, 4, or 5 amino acid substitutions. The sequence ASLRHYYNWLTRQRY (SEQ ID NO:307) (i.e., Z3 in SEQ ID NO:286) was selected as a reference sequence. Table 1 summarizes (see page 39ff) the number of substitutions in Z3, the positions of substituted Z3, and exemplary amino acids in the substitutions compared to the reference sequence (i.e., SEQ ID NO:286). As shown in Table 1, amino acid position X was found... 35 X 36 X 37 X 38 X 39 X 41 X 42 X 43 X 44 X 46 X 47 X 48 or X 49 Tolerance to substitution. Therefore, in a preferred embodiment, one, two, three, four, or five substitutions in the Z3 derivative are present at amino acid position X. 35 X 36 X 37 X 38 X 39 X 41 X 42 X 43 X 44 X 46 X 47 X 48 or X 49 In any position. In a preferred embodiment, Z3 has 1, 2, or 3 substitutions. More preferably, Z3 has 1 or 2 substitutions. Most preferably, Z3 has 1 substitution. Therefore, the Z3 derivative is a Z3 peptide analog of the amino acid sequence SEQ ID NO:307 (i.e., Z3 in SEQ ID NO:286) having one or more amino acid substitutions compared to SEQ ID NO:307.

[0043] In a highly preferred embodiment, one or more substitutions in the derivatives of Z3 are selected as follows: X 35 The options are Q, I, V, E, or L; X 36 The choice is E, T, D, or L; X 37Selected as Aib, V, D-Leu, or I, or preferably selected as Aib, V, D-Leu, I, or Tle; X 38 Selected as L or Aib; X 39 Selected as Aib, D-His, or Tle; X 41 The options are L, Aib, I, or Tle; X 42 Selected as Aib; X 43 Selected as H, L, R, or Aib; X 44 Selected as Aib, D-Arg, or D-Asp, or preferably selected as Aib, D-Arg, D-Asp, or Tle; X 46 Selected as hArg or D-Arg; X 47 Selected as bh-Gln or NMeQ; X 48 NMeR;X was selected. 49 The selected values ​​are Tle, Chg, D-Tyr, and Phg.

[0044] Z3 may consist of or contain the amino acid sequence ASLRHYYNWLTRQRY (SEQ ID NO:307), or may be a derivative thereof, wherein the derivative is located at amino acid position X. 35 X 36 X 37 X 38 X 39 X 41 X 44 X 47 or X 48 Any position has 1, 2, or 3 amino acid substitutions, wherein one or more substitutions are selected as follows: X 35 The options are Q, I, V, E, or L; X 36 T and X were selected. 37 The choice is Aib, V, I, or Tle; X 38 Selected as Aib; X 39 Selected as Tle;X 41 Selected as I, L, or Tle; X 44 Selected as Tle;X 47 NMeQ was selected; X 48 NMeR was selected.

[0045] Z3 may be composed of or contain the amino acid sequence ASLRHYYNWLTRQRY (SEQ ID NO:307), or may be a derivative thereof, wherein the derivative is located at amino acid position X. 35 X 37 X47 or X 48 Any position may have one or two, preferably one, amino acid substitutions, wherein one or more substitutions are selected as follows: X 35 Q and V were selected; X 37 I; X were selected. 47 NMeQ was selected; X 48 NMeR was selected.

[0046] In general, compared with SEQ ID NO:286, the polypeptides Z1-Z2-Z3 of the first aspect of the present invention and any or more embodiments disclosed in the present invention preferably have 0, 1, 2, 3, 4, 5 or 6 amino acid substitutions, more preferably 0, 1, 2, 3 or 4 amino acid substitutions, and highly preferably 0, 1, 2 or 3 substitutions.

[0047] In a second aspect, the present invention provides a polypeptide of the general structure according to formula (I) or a salt thereof or a pharmaceutically acceptable salt thereof. Z1-Z2-Z3 (SEQ ID NO:647) (I), in, Z1 is a GIP / GLP1 hybrid polypeptide containing or composed of the following amino acid sequences. Y-Aib-X3-GTFTSDX 10 -SIX 13 -LX 15 -X 16 -X 17 -AX 19 -X 20 -X 21 -FX 23 -X 24 -X 25 -LX 27 -K(SEQ ID NO:646), X3 was selected as either E or D; X 10 Selected as Y or L; X 13 Selected as Aib or L; X 15 The answer is E, D, or A; X 16 The options are K, E, D, Aib, G, LysAc, A, L, S, Q, or R; X 17 The answer is Q, E, K, or A; X 19 The answer is Q or E; X 20 Selected as Aib, D-Asp, or D-Arg; X 21 The answer is A, E, or K; X 23 V or I; X24 The answer is E or Q; X 25 The choice is W or Y; X 27 It is I or L; or Z1 is its derivative having one amino acid substitution; Z2 contains the amino acid sequence GGX. 31 -X 32 -X 33 -X 34 Or a linking base composed of them, where X 31 Selected as P, G, or Q; X 32 Selected as S, E, or R; X 33 The choice is S, E, Y, or T; X 34 It is selected as G, P, Y or A; or Z2 is its derivative having one amino acid substitution.

[0048] Z3 is a polypeptide containing or composed of the following amino acid sequences. X 35 -X 36 -X 37 -X 38 -X 39 -YX 41 -X 42 -X 43 -X 44 -TX 46 -X 47 -X 48 -X 49 , Where X 35 The answer is A, Q, I, V, E, or L; X 36 Selected as S, E, T, D, or L; X 37 The options are L, Aib, V, D-Leu, I, or Tle; X 38 Selected as R, L, or Aib; X 39 Selected as H, Aib, D-His, or Tle; X 41 The options are Y, L, Aib, I, or Tle; X 42 Selected as N or Aib; X 43 The options are W, H, L, R, or Aib; X 44 Selected as L, Aib, D-Arg, D-Asp, or Tle; X 46 Selected as R, hArg, or D-Arg; X 47 Selected as Q, bh-Gln, or NMeQ; X 48 Selected as R or NMeR; X 49The selected values ​​are Y, Tle, Chg, D-Tyr, Phg; or Z3 is a derivative having one amino acid substitution. Preferred amino acids in Z1

[0049] In a preferred embodiment (Z1-Emb1), X3 is selected as E or D; X 10 The answer is either Y or L; X 13 The option was chosen as Aib or L; X 15 The answer is either E or D; X 16 The options are K, E, D, G, A, S, Q, or R; X 17 The answer is Q, E, or A; X 19 The answer is either E or Q; X 20 Aib was selected; X 21 The answer is A, E, or K; X 23 The choice is V or I; X 24 The answer is either E or Q; X 25 The choice is either W or Y; X 27 It was chosen to be either I or L; Z1 is its derivative with one amino acid substitution;

[0050] In a preferred embodiment (Z1-Emb2), X3 is selected as E or D; X 10 The answer is either Y or L; X 13 The option was chosen as Aib or L; X 15 The answer is either E or D; X 16 The options are K, E, D, G, A, S, Q, or R; X 17 The answer is Q, E, or A; X 19 Q was selected; X 20 Aib was selected; X 21 The answer is either A or E; X 23 The choice is V or I; X 24The answer is either E or Q; X 25 The choice is either W or Y; X 27 For I; Z1 is its derivative with one amino acid substitution;

[0051] In a preferred embodiment (Z1-Emb3), X3 is selected as E; X 10 Y was selected; X 13 Aib was selected; X 15 The answer is E. X 16 K was selected; X 17 Q was selected; X 19 Q was selected; X 20 Aib was selected; X 21 The answer is either A or E; X 23 V was selected; X 24 The answer is either E or Q; X 25 W was selected; X 27 For I; Z1 is a derivative of which has one amino acid substitution.

[0052] In a preferred embodiment, X3 in Z1 is selected as E. In a preferred embodiment, X in Z1 10 Y was selected. In a preferred embodiment, X in Z1 13 Aib was selected. In a preferred embodiment, X in Z1 15 E was selected. In a preferred embodiment, X in Z1 16 K was selected. In a preferred embodiment, X in Z1 17 Q is selected. In a preferred embodiment, X in Z1 19 Q is selected. In a preferred embodiment, X in Z1 20 Aib was selected. In a preferred embodiment, X in Z1 21 A was selected. In a preferred embodiment, X in Z1 23 V was selected. In a preferred embodiment, X in Z1 24E was selected. In a preferred embodiment, X in Z1 25 W was selected. In a preferred embodiment, X in Z1 27 It was selected as I.

[0053] In a highly preferred embodiment, X3 in Z1 is selected as E; X in Z1 10 Y was chosen; and X in Z1 13 Aib was selected. In a highly preferred embodiment, X in Z1 15 X in E and Z1 were selected. 16 K was chosen; and X in Z1 17 Q is selected. In a highly preferred embodiment, X in Z1 19 X was selected as Q; Z1 20 The result is selected as Aib; and X in Z1 21 A was selected. In a highly preferred embodiment, X in Z1 23 X is selected as V; Z1 24 X in E and Z1 were selected. 25 W was chosen; and X in Z1 27 It was selected as I. Preferred amino acids in Z2

[0054] In a preferred embodiment (Z2-Emb1), Z2 contains the amino acid sequence GGX. 31 X 32 X 33 X 34 Or composed of, where X 31 Selected as P, G, or Q; X 32 Selected as S, E, or R; X 33 The choice is S, E, Y, or T; X 34 It is selected as G, P, Y or A; or Z2 is its derivative having one amino acid substitution.

[0055] In a preferred embodiment (Z2-Emb2), Z2 contains the amino acid sequence GGX. 31 -X 32 -X 33 -X 34 Or composed of, where X 31 Selected as P or Q; X 32 S or E; X 33 The choice is S, E, Y, or T; X 34 It is selected as G, P, Y or A; or Z2 is its derivative having one amino acid substitution.

[0056] In a highly preferred embodiment (Z2-Emb3), Z2 comprises or consists of the amino acid sequence GGPSEG (SEQ ID NO:311) or GGPSSG (SEQ ID NO:320); or Z2 is a derivative thereof having one amino acid substitution.

[0057] In a preferred embodiment, X in Z2 31 P was selected. In a preferred embodiment, X in Z2 32 S was selected. In a preferred embodiment, X in Z2 33 S was selected. In a preferred embodiment, X in Z2 34 G was selected.

[0058] In another implementation (Z2-Emb4), Z2 is selected from the group consisting of: GGPEEG (SEQ ID NO:313), GGPEEP (SEQ ID NO:314), GGPESG (SEQ ID NO:315), GGPESP (SEQ ID NO:316), GGPSEG (SEQ ID NO:311), GGPSEP (SEQ ID NO:317), GGPSEY (SEQ ID NO:318), GGPSSA (SEQ ID NO:319), GGPSSG (SEQ ID NO:320), GGPSSP (SEQ ID NO:321), GGPSSY (SEQ ID NO:322), GGPSTG (SEQ ID NO:323), GGPSYG (SEQ ID NO:324), GGQSSG (SEQ ID NO:325), GGGSEY (SEQ ID NO:648), GGPEYY (SEQ ID NO:649), GGPRSG (SEQ ID NO:650), GGPRYY (SEQ ID NO:313), GGPEEG (SEQ ID NO:314), GGPEEP (SEQ ID NO:315), GGPESG (SEQ ID NO:316), GGPESG (SEQ ID NO:316), GGPSEG (SEQ ID NO:311), GGPSEP (SEQ ID NO:317), GGPSEY (SEQ ID NO:318), GGPSSA (SEQ ID NO:319), GGPSSG (SEQ ID NO:320), GGPSSP (SEQ ID NO:321), GGPSSY (SEQ ID NO:322), GGPSTG (SEQ ID NO:323), GGPSYG (SEQ ID NO:324), GGQSSG (SEQ ID NO:325), GGGSEY (SEQ ID NO:648), GGPEYY (SEQ ID NO:649), GGPRSG (SEQ ID NO:650), GGPRYY (SEQ ID NO:314), GGPEEG (SEQ ID NO:315), GGPEEG (SEQ ID NO:316), GGPESG ( NO:651), GGPSYY (SEQ ID NO:652), GGQRSY (SEQ ID NO:653), GGQRYY (SEQ ID NO:654), GGQSSY (SEQ ID NO:655).

[0059] In another implementation (Z2-Emb5), Z2 is selected from the group consisting of: GGPEEG (SEQ ID NO:313), GGPEEP (SEQ ID NO:314), GGPESG (SEQ ID NO:315), GGPESP (SEQ ID NO:316), GGPSEG (SEQ ID NO:311), GGPSEP (SEQ ID NO:317), GGPSEY (SEQ ID NO:318), GGPSSA (SEQ ID NO:319), GGPSSG (SEQ ID NO:320), GGPSSP (SEQ ID NO:321), GGPSSY (SEQ ID NO:322), GGPSTG (SEQ ID NO:323), GGPSYG (SEQ ID NO:324), GGQSSG (SEQ ID NO:325), GGPRSG (SEQ ID NO:650), GGPRYY (SEQ ID NO:651), and GGPSYY (SEQ ID NO:652).

[0060] In another implementation (Z2-Emb6), Z2 is selected from the group consisting of: GGPEEG (SEQ ID NO:313), GGPEEP (SEQ ID NO:314), GGPESG (SEQ ID NO:315), GGPESP (SEQ ID NO:316), GGPSEG (SEQ ID NO:311), GGPSEP (SEQ ID NO:317), GGPSEY (SEQ ID NO:318), GGPSSA (SEQ ID NO:319), GGPSSG (SEQ ID NO:320), GGPSSP (SEQ ID NO:321), GGPSSY (SEQ ID NO:322), GGPSTG (SEQ ID NO:323), GGPSYG (SEQ ID NO:324), and GGQSSG (SEQ ID NO:325).

[0061] In another implementation (Z2-Emb7), Z2 is selected from the group consisting of: GGPEEG (SEQ ID NO:313), GGPESG (SEQ ID NO:315), GGPESP (SEQ ID NO:316), GGPSEG (SEQ ID NO:311), GGPSEP (SEQ ID NO:317), GGPSEY (SEQ ID NO:318), GGPSSA (SEQ ID NO:319), GGPSSG (SEQ ID NO:320), GGPSSP (SEQ ID NO:321), GGPSSY (SEQ ID NO:322), GGPSTG (SEQ ID NO:323), GGPSYG (SEQ ID NO:324), and GGQSSG (SEQ ID NO:325). Preferred amino acids in Z3

[0062] In another implementation (Z3-Emb1), X 35 The options selected are A, E, I, L, Q, and V; X 36 The option is selected as S or T; X 37 The options selected are Aib, I, L, Tle, and V; X 38 The choice is either Aib or R; X 39 The choice is either H or Tle; X 41 The options are I, L, Tle, or Y; X 42 N was chosen; X 43 W was selected; X 44 The choice is L or Tle; X 46 R was selected; X 47 It was selected as NMeQ or Q; X 48 It was selected as NMeR or R; X 49 Y was selected; Z3 is a derivative of which has one amino acid substitution.

[0063] In a preferred embodiment (Z3-Emb2), X 35 The answer is A, Q, or V; X 36 S was selected. X 37 It was chosen to be either I or L; X 38 R was selected; X 39 H was selected; X 41 Y was selected; X 42 N was chosen; X 43 W was selected; X 44 L was selected; X 46 R was selected; X 47 The choice is either Q or NMeQ; X 48 It was selected as R or NMeR; X 49 Y was selected; Z3 is a derivative of which has one amino acid substitution.

[0064] In a preferred embodiment, X in Z3 35 A was selected. In a preferred embodiment, X in Z3 36 S was selected. In a preferred embodiment, X in Z3 37 L was selected. In a preferred embodiment, X in Z3 38 R is selected. In a preferred embodiment, X in Z3 39 H was selected. In a preferred embodiment, X in Z3 41 Y was selected. In a preferred embodiment, X in Z3 42 N is selected. In a preferred embodiment, X in Z3 43 W was selected. In a preferred embodiment, X in Z3 44 L was selected. In a preferred embodiment, X in Z3 46 R is selected. In a preferred embodiment, X in Z3 47 Q is selected. In a preferred embodiment, X in Z3 48 R is selected. In a preferred embodiment, X in Z3 49 Y was selected.

[0065] In a highly preferred embodiment, X 35 X 36 X 37 X 38 X 39The selected value is ASLRH (SEQ ID NO: 645). In a highly preferred embodiment, X 41 X 42 X 43 X 44 YNWL (SEQ ID NO:326) was selected. In a highly preferred embodiment, X 46 X 47 X 48 X 49 RQRY (SEQ ID NO:327) was selected.

[0066] It should be understood that the second aspect of the present invention and / or any related embodiments disclosed above and below may be subordinate to the first aspect of the present invention and / or any related embodiments disclosed above and below.

[0067] It should be understood that, according to the first or second aspect of the invention, one or more embodiments describing the preferred amino acid at position Z1 can be combined with one or more embodiments describing the preferred amino acid at positions Z2 and / or Z3, and vice versa. Therefore, any combination of one or more embodiments mentioned under "preferred amino acid in Z1" can be combined with one or more embodiments mentioned under "preferred amino acid in Z2" and / or "preferred amino acid in Z3," and vice versa. Any such combination of embodiments should be understood as a direct and explicit part of the invention.

[0068] Referring to the second aspect of the present invention, an embodiment combining the above-mentioned embodiments is as follows: According to the second aspect Z1-Z2-Z3, where Z2 is Z2-Emb4; Z1-Emb1, Z2-Emb2 and Z3-Emb1; Z1-Emb1, Z2-Emb5 and Z3-Emb1; Z1-Emb1, Z2-Emb6 and Z3-Emb1; Z1-Emb2, Z2-Emb2 and Z3-Emb1; Z1-Emb2, Z2-Emb7 and Z3-Emb1; Z1-Emb3, Z2-Emb3 and Z3-Emb2. Preferred lipid / linker

[0069] The polypeptide according to the first and / or second aspects of the present invention can be of the general formula LY 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 -Y 7 -Y 8The structure (i.e., the lipid / linker group) is located at the lysine (K) residue, preferably at the amino acid position X. 28 Lipids are esterified at the lysine (K) residue, where L is a lipid selected from 17-carboxy-heptadecanoyl (abbreviated C18DA) and 19-carboxy-nonadecanoyl (abbreviated C20DA), and Y is also present. 1 -Y 8 Each of the elements is independently selected from: non-existent, [γE], [E], [OEG], [eLys], or [AHX].

[0070] Preferably, the lipid / linker has the general formula LY 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 -Y 7 -Y 8 The structure, wherein L is a lipid selected from C18DA or C20DA, wherein Y 1 -Y 8 Each of the elements is independently selected from: non-existent, [γE], [E], [OEG], [eLys], or [AHX], where Y 1 -Y 3 The terms in the text are [γE], or Y. 1 -Y 3 The elements in the equation are [E], where Y is... 4 The value is selected from: [γE], [E], or [OEG], where Y is selected from: [γE], [E], or [OEG]. 5 -Y 8 Each of the elements is independently selected from: non-existent, [γE], [E], [OEG], [eLys], or [AHX].

[0071] Preferably, the lipid / linker has the general formula LY 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 -Y 7 -Y 8 The structure is given by L, where L is C20DA and Y is... 1 -Y 8 Each of the elements is independently selected from: non-existent, [γE], [E], [OEG], or [eLys], where Y 1 -Y 4 The terms in the text are [γE], or Y. 1 -Y 4 The elements in the equation are [E], where Y is... 5The value is selected from: [γE], [E], [OEG] or [eLys], where Y is selected from: [γE], [E], [OEG] or [eLys]. 6 -Y 8 Each of the elements is independently selected from: non-existent, [γE], [E], [OEG], or [eLys].

[0072] For example, the polypeptide of the present invention is located at amino acid position X. 28 The lysine (K) residues are lipidized, and the lipid / linker group is selected from the following group: C18DA[E][E][E][E]-(SEQ ID NO:640)、C18DA[E][E][E][E][E]-(SEQ ID NO:636)、C18DA[E][E][E][E][E][E]-(SEQ ID NO:637)、C18DA[γE][γE][γE][γE]-、C18DA[γE][γE][γE][γE][γE]- 、 C18DA[γE][γE][γE][γE][γE][γE][γE][γE][γE][γE][γE][γE][γE][γE] 、C18DA[γE][γE][γE][γE][γE][γE][γE]- 、 C20DA[γE][γE][γE][γE]- 、C20DA[γE][γ[E][γE][γE][γE][γE][γE][γE] C20DA[γE][γE][γE][γE][γE][γE]- 、C20DA[γE][γE][γE][γE][γE][γE][γE]-、C18DA[E][E][E][E][E][E][E] NO:635)、C18DA[E][E][E][E][E][E][eLys]-(SEQ ID NO:643)、C18DA[γE][γE][γE][γE][eLys]-、C18DA[γE][γE][γE][γE][γE][eLys]- 、C18DA[γE][γE][γE][γE][γE][γE][eLys]-、C20DA[E][E][E][E][E][eLys]-(SEQ ID NO:639)、C20DA[γE][γE][γE][γE][eLys]-、C20DA[γE][γE][γE][γE][γE][γE] ][eLys]-、C20DA[γE][γE][γE][γE][γE][γE][eLys]-、C20DA[γE][γE][γ E][γE][γE][γE][γE][eLys]-、C20DA[γE][γE][γE][γE][γE][eLys][eLy s]-、C18DA[E][E][E][OEG][OEG]-、C18DA[E][E][E][E][OEG][OEG]-(SEQ IDNO:634)、C18DA[γE][γE][γE][OEG][OEG]-、C18DA[γE][γE][γE][γE][OEG][OEG] -、C18DA[γE][γE][γE][γE][γE][OEG][OEG]-、C20DA[E][E][E][E][OEG][OEG]-(SEQ IDNO: 638), C20DA[γE][γE][γE][OEG]-, C20DA[γE][γE][γE][γE][OEG]-, C20DA[γE][γE][γE][γE][γE][OEG]-, C18DA[γE][γE][γE][OEG]-, C18DA[γE][γE][γE][γE][OEG]-, C18DA[γE][γE][γE][γE][γE][OEG]-, C18DA[γE][γE][γE][γE][γE][γE][OEG]-, C20DA[γE][γE][γE][OEG]-, C20DA[γE][γE][γE][γE][OEG]-, C20DA[γE][γE][γE][γE][γE][OEG]-, C20DA[γE][γE][γE][γE][γE][γE][OEG]-, C18DA[γE][γE][γE][OEG][eLys]-, C18DA[γE][γE][γE][γE][OEG][eLys]-, C18DA[γE][γE][γE][γE][γE][OEG][eLys]-, C20DA[γE][γE][γE][OEG][eLys]-, C20DA[γE][γE][γE][γE][OEG][eLys]-, C20DA[γE][γE][γE][γE][γE][OEG][eLys]-, C18DA[γE][γE][γE][OEG][OEG][eLys]-, C18DA[γE][γE][γE][γE][OEG][OEG][eLys]-, C20DA[γE][γE][γE][OEG][OEG][eLys]-, C20DA[γE][γE][γE][γE][OEG][OEG][eLys]-, C18DA[γE][γE][γE][γE][AHX]-, C18DA[γE][γE][γE][γE][γE][AHX]-, C18DA[γE][γE][γE][γE][γE][γE][AHX]-, C20DA[γE][γE][γE][γE][AHX]-, C20DA[γE][γE][γE][γE][γE][AHX]-, or C20DA[γE][γE][γE][γE][γE][γE][AHX]-.

[0073] For example, the polypeptide of the present invention is lipidated at the lysine (K) residue at amino acid position X 28 and the lipid / linker is selected from the group consisting of: C20DA[γE][γE][γE][γE][γE]-, C20DA[γE][γE][γE][γE][γE][γE]-, C20DA[γE][γE][γE][γE][γE][γE][γE]-, C18DA[E][E][E][E][E][eLys]-(SEQ ID NO:635), C20DA[E][E][E][E][E][eLys]-(SEQ ID NO: 639), C20DA[γE][γE][γE][γE][eLys]-, C20DA[γE][γE][γE][γE][γE][eLys]-, C20DA[γE][γE][γE][γE][γE][γE][eLys]-, C2 0DA[γE][γE][γE][γE][γE][γE][γE][eLys]-, C20DA[γE][γE][γE][γE][γE][eLys][eLys]-, C20DA[E][E][E][E][OEG][OEG]-(SEQ ID NO: 638), C20DA[γE][γE][γE][γE][OEG][OEG]-, C20DA[γE][γE][γE][γE][γE][OEG] [OEG]-, C20DA[γE][γE][γE][γE][OEG]-, C20DA[γE][γE][γE][γE][γE][OEG]-, C20D A[γE][γE][γE][γE][γE][γE][OEG]-, C20DA[γE][γE][γE][γE][OEG][eLys]-, C20DA [γE][γE][γE][γE][γE][OEG][eLys]-, C20DA[γE][γE][γE][γE][OEG][OEG][eLys]-.

[0074] The triple agonist of the present invention is generally soluble at about pH 7. Several techniques for determining solubility are known to those skilled in the art. Preferably, the solubility of the peptide of the present invention is determined as disclosed in Example 2 below.

[0075] In some embodiments, the solubility of the compounds of the present invention is greater than or equal to 1.0 mg / ml at about pH 7.

[0076] In some embodiments, the solubility of the compounds of the present invention is greater than 3.0 mg / ml at about pH 7.

[0077] In some embodiments, the solubility of the compounds of the present invention is greater than 5.0 mg / ml at about pH 7.

[0078] In some embodiments, the solubility of the compounds of the present invention is equal to or greater than 6.0 mg / ml, 7.0 mg / ml, 8.0 mg / ml or 9.0 mg / ml at about pH 7.

[0079] The hybrid peptides of the present invention are capable of activating hGLP1R, GIPR, and hNPY2R (see Table 3) in the presence of human serum albumin (the major protein present in human plasma). The activity of the peptides of the present invention in the presence of human plasma is an important prerequisite for feasible compounds suitable for treating the disclosed diseases. Those skilled in the art will understand suitable analytical formats, and examples are provided below. For example, for the peptides of the present invention, the EC50 of hGLP1R, GIPR, and hNPY2R was evaluated in the presence of 100% human plasma (100% hP) by the analysis described in Example 1 below. 50 value.

[0080] In some embodiments of the peptides of the present invention, the EC50 of hGLP1R 100% hP and GIPR 100% hP is... 50 Below 100 nM (e.g., 0.01 nM to 100 nM), and EC for hNPY2R 100% hP 50 Below 1000 nM (e.g., 0.01 nM to 1000 nM).

[0081] In some embodiments of the peptides of the present invention, the EC50 of hGLP1R 100% hP and GIPR 100% hP is... 50 Less than or equal to 30 nM (e.g., 0.01 nM to 50 nM), and EC for hNPY2R 100% hP 50 Below 300 nM (e.g., 0.01 nM to 300 nM).

[0082] In some embodiments of the peptides of the present invention, the EC50 of hGLP1R 100% hP and GIPR 100% hP is... 50 Less than or equal to 10 nM (e.g., 0.01 nM to 10 nM), and EC for hNPY2R 100% hP 50 Below 100 nM (e.g., 0.01 nM to 100 nM).

[0083] In a preferred embodiment of the peptide of the present invention, the EC of hGLP1R 100% hP and GIPR 100% hP is... 50 Less than or equal to 10 nM (e.g., 0.01 nM to 10 nM), and EC for hNPY2R 100% hP 50 Below 100 nM (e.g., 0.01 nM to 100 nM), and with a solubility greater than or equal to 1.0 mg / ml at about pH 7.

[0084] In some embodiments, the peptides of the present invention have favorable pharmacokinetic properties. In this regard, the in vivo half-life of the peptides of the present invention in mice (NMRI mice, see measurements described in Example 3) may be greater than 6 hours, greater than 8 hours, or greater than 10 hours.

[0085] In a preferred embodiment of the peptide of the present invention, the EC of hGLP1R 100% hP and GIPR 100% hP is... 50 Less than or equal to 10 nM (e.g., 0.01 nM to 10 nM), and EC for hNPY2R 100% hP 50 It has a solubility of ≥1.0 mg / ml at about pH 7 below 100 nM (e.g., 0.01 nM to 100 nM) and an in vivo half-life of ≥8 hours.

[0086] In a third aspect, the present invention provides a polypeptide for use as a pharmaceutical agent. Because the Y2 receptor has an appetite-suppressing effect, a polypeptide with Y2 agonist activity is suitable for treating symptoms associated with eating disorders, obesity (e.g., simple obesity or symptomatic obesity), and / or diabetes. Furthermore, the intestinal hormones GLP-1 and GIP (called incretins) promote insulin secretion from the pancreas. Because incretins are closely related to glucose metabolism, a polypeptide with GLP-1 receptor agonist activity and GIP receptor agonist activity is suitable for treating symptoms associated with glucose metabolism disorders (including diabetes and obesity). Therefore, the polypeptide of the present invention can have appetite-suppressing and / or weight-loss effects. In a preferred embodiment, the present invention provides a polypeptide for the prevention, treatment, and / or improvement of diseases, conditions, or symptoms selected from the list of the following: overweight, obesity (e.g., simple obesity (long-term weight management) or symptomatic obesity), insulin resistance, diabetes (e.g., type 1 diabetes or type 2 diabetes) or prediabetes, eating disorders, hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, hyperLDL-cholesterolemia, hypoHDL-cholesterolemia, postprandial hyperlipidemia), metabolic syndrome (the following five medical conditions) Three of the symptoms are: abdominal obesity, hypertension, hyperglycemia, high serum triglycerides and low serum high-density lipoprotein (HDL); liver disease, such as metabolic-associated fatty liver disease (MAFLD), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), portal hypertension; cardiovascular disease (such as hypertension, atherosclerosis, stroke or heart failure); kidney disease, such as diabetic nephropathy (DKD) and chronic kidney disease (CKD); and neurodegenerative diseases (Alzheimer's disease or Parkinson's disease), as well as other obesity-related diseases, such as osteoporosis, sleep apnea, obesity-related cancers and obesity-related asthma. Examples of symptomatic obesity include endocrine obesity (e.g., Cushing syndrome, hypothyroidism, insulinoma, type 2 diabetes, pseudohypoparathyroidism, hypogonadism, and related endocrine disorders such as polycystic ovary syndrome (PCOS)), central obesity (e.g., hypothalamic obesity, frontal lobe syndrome, Kleine-Levin syndrome), hereditary obesity (e.g., Prader-Willi syndrome, Laurence-Moon-Biedl syndrome), and drug-induced obesity (e.g., obesity induced by steroids, phenothiazines, insulin, sulfonylureas, and beta-blockers).

[0087] The peptides of the present invention can also be used to prevent obesity, or to prevent or reverse obesity and / or overweight comorbidities, such as type 2 diabetes, hypertension, NAFLD, NASH, DKD, CKD, sleep apnea, obesity-related cancers or obesity-related asthma.

[0088] In a fourth aspect, the present invention provides a method for treating a disease, condition, and / or symptom, the method comprising administering to an individual in need a therapeutically effective amount of a polypeptide or a pharmaceutically acceptable salt thereof according to any of the aspects and embodiments disclosed herein. Preferably, the disease, condition, and / or symptom is selected from a list consisting of: overweight, obesity, diabetes (type 1 or type 2) or prediabetes, eating disorders, hyperlipidemia, metabolic syndrome, NAFLD, NASH, and / or cardiovascular disease. Most preferably, the disease, condition, and / or symptom is obesity, prediabetes, and / or diabetes (type 1 or type 2).

[0089] Furthermore, the present invention provides a method for binding to and / or activating GLP-1, GIP, and hNPY2 receptors in an individual in need, the method comprising administering a therapeutically effective amount of a polypeptide or a pharmaceutically acceptable salt thereof according to any of the aspects and embodiments disclosed herein.

[0090] Similarly, the present invention relates to the use of polypeptides or pharmaceutically acceptable salts thereof according to any of the aspects and embodiments disclosed herein for the manufacture of medicaments for treating diseases, conditions and / or symptoms.

[0091] For humans (subcutaneous administration), the appropriate weekly dose range for peptides with the general structure of formula (I) is typically 0.01 to 100 mg.

[0092] The polypeptides of the present invention can be administered subcutaneously using suitable devices, such as pre-filled ready-to-use injection devices, syringes, pen syringes, or auto-injectors.

[0093] The actual pharmaceutically effective or therapeutic dose will generally depend on factors known to those skilled in the art, such as the patient's age and weight, route of administration, and severity of disease. In any case, the compound will be administered in a dosage and manner that allows for the delivery of a pharmaceutically effective dose based on the patient's unique condition. Example A general procedure for solid-phase synthesis of peptides

[0094] All peptides were synthesized on Tentagel S RAM resin (loading 0.23 to 0.25 mmol / g, bead size 90 μm) supplied by Iris Biotech GmbH or RappPolymere GmbH using standard Fmoc-based solid-phase peptide chemistry methods.

[0095] Use the following protected amino acids: Fmoc-Ala-OH, Fmoc-Aib-OH, Fmoc-Arg(Pbf)-OH, Fmoc-NMeArg(Pbf)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Asp(tBu)-OH, Fmoc-Gln(Trt)-OH, Fmoc-NMeGln(Trt)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Glu-OtBu, Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmoc- Ile-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH, Fmoc-Lys(Dde)-OH, Fmoc-Lys(Mtt)-OH, Fmoc-Phe-OH, Fmoc-Pro-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Trp(Boc)-OH, Fmoc-Tyr(tBu)-OH, Boc-Tyr(tBu)-OH, Fmoc-D-Tyr(tBu)-OH, Fmoc-Val-OH. Unless otherwise specified, amino acid structural units in the L form are used.

[0096] The modular half-life extension group is constructed using protected structural units via solid-phase peptide synthesis (SPPS), such structural units as (but not limited to) C18DA(tBu), C20DA(tBu), Fmoc-OEG-OEG-OH, Fmoc-OEG-OH, Boc-Lys(Fmoc)-OH, Fmoc-Glu-OtBu, Fmoc-Glu(tBu)-OH, Fmoc-Ahx-OH, Fmoc-Trx-OH, and Fmoc-Sar-OH.

[0097] Amino acids, Fmoc-Glu-OtBu, Oxyma, and DIC were purchased from standard suppliers such as Bachem, Novabiochem, ABCR GmbH & Co. KG., Iris Biotech GmbH, and Sigma-Aldrich. C18DA(tBu) and C20DA(tBu) were supplied by Cool Pharm Ltd. or AstraTech. Fmoc-OEG-OEG-OH was supplied by ABCR GmbH & Co. KG. or Iris Biotech GmbH. Fmoc-OEG-OH was supplied by Angene International Limited, Combi Blocks Inc., Iris Biotech GmbH, or Hangzhou APIChem Technology Co., Ltd. Fmoc-Ahx-OH was purchased from Activate Scientific GmbH, and Fmoc-Trx-OH was purchased from ABCR GmbH & Co. KG.

[0098] Peptide assembly begins at the C-terminus and proceeds sequentially towards the N-terminus according to individual sequences until the N-terminal amino acid is reached. After the deprotection of the side chains of the branched amino acids (e.g., Lys(Dde)), the half-life-extending groups are assembled.

[0099] The peptide was obtained in the form of TFA salt by cleavage / deprotection or by HPLC purification. The trifluoroacetate could be exchanged using common procedures such as resin ion exchange procedures, as disclosed in Roux, St. et al., J. Pept. Sci. 2008; 14:354-359. Synthesis Method 1 (S01)

[0100] Peptides were synthesized using microwave-assisted solid-phase peptide synthesis (SPPS) on Tentagel S RAM resin at a scale of 0.25 mmol on a CEM Liberty Blue peptide synthesizer. The stoichiometry and concentrations of the peptide coupling reactions were 4 equivalents of DMF containing appropriate protected amino acids (0.2 mol / L, 5 mL), 4 equivalents of DMF containing Oxyma (1 mol / L, 1 mL), and 8 equivalents of DMF containing DIC (1 mol / L, 2 mL).

[0101] The reaction time and temperature vary for amino acids. A single coupling at 90°C for 4 minutes is suitable for all standard amino acids except those listed below. A single coupling at 75°C for 20 minutes is suitable for Fmoc-Aib-OH, with amino acids after Aib coupled twice. A double coupling at 90°C for 4 minutes is suitable for Fmoc-Arg(Pbf)-OH, C18DA(tBu), C20DA(tBu), Fmoc-OEG-OH, FmocNMeArg(Pbf)-OH, and Fmoc-NMeGln(Trt)-OH. Amino acids after NMeArg and NMeGln are coupled twice. The last 8 standard amino acids in the main chain are coupled at 90°C for 8 minutes.

[0102] Before and after Fmoc-Glu-OtBu coupling, and before C18DA(tBu) and C20DA(tBu) coupling, a capping step was performed for 5 minutes at 65°C with DMF (10 ml) containing 20% ​​acetic anhydride. N-terminal encapsulation was then performed at 90°C with 10% piperidine / DMF (10 ml). α Fmoc deprotection was performed for 1 minute. The Lys(Dde)- group was deprotected twice at 90°C with DMF (10 ml) containing 5% hydrazine hydrate for 3 minutes each time. The original product was washed on the resin with DCM and dried before lysis. Self-resin lysis and deprotection were performed at 40°C with a mixture of 95% TFA / water (10 ml) and triisopropylsilane (250 μl) for 45 minutes. The crude peptide was precipitated with cold tert-butyl methyl ether, dissolved in 50% acetonitrile / water, and purified by preparative HPLC. Synthesis method 2 (S02)

[0103] Peptides were synthesized by SPPS at a scale of 0.2 mmol on a MultiSynTech SYRO II. Standard coupling of amino acids was achieved using 4 equivalents of appropriately protected amino acids (0.5 mol / L) dissolved in 0.5 mol / L Oxyma-DMF solution and 4.5 equivalents of DMF containing DIC (1 mol / L). Fmoc-Phe-OH was dissolved in 0.5 mol / L Oxyma-NMP, and 4 equivalents were used for coupling (0.5 mol / L). Coupling of the first 23 amino acids, starting from the C-terminus, was performed at 75 °C for 15 min (Cys and His were coupled at 50 °C). Further extension was performed by double coupling (2 × 15 min at 75 °C). Deprotection of the Lys(Mtt)- group was selectively achieved using hexafluoroisopropanol (10 × 10 min, 10 mL at room temperature). Deprotected lysine intermediates were derivatized by doubling four equivalent related linker structural units (Fmoc-OEG-OEG-OH, Fmoc-Glu-OtBu, Boc-Lys(Fmoc)-OH, C18DA(tBu), C20DA(tBu)) at 75 °C for 15 minutes. α Fmoc deprotection was performed using NMP (4 ml) containing 40% piperidine for 3 minutes, followed by NMP (4 ml) containing 20% ​​piperidine at 45°C for 15 minutes. The protection of the appropriately protected Fmoc-Asp, Fmoc-Cys, and Fmoc-His intermediates was removed at room temperature. The peptide was cleaved from the resin and the side chains were deprotected by adding 15 ml of 95:2:1:2 TFA / DODT / TES / water at room temperature for 4 hours or at 45°C for 60 minutes. The peptide was precipitated with cold diethyl ether, dissolved in acetonitrile / water, and purified by preparative HPLC (purification method 3, PO2). Purification method 1 (P01)

[0104] The crude peptide was dissolved in DMF / acetonitrile / water and purified by reverse-phase chromatography using an Agilent preparative HPLC-MS system equipped with preparative pumps G7161B, G7111B, and G7110B, a diode array detector G7115A, a mass spectrometer G6135B, and a fraction collector G7158B. A Waters Luna preparative C8(3) column was used. A 10 μm, 300 g, self-filled steel column was used as the stationary phase. The mobile phase was run at 40 °C with a flow rate of 150 mL / min using a gradient of buffer A (ACN) and buffer (H₂O + 0.1% TFA). The fractions were then lyophilized. The final products were characterized by analytical HPLC-MS (U046_001 and U046_006).

[0105] Table 2-1 Purification method 2 (P02)

[0106] The crude peptide was dissolved in DMF / acetonitrile / water and purified by reverse-phase chromatography using a GILSON preparative HPLC system with a preparative pump AP-MOD (maximum flow rate: 200 mL / min), an ECOMFlash 10 diode array detector, and a GILSON GX 281 fraction collector. The stationary phase was a Phenomenex LUNAC8 10 μm preparative column (50 × 250 mm). The peptide was eluted using a focused gradient with water (eluent A) and acetonitrile (eluent B) at a flow rate of 120 mL / min and 40 °C; a modifier solution was added in "column dilution mode" to maintain a constant volume of 0.1% TFA in the mobile phase. Homogeneous fractions were then lyophilized. The final product was characterized by HPLC-MS (U046_001 and U046_006).

[0107] Table 2-2 Purification method 3 (P03)

[0108] The crude peptide was purified by reverse-phase HPLC using a Waters preparative HPLC system with a C8 column (Reprosil Gold). The equipment included a 5 μm, 40 mm × 250 mm micrometer, a preparative pump (Waters 2545), a UV / VIS detector (Waters 2489), and a Waters fraction collector III. The mobile phase was run at 50 mL / min at room temperature using a gradient of buffer A (H₂O containing 0.1% TFA) and buffer B (ACN containing 0.1% TFA, gradient: 35% to 45% over 20 minutes). Fractions were analyzed, combined, and lyophilized. The final product was characterized by analytical UPLC-MS (A02). Analysis Method 1 (A01-A / B)

[0109] Peptide purity and mass were estimated by analytical HPLC-MS using an Agilent 1260 HPLC system equipped with a G6135 mass detector on a Kinetex C8 column (4.6 mm × 150 mm, 2.6 μm, Phenomenex). Analysis was performed at 40 °C by gradient elution with buffer A (H₂O containing 0.3% TFA) and buffer B (ACN containing 0.24% TFA). Details of the gradient and flow rate are summarized in the table below. Retention times and masses were recorded.

[0110] The peptide purity (relative peak area at 214 nm) is in the range of 80% to 99%, preferably greater than 95%.

[0111] Table 2-3

[0112] Table 2-4 Analysis Method 2 (A02-A / B)

[0113] Using a Waters Acquity HPLC system equipped with a 3100 mass detector, the parameters were analyzed on a Kinetex C8 column (Phenomenex). Peptide purity and mass were determined by analytical HPLC-MS on a 2.6 μm (4.6 mm × 150 mm) microscope. Analysis was performed at 40 °C using gradient elution with buffer A (H₂O containing 0.3% TFA) and buffer B (ACN containing 0.3% TFA). Details of the gradient and flow rate are summarized in the table below. Retention times and masses were recorded.

[0114] Table 2-5

[0115] Table 2-6 List of abbreviations ACN: Acetonitrile AHX: 6-Aminohexanoic acid Aib: Amino-isobutyric acid aMeF: α-Methyl-L-phenylalanine bh-Gln: β-iso-L-glutamine Boc: tert-butoxycarbonyl Chg: Cyclohexyl-glycine C18DA(tBu): 18-(tert-butoxy)-18-oxo-octadecanoic acid C20DA(tBu): 20-(tert-butoxy)-20-oxoeicosanoic acid D-Arg: D-arginine D-Asp: D-Aspartic Acid DCM: Dichloromethane DIC: Diisopropylcarbodiimide DIPEA: Diisopropylethylamine Dde: (4,4-Dimethyl-2,6-dioxocyclohexyl-1-ethylene)ethyl D-His: D-histidine D-Leu: D-Leucine DMF: N,N-dimethylformamide DODT: 3,6-dioxa-1,8-octanedithiol DPBS: Dulbecco's phosphate-buffered saline D-Tyr: D-Tyrosine eLys: N-ε-L-lysine Fmoc: 9H-fluorene-9-ylmethoxycarbonyl Fmoc-Ahx: 6-{[(9H-fluorene-9-ylmethoxy)carbonyl]amino}hexanoic acid Fmoc-OEG-OH: 2-[2-[2-(9H-fluoren-9-ylmethoxycarbonylamino)ethoxy]ethoxy]acetic acid Fmoc-OEG-OEG-OH: 2-[2-[2-[2-[2-[2-(9H-fluoren-9-ylmethoxycarbonylamino)ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetic acid gGlu: C-γ-L-glutamic acid hArg: homo-L-arginine HTRF: Homogeneous Time-of-Flight Fluorescence IBMX: 3-Isobutyl-1-methylxanthine Iva: 2-Amino-2-methylbutyric acid iVal: 3-Methylbutyroyl (isovaleryl) MRT: Mean Retention Time Mtt: 4-Methyltriphenylmethyl NMeR: N-methyl-L-arginine NMeQ: N-methyl-L-glutamine NMeY: N-methyl-L-tyrosine NMP: 1-Methylpyrrolidone-2-one Oxyma: Ethyl 2-cyano-2-(hydroxyimino)acetate OEG: 2-[2-(2-aminoethoxy)ethoxy]acetic acid Phg: S-phenylglycine Pbf: 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl Rt: Retention time RT: Room temperature Creatine: N-methyl-glycine SPPS: Solid-phase peptide synthesis tBu: tert-butyl Tle: L-tert-butylglycine Trt: Triphenylmethyl TRX: Tranexamic acid, trans-4-(aminomethyl)cyclohexane-1-carboxylic acid TES: Triethylsilane TFA: Trifluoroacetic acid

[0116] Synthesize the following compounds. All compounds were obtained as TFA salts:

[0117] Compound 2 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGIELRHFLNHLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:328) MW (calculated value): 6869.8 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 35.8 minutes; m / 3:m / 4:1718.1m / 5:

[0118] Compound 3 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGQRSYASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:329) MW (calculated value): 7106.0 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.7 minutes; m / 3: 2370.2m / 4: 1777.9m / 5:

[0119] Compound 4 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGAS-Aib-RHY-Aib-NR-Aib-TRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:330) MW (calculated value): 6736.5 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 34.0 minutes; m / 3:m / 4:1684.9m / 5:

[0120] Compound 5 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGAS-DLeu-R-DHis-YYNWLT-DArg-QR-DTyr-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2) (SEQ ID NO: 331) MW (calculated value): 6900.7 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 34.8 minutes; m / 3:m / 4:1726.0m / 5:

[0121] Compound 6 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGQRYYASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:332) MW (calculated value): 7182.1 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 8.0 minutes; m / 3: 2395.5m / 4: 1797.0m / 5:

[0122] Compound 7 Y-Aib-EGTFTSDYSI-Aib-LEEEAQ-Aib-AFVQWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys-eLys(1,2)(SEQ ID NO:333) MW (calculated value): 6900.7 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 35.9 minutes; m / 3:m / 4:1725.9m / 5:

[0123] Compound 8 Y-Aib-EGTFTSDYSI-Aib-LEEQAQ-Aib-AFVQWLIK(1,3)-GGPSSGQSLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:334) MW (calculated value): 6957.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.5 minutes; m / 3: 2320.3m / 4: 1740.7m / 5:

[0124] Compound 9 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSYVSIRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:335) MW (calculated value): 7034.9 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.7 minutes; m / 3: 2346.7m / 4: 1760.1m / 5:

[0125] Compound 10 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSPES-Aib-RHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eK (SEQ ID NO: 336) MW (calculated value): 6970.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 6.1 minutes; m / 3: 2324.9m / 4: 1743.9m / 5:

[0126] Compound 11 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPESPASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(SEQ ID NO:337) MW (calculated value): 6724.6 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.8 minutes; m / 3: 2242.2m / 4: 1681.8m / 5:

[0127] Compound 12 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPESPASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(SEQ ID NO:338) MW (calculated value): 6696.5 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.1 minutes; m / 3: 2232.7m / 4: 1674.9m / 5:

[0128] Compound 13 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGAS-Aib-RHYYNR-Aib-TRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:339) MW (calculated value): 6814.6 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 33.6 minutes; m / 3:m / 4:1704.5m / 5:

[0129] Compound 14 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPRYYASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:340) MW (calculated value): 7151.1 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.2 minutes; m / 3: 2385.6m / 4: 1789.2m / 5:

[0130] Compound 15 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSSYVSLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:341) MW (calculated value): 7033.9 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.6 minutes; m / 3: 2346.2m / 4: 1759.9m / 5:

[0131] Compound 16 Y-Aib-EGTFTSDYSI-Aib-LE-Aib-EAQ-Aib-KFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:342) MW (calculated value): 6915.7 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 38.2 minutes; m / 3:m / 4:1729.7m / 5:

[0132] Compound 17 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYLNL-Aib-TRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:343) MW (calculated value): 6749.6 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 35.1 minutes; m / 3:m / 4:1688.1m / 5:

[0133] Compound 18 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHY-Aib-NR-Aib-TRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:344) MW (calculated value): 6764.6 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 34.3 minutes; m / 3:m / 4:1691.9m / 5:

[0134] Compound 19 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSYYVSLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:345) MW (calculated value): 7110.0 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.6 minutes; m / 3: 2370.9m / 4: 1778.2m / 5:

[0135] Compound 20 Y-Aib-EGTFTSDYSI-Aib-LAAAAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:346) MW (calculated value): 6728.5 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 39.8 minutes; m / 3:m / 4:1682.9m / 5:

[0136] Compound 21 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLR-DHis-YYNWLT-DArg-QR-DTyr-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:347) MW (calculated value): 6900.7 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 35.0 minutes; m / 3:m / 4:1725.9m / 5:

[0137] Compound 22 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGQSSYASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:348) MW (calculated value): 7036.9 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.2 minutes; m / 3: 2347.4m / 4: 1760.7m / 5:

[0138] Compound 23 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPEYYASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:349) MW (calculated value): 6994.9 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.4 minutes; m / 3: 2331.8m / 4: 1749.4m / 5:

[0139] Compound 24 Y-Aib-EGTFTSDYSI-Aib-LE-Aib-KAQ-Aib-EFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:350) MW (calculated value): 6915.7 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 36.6 minutes; m / 3:m / 4:1723.2m / 5:

[0140] Compound 25 Y-Aib-EGTFTSDYSI-Aib-LEAAKQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:351) MW (calculated value): 6843.7 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 37.2 minutes; m / 3:m / 4:1711.7m / 5:

[0141] Compound 26 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGAS-Aib-RHYYNWLT-hArg-QR-DTyr-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:352) MW (calculated value): 6886.7 Da Synthesis and purification methods: S01; P01 LCMS: A01-B; Rt: 34.3 minutes; m / 3:m / 4:1722.4m / 5:

[0142] Compound 27 absolute Structure disclosed SEQ ID NO:353 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGVSIRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:353) MW (calculated value): 6928.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.3 minutes; m / 3: 2311.6m / 4: 1733.8m / 5:

[0143] Compound 28 absolute Structure disclosed SEQ ID NO:354 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVQWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(SEQ ID NO:354) MW (calculated value): 6829.6 Da Synthesis and purification methods: S01; P02 LCMS: A01-A; Rt: 13.3 minutes; m / 3:m / 4:1708.0m / 5:

[0144] Compound 29 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPESGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(SEQ ID NO:355) MW (calculated value): 6684.5 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.7 minutes; m / 3: 2228.8m / 4: 1672.0m / 5:

[0145] Compound 30 Y-Aib-EGTFTSDYSI-Aib-LEEQAQ-Aib-AFVQWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:356) MW (calculated value): 6900.7 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 36.2 minutes; m / 3:m / 4:1725.9m / 5:

[0146] Compound 31 Y-Aib-EGTFTSDYSI-Aib-LEEQAQ-Aib-AFVEWLIK(1,3)-GGPSSGQSLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:357) MW (calculated value): 6958.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.6 minutes; m / 3: 2320.8m / 4: 1740.7m / 5:

[0147] Compound 32 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPESGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:358) MW (calculated value): 6974.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.7 minutes; m / 3: 2325.7m / 4: 1744.4m / 5:

[0148] Compound 33 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSAVSLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:359) MW (calculated value): 6942.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.5 minutes; m / 3: 2316.3m / 4: 1737.1m / 5:

[0149] Compound 34 Y-Aib-EGTFTSDYSI-Aib-LEEQAQ-Aib-AFVQWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:360) MW (calculated value): 6771.6 Da Synthesis and purification methods: S01; P01 LCMS: A01-B; Rt: 36.4 minutes; m / 3:m / 4:1693.6m / 5:

[0150] Compound 35 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSSGESLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eK(SEQ ID NO:361) MW (calculated value): 6957.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 6.2 minutes; m / 3: 2320.5m / 4: 1740.4m / 5:

[0151] Compound 36 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVQWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:362) MW (calculated value): 6990.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.6 minutes; m / 3: 2331.2m / 4: 1748.3m / 5:

[0152] Compound 37 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPESGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:363) MW (calculated value): 6941.8 Da Synthesis and purification methods: S01; L20 LCMS: A01-A; Rt: 7.2 minutes; m / 3: 2314.9m / 4: 1736.3m / 5:

[0153] Compound 38 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGVS-Aib-RHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:364) MW (calculated value): 6900.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 6.1 minutes; m / 3: 2301.4m / 4: 1726.2m / 5:

[0154] Compound 39 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGAS-Aib-RHYYNWLTRQ-NMeR-Y-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:365) MW (calculated value): 6886.7 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 34.4 minutes; m / 3:m / 4:1722.3m / 5:

[0155] Compound 40 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSYVSLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:366) MW (calculated value): 7034.9 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.5 minutes; m / 3: 2345.5m / 4: 1759.4m / 5:

[0156] Compound 41 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSPQSLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:367) MW (calculated value): 6997.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 10.4 minutes; m / 3: 2333.6m / 4: 1750.6m / 5:

[0157] Compound 42 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEYVSIRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:368) MW (calculated value): 7076.9 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.7 minutes; m / 3: 2360.0m / 4: 1770.6m / 5:

[0158] Compound 43 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVQWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:369) MW (calculated value): 7086.9 Da Synthesis and purification methods: S01; P02 LCMS: A01-A; Rt: 12.3 minutes; m / 3:m / 4:1772.6m / 5:

[0159] Compound 44 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGQS-Aib-RHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:370) MW (calculated value): 6929.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 6.0 minutes; m / 3: 2311.2m / 4: 1733.2m / 5:

[0160] Compound 45 Y-Aib-EGTFTSDYSI-Aib-LEEQAQ-Aib-AFVQWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-OEG-eLys(1,2)(SEQ ID NO:371) MW (calculated value): 6916.7 Da Synthesis and purification methods: S01; P01 LCMS: A01-B; Rt: 36.2 minutes; m / 3:m / 4:1729.8m / 5:

[0161] Compound 46 Y-Aib-EGTFTSDYSI-Aib-LEKEAQ-Aib-KFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:372) MW (calculated value): 6958.8 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 34.6 minutes; m / 3:m / 4:1740.5m / 5:

[0162] Compound 47 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSSGVSLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:373) MW (calculated value): 6927.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 10.7 minutes; m / 3: 2310.9m / 4: 1733.2m / 5:

[0163] Compound 48 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLI- K(1,3)-GGPSEPQSIRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:374) MW (calculated value): 7039.9 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 10.1 minutes; m / 3: 2347.9m / 4: 1761.1m / 5:

[0164] Compound 49 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGES-Aib-RHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:375) MW (calculated value): 6930.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 6.1 minutes; m / 3: 2311.3m / 4: 1733.7m / 5:

[0165] Compound 50 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSYESLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:376) MW (calculated value): 7064.9 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.4 minutes; m / 3: 2356.2m / 4: 1767.5m / 5:

[0166] Compound 51 Y-Aib-EGTFTSDYSI-Aib-LEKQAE-Aib-AFVQWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:377) MW (calculated value): 6872.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 5.7 minutes; m / 3: 2291.8m / 4: 1719.6m / 5:

[0167] Compound 52 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPESGASLRHYYNWLTRQRY-NH2.C18DA-EEEE-OEG-OEG(1,2)(SEQ IDNO:378) MW (calculated value): 6817.6 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 10.3 minutes; m / 3: 2273.8m / 4: 1705.5m / 5:

[0168] Compound 53 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPESGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(SEQ ID NO:379) MW (calculated value): 6656.4 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.9 minutes; m / 3: 2219.5m / 4: 1664.9m / 5:

[0169] Compound 54 Y-Aib-EGTFTSDYSI-Aib-LEKQAE-Aib-AFVQWLIK(1,3)-GGPSEPASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:380) MW (calculated value): 6696.5 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 5.9 minutes; m / 3: 2232.8m / 4: 1675.3m / 5:

[0170] Compound 55 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPESGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:381) MW (calculated value): 6946.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.1 minutes; m / 3: 2316.4m / 4: 1737.6m / 5:

[0171] Compound 56 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVEWLIK(1,3)-GGPSSPASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:382) MW (calculated value): 6874.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.2 minutes; m / 3: 2292.4m / 4: 1719.8m / 5:

[0172] Compound 57 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPEEPASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:383) MW (calculated value): 6899.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.1 minutes; m / 3: 2300.8m / 4: 1725.9m / 5:

[0173] Compound 58 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPESGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:384) MW (calculated value): 6817.6 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 10.0 minutes; m / 3: 2273.4m / 4: 1705.5m / 5:

[0174] Compound 59 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSYYASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:385) MW (calculated value): 6952.9 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: minutes; m / 3: 2318.5m / 4: 1738.9m / 5:

[0175] Compound 60 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPESGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:386) MW (calculated value): 6784.6 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 9.2 minutes; m / 3: 2262.5m / 4: 1697.3m / 5:

[0176] Compound 61 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPESGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:387) MW (calculated value): 6812.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.4 minutes; m / 3: 2271.8m / 4: 1704.2m / 5:

[0177] Compound 62 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPRYYASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:388) MW (calculated value): 7152.1 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 35.2 minutes; m / 3:m / 4:1788.8m / 5:

[0178] Compound 63 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPESGASLRHYYNWLTRQRY-NH2.C18DA-EEEEE-eLys(1,2) (SEQ ID NO 389 and 635 respectively) MW (calculated value): 6784.6 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 9.6 minutes; m / 3: 2262.4m / 4: 1697.1m / 5:

[0179] Compound 64 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPESPASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:390) MW (calculated value): 6858.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.1 minutes; m / 3: 2286.9m / 4: 1715.2m / 5:

[0180] Compound 65 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGGSEYVSLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(SEQ ID NO:391) MW (calculated value): 6908.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.4 minutes; m / 3: 2345.9m / 4: 1760.1m / 5:

[0181] Compound 66 Y-Aib-EGTFTSDYSI-Aib-LEEEAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:392) MW (calculated value): 6902.7 Da Synthesis and purification methods: S01; P02 LCMS: A01-A; Rt: 14.1 minutes; m / 3:m / 4:1726.5m / 5:

[0182] Compound 67 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPEEPASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:393) MW (calculated value): 6894.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.1 minutes; m / 3: 2298.9m / 4: 1724.2m / 5:

[0183] Compound 68 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNR-Aib-TRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:394) MW (calculated value): 6842.7 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 34.3 minutes; m / 3:m / 4:1711.4m / 5:

[0184] Compound 69 Y-Aib-EGTFTSDYSI-Aib-LEKEKQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:395) MW (calculated value): 6958.8 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 33.8 minutes; m / 3:m / 4:1740.4m / 5:

[0185] Compound 70 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPESPASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:396) MW (calculated value): 6853.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.3 minutes; m / 3: 2284.9m / 4: 1714.4m / 5:

[0186] Compound 71 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLT-hArg-QR-DTyr-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:397) MW (calculated value): 6914.8 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 34.7 minutes; m / 3:m / 4:1729.4m / 5:

[0187] Compound 72 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGADLRHYLNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:398) MW (calculated value): 6878.7 Da Synthesis and purification methods: S01; P01 LCMS: A01-B; Rt: 36.2 minutes; m / 3:m / 4:1720.4m / 5:

[0188] Compound 73 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSPESLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:399) MW (calculated value): 6998.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 6.3 minutes; m / 3: 2334.1m / 4: 1751.0m / 5:

[0189] Compound 74 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGAS-Aib-RHYYNWLTRQR-DTyr-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:400) MW (calculated value): 6872.7 Da Synthesis and purification methods: S01; P01 LCMS: A01-B; Rt: 34.3 minutes; m / 3:m / 4:1718.8m / 5:

[0190] Compound 75 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSYYVSLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:401) MW (calculated value): 6981.9 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.6 minutes; m / 3: 2328.1m / 4: 1746.1m / 5:

[0191] Compound 76 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGAS-Aib-RHY-Aib-NWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:402) MW (calculated value): 6794.6 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 34.9 minutes; m / 3:m / 4:1699.4m / 5:

[0192] Compound 77 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPEEPASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:403) MW (calculated value): 6927.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.8 minutes; m / 3: 2310.2m / 4: 1733.1m / 5:

[0193] Compound 78 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEYVSLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:404) MW (calculated value): 7076.0 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.4 minutes; m / 3: 2358.9m / 4: 1769.7m / 5:

[0194] Compound 79 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLI- K(1,3)-GGPSSGASLRHYYNL-Aib-TRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:405) MW (calculated value): 6799.6 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 34.9 minutes; m / 3:m / 4:1700.6m / 5:

[0195] Compound 80 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSYYVSLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:406) MW (calculated value): 7111.0 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 9.7 minutes; m / 3: 2370.9m / 4: 1778.5m / 5:

[0196] Compound 81 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVEWLIK(1,3)-GGPESGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:407) MW (calculated value): 6747.5 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 6.1 minutes; m / 3: 2250.8m / 4: 1688.3m / 5:

[0197] Compound 82 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPESPASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:408) MW (calculated value): 6886.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 11.4 minutes; m / 3: 2296.2m / 4: 1722.4m / 5:

[0198] Compound 83 absolute Structure disclosed SEQ ID NO:409 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQ-NMeR-Y-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:409) MW (calculated value): 6914.8 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 35.0 minutes; m / 3:m / 4:1729.4m / 5:

[0199] Compound 84 absolute Structure disclosed SEQ ID NO:410 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGQSLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:410) MW (calculated value): 6957.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.1 minutes; m / 3: 2320.5m / 4: 1740.5m / 5:

[0200] Compound 85 absolute Structure disclosed SEQ ID NO:411 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTR-NMeQ-RY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:411) MW (calculated value): 6914.8 Da Synthesis and purification methods: S01; P02 LCMS: A01-A; Rt: 12.7 minutes; m / 3:m / 4:m / 5:1383.8

[0201] Compound 86 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYLNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:412) MW (calculated value): 6850.7 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 35.9 minutes; m / 3:m / 4:1713.5m / 5:

[0202] Compound 87 Y-Aib-DGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:413) MW (calculated value): 6886.7 Da Synthesis and purification methods: S01; P01 LCMS: A01-B; Rt: 35.4 minutes; m / 3:m / 4:1722.4m / 5:

[0203] Compound 88 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:414) MW (calculated value): 7087.9 Da Synthesis and purification methods: S01; P02 LCMS: A01-A; Rt: 12.4 minutes; m / 3:m / 4:1772.7m / 5:

[0204] Compound 89 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPEEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:415) MW (calculated value): 6983.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 10.6 minutes; m / 3: 2328.9m / 4: 1746.9m / 5:

[0205] Compound 90 Y-Aib-EGTFTSDYSI-Aib-LEDQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:416) MW (calculated value): 6887.6 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 36.3 minutes; m / 3:m / 4:1722.7m / 5:

[0206] Compound 91 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGATLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:417) MW (calculated value): 6914.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.4 minutes; m / 3: 2306.6m / 4: 1730.1m / 5:

[0207] Compound 92 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:418) MW (calculated value): 7028.9 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.3 minutes; m / 3: 2343.6m / 4: 1758.1m / 5:

[0208] Compound 93 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEYESLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:419) MW (calculated value): 7106.9 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 10.8 minutes; m / 3: 2370.5m / 4: 1777.8m / 5:

[0209] Compound 94 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGISLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:420) MW (calculated value): 6942.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 11.1 minutes; m / 3: 2315.9m / 4: 1737.1m / 5:

[0210] Compound 95 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSPASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:421) MW (calculated value): 6940.8 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 34.8 minutes; m / 3:m / 4:1735.9m / 5:

[0211] Compound 96 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGVSLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:422) MW (calculated value): 6928.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.3 minutes; m / 3: 2310.1m / 4: 1732.7m / 5:

[0212] Compound 97 Y-Aib-EGTFTSDYSI-Aib-LEEQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:423) MW (calculated value): 6643.4 Da Synthesis and purification methods: S01; P01 LCMS: A01-B; Rt: 36.9 minutes; m / 3:m / 4:1661.5m / 5:

[0213] Compound 98 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSAASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:424) MW (calculated value): 6914.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 11.0 minutes; m / 3: 2306.3m / 4: 1730.1m / 5:

[0214] Compound 99 Y-Aib-EGTFTSDYSI-Aib-LEGQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:425) MW (calculated value): 6829.6 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 36.8 minutes; m / 3:m / 4:1708.1m / 5:

[0215] Compound 100 Y-Aib-EGTFTSDYSI-Aib-LEEQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG-eLys(1,2)(SEQ ID NO:426) MW (calculated value): 6933.8 Da Synthesis and purification methods: S01; P01 LCMS: A01-B; Rt: 36.5 minutes; m / 3:m / 4:1734.0m / 5:

[0216] Compound 101 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEPASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:427) MW (calculated value): 6981.8 Da Synthesis and purification methods: S01; L20 LCMS: A01-B; Rt: 7.4 minutes; m / 3: 2328.2m / 4: 1746.3m / 5:

[0217] Compound 102 Y-Aib-EGTFTSDYSI-Aib-LEAQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:428) MW (calculated value): 6843.6 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 37.5 minutes; m / 3:m / 4:m / 5:1369.4

[0218] Compound 103 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGAS-Tle-RHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:429) MW (calculated value): 6900.7 Da Synthesis and purification methods: S01; P01 LCMS: A01-B; Rt: 34.9 minutes; m / 3:m / 4:m / 5:1380.9

[0219] Compound 104 Y-Aib-EGTFTSDYSILLEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:430) MW (calculated value): 6928.8 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 35.4 minutes; m / 3:m / 4:1732.9m / 5:

[0220] Compound 105 Y-Aib-EGTFTSDYSI-Aib-LEEQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys-eLys(1,2)(SEQ ID NO:431) MW (calculated value): 6900.7 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 35.9 minutes; m / 3:m / 4:1725.9m / 5:

[0221] Compound 106 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYINWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:432) MW (calculated value): 6850.7 Da Synthesis and purification methods: S01; P01 LCMS: A01-B; Rt: 35.9 minutes; m / 3:m / 4:m / 5:1370.8

[0222] Compound 107 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGSLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:433) MW (calculated value): 6942.8 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 35.7 minutes; m / 3:m / 4:1736.4m / 5:

[0223] Compound 108 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPEEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:434) MW (calculated value): 6854.7 Da Synthesis and purification methods: S01; P02 LCMS: A01-A; Rt: 12.9 minutes; m / 3:m / 4:1714.4m / 5:

[0224] Compound 109 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLLK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:435) MW (calculated value): 6900.7 Da Synthesis and purification methods: S01; P01 LCMS: A01-B; Rt: 35.2 minutes; m / 3:m / 4:1725.9m / 5:

[0225] Compound 110 Y-Aib-EGTFTSDYSI-Aib-LEEQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-OEG-eLys(1,2)(SEQ ID NO:436) MW (calculated value): 6917.7 Da Synthesis and purification methods: S01; P01 LCMS: A01-B; Rt: 36.5 minutes; m / 3:m / 4:1730.1m / 5:

[0226] Compound 111 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEPASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:437) MW (calculated value): 7014.9 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 9.8 minutes; m / 3: 2339.5m / 4: 1754.9m / 5:

[0227] Compound 112 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:438) MW (calculated value): 6932.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.8 minutes; m / 3: 2312.2m / 4: 1734.1m / 5:

[0228] Compound 113 Y-Aib-EGTFTSDLSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:439) MW (calculated value): 6891.8 Da Synthesis and purification methods: S01; P02 LCMS: A01-A; Rt: 13.7 minutes; m / 3:m / 4:1723.7m / 5:

[0229] Compound 114 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGVSLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:440) MW (calculated value): 6969.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.3 minutes; m / 3: 2323.6m / 4: 1743.1m / 5:

[0230] Compound 115 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRYYNWLTR-NMeQ-RY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:441) MW (calculated value): 6955.8 Da Synthesis and purification methods: S01; P02 LCMS: A01-A; Rt: 12.8 minutes; m / 3:m / 4:1739.6m / 5:

[0231] Compound 116 Y-Aib-EGTFTSDYSI-Aib-LEEQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:442) MW (calculated value): 6901.7 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 36.7 minutes; m / 3:m / 4:1726.2m / 5:

[0232] Compound 117 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASVRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:443) MW (calculated value): 6886.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.2 minutes; m / 3: 2297.3m / 4: 1722.9m / 5:

[0233] Compound 118 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGAS-Aib-RHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:444) MW (calculated value): 6872.7 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 34.5 minutes; m / 3:m / 4:1718.9m / 5:

[0234] Compound 119 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLR-Tle-YYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:445) MW (calculated value): 6876.7 Da Synthesis and purification methods: S01; P01 LCMS: A01-B; Rt: 36.0 minutes; m / 3:m / 4:m / 5:1376.1

[0235] Compound 120 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSPASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:446) MW (calculated value): 6973.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.9 minutes; m / 3: 2325.1m / 4: 1744.6m / 5:

[0236] Compound 121 Y-Aib-EGTFTSDYSI-Aib-LESQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:447) MW (calculated value): 6859.6 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 39.8 minutes; m / 3:m / 4:1715.6m / 5:

[0237] Compound 122 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEPESLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:448) MW (calculated value): 7040.9 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 9.3 minutes; m / 3: 2347.9m / 4: 1761.4m / 5:

[0238] Compound 123 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGQSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:449) MW (calculated value): 6931.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 10.9 minutes; m / 3: 2312.0m / 4: 1732.4m / 5:

[0239] Compound 124 Y-Aib-EGTFTSDYSI-Aib-LEQQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:450) MW (calculated value): 6900.7 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 36.0 minutes; m / 3:m / 4:m / 5:1381.0

[0240] Compound 125 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQ-NMeR-Y-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:451) MW (calculated value): 6955.8 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 35.5 minutes; m / 3:m / 4:1739.8m / 5:

[0241] Compound 126 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSYASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:452) MW (calculated value): 7006.9 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 34.7 minutes; m / 3:m / 4:1752.5m / 5:

[0242] Compound 127 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGESLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:453) MW (calculated value): 6958.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.3 minutes; m / 3: 2320.8m / 4: 1740.8m / 5:

[0243] Compound 128 Y-Aib-EGTFTSDYSI-Aib-LDKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:454) MW (calculated value): 6886.7 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 34.9 minutes; m / 3:m / 4:1722.3m / 5:

[0244] Compound 129 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASL-Aib-HYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:455) MW (calculated value): 6829.6 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 36.0 minutes; m / 3:m / 4:1708.2m / 5:

[0245] Compound 130 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFIEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:456) MW (calculated value): 6914.8 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 35.4 minutes; m / 3:m / 4:1729.3m / 5:

[0246] Compound 131 Y-Aib-EGTFTSDYSI-Aib-LERQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:457) MW (calculated value): 6928.7 Da Synthesis and purification methods: S01; P01 LCMS: A01-B; Rt: 35.4 minutes; m / 3:m / 4:m / 5:1386.5

[0247] Compound 132 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASIRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:458) MW (calculated value): 6900.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.3 minutes; m / 3: 2301.5m / 4: 1726.6m / 5:

[0248] Compound 133 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHY-Tle-NWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:459) MW (calculated value): 6851.7 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 36.0 minutes; m / 3:m / 4:1713.4m / 5:

[0249] Compound 134 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGQSIRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:460) MW (calculated value): 6999.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.1 minutes; m / 3: 2334.4m / 4: 1750.9m / 5:

[0250] Compound 135 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEYLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:461) MW (calculated value): 6877.7 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 34.2 minutes; m / 3:m / 4:1720.1m / 5:

[0251] Compound 136 Y-Aib-EGTFTSDYSI-Aib-LEKAAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:462) MW (calculated value): 6843.7 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 36.1 minutes; m / 3:m / 4:1711.7m / 5:

[0252] Compound 137 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNW-Tle-TRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:463) MW (calculated value): 6900.7 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 35.4 minutes; m / 3:m / 4:1725.9m / 5:

[0253] Compound 138 Y-Aib-EGTFTSDYSI-Aib-LEKQAE-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:464) MW (calculated value): 6785.6 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.0 minutes; m / 3: 2262.8m / 4: 1697.6m / 5:

[0254] Compound 139 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-AHX(1,2)(SEQ ID NO:465) MW (calculated value): 6856.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.1 minutes; m / 3: 2286.8m / 4: 1713.0m / 5:

[0255] Compound 140 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSPASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:466) MW (calculated value): 6945.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.3 minutes; m / 3: 2316.6m / 4: 1737.6m / 5:

[0256] Compound 141 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(SEQ ID NO:467) MW (calculated value): 6714.5 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 9.8 minutes; m / 3: 2239.3m / 4: 1679.7m / 5:

[0257] Compound 142 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEPASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:468) MW (calculated value): 6986.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.0 minutes; m / 3: 2329.8m / 4: 1747.6m / 5:

[0258] Compound 143 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPEEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:469) MW (calculated value): 6826.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 6.8 minutes; m / 3: 2276.4m / 4: 1707.7m / 5:

[0259] Compound 144 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPEEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:470) MW (calculated value): 6730.6 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 10.2 minutes; m / 3: 2244.5m / 4: 1683.6m / 5:

[0260] Compound 145 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:471) MW (calculated value): 6834.6 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 9.8 minutes; m / 3: 2279.3m / 4: 1709.6m / 5:

[0261] Compound 146 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPEEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:472) MW (calculated value): 6859.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 10.0 minutes; m / 3: 2287.7m / 4: 1716.0m / 5:

[0262] Compound 147 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(SEQ ID NO:473) MW (calculated value): 6743.5 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.1 minutes; m / 3: 2248.8m / 4: 1686.9m / 5:

[0263] Compound 148 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEPASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:474) MW (calculated value): 6824.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 6.8 minutes; m / 3: 2275.9m / 4: 1707.1m / 5:

[0264] Compound 149 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPEEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:475) MW (calculated value): 6955.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 9.2 minutes; m / 3: 2319.9m / 4: 1740.0m / 5:

[0265] Compound 150 Y-Aib-EGTFTSDYSI-Aib-LEKQAE-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:476) MW (calculated value): 6777.6 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 6.2 minutes; m / 3: 2260.5m / 4: 1695.4m / 5:

[0266] Compound 151 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVQWLIK(1,3)-GGPSEGASLRYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(SEQ ID NO:477) MW (calculated value): 6843.6 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 6.9 minutes; m / 3: 2281.9m / 4: 1711.8m / 5:

[0267] Compound 152 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPESGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:478) MW (calculated value): 6785.6 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 6.9 minutes; m / 3: 2263.3m / 4: 1697.4m / 5:

[0268] Compound 153 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:479) MW (calculated value): 6971.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 7.5 minutes; m / 3: 2325.0m / 4: 1743.9m / 5:

[0269] Compound 154 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:480) MW (calculated value): 6842.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 8.9 minutes; m / 3: 2282.1m / 4: 1711.6m / 5:

[0270] Compound 155 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPEEGASLRHYYNWLTRQRY-NH2.C18DA-EEEEE-eLys(1,2) (SEQ ID NO 481 and 635 respectively) MW (calculated value): 6826.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 9.6 minutes; m / 3: 2276.8m / 4: 1707.6m / 5:

[0271] Compound 156 Y-Aib-EGTFTSDYSI-Aib-LEKQAE-Aib-AFVQWLIK(1,3)-GGPSEGASLRYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:482) MW (calculated value): 6818.6 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.3 minutes; m / 3: 2273.6m / 4: 1705.4m / 5:

[0272] Compound 157 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-EEE-OEG-OEG(1,2)(SEQ IDNO:483) MW (calculated value): 6688.5 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.1 minutes; m / 3: 2249.8m / 4: 1687.8m / 5: 6746.5

[0273] Compound 158 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSPASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:484) MW (calculated value): 6816.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.4 minutes; m / 3: 2273.2m / 4: 1705.2m / 5:

[0274] Compound 159 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:485) MW (calculated value): 6801.6 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 6.6 minutes; m / 3: 2268.2m / 4: 1701.4m / 5:

[0275] Compound 160 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:486) MW (calculated value): 6746.6 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 9.8 minutes; m / 3: 2249.8m / 4: 1687.6m / 5:

[0276] Compound 161 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPEEPASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:487) MW (calculated value): 6900.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.2 minutes; m / 3: 2301.2m / 4: 1726.2m / 5:

[0277] Compound 162 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPEEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-AHX(1,2)(SEQ ID NO:488) MW (calculated value): 6811.6 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 8.8 minutes; m / 3: 2271.5m / 4: 1704.1m / 5:

[0278] Compound 163 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPESGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:489) MW (calculated value): 6818.6 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.2 minutes; m / 3: 2273.8m / 4: 1705.6m / 5:

[0279] Compound 164 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-AHX(1,2)(SEQ ID NO:490) MW (calculated value): 6956.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 8.2 minutes; m / 3: 2319.5m / 4: 1740.3m / 5:

[0280] Compound 165 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEPASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:491) MW (calculated value): 6885.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 10.8 minutes; m / 3: 2295.9m / 4: 1722.1m / 5:

[0281] Compound 166 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPESGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:492) MW (calculated value): 6689.5 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 6.2 minutes; m / 3: 2231.0m / 4: 1673.6m / 5:

[0282] Compound 167 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:493) MW (calculated value): 6904.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.1 minutes; m / 3: 2302.7m / 4: 1727.3m / 5:

[0283] Compound 168 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPRSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:494) MW (calculated value): 6969.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 9.9 minutes; m / 3: 2324.9m / 4: 1743.5m / 5:

[0284] Compound 169 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEPASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:495) MW (calculated value): 6853.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.2 minutes; m / 3: 2285.1m / 4: 1714.0m / 5:

[0285] Compound 170 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:496) MW (calculated value): 6871.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 6.7 minutes; m / 3: 2291.8m / 4: 1719.1m / 5:

[0286] Compound 171 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:497) MW (calculated value): 6705.5 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 10.1 minutes; m / 3: 2236.5m / 4: 1677.6m / 5:

[0287] Compound 172 Y-Aib-EGTFTSDLSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:498) MW (calculated value): 6850.7 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 36.4 minutes; m / 3:m / 4:1713.4m / 5:

[0288] Compound 173 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEPASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:499) MW (calculated value): 6857.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 10.0 minutes; m / 3: 2286.9m / 4: 1715.5m / 5:

[0289] Compound 174 Y-Aib-EGTFTSDYSI-Aib-LEKQAE-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:500) MW (calculated value): 6656.5 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 5.9 minutes; m / 3: 2220.1m / 4: 1665.7m / 5:

[0290] Compound 175 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSPASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:501) MW (calculated value): 6844.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 8.0 minutes; m / 3: 2282.2m / 4: 1712.2m / 5:

[0291] Compound 176 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-EEEEE(1,2) (SEQ ID NO 502 and 636 respectively) MW (calculated value): 6714.5 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.1 minutes; m / 3: 2239.9m / 4: 1679.8m / 5:

[0292] Compound 177 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPEEGASLRHYYNWLTRQRY-NH2.C18DA-EEEE-OEG-OEG(1,2) (SEQ ID NO 503 and 634 respectively) MW (calculated value): 6859.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 10.3 minutes; m / 3: 2287.1m / 4: 1716.0m / 5:

[0293] Compound 178 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSPASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(SEQ ID NO:504) MW (calculated value): 6683.5 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.7 minutes; m / 3: 2228.3m / 4: 1671.5m / 5:

[0294] Compound 179 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-EEEEEE(1,2) (SEQ ID NO 505 and 637 respectively) MW (calculated value): 6843.6 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 10.0 minutes; m / 3: 2282.2m / 4: 1711.8m / 5:

[0295] Compound 180 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSPASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(SEQ ID NO:506) MW (calculated value): 6655.5 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.1 minutes; m / 3: 2218.6m / 4: 1664.3m / 5:

[0296] Compound 181 Y-Aib-EGTFTSDYSI-Aib-LEEQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:507) MW (calculated value): 6772.6 Da Synthesis and purification methods: S01; P01 LCMS: A01-B; Rt: 36.8 minutes; m / 3:m / 4:1693.8m / 5:

[0297] Compound 182 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLR-Aib-YYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:508) MW (calculated value): 6848.7 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 36.1 minutes; m / 3:m / 4:1712.9m / 5:

[0298] Compound 183 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSYASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:509) MW (calculated value): 6877.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.4 minutes; m / 3: 2293.2m / 4: 1720.3m / 5:

[0299] Compound 184 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHY-Aib-NWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:510) MW (calculated value): 6822.7 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 35.2 minutes; m / 3:m / 4:1706.5m / 5:

[0300] Compound 185 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVQWLIK(1,3)-GGPSEGASLRYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(SEQ ID NO:511) MW (calculated value): 6871.6 Da Synthesis and purification methods: S01; P02 LCMS: A01-A; Rt: 13.3 minutes; m / 3:m / 4:1718.7m / 5:

[0301] Compound 186 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRYYNWLTR-bHGln-RY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:512) MW (calculated value): 6955.8 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 35.0 minutes; m / 3:m / 4:1739.6m / 5:

[0302] Compound 187 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:513) MW (calculated value): 6930.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 8.6 minutes; m / 3: 2311.2m / 4: 1733.4m / 5:

[0303] Compound 188 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPEEGASLRHYYNWLTRQRY-NH2.C18DA-EEE-OEG-OEG(1,2)(SEQ IDNO:514) MW (calculated value): 6730.6 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 10.5 minutes; m / 3: 2243.9m / 4: 1683.6m / 5:

[0304] Compound 189 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEYASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:515) MW (calculated value): 6918.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.3 minutes; m / 3: 2306.7m / 4: 1730.5m / 5:

[0305] Compound 190 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNW-DArg-TRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:516) MW (calculated value): 6943.8 Da Synthesis and purification methods: S01; P01 LCMS: A01-B; Rt: 34.1 minutes; m / 3:m / 4:1736.6m / 5:

[0306] Compound 191 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQR-Tle-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:517) MW (calculated value): 6850.7 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 35.4 minutes; m / 3:m / 4:1713.4m / 5:

[0307] Compound 192 Y-Aib-EGTFTSDYSI-Aib-LE-KAc-QAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:518) MW (calculated value): 6942.8 Da Synthesis and purification methods: S01; P01 LCMS: A01-B; Rt: 37.0 minutes; m / 3:m / 4:1736.3m / 5:

[0308] Compound 193 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPEEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:519) MW (calculated value): 6887.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 6.6 minutes; m / 3: 2297.1m / 4: 1723.5m / 5:

[0309] Compound 194 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu(1,2)(SEQ ID NO:520) MW (calculated value): 6613.4 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.7 minutes; m / 3: 2205.7m / 4: 1654.4m / 5:

[0310] Compound 195 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNLLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:521) MW (calculated value): 6827.7 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 35.0 minutes; m / 3:m / 4:1707.7m / 5:

[0311] Compound 196 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPEEGASLRHYYNWLTRQRY-NH2.C18DA-EEEEEE-eLys(1,2) (SEQ ID NO 522 and 643 respectively) MW (calculated value): 6955.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 9.4 minutes; m / 3: 2319.1m / 4: 1739.8m / 5:

[0312] Compound 197 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGALLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:523) MW (calculated value): 6927.8 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 36.7 minutes; m / 3:m / 4:1732.4m / 5:

[0313] Compound 198 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(SEQ ID NO:524) MW (calculated value): 6830.6 Da Synthesis and purification methods: S01; P02 LCMS: A01-A; Rt: 13.4 minutes; m / 3:m / 4:1708.3m / 5:

[0314] Compound 199 Y-Aib-EGTFTSDYSI-Aib-LE-Aib-QAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:525) MW (calculated value): 6857.7 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 38.5 minutes; m / 3:m / 4:1715.2m / 5:

[0315] Compound 200 Y-Aib-EGTFTSDYSI-Aib-LEKQAE-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:526) MW (calculated value): 6813.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 6.5 minutes; m / 3: 2272.0m / 4: 1704.7m / 5:

[0316] Compound 201 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:527) MW (calculated value): 6963.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 6.9 minutes; m / 3: 2322.1m / 4: 1742.1m / 5:

[0317] Compound 202 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu(1,2)(SEQ ID NO:528) MW (calculated value): 6585.4 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 9.9 minutes; m / 3: 2196.5m / 4: 1647.5m / 5:

[0318] Compound 203 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSYYASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:529) MW (calculated value): 6953.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.5 minutes; m / 3: 2318.6m / 4: 1739.0m / 5:

[0319] Compound 204 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNW-DAsp-TRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:530) MW (calculated value): 6902.7 Da Synthesis and purification methods: S01; P01 LCMS: A01-B; Rt: 34.6 minutes; m / 3:m / 4:1726.4m / 5:

[0320] Compound 205 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:531) MW (calculated value): 6862.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.8 minutes; m / 3: 2288.4m / 4: 1716.7m / 5:

[0321] Compound 206 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPEEPASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:532) MW (calculated value): 6928.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.9 minutes; m / 3: 2310.6m / 4: 1733.1m / 5:

[0322] Compound 207 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:533) MW (calculated value): 7128.9 Da Synthesis and purification methods: S01; P02 LCMS: A01-A; Rt: 12.4 minutes; m / 3:m / 4:1783.0m / 5:

[0323] Compound 208 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTR-bHGln-RY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:534) MW (calculated value): 6914.8 Da Synthesis and purification methods: S01; P01 LCMS: A01-B; Rt: 35.1 minutes; m / 3:m / 4:1729.5m / 5:

[0324] Compound 209 Y-Aib-EGTFTSDYSI-Aib-LELQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:535) MW (calculated value): 6885.7 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 39.6 minutes; m / 3:m / 4:1722.1m / 5:

[0325] Compound 210 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLLHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:536) MW (calculated value): 6857.7 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 37.1 minutes; m / 3:m / 4:1715.2m / 5:

[0326] Compound 211 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-DAsp-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:537) MW (calculated value): 6930.7 Da Synthesis and purification methods: S01; P01 LCMS: A01-B; Rt: 35.1 minutes; m / 3:m / 4:1733.4m / 5:

[0327] Compound 212 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLI- K(1,3)-GGPSSGVSLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(SEQ ID NO:538) MW (calculated value): 6800.6 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 11.7 minutes; m / 3: 2268.3m / 4: 1701.3m / 5:

[0328] Compound 213 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYY-Aib-WLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:539) MW (calculated value): 6871.7 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 36.5 minutes; m / 3:m / 4:1718.6m / 5:

[0329] Compound 214 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQR-DTyr-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:540) MW (calculated value): 6900.7 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 34.8 minutes; m / 3:m / 4:1725.8m / 5:

[0330] Compound 215 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:541) MW (calculated value): 6958.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 6.1 minutes; m / 3: 2320.6m / 4: 1740.7m / 5:

[0331] Compound 216 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-DArg-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:542) MW (calculated value): 6971.8 Da Synthesis and purification methods: S01; P01 LCMS: A01-B; Rt: 34.0 minutes; m / 3:m / 4:1743.7m / 5:

[0332] Compound 217 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEYVSLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:543) MW (calculated value): 7076.9 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.5 minutes; m / 3: 2359.6m / 4: 1769.8m / 5:

[0333] Compound 218 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYN-Aib-LTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:544) MW (calculated value): 6799.6 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 35.0 minutes; m / 3:m / 4:1700.6m / 5:

[0334] Compound 219 Y-Aib-EGTFTSDYSI-Aib-LEKQAE-Aib-AFVQWLIK(1,3)-GGPSEGASLRYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:545) MW (calculated value): 6846.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 11.7 minutes; m / 3: 2283.3m / 4: 1712.5m / 5:

[0335] Compound 220 absolute Structure disclosed SEQ ID NO:546 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:546) MW (calculated value): 6941.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 14.5 minutes; m / 3: 2314.5m / 4: 1736.1m / 5:

[0336] Compound 221 absolute Structure disclosed SEQ ID NO:547 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:547) MW (calculated value): 6900.7 Da Synthesis and purification methods: S01; P02 LCMS: A01-A; Rt: 12.8 minutes; m / 3:m / 4:1725.9m / 5:

[0337] Compound 222 absolute Structure disclosed SEQ ID NO:548 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTR-NMeQ-RY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:548) MW (calculated value): 6956.8 Da Synthesis and purification methods: S01; P02 LCMS: A01-A; Rt: 12.7 minutes; m / 3:m / 4:1740.0m / 5:

[0338] Compound 223 absolute Structure disclosed SEQ ID NO:549 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(SEQ ID NO:549) MW (calculated value): 6813.6 Da Synthesis and purification methods: S01; L20 LCMS: A01-A; Rt: 6.7 minutes; m / 3: 2272.1m / 4: 1704.5m / 5:

[0339] Compound 224 absolute Structure disclosed SEQ ID NO:550 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:550) MW (calculated value): 7070.9 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 34.4 minutes; m / 3:m / 4:m / 5:1415.0

[0340] Compound 225 absolute Structure disclosed SEQ ID NO:551 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:551) MW (calculated value): 7029.8 Da Synthesis and purification methods: S01; P02 LCMS: A01-A; Rt: 12.6 minutes; m / 3:m / 4:1758.2m / 5:

[0341] Compound 226 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEPASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:552) MW (calculated value): 6886.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 11.6 minutes; m / 3: 2296.6m / 4: 1722.6m / 5:

[0342] Compound 227 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGQSLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:553) MW (calculated value): 6999.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 10.2 minutes; m / 3: 2334.1m / 4: 1750.9m / 5:

[0343] Compound 228 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:554) MW (calculated value): 6974.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.7 minutes; m / 3: 2326.1m / 4: 1744.6m / 5:

[0344] Compound 229 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:555) MW (calculated value): 6933.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.8 minutes; m / 3: 2312.1m / 4: 1734.4m / 5:

[0345] Compound 230 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPEEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:556) MW (calculated value): 6855.7 Da Synthesis and purification methods: S01; P02 LCMS: A01-A; Rt: 13.0 minutes; m / 3:m / 4:1714.6m / 5:

[0346] Compound 231 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFIEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:557) MW (calculated value): 6860.7 Da Synthesis and purification methods: S01; P02 LCMS: A01-A; Rt: 13.7 minutes; m / 3:m / 4:1716.0m / 5:

[0347] Compound 232 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSYGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:558) MW (calculated value): 6976.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.4 minutes; m / 3: 2326.8m / 4: 1745.9m / 5:

[0348] Compound 233 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEPASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:559) MW (calculated value): 6982.8 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 34.6 minutes; m / 3:m / 4:1746.4m / 5:

[0349] Compound 234 Y-Aib-EGTFTSDLSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:560) MW (calculated value): 6892.8 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 36.4 minutes; m / 3:m / 4:1723.9m / 5:

[0350] Compound 235 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(SEQ ID NO:561) MW (calculated value): 6772.6 Da Synthesis and purification methods: S01; L20 LCMS: A01-A; Rt: 6.7 minutes; m / 3: 2259.1m / 4: 1694.4m / 5:

[0351] Compound 236 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQ-NMeR-Y-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:562) MW (calculated value): 6956.8 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 35.7 minutes; m / 3:m / 4:1739.9m / 5:

[0352] Compound 237 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGESLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:563) MW (calculated value): 7000.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 6.2 minutes; m / 3: 2334.9m / 4: 1751.3m / 5:

[0353] Compound 238 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLI- K(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(SEQ ID NO:564) MW (calculated value): 6643.4 Da Synthesis and purification methods: S01; P02 LCMS: A01-A; Rt: 13.7 minutes; m / 3:m / 4:1661.6m / 5:

[0354] Compound 239 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-EEEE-OEG-OEG(1,2) (SEQ ID NO 565 and 638 respectively) MW (calculated value): 6845.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.9 minutes; m / 3: 2283.0m / 4: 1712.3m / 5:

[0355] Compound 240 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-EEEEE-eLys(1,2) (SEQ ID NO 566 and 639 respectively) MW (calculated value): 6812.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.5 minutes; m / 3: 2272.1m / 4: 1704.2m / 5:

[0356] Compound 241 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGVSLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:567) MW (calculated value): 6970.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.3 minutes; m / 3: 2323.8m / 4: 1743.4m / 5:

[0357] Compound 242 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:568) MW (calculated value): 6812.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 10.6 minutes; m / 3: 2272.0m / 4: 1704.2m / 5:

[0358] Compound 243 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(SEQ ID NO:569) MW (calculated value): 6684.5 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.8 minutes; m / 3: 2228.7m / 4: 1672.1m / 5:

[0359] Compound 244 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSTGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:570) MW (calculated value): 6914.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 10.8 minutes; m / 3: 2306.2m / 4: 1729.9m / 5:

[0360] Compound 245 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-AHX(1,2)(SEQ ID NO:571) MW (calculated value): 6898.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 8.6 minutes; m / 3: 2300.5m / 4: 1725.9m / 5:

[0361] Compound 246 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:572) MW (calculated value): 6946.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.0 minutes; m / 3: 2316.7m / 4: 1737.6m / 5:

[0362] Compound 247 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFIEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu(1,2)(SEQ ID NO:573) MW (calculated value): 6542.3 Da Synthesis and purification methods: S01; P02 LCMS: A01-A; Rt: 12.7 minutes; m / 3:m / 4:1636.4m / 5:

[0363] Compound 248 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPEEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:574) MW (calculated value): 6731.5 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.3 minutes; m / 3: 2245.0m / 4: 1684.0m / 5:

[0364] Compound 249 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-EEEEEE-eLys(1,2) (SEQ ID NO 575 and 643 respectively) MW (calculated value): 6913.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 6.8 minutes; m / 3: 2305.4m / 4: 1729.5m / 5:

[0365] Compound 250 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(SEQ ID NO:576) MW (calculated value): 6656.4 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.0 minutes; m / 3: 2219.5m / 4: 1664.9m / 5:

[0366] Compound 251 Y-Aib-EGTFTSDYSI-Aib-LEKQAE-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:577) MW (calculated value): 6819.6 Da Synthesis and purification methods: S01; L20 LCMS: A01-A; Rt: 6.2 minutes; m / 3: 2274.4m / 4: 1705.9m / 5:

[0367] Compound 252 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(SEQ ID NO:578) MW (calculated value): 6785.6 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 9.8 minutes; m / 3: 2263.0m / 4: 1697.4m / 5:

[0368] Compound 253 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(SEQ ID NO:579) MW (calculated value): 6615.4 Da Synthesis and purification methods: S01; P02 LCMS: A01-A; Rt: 12.4 minutes; m / 3:m / 4:1654.7m / 5:

[0369] Compound 254 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:580) MW (calculated value): 6776.6 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.2 minutes; m / 3: 2259.7m / 4: 1695.0m / 5:

[0370] Compound 255 absolute Structure disclosed SEQ ID NO:581 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:581) MW (calculated value): 6972.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 6.6 minutes; m / 3: 2325.1m / 4: 1744.1m / 5:

[0371] Compound 256 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEPASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:582) MW (calculated value): 6858.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 10.2 minutes; m / 3: 2286.9m / 4: 1715.7m / 5:

[0372] Compound 257 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-EEEEE(1,2) (SEQ ID NO 583 and 636 respectively) MW (calculated value): 6656.4 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 10.4 minutes; m / 3: 2220.0m / 4: 1665.3m / 5:

[0373] Compound 258 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFIEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:584) MW (calculated value): 6832.7 Da Synthesis and purification methods: S01; P02 LCMS: A01-A; Rt: 12.5 minutes; m / 3:m / 4:1708.9m / 5:

[0374] Compound 259 absolute Structure disclosed SEQ ID NO:585 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:585) MW (calculated value): 6872.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 6.8 minutes; m / 3: 2291.5m / 4: 1719.2m / 5:

[0375] Compound 260 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-AHX(1,2)(SEQ ID NO:586) MW (calculated value): 6728.5 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.3 minutes; m / 3: 2243.7m / 4: 1683.2m / 5:

[0376] Compound 261 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:587) MW (calculated value): 6905.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.1 minutes; m / 3: 2303.4m / 4: 1727.7m / 5:

[0377] Compound 262 Y-Aib-EGTFTSDYSI-Aib-LEKQAE-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu(1,2)(SEQ ID NO:588) MW (calculated value): 6529.3 Da Synthesis and purification methods: S01; P02 LCMS: A01-A; Rt: 12.9 minutes; m / 3:m / 4:1633.1m / 5:

[0378] Compound 263 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEPASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:589) MW (calculated value): 6825.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 12.5 minutes; m / 3: 2275.8m / 4: 1707.2m / 5:

[0379] Compound 264 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-EEEEEE(1,2) (SEQ ID NO 590 and 637 respectively) MW (calculated value): 6785.6 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 10.3 minutes; m / 3: 2263.0m / 4: 1697.4m / 5:

[0380] Compound 265 absolute Structure disclosed SEQ ID NO:591 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:591) MW (calculated value): 6913.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 8.9 minutes; m / 3: 2305.4m / 4: 1729.3m / 5:

[0381] Compound 266 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:592) MW (calculated value): 6688.5 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 10.2 minutes; m / 3: 2230.3m / 4: 1673.1m / 5:

[0382] Compound 267 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:593) MW (calculated value): 6784.6 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 9.3 minutes; m / 3: 2263.0m / 4: 1697.2m / 5:

[0383] Compound 268 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu(1,2)(SEQ ID NO:594) MW (calculated value): 6527.3 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 10.3 minutes; m / 3: 2176.8m / 4: 1632.9m / 5:

[0384] Compound 269 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:595) MW (calculated value): 6845.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.7 minutes; m / 3: 2282.5m / 4: 1712.3m / 5:

[0385] Compound 270 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:596) MW (calculated value): 6817.6 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 10.1 minutes; m / 3: 2273.8m / 4: 1705.2m / 5:

[0386] Compound 271 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu(1,2)(SEQ ID NO:597) MW (calculated value): 6614.4 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.8 minutes; m / 3: 2205.7m / 4: 1654.6m / 5:

[0387] Compound 272 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPEEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu(1,2)(SEQ ID NO:598) MW (calculated value): 6570.3 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.4 minutes; m / 3: 2191.6m / 4: 1644.1m / 5:

[0388] Compound 273 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:599) MW (calculated value): 6775.6 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.8 minutes; m / 3: 2259.7m / 4: 1694.9m / 5:

[0389] Compound 274 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-OEG(1,2)(SEQID NO:600) MW (calculated value): 6602.4 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 8.9 minutes; m / 3: 2201.8m / 4: 1651.7m / 5:

[0390] Compound 275 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:601) MW (calculated value): 7000.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.3 minutes; m / 3: 2335.4m / 4: 1751.1m / 5:

[0391] Compound 276 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu(1,2)(SEQ ID NO:602) MW (calculated value): 6586.3 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.1 minutes; m / 3: 2196.1m / 4: 1647.5m / 5:

[0392] Compound 277 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTR-bHGln-RY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:603) MW (calculated value): 6956.8 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 35.1 minutes; m / 3:m / 4:1740.0m / 5:

[0393] Compound 278 Y-Aib-EGTFTSDYSI-Aib-LEKQAE-Aib-AFVEWLI- K(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:604) MW (calculated value): 6847.7 Da Synthesis and purification methods: S01; P02 LCMS: A01-A; Rt: 13.8 minutes; m / 3:m / 4:1712.7m / 5:

[0394] Compound 279 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-AHX(1,2)(SEQ ID NO:605) MW (calculated value): 6957.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 8.4 minutes; m / 3: 2320.4m / 4: 1741.0m / 5:

[0395] Compound 280 Y-Aib-EGTFTSDYSI-Aib-LEKQAE-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu(1,2)(SEQ ID NO:606) MW (calculated value): 6557.3 Da Synthesis and purification methods: S01; P02 LCMS: A01-A; Rt: 14.1 minutes; m / 3:m / 4:1640.2m / 5:

[0396] Compound 281 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-EEEE(1,2) (SEQ ID NO 607 and 640 respectively) MW (calculated value): 6527.3 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.3 minutes; m / 3: 2177.4m / 4: 1632.6m / 5:

[0397] Compound 282 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-OEG-OEG(1,2)(SEQ IDNO:608) MW (calculated value): 6489.3 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.5 minutes; m / 3: 2163.1m / 4: 1623.1m / 5:

[0398] Compound 283 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFIEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu(1,2)(SEQ ID NO:609) MW (calculated value): 6570.4 Da Synthesis and purification methods: S01; P02 LCMS: A01-A; Rt: 14.0 minutes; m / 3:m / 4:1643.5m / 5:

[0399] Compound 284 absolute Structure disclosed SEQ ID NO:610 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:610) MW (calculated value): 6747.5 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.1 minutes; m / 3: 2249.9m / 4: 1687.7m / 5:

[0400] Compound 285 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPEEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:611) MW (calculated value): 6984.8 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 10.7 minutes; m / 3: 2329.3m / 4: 1747.2m / 5:

[0401] Compound 286 absolute Structure disclosed SEQ ID NO:612 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:612) MW (calculated value): 6942.8 Da Synthesis and purification methods: S01; P02 LCMS: A01-A; Rt: 12.7 minutes; m / 3: 2315.4m / 4: 1736.7m / 5:

[0402] Compound 287 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:613) MW (calculated value): 6846.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.9 minutes; m / 3: 2283.2m / 4: 1712.5m / 5:

[0403] Compound 288 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:614) MW (calculated value): 7071.9 Da Synthesis and purification methods: S01; P02 LCMS: A01-A; Rt: 12.9 minutes; m / 3:m / 4:1768.6m / 5:

[0404] Compound 289 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(SEQ ID NO:615) MW (calculated value): 6685.5 Da Synthesis and purification methods: S01; P02 LCMS: A01-A; Rt: 13.6 minutes; m / 3:m / 4:1672.2m / 5:

[0405] Compound 290 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:616) MW (calculated value): 6813.7 Da Synthesis and purification methods: S01; P02 LCMS: A01-A; Rt: 13.0 minutes; m / 3:m / 4:m / 5:1363.6

[0406] Compound 291 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-EEEE(1,2) (SEQ ID NO 617 and 640 respectively) MW (calculated value): 6657.4 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 10.6 minutes; m / 3: 2117.4m / 4: 1633.3m / 5:

[0407] Compound 292 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(SEQ ID NO:618) MW (calculated value): 6657.4 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 10.6 minutes; m / 3: 2220.6m / 4: 1665.5m / 5:

[0408] Compound 293 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:619) MW (calculated value): 6914.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 6.8 minutes; m / 3: 2306.3m / 4: 1729.9m / 5:

[0409] Compound 294 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu(1,2)(SEQ ID NO:620) MW (calculated value): 6528.3 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 10.5 minutes; m / 3: 2177.2m / 4: 1633.1m / 5:

[0410] Compound 295 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(SEQ ID NO:621) MW (calculated value): 6785.6 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 9.4 minutes; m / 3: 2262.9m / 4: 1697.4m / 5:

[0411] Compound 296 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(SEQ ID NO:622) MW (calculated value): 6786.5 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 10.1 minutes; m / 3: 2263.2m / 4: 1697.7m / 5:

[0412] Compound 297 absolute Structure disclosed SEQ ID NO:623 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:623) MW (calculated value): 6818.6 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 10.2 minutes; m / 3: 2273.9m / 4: 1705.6m / 5:

[0413] Compound 298 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-EEE-OEG-OEG(1,2)(SEQ IDNO:624) MW (calculated value): 6689.5 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 10.6 minutes; m / 3: 2230.7m / 4: 1673.3m / 5:

[0414] Compound 299 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO:625) MW (calculated value): 6689.5 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 10.4 minutes; m / 3: 2230.9m / 4: 1673.4m / 5:

[0415] Compound 300 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-OEG(1,2)(SEQID NO:626) MW (calculated value): 6544.4 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 9.3 minutes; m / 3: 2182.3m / 4: 1637.3m / 5:

[0416] Compound 301 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-AHX(1,2)(SEQ ID NO:627) MW (calculated value): 6798.6 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 10.4 minutes; m / 3: 2267.1m / 4: 1700.9m / 5:

[0417] Compound 302 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-EEEEEE(1,2) (SEQ ID NO 628 and 637 respectively) MW (calculated value): 6786.5 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-B; Rt: 10.5 minutes; m / 3: 2263.1m / 4: 1697.6m / 5:

[0418] Compound 303 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-AHX(1,2)(SEQ ID NO:629) MW (calculated value): 6899.7 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.2 minutes; m / 3: 2301.3m / 4: 1726.1m / 5:

[0419] Compound 304 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-AHX(1,2)(SEQ ID NO:630) MW (calculated value): 6770.6 Da Synthesis and purification methods: SO2; PO3 LCMS: A02-A; Rt: 7.2 minutes; m / 3: 2258.0m / 4: 1694.0m / 5:

[0420] Compound 305 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(SEQ ID NO:631) MW (calculated value): 6814.6 Da Synthesis and purification methods: S01; P02 LCMS: A01-B; Rt: 35.5 minutes; m / 3:m / 4:m / 5:1363.7

[0421] Reference 1 NMeY-Aib-EGT-aMeF-TSDK(1,3)-SI-Aib-LEKQRQ-Iva-EFVRHLLNK-Aib-TRQRY-NH2.C16A-GGGG(1,2) (SEQ ID NO 632 and 641 respectively) Example 41 of EP3467106 Solubility: <1 mg / ml (pH 7)

[0422] Reference Item 2 NMeY-Aib-EGT-aMeF-TSDK(1,3)-SI-Aib-LEKQRQ-Iva-EFVRHLLNK-Aib-TRQRY-NH2.C18DA-GGGG(1,2) (SEQ ID NO 633 and 642 respectively) Example 42 of EP3467106 Solubility: <1 mg / ml (pH 7) Example

[0423] The following examples illustrate certain specific embodiments of the present invention. Unless otherwise described in detail, the following examples are performed using standard techniques well known and commonly used by those skilled in the art. Example 1: Analysis of hGLP1R / hGIPR / hNPY2R CreLuc in 0.5% and 100% plasma

[0424] The CHO and HEK-293 recombinant cell lines expressed the luciferase reporter gene under the control of a cAMP reaction assembly (CRE). GLP-1 and NPY2 receptors, as second recombinant proteins, were expressed in HEK reporter gene cells, and the GIP receptor in CHO reporter gene cells. Stimulation of these recombinant cells with an agonist resulted in an increase in intracellular cAMP levels. In the presence of cAMP, the transcription factor CRE-binding protein (CREB) binds to both CRE and CREB-binding protein (CBP), leading to transcription of the luciferase reporter gene. Using acoustic dispensing on a Labcyte ECHO, serially diluted peptides in 100% DMSO were transferred to 384-well analytical trays containing 5 μl of pre-split analytical buffer (1×HBSS, 20 mM HEPES, pH 7.4, supplemented with 0.5% human plasma). The cryopreserved gene-transfected reporter gene cells were thawed in analytical buffer. Add 20 μl (10,000 cells / well) of the peptide to the pan and incubate at 37°C for 4 hours in a humidified incubator. After incubation, allow the pan to equilibrate to room temperature, then add 25 μl of Bright-Glo. TM Luciferase reagent was used, incubated at room temperature for 10 minutes, and analyzed under cold light (Envision reader). Concentration-response assessment of compounds was performed using eight peptide concentrations (covering forty years). EC50 values ​​were calculated using a sigmoid concentration-response model with a variable slope via nonlinear regression.

[0425] The same analysis was performed in the presence of 100% plasma without additional buffer components.

[0426] The results are summarized in Table 3 below.

[0427] Table 3 Example 2: Solubility

[0428] The peptide (in TFA salt form) was weighed out in a filter unit (Mini-UniPrep non-needle filter 0.45 μM, Whatman PVDF) and 0.1 M phosphate buffer at pH 7 was added to achieve a final peptide concentration of 10 mg / mL. The peptide was dissolved by horizontally shaking the filter unit at 600 rpm for 2 hours at room temperature. The sample was then filtered to remove any insoluble particles. A control was prepared by weighing out the corresponding peptide solid and dissolving it in a suitable medium (e.g., ACN:H2O) to a final concentration of 1 mg / mL. Both the control and the sample were analyzed by reverse-phase chromatography. The peak area under the sample was compared with that of the control, and the solubility was calculated based on the ratio. The pH was measured and recorded for each sample. Example 3: Mouse PK

[0429] Pharmacokinetic parameters of the peptides were determined after intravenous administration to NMRI mice. Male NMRI mice, obtained from Janvier Laboratories (France), weighing 30 to 40 g, were used. Mice were housed in standard cages with a 12:12 hour light:dark cycle and freely available standard food and water. Each test peptide was dissolved in 50 mM phosphate buffer (pH 7.4) / 3.5% mannitol. Intravenous administration of 30 to 60 nmol / kg was performed via the tail vein. At different time points up to 56 hours post-administration, serial blood samples were collected from conscious mice via the saphenous vein in vials containing EDTA. Plasma was then prepared by centrifugation at approximately 5000 rpm for 5 minutes and stored at -20°C until the plasma peptide levels were quantified by liquid chromatography-mass spectrometry (LC-MS). Individual plasma concentration-time profiles were analyzed using a non-compartmental method, and the resulting pharmacokinetic parameters were calculated. The mean retention time (MRT) of the GGY peptides according to the invention in mice has been measured and is summarized in Table 4 (below).

[0430] Table 4 Example 4: Effects of acute food intake on normal NMRI mice

[0431] Three-week-old male NMRI mice were obtained from Janvier (Janvier Labs, France) or Charles River (Charles River Research Models & Services Germany GmbH). Animals were given microchips (Datamars, Slim Microchip T-SL) for individual identification after delivery. The animals were housed in captivity under a 12 / 12 dark-light cycle, four mice per cage, with lights turned off at 3 PM. Room temperature was maintained at 21°C ± 1°C and humidity at 60% ± 20%. Mice had free access to standard rodent food (KLIBA Nafag 3040 or Altromin 1324, Brogaarden, Denmark) and tap water.

[0432] Five days prior to the start of the study, animals were transferred to the HM2 system (a real-time monitoring system for food and water intake) from MBRose, Denmark, to acclimatize to experimental conditions. Since animals are uniquely identified by microchips, individual animals were identified by their own microchips upon entering and leaving the food channel via the antenna. Mice in each study group (n=8; oldest 6 weeks old) were randomly assigned based on their food intake (mid-24-hour intervals between the last three days) and body weight prior to the start of the study. Each experiment included a mediator treatment group (50 mM phosphate buffer, pH 7.4, containing 3.5% mannitol). To ensure consistent nutritional standards for all animals, food access was locked eight hours before the dark phase. One hour before nightfall, animals were subcutaneously treated with the test peptide. Food intake was reported hourly over a 24-hour period. Food intake was normalized [%] to the mean food intake of the mediator group, and the values ​​are summarized in Table 5 (below).

[0433] Table 5

[0434] Project A 1. A polypeptide of the general structure according to formula (I) or a pharmaceutically acceptable salt thereof, Z1-Z2-Z3 (SEQ ID NO:647) (I), in, Z1 is a hybrid polypeptide containing the following amino acid sequence. Y-Aib-X3-GTFTSDX 10 -SIX 13 -LX 15 -X 16 -X 17 -AX 19 -X 20 -X 21 -FX 23 -X 24 -X 25 -LX 27 -K(SEQ ID NO:646), X3 was selected as either E or D; X 10 Selected as Y or L; X 13 Selected as Aib or L; X 15 The answer is E, D, or A; X 16 The options are K, E, D, Aib, G, LysAc, A, L, S, Q, or R; X 17 The answer is Q, E, K, or A; X 19 The answer is Q or E; X 20 Selected as Aib, D-Asp, or D-Arg; X 21 The answer is A, E, or K; X 23 V or I; X 24 The answer is E or Q; X 25 The choice is W or Y; X 27 It is I or L; or Z1 is its derivative having one amino acid substitution; Z2 contains the amino acid sequence GGX. 31 -X 32 -X 33 -X 34 The connection base, where X 31 Selected as P, G, or Q; X 32 Selected as S, E, or R; X 33 The choice is S, E, Y, or T; X 34 It is selected as G, P, Y or A; or Z2 is its derivative having one amino acid substitution; Z3 is a polypeptide containing the following amino acid sequence. X 35 -X 36 -X 37 -X 38 -X 39 -YX 41 -X 42 -X 43 -X 44-TX 46 -X 47 -X 48 -X 49 , Where X 35 The answer is A, Q, I, V, E, or L; X 36 Selected as S, E, T, D, or L; X 37 The options are L, Aib, V, D-Leu, I, or Tle; X 38 Selected as R, L, or Aib; X 39 Selected as H, Aib, D-His, or Tle; X 41 The options are Y, L, Aib, I, or Tle; X 42 Selected as N or Aib; X 43 The options are W, H, L, R, or Aib; X 44 Selected as L, Aib, D-Arg, D-Asp, or Tle; X 46 Selected as R, hArg, or D-Arg; X 47 Selected as Q, bh-Gln, or NMeQ; X 48 Selected as R or NMeR; X 49 The selected values ​​are Y, Tle, Chg, D-Tyr, Phg; or Z3 is a derivative having one amino acid substitution. 2. For example, in the polypeptide of Project 1, X3 in Z1 is selected as E. 3. The polypeptide of any of the aforementioned projects, wherein X in Z1 10 Y was selected. 4. The polypeptide of any of the aforementioned projects, wherein X in Z1 13 Aib was selected. 5. The polypeptide of any of the aforementioned projects, wherein X in Z1 15 The answer is E. 6. The polypeptide of any of the aforementioned projects, wherein X in Z1 16 K was selected. 7. A polypeptide as described in any of the aforementioned projects, wherein X in Z1 17 Q was selected. 8. A polypeptide as described in any of the preceding items, wherein X in Z1 19 Q was selected. 9. A polypeptide as described in any of the preceding items, wherein X in Z1 20 Aib was selected. 10. A polypeptide as described in any of the preceding items, wherein X in Z1 21 The options are A or E, with A being the preferred choice. 11. A polypeptide as described in any of the preceding items, wherein X in Z1 23 V was selected. 12. A polypeptide as described in any of the preceding items, wherein X in Z1 24 The choice is between E and Q, with E being the preferred option. 13. A polypeptide as described in any of the preceding items, wherein X in Z1 25 W was selected. 14. A polypeptide as described in any of the preceding items, wherein X in Z1 27 It was selected as I. 15. A polypeptide as described in any of the preceding items, wherein X in Z2 31 P was selected. 16. A polypeptide as described in any of the preceding items, wherein X in Z2 32 S was selected. 17. A polypeptide as described in any of the preceding items, wherein X in Z2 33 The choice is between E and S, with S being the preferred option. 18. A polypeptide as described in any of the preceding items, wherein X in Z2 34 G was selected. 19. A polypeptide as described in any of the preceding items, wherein X in Z3 35 The options are A, Q, or V, with A being the preferred choice. 20. A polypeptide as described in any of the preceding items, wherein X in Z3 36 S was selected. 21. A polypeptide as described in any of the aforementioned projects, wherein X in Z3 37 The choice is between I and L, with L being the preferred option. 22. A polypeptide as described in any of the aforementioned projects, wherein X in Z3 38 R was selected. 23. A polypeptide as described in any of the aforementioned projects, wherein X in Z3 39 H was selected. 24. A polypeptide as described in any of the preceding items, wherein X in Z3 41 Y was selected. 25. A polypeptide as described in any of the preceding items, wherein X in Z3 42 N was selected. 26. A polypeptide as described in any of the preceding items, wherein X in Z3 43 W was selected. 27. A polypeptide as described in any of the preceding items, wherein X in Z3 44 L was selected. 28. A polypeptide as described in any of the preceding items, wherein X in Z3 46R was selected. 29. A polypeptide as described in any of the preceding items, wherein X in Z3 47 The selection is either Q or NMeQ, with Q being the preferred choice. 30. A polypeptide as described in any of the preceding items, wherein X in Z3 48 R or NMeR was selected, with R being preferred. 31. The polypeptide of any of the aforementioned projects, wherein X in Z3 49 Y was selected. 32. A polypeptide as described in any of the aforementioned projects, wherein X 35 X 36 X 37 X 38 X 39 The selected result is ASLRH (SEQ ID NO:645). 33. A polypeptide as described in any of the aforementioned projects, wherein X 41 X 42 X 43 X 44 YNWL (SEQ ID NO:326) was selected. 34. A polypeptide as described in any of the aforementioned projects, wherein X 46 X 47 X 48 X 49 RQRY (SEQ ID NO:327) was selected. 35. The polypeptide of any of the preceding items, wherein the polypeptide is capable of binding to and / or activating GLP-1, GIP and hY2 (hNPY2) receptors.

[0435] Project B 1. A polypeptide of the general structure according to formula (I) or a pharmaceutically acceptable salt thereof, Z1-Z2-Z3(I), in, Z1 is a hybrid polypeptide containing the following amino acid sequence. Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK (SEQ IDNO: 306), Or its derivatives having one, two or three substitutions; Z2 is the linker; Z3 is a polypeptide containing the following amino acid sequence. ASLRHYYNWLTRQRY(SEQ ID NO:307) Or its derivatives having 1, 2, 3, 4 or 5 substitutions. 2. The polypeptide of technical solution 1, wherein the linker is composed of 1 to 10 amino acid residues. 3. The polypeptide of any of the foregoing technical solutions, wherein Z2 has the amino acid sequence GGPSEG (SEQ ID NO:311) or is a derivative thereof having 1, 2, 3 or 4 amino acid substitutions. 4. The polypeptide of technical solution 3, wherein the substitution of amino acids 1, 2, 3 or 4 in Z2 is present at position X. 31 X 32 X 33 or X 34 Any location within. 5. The polypeptide of any of the foregoing technical solutions, wherein Z2 has the amino acid sequence GGX 31 X 32 X 33 X 34 , where X 31 Selected as P, G, or Q; X 32 Selected as S, E, or R; X 33 The choice is S, E, or Y; X 34 It is selected as G, P, Y or A; or as a derivative having one amino acid substitution. 6. The polypeptide of any of the foregoing technical solutions, wherein one, two, or three substitutions of the Z1 derivative are present at amino acid positions X3, X... 10 X 13 X 15 X 16 X 17 X 19 X 20 X 21 X 23 X 24 X 25 or X 27 Any location within. 7. The polypeptide of any of the foregoing technical solutions, wherein one, two, three, four, or five substitutions of the Z3 derivative are present at amino acid position X. 35 X 36 X 37 X 38 X 39 X 41 X 42 X 43 X 44 X 46 X 47 X 48 or X 49 Any location within. 8. The polypeptide of any of the foregoing technical solutions, wherein the derivative of Z3 has 1, 2 or 3 substitutions, preferably 1 or 2 substitutions, and most preferably 1 substitution. 9. The polypeptide of any of the foregoing technical solutions, wherein the derivative of Z1 has one or two substitutions, preferably one substitution. 10. The polypeptide of any of the foregoing technical solutions, wherein one or more substitutions in the Z1 derivative are selected as follows: X3 was selected as D; X 10 L and X were selected. 13 L and X were selected. 15 The answer is D or A; X 16 The options selected are E, D, Aib, G, LysAc, A, L, S, Q, or R; X 17 The answer is E, K, or A; X 19 E and X were selected. 20 Selected as D-Asp or D-Arg; X 21 E and X were selected. 23 I; X were selected. 24 Q and X were selected. 25 Y was selected as the answer; X was selected as the answer. 27 L was selected. 11. The polypeptide of any of the foregoing technical solutions, wherein one or more substitutions in the Z3 derivative are selected as follows: X 35 The options are Q, I, V, E, or L; X 36 The choice is E, T, D, or L; X 37 The selected values ​​are Aib, V, D-Leu, or I; X 38 Selected as L or Aib; X 39 Selected as Aib, D-His, or Tle; X 41 The options are L, Aib, I, or Tle; X 42 Selected as Aib; X 43 Selected as H, L, R, or Aib; X 44 Selected as Aib, D-Arg, or D-Asp; X 46 Selected as hArg or D-Arg; X 47 Selected as bh-Gln or NMeQ; X 48 NMeR;X was selected. 49 The selected values ​​are Tle, Chg, D-Tyr, and Phg. 12. The polypeptide of any of the foregoing technical solutions, wherein the polypeptide is at the lysine (K) residue, preferably at the amino acid position X. 28 Lipidification occurs at the lysine (K) residue in the protein. 13. The polypeptide of any of the foregoing technical solutions, wherein the polypeptide is expressed in the form of the general formula LY 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 -Y 7 -Y 8 The structure of lipidation, wherein L is a lipid selected from C18DA or C20DA and wherein Y is a lipid selected from C20DA. 1 -Y 8 Each of the options is independently selected from: non-existent, [γE], [OEG], [eLys], or [AHX]. 14. The polypeptide according to any one of the foregoing technical solutions, wherein the lipid is selected from the list consisting of: C18DA, C18DA[γE]-, C18DA[γE][γE]-, C18DA[γE][γE][γE]-, C18DA[γE][γE][γE][γE]-, C18DA[γE][γE][γE][γE][γE]-, C18DA[γE][γE][γE][γE][γE][γE]-, C18DA[γE][γE][γE][γE][γE][γE][γE]-, C20DA, C20DA[γE]-, C20DA[γE][γE]-, C20DA[γE][γE][γE]-, C20DA[γE][γE][γE][γE]-, C20DA[γE][γE][γE][γE][γE]-, C20DA[γE][γE][γE][γE][γE][γE]-, C20DA[γE][γE][γE][γE][γE][γE][γE]-, C18DA[eLys], C18DA[γE][eLys]-, C18DA[γE][γE][eLys]-, C18DA[γE][γE][γE][eLys]-, C18DA[γE][γE][γE][γE][eLys]-, C18DA[γE][γE][γE][γE][γE][eLys]-, C18DA[γE][γE][γE][γE][γE][γE][eLys]-, C20DA[eLys], C20DA[γE][eLys]-, C20DA[γE][γE][eLys]-, C20DA[γE][γE][γE][eLys]-, C20DA[γE][γE][γE][γE][eLys]-, C20DA[γE][γE][γE][γE][γE][eLys]-, C20DA[γE][γE][γE][γE][γE][γE][eLys]-, C18DA[OEG][OEG]-, C18DA[γE][OEG][OEG]-, C18DA[γE][γE][OEG][OEG]-, C18DA[γE][γE][γE][OEG][OEG]-, C18DA[γE][γE][γE][γE][OEG][OEG]-, C18DA[γE][γE][γE][γE][γE][OEG][OEG]-、C20DA[OEG][OEG]-、C20DA[γE][OEG][OEG]-、C20DA[γE][γE][OEG][OEG]-、C20DA[γE][γE][OEG][OEG]-、C20DA[γE][γE][γE][OEG][OEG][OEG]-、C20DA[γE][γE][γE][γE][OEG][OEG]-、C20DA[γE][γE][γE][γE][γE][OEG][OEG]-、C18DA[γE][γE][OEG][OEG][OEG][OEG]-、C18DA[γE][γE][OEG][OEG][OEG][OEG]-、C18DA[γE][γE][OEG][OEG][OEG][OEG][OEG]-、C18DA[γE][γE][OEG][OEG][OEG][OEG][OEG]-、C18DA[γE][γE][OEG][OEG][OEG][OEG][OEG]-、C18DA[γE][γE][OEG][OEG][OEG][OEG][OEG][OEG]-、C18DA[γE][γE][OEG][OEG][OEG][OEG][OEG][OEG]-、C18DA[γE][γE][OEG][OEG][OEG][OEG][OEG][OEG][OEG]-、C18DA[γE][γE][OEG][OEG][OEG][OEG][OEG][OEG][OEG]-、C18DA[γE][γE][OEG][OEG][OEG][OEG][OEG][OEG][OEG][OEG]-、C18DA[γE][γE][OEG][OEG][OEG][OEG][OEG][OEG][OEG][OEG][OEG ][OEG]-、C18DA[γE][γE][OEG]-、C18DA[γE][γE][γE][OEG]-、C18DA[γE][γE][γE][γE][OEG]-、C18DA[γE][γE][γE][γE][γE][OEG]-、C18DA[γE][γE][γE][γE][γE][OEG]-、C18DA[γE][γE][γE][γE][γE][γE][OEG]-、C20DA[γE][OEG]-、C20DA[γE][γE][OEG]-、C20DA[γE][γE][OEG]-、C20DA[γE][γE][OEG]-、C20DA[γE][γE][OEG]-、C20DA[γE][γE][OEG]-、C20DA[γE][γE][OEG]-、C20DA[γE][γE][OEG]-、C20DA[γE][γE][OEG]-、C20DA[γE][γE][OEG]-、C20DA[γE][γE][OEG]-、 C20DA[γE][γE][γE][γE][OEG]-、C20DA[γE][γE][γE][γE][γE][OEG]-、C20DA[γE][γE][γE][γE][γE][γE][γE][OEG]-、C18DA[OEG][eLys]-、C18DA[γE][20DA[OEG] [eLys]-、C20DA[γE][OEG][eLys]-、C20DA[γE][γE][OEG][eLys]-、C20DA[γE][γE][γE][OEG][eLys]-、C20DA[γE][γE][γE][γE][OEG][eLys]-、C20DA[γE][γE][γE][γE][γE][OEG][eLys]-、C18DA[OEG][OEG][eLys]-、C18DA[γE][OEG][OEG][eLys]-、C18DA[γE][OEG][OEG][OEG][eLys]-、C18DA[γE][γE][OEG][OEG][eLys]-、C18DA[γE][γE][OEG][OEG][OEG][eLys]-、C18DA[γE][γE][OEG][OEG][OEG][eLys]-、C18DA[γE][γE][OEG][OEG][eLys]-、C18DA[γE][γE][OEG][OEG][OEG][eLys]-、 C18DA[γE][γE][γE][γE][OEG][OEG][eLys]-, C20DA[OEG][OEG][eLys]-, C20DA[γE][OEG][ OEG][eLys]-, C20DA[γE][γE][OEG][OEG][eLys]-, C20DA[γE][γE][γE][OEG][OEG][eLys]-, C20DA[γE][γE][γE][γE][OEG][OEG][eLys]-, C18DA[AHX], C18DA[γE][AHX]-, C18 DA[γE][γE][AHX]-, C18DA[γE][γE][γE][AHX]-, C18DA[γE][γE][γE][γE][AHX]-, C18DA[γE][γE][γE][γE][γE][AHX]-, C18DA[γE][γE][γE][γE][γE][γE][AHX]-, C 20DA[AHX], C20DA[γE][AHX]-, C20DA[γE][γE][AHX]-, C20DA[γE][γE][γE][AHX]-, C20DA[γE][γE][γE][γE][AHX]-, C20DA[γE][γE][γE][γE][γE][AHX]-, C20DA[γE][γE][γE][γE][γE][γE][AHX]-. 15. The polypeptide of any of the foregoing technical solutions, wherein the polypeptide is selected from the group consisting of compounds 1 to 305.

[0436] Project C 1. A polypeptide of the general structure according to formula (I), or a salt thereof or a pharmaceutically acceptable salt thereof. Z1-Z2-Z3(I), in, Z1 is a hybrid polypeptide X1-X consisting of or containing the following amino acid sequence. 28 , Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK (SEQ IDNO: 306), Or its derivatives having one, two or three amino acid substitutions; Z2 is a peptide X consisting of or containing the amino acid sequence GGPSEG (SEQ ID NO:311). 29 -X 34, Or its derivatives having substituted 1, 2, 3 or 4 amino acids; Z3 is a polypeptide X consisting of or containing the following amino acid sequence. 35 -X 49 , ASLRHYYNWLTRQRY(SEQ ID NO:307) Or its derivatives having substituted amino acids of 1, 2, 3, 4 or 5; Preferably, Z1-Z2-Z3 have 0, 1, 2, 3, 4, 5 or 6 amino acid substitutions. 2. For example, the polypeptide in Project 1, Z1 is composed of or contains the amino acid sequence Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK (SEQ ID NO:306) or is a derivative thereof, and the derivative is located at amino acid positions X3 and X4. 10 X 13 X 15 X 16 X 17 X 19 X 20 X 21 X 23 X 24 X 25 or X 27 Any position has 1, 2, or 3 amino acid substitutions, and the one or more substitutions are selected as follows: X3 is selected as D; X 10 L and X were selected. 13 L and X were selected. 15 The answer is D or A; X 16 The options selected are E, D, Aib, G, LysAc, A, L, S, Q, or R; X 17 The answer is E, K, or A; X 19 E and X were selected. 20 Selected as D-Asp or D-Arg; X 21 E or K were chosen; X 23 I; X were selected. 24 Q and X were selected. 25 Y was selected as the answer; X was selected as the answer. 27 L was selected; Z2 is composed of the amino acid sequence GGX. 31 X 32 X 33 X 34 This amino acid sequence consists of or contains, wherein X31 Selected as P, G, or Q; X 32 Selected as S, E, or R; X 33 The choice is S, E, Y, or T; X 34 The choice is G, P, Y, or A; Z3 is composed of or contains the amino acid sequence ASLRHYYNWLTRQRY (SEQ ID NO:307) or is a derivative thereof, wherein the derivative is located at amino acid position X. 35 X 36 X 37 X 38 X 39 X 41 X 42 X 43 X 44 X 46 X 47 X 48 or X 49 Any position has 1, 2, 3, 4, or 5 substitutions, and the one or more substitutions are chosen as follows: X 35 The options are Q, I, V, E, or L; X 36 The choice is E, T, D, or L; X 37 The selected values ​​are Aib, V, D-Leu, I, or Tle; X 38 Selected as L or Aib; X 39 Selected as Aib, D-His, or Tle; X 41 The options are L, Aib, I, or Tle; X 42 Selected as Aib; X 43 Selected as H, L, R, or Aib; X 44 Selected as Aib, D-Arg, D-Asp, or Tle; X 46 Selected as hArg or D-Arg; X 47 Selected as bh-Gln or NMeQ; X 48 NMeR;X was selected. 49 The selected values ​​are Tle, Chg, D-Tyr, and Phg. 3. The polypeptide as described in any of the aforementioned projects, Z1 is composed of or contains the amino acid sequence Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK (SEQ ID NO:306) or is a derivative thereof, and the derivative is located at amino acid positions X3 and X4. 10 X 13 X15 X 16 X 17 X 19 X 20 X 21 X 23 X 24 X 25 or X 27 Any position has 1, 2, or 3 amino acid substitutions, and the one or more substitutions are selected as follows: X3 is selected as D; X 10 L and X were selected. 13 L and X were selected. 15 The answer is D; X 16 The answer is E, D, G, A, S, Q, or R; X 17 The answer is either E or A; X 19 E and X were selected. 21 E or K were chosen; X 23 I; X were selected. 24 Q and X were selected. 25 Y was selected as the answer; X was selected as the answer. 27 L was selected; Z2 is composed of the amino acid sequence GGX. 31 -X 32 -X 33 -X 34 This amino acid sequence consists of or contains, wherein X 31 Selected as P or Q; X 32 S or E; X 33 The choice is S, E, Y, or T; X 34 The choice is G, P, Y, or A; Z3 is composed of or contains the amino acid sequence ASLRHYYNWLTRQRY (SEQ ID NO:307) or is a derivative thereof, wherein the derivative is located at amino acid position X. 35 X 36 X 37 X 38 X 39 X 41 X 42 X 43 X 44 X 46 X 47 X 48 or X 49 Any position has 1, 2, or 3 amino acid substitutions, and the one or more substitutions are selected as follows: X 35 The options are Q, I, V, E, or L; X 36 T and X were selected.37 The choice is Aib, V, I, or Tle; X 38 Selected as Aib; X 39 Selected as Tle;X 41 Selected as I, L, or Tle; X 44 Selected as Tle;X 47 NMeQ was selected; X 48 NMeR was selected. 4. The polypeptide as described in any of the aforementioned items, Z1 is composed of or contains the amino acid sequence Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK (SEQ ID NO:306) or is a derivative thereof, and the derivative is located at amino acid positions X3 and X4. 10 X 13 X 15 X 16 X 17 X 21 X 23 X 24 or X 25 Any position has 1, 2, or 3 amino acid substitutions, and the one or more substitutions are selected as follows: X3 is selected as D; X 10 L and X were selected. 13 L and X were selected. 15 The answer is D; X 16 The answer is E, D, G, A, S, Q, or R; X 17 The answer is either E or A; X 21 E and X were selected. 23 I; X were selected. 24 Q and X were selected. 25 Y was selected; Z2 is composed of the amino acid sequence GGX. 31 -X 32 -X 33 -X 34 This amino acid sequence consists of or contains, wherein X 31 Selected as P or Q; X 32 S or E; X 33 The choice is S, E, Y, or T; X 34 The choice is G, P, Y, or A; Z3 is composed of or contains the amino acid sequence ASLRHYYNWLTRQRY (SEQ ID NO:307) or is a derivative thereof, wherein the derivative is located at amino acid position X. 35X 36 X 37 X 38 X 39 X 41 X 44 X 47 X 48 or X 49 Any position has one or two amino acid substitutions, and the one or more substitutions are selected as follows: X 35 The options are Q, I, V, E, or L; X 36 T and X were selected. 37 The choice is Aib, V, I, or Tle; X 38 Selected as Aib; X 39 Selected as Tle;X 41 Selected as I, L, or Tle; X 44 Selected as Tle;X 47 NMeQ was selected; X 48 NMeR was selected. 5. The polypeptide as described in any of the aforementioned projects, Z1 is composed of or contains the amino acid sequence Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK (SEQ ID NO:306) or is a derivative thereof, wherein the derivative is located at amino acid position X. 21 or X 24 Any position may have one or two, preferably one, amino acid substitutions, and the one or more substitutions may be selected as follows: X 21 The answer is A or E; X 24 The answer is either E or Q; Z2 consists of or contains the amino acid sequence GGPSEG (SEQ ID NO:311) or GGPSSG (SEQ ID NO:320); Z3 is composed of or contains the amino acid sequence ASLRHYYNWLTRQRY (SEQ ID NO:307) or is a derivative thereof, wherein the derivative is located at amino acid position X. 35 X 37 X 47 or X 48 Any position may have one or two, preferably one, amino acid substitutions, and the one or more substitutions may be selected as follows: X 35 Q and V were selected; X 37 I; X were selected. 47 NMeQ was selected; X 48NMeR was selected. This disclosure also includes the following implementation schemes. 1. A polypeptide with a general structure according to formula (I), Z1-Z2-Z3(I)(SEQ ID NO:647), in, Z1 is a hybrid polypeptide composed of the following amino acid sequence. Y-Aib-X3-GTFTSDX 10 -SIX 13 -LX 15 -X 16 -X 17 -AX 19 -X 20 -X 21 -FX 23 -X 24 -X 25 -LX 27 -K(SEQ ID NO:646), X3 was selected as either E or D; X 10 Selected as Y or L; X 13 Selected as Aib or L; X 15 The answer is E, D, or A; X 16 The options are K, E, D, Aib, G, LysAc, A, L, S, Q, or R; X 17 The answer is Q, E, K, or A; X 19 The answer is Q or E; X 20 Selected as Aib, D-Asp, or D-Arg; X 21 The answer is A, E, or K; X 23 V or I; X 24 The answer is E or Q; X 25 The choice is W or Y; X 27 For I or L; Z2 is composed of the amino acid sequence GGX. 31 -X 32 -X 33 -X 34 The connecting base is composed of X 31 Selected as P, G, or Q; X 32 Selected as S, E, or R; X 33 The choice is S, E, Y, or T; X 34 The choice is G, P, Y, or A; Z3 is a polypeptide composed of the following amino acid sequence. X 35 -X 36 -X37 -X 38 -X 39 -YX 41 -X 42 -X 43 -X 44 -TX 46 -X 47 -X 48 -X 49 , Where X 35 The answer is A, Q, I, V, E, or L; X 36 Selected as S, E, T, D, or L; X 37 The options are L, Aib, V, D-Leu, I, or Tle; X 38 Selected as R, L, or Aib; X 39 Selected as H, Aib, D-His, or Tle; X 41 The options are Y, L, Aib, I, or Tle; X 42 Selected as N or Aib; X 43 The options are W, H, L, R, or Aib; X 44 Selected as L, Aib, D-Arg, D-Asp, or Tle; X 46 Selected as R, hArg, or D-Arg; X 47 Selected as Q, bh-Gln, or NMeQ; X 48 Selected as R or NMeR; X 49 The selected values ​​are Y, Tle, Chg, D-Tyr, and Phg. 2. The polypeptide as described in Implementation Scheme 1, wherein in Z3 X 35 The options selected are A, E, I, L, Q, and V; X 36 S or T; X 37 The selected values ​​are Aib, I, L, Tle, and V; X 38 Selected as Aib or R;X 39 Selected as H or Tle; X 41 Selected as I, L, Tle, or Y; X 42 N was chosen as the candidate for N; X 43 W and X were selected. 44 Selected as L or Tle; X 46 R; X were selected. 47 Selected as NMeQ or Q;X 48 Selected as NMeR or R;X 49 Y was selected. 3. The polypeptide as described in any of the foregoing embodiments, wherein in Z1 X3 is selected as either E or D; X 10 Selected as Y or L; X 13 Selected as Aib or L; X 15 The answer is either E or D; X 16 The options are K, E, D, G, A, S, Q, or R; X 17 The answer is Q, E, or A; X 19 The answer is E or Q; X 20 Selected as Aib; X 21 The answer is A, E, or K; X 23 V or I; X 24 The answer is E or Q; X 25 The choice is W or Y; X 27 It was selected as I or L. 4. The polypeptide as described in any of the foregoing implementation schemes, Z2 is composed of the amino acid sequence GGX. 31 -X 32 -X 33 -X 34 Composition, in which X 31 Selected as P or Q; X 32 S or E; X 33 The choice is S, E, Y, or T; X 34 The choice is G, P, Y, or A; Preferably, Z2 is selected from the group consisting of: GGPEEG (SEQ ID NO:313), GGPEEP (SEQ ID NO:314), GGPESG (SEQ ID NO:315), GGPESP (SEQ ID NO:316), GGPSEG (SEQ ID NO:311), GGPSEP (SEQ ID NO:317), GGPSEY (SEQ ID NO:318), GGPSSA (SEQ ID NO:319), GGPSSG (SEQ ID NO:320), GGPSSP (SEQ ID NO:321), GGPSSY (SEQ ID NO:322), GGPSTG (SEQ ID NO:323), GGPSYG (SEQ ID NO:324), GGQSSG (SEQ ID NO:325), GGPRSG (SEQ ID NO:650), GGPRYY (SEQ ID NO:651), and GGPSYY (SEQ ID NO:652). 5. The polypeptide as described in any of the foregoing implementation schemes, In Z1, X3 is selected as E; X 10 Y was selected as the answer; X was selected as the answer.13 Selected as Aib; X 15 E and X were selected. 16 K and X were selected. 17 Q and X were selected. 19 Q and X were selected. 20 Selected as Aib; X 21 The answer is A or E; X 23 V and X were selected. 24 The answer is E or Q; X 25 W and X were selected. 27 For I; Z2 is composed of the amino acid sequence GGPSEG (SEQ ID NO:311) or GGPSSG (SEQ ID NO:320); In Z3, X 35 The answer is A, Q, or V; X 36 S and X were selected. 37 Selected as I or L; X 38 R; X were selected. 39 H and X were selected. 41 Y was selected as the answer; X was selected as the answer. 42 N was chosen as the candidate for N; X 43 W and X were selected. 44 L and X were selected. 46 R; X were selected. 47 Selected as Q or NMeQ; X 48 Selected as R or NMeR; X 49 Y was selected. 6. A polypeptide with a general structure according to formula (I), Z1-Z2-Z3(I), in, Z1 is composed of the amino acid sequence X1-X 28 The hybrid polypeptides that make up the composition Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK (SEQ IDNO: 306), Or its derivatives having one, two or three amino acid substitutions; Z2 is composed of amino acid sequence X 29 -X 34 The peptides that make up the composition GGPSEG (SEQ ID NO:311), Or its derivatives having substituted 1, 2, 3 or 4 amino acids; Z3 is composed of amino acid sequence X 35 -X49 The polypeptides that make up the composition ASLRHYYNWLTRQRY(SEQ ID NO:307), Or its derivatives having 1, 2, 3, 4 or 5 amino acid substitutions. 7. The polypeptide as described in implementation scheme 6, In Z1, the substitution of 1, 2, or 3 amino acids occurs at amino acid positions X3 and X4. 10 X 13 X 15 X 16 X 17 X 19 X 20 X 21 X 23 X 24 X 25 or X 27 Any position within, and the one or more alternatives are chosen as follows: X3 is selected as D; X 10 L and X were selected. 13 L and X were selected. 15 The answer is D or A; X 16 The options selected are E, D, Aib, G, LysAc, A, L, S, Q, or R; X 17 The answer is E, K, or A; X 19 E and X were selected. 20 Selected as D-Asp or D-Arg; X 21 E or K were chosen; X 23 I; X were selected. 24 Q and X were selected. 25 Y was selected as the answer; X was selected as the answer. 27 L was selected; Z2 is composed of amino acid GGX. 31 X 32 X 33 X 34 Composition, in which X 31 Selected as P, G, or Q; X 32 Selected as S, E, or R; X 33 The choice is S, E, Y, or T; X 34 The choice is G, P, Y, or A; In Z3, the 1, 2, 3, 4, or 5 substitutions are present at amino acid position X. 35 X 36 X 37 X 38 X 39 X 41 X 42 X43 X 44 X 46 X 47 X 48 or X 49 Any position within, and the one or more alternative choices are as follows: X 35 The options are Q, I, V, E, or L; X 36 The choice is E, T, D, or L; X 37 The selected values ​​are Aib, V, D-Leu, I, or Tle; X 38 Selected as L or Aib; X 39 Selected as Aib, D-His, or Tle; X 41 The options are L, Aib, I, or Tle; X 42 Selected as Aib; X 43 Selected as H, L, R, or Aib; X 44 Selected as Aib, D-Arg, D-Asp, or Tle; X 46 Selected as hArg or D-Arg; X 47 Selected as bh-Gln or NMeQ; X 48 NMeR;X was selected. 49 The selected values ​​are Tle, Chg, D-Tyr, and Phg. 8. The polypeptide as described in implementation scheme 6, In Z1, the substitution of 1, 2, or 3 amino acids occurs at amino acid positions X3 and X4. 10 X 13 X 15 X 16 X 17 X 19 X 20 X 21 X 23 X 24 X 25 or X 27 Any position within, and the one or more alternatives are chosen as follows: X3 is selected as D; X 10 L and X were selected. 13 L and X were selected. 15 The answer is D; X 16 The answer is E, D, G, A, S, Q, or R; X 17 The answer is either E or A; X 19 E and X were selected. 21 E or K were chosen; X 23 I; X were selected. 24 Q and X were selected. 25 Y was selected as the answer; X was selected as the answer. 27 L was selected; Z2 is composed of the amino acid sequence GGX. 31 -X 32 -X 33 -X 34 Composition, in which X 31 Selected as P or Q; X 32 S or E; X 33 The choice is S, E, Y, or T; X 34 The choice is G, P, Y, or A; In Z3, the 1, 2, or 3 substitutions are located at amino acid position X. 35 X 36 X 37 X 38 X 39 X 41 X 42 X 43 X 44 X 46 X 47 X 48 or X 49 Any position within, and the one or more alternative choices are as follows: X 35 The options are Q, I, V, E, or L; X 36 T and X were selected. 37 The choice is Aib, V, I, or Tle; X 38 Selected as Aib; X 39 Selected as Tle;X 41 Selected as I, L, or Tle; X 44 Selected as Tle;X 47 NMeQ was selected; X 48 NMeR was selected. 9. The polypeptide of any of the foregoing embodiments, wherein the polypeptide is at the lysine (K) residue, preferably at the amino acid position X. 28 Lipidification occurs at the lysine (K) residue in the protein. 10. The polypeptide of any of the foregoing embodiments, wherein the polypeptide is expressed in the form of general formula LY 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 -Y 7 -Y 8 The structure of lipidation, wherein L is a lipid selected from 17-carboxy-heptadecanoyl (C18DA) and 19-carboxy-nonadecanoyl (C20DA), and wherein Y 1 -Y 8Each of the elements is independently selected from: non-existent, [γE], [E], [OEG], [eLys], or [AHX]. 11. The polypeptide of any of the foregoing embodiments, wherein the polypeptide is expressed in the form of general formula LY 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 -Y 7 -Y 8 The structure of lipidation, wherein L is a lipid selected from 17-carboxy-heptadecanoyl (C18DA) and 19-carboxy-nonadecanoyl (C20DA), wherein Y 1 -Y 8 Each of the elements is independently selected from: non-existent, [γE], [E], [OEG], [eLys], or [AHX], where Y 1 -Y 3 The terms in the text are [γE] or Y. 1 -Y 3 The elements in the equation are [E], where Y is... 4 The value is selected from: [γE], [E], or [OEG], where Y is selected from: [γE], [E], or [OEG]. 5 -Y 8 Each of the elements is independently selected from: non-existent, [γE], [E], [OEG], [eLys], or [AHX]. 12. The polypeptide of any of the foregoing embodiments, wherein the polypeptide is selected from the group consisting of compounds 2 to 305 according to Table 3. 13. The polypeptide of any of the foregoing embodiments, wherein the polypeptide is in the form of a salt or in the form of a pharmaceutically acceptable salt. 14. The polypeptide of any of the foregoing embodiments, wherein the polypeptide or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical composition together with one or more pharmaceutically acceptable carriers and / or excipients. 15. The polypeptide of any of the foregoing embodiments, wherein the polypeptide is used as a pharmaceutical agent. 16. The polypeptide of any of the foregoing embodiments, wherein the polypeptide is used for treating and / or preventing the following methods: Overweight, long-term weight management, obesity, symptomatic obesity, eating disorders; Insulin resistance, diabetes, type 1 diabetes, type 2 diabetes, prediabetes; Endocrine obesity: Cushing syndrome, hypothyroidism, insulinoma, type 2 diabetes, pseudoparathyroid hypothyroidism, hypogonadism; Obesity-related endocrine disorders: Polycystic ovary syndrome (PCOS); Central obesity: hypothalamic obesity, frontal lobe syndrome, Kleine-Levin syndrome; Hereditary obesity: Prader-Willi syndrome, Laurence-Moon-Biedl syndrome; Drug-induced obesity: steroid-induced obesity, phenothiazine-induced obesity, insulin-induced obesity, sulfonylurea-induced obesity, and beta-blocker-induced obesity; Comorbidities associated with obesity and / or overweight: associated type 2 diabetes, associated hypertension, associated NAFLD, associated NASH, associated DKD, associated CKD, associated osteoporosis, associated sleep apnea, associated cancer, associated asthma; Hyperlipidemia: hypertriglyceridemia, hypercholesterolemia, hyperLDL-cholesterolemia, lowHDL-cholesterolemia, postprandial hyperlipidemia; Metabolic syndrome: abdominal obesity, hypertension, hyperglycemia, high serum triglycerides, and low serum high-density lipoprotein (HDL); Liver diseases: Metabolic fatty liver disease (MAFLD), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), portal hypertension; Cardiovascular diseases: hypertension, atherosclerosis, stroke, heart failure; Kidney diseases: Diabetic kidney disease (DKD), chronic kidney disease (CKD); Neurodegenerative diseases: Alzheimer's disease, Parkinson's disease.

Claims

1. A polypeptide with a general structure according to formula (I), Z1-Z2-Z3(I)(SEQ ID NO:647), in, Z1 is a hybrid polypeptide composed of the following amino acid sequence. Y-Aib-X3-G-T-F-T-S-D-X 10 -S-I-X 13 -L-X 15 -X 16 -X 17 -A-X 19 -X 20 -X 21 -F-X 23 -X 24 -X 25 -L-X 27 -K(SEQ ID NO:646), X3 was selected as either E or D; X 10 Selected as Y or L; X 13 Selected as Aib or L; X 15 The answer is E, D, or A; X 16 The options are K, E, D, Aib, G, LysAc, A, L, S, Q, or R; X 17 The answer is Q, E, K, or A; X 19 The answer is Q or E; X 20 Selected as Aib, D-Asp, or D-Arg; X 21 The answer is A, E, or K; X 23 V or I; X 24 The answer is E or Q; X 25 The choice is W or Y; X 27 For I or L; Z2 is composed of the amino acid sequence GGX. 31 -X 32 -X 33 -X 34 The connecting base is composed of X 31 Selected as P, G, or Q; X 32 Selected as S, E, or R; X 33 The choice is S, E, Y, or T; X 34 The choice is G, P, Y, or A; Z3 is a polypeptide composed of the following amino acid sequence. X 35 -X 36 -X 37 -X 38 -X 39 -Y-X 41 -X 42 -X 43 -X 44 -T-X 46 -X 47 -X 48 -X 49 , Where X 35 The answer is A, Q, I, V, E, or L; X 36 Selected as S, E, T, D, or L; X 37 The options are L, Aib, V, D-Leu, I, or Tle; X 38 Selected as R, L, or Aib; X 39 Selected as H, Aib, D-His, or Tle; X 41 The options are Y, L, Aib, I, or Tle; X 42 Selected as N or Aib; X 43 The options are W, H, L, R, or Aib; X 44 Selected as L, Aib, D-Arg, D-Asp, or Tle; X 46 Selected as R, hArg, or D-Arg; X 47 Selected as Q, bh-Gln, or NMeQ; X 48 Selected as R or NMeR; X 49 The selected values ​​are Y, Tle, Chg, D-Tyr, and Phg.

2. The polypeptide of claim 1, wherein in Z3 X 35 The options selected are A, E, I, L, Q, and V; X 36 S or T; X 37 The selected values ​​are Aib, I, L, Tle, and V; X 38 Selected as Aib or R;X 39 Selected as H or Tle; X 41 Selected as I, L, Tle, or Y; X 42 N was chosen as the candidate for N; X 43 W and X were selected. 44 Selected as L or Tle; X 46 R; X were selected. 47 Selected as NMeQ or Q;X 48 Selected as NMeR or R;X 49 Y was selected.

3. The polypeptide of any of the preceding claims, wherein in Z1 X3 is selected as either E or D; X 10 Selected as Y or L; X 13 Selected as Aib or L; X 15 The answer is either E or D; X 16 The options are K, E, D, G, A, S, Q, or R; X 17 The answer is Q, E, or A; X 19 The answer is E or Q; X 20 Selected as Aib; X 21 The answer is A, E, or K; X 23 V or I; X 24 The answer is E or Q; X 25 The choice is W or Y; X 27 It was selected as I or L.

4. The polypeptide as claimed in any of the preceding claims, Z2 is composed of the amino acid sequence GGX. 31 -X 32 -X 33 -X 34 Composition, in which X 31 Selected as P or Q; X 32 S or E; X 33 The choice is S, E, Y, or T; X 34 The choice is G, P, Y, or A; Preferably, Z2 is selected from the group consisting of: GGPEEG (SEQ ID NO:313), GGPEEP (SEQ ID NO:314), GGPESG (SEQ ID NO:315), GGPESP (SEQ ID NO:316), GGPSEG (SEQ ID NO:311), GGPSEP (SEQ ID NO:317), GGPSEY (SEQ ID NO:318), GGPSSA (SEQ ID NO:319), GGPSSG (SEQ ID NO:320), GGPSSP (SEQ ID NO:321), GGPSSY (SEQ ID NO:322), GGPSTG (SEQ ID NO:323), GGPSYG (SEQ ID NO:324), GGQSSG (SEQ ID NO:325), GGPRSG (SEQ ID NO:650), GGPRYY (SEQ ID NO:651), and GGPSYY (SEQ ID NO:652).

5. The polypeptide as claimed in any of the preceding claims, In Z1, X3 is selected as E; X 10 Y was selected as the answer; X was selected as the answer. 13 Selected as Aib; X 15 E and X were selected. 16 K and X were selected. 17 Q and X were selected. 19 Q and X were selected. 20 Selected as Aib; X 21 The answer is A or E; X 23 V and X were selected. 24 The answer is E or Q; X 25 W and X were selected. 27 For I; Z2 is composed of the amino acid sequence GGPSEG (SEQ ID NO:311) or GGPSSG (SEQ ID NO:320); In Z3, X 35 The answer is A, Q, or V; X 36 S and X were selected. 37 Selected as I or L; X 38 R; X were selected. 39 H and X were selected. 41 Y was selected as the answer; X was selected as the answer. 42 N was chosen as the candidate for N; X 43 W and X were selected. 44 L and X were selected. 46 R; X were selected. 47 Selected as Q or NMeQ; X 48 Selected as R or NMeR; X 49 Y was selected.

6. The polypeptide of any of the preceding claims, wherein the polypeptide is located at the amino acid position X of the ε (epsilon) amino group. 28 Lipidification occurs at the lysine (K) residue in the protein.

7. The polypeptide of claim 6, wherein the polypeptide is in the form of the general formula LY 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 -Y 7 -Y 8 The structure of lipidation, wherein L is a lipid selected from 17-carboxy-heptadecanoyl (C18DA) and 19-carboxy-nonadecanoyl (C20DA), and wherein Y 1 -Y 8 Each of the elements is independently selected from: absent, [γE], [E], [OEG], [eLys], or [AHX], and wherein the esterification refers to lipid (L) optionally via a linker / spacer -Y 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 -Y 7 -Y 8 Covalently linked to the polypeptide; preferably wherein L--Y 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 -Y 7 -Y 8 Choose from the following groups: C20DA[γE][γE][γE][γE][γE]-, C20DA[γE][γE][γE][γE][γE][γE]-, C20DA[γE][γE][γE][γE][γE][γE][γE]-, C18DA[E][E][E][E][E][eLys]-(SEQ IDNO:635),C20DA[E][E][E][E][E][eLys]-(SEQ ID NO: 639),C20DA[γE][γE][γE][γE][eLys]-, C20DA[γE][γE][γE][γE][γE][eLys]-, C20DA[γE][γE][γE][γE][γE][γE][eLys]-, C2 0DA[γE][γE][γE][γE][γE][γE][γE][eLys]-, C20DA[γE][γE][γE][γE][γE][eLys][eLys]-, C20DA[E][E][E][E][OEG][OEG]-(SEQ ID NO: 638),, C20DA[γE][γE][γE][γE][OEG][OEG]-,C20DA[γE][γE][γE][γE][γE][OEG ][OEG]-,C20DA[γE][γE][γE][γE][OEG]-,C20DA[γE][γE][γE][γE][γE][OEG]-,C20D A[γE][γE][γE][γE][γE][γE][OEG]-,C20DA[γE][γE][γE][γE][OEG][eLys]-,C20DA [γE][γE][γE][γE][γE][OEG][eLys]-,C20DA[γE][γE][γE][γE][OEG][OEG][eLys]-.

8. The polypeptide of any of the preceding claims, wherein the polypeptide is selected from the group consisting of compounds 2 to 305 according to the following table:

9. The polypeptide of any of the preceding claims, wherein the polypeptide is in the form of a salt or in the form of a pharmaceutically acceptable salt.

10. Use of the polypeptide of any of the preceding claims in the preparation of a medicament for the treatment and / or prevention of: Overweight, long-term weight management, obesity, symptomatic obesity, eating disorders; Insulin resistance, diabetes, type 1 diabetes, type 2 diabetes, prediabetes; Endocrine obesity: Cushing syndrome, hypothyroidism, insulinoma, type 2 diabetes, pseudoparathyroid hypothyroidism, hypogonadism; Obesity-related endocrine disorders: Polycystic ovary syndrome (PCOS); Central obesity: hypothalamic obesity, frontal lobe syndrome, Kleine-Levin syndrome; Hereditary obesity: Prader-Willi syndrome, Laurence-Moon-Biedl syndrome; Drug-induced obesity: steroid-induced obesity, phenothiazine-induced obesity, insulin-induced obesity, sulfonylurea-induced obesity, and beta-blocker-induced obesity; Comorbidities associated with obesity and / or overweight: associated type 2 diabetes, associated hypertension, associated NAFLD, associated NASH, associated DKD, associated CKD, associated osteoporosis, associated sleep apnea, associated cancer, associated asthma; Hyperlipidemia: hypertriglyceridemia, hypercholesterolemia, hyperLDL-cholesterolemia, lowHDL-cholesterolemia, postprandial hyperlipidemia; Metabolic syndrome: abdominal obesity, hypertension, hyperglycemia, high serum triglycerides, and low serum high-density lipoprotein (HDL); Liver diseases: Metabolic fatty liver disease (MAFLD), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), portal hypertension; Cardiovascular diseases: hypertension, atherosclerosis, stroke, heart failure; Kidney diseases: Diabetic kidney disease (DKD), chronic kidney disease (CKD); Neurodegenerative diseases: Alzheimer's disease, Parkinson's disease.

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