GLP1 / GIP / NPY2 receptor triple agonist

Abstract

Hybrid polypeptides that stimulate GIP, GLP-1, and neuropeptide Y2 (NPY2) receptors and their pharmaceutical uses in the treatment of various diseases, conditions, or disorders, such as obesity, diabetes, and / or NASH, are disclosed. The polypeptides have the general structure Z1-Z2-Z3, where Z1 is a hybrid polypeptide that provides GIP and GLP1R agonism, Z2 is a linker, and Z3 is a polypeptide that provides NPY2R agonism.

Description

[Technical Field]

[0001] The present invention relates to hybrid polypeptides that stimulate GIP, GLP-1, and neuropeptide Y2 (NPY2) receptors, and their pharmaceutical applications in the treatment of various diseases, symptoms, or disorders, such as obesity, diabetes, and / or NASH. [Background technology]

[0002] Obesity is defined as an abnormal or excessive accumulation of fat that poses a health risk. (27 kg / m²) 2 A Body Mass Index (BMI) exceeding 30 kg / m² is considered overweight. 2 A BMI exceeding 100% is considered obese. BMI is calculated based on weight and height. In the last 50 years, obesity has reached pandemic levels. Globally, obesity has nearly tripled since 1975. In 2016, more than 1.9 billion adults and more than 340 million children and adolescents were overweight or obese. Both overweight and obesity are major risk factors for numerous chronic diseases, including type 2 diabetes, cardiovascular disease, and cancer, which are major causes of morbidity and mortality in the United States. Obesity is, therefore, a serious condition, associated with worsening mental health, a decline in quality of life, and a reduction in life expectancy (Abdelaal 2017). According to the WHO, overweight and obesity are no longer limited to high-income countries, but are now rapidly increasing in low- and middle-income countries as well. WHO World Health Statistics showed 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 having the sequence YPIKPEAPREDASPEELNRYYASLRHYLNLVTRQRY (SEQ ID NO: 308), and is present in the mucosa of the gastrointestinal tract, particularly in the endocrine L - cells of the ileum and colon. PYY belongs to the pancreatic polypeptide (PP) family, together with neuropeptide Y (NPY) and pancreatic polypeptide (PP). This peptide family acts on NPY receptors, which refer to NPY1R (Y1), NPY2R (Y2), NPY4R (Y4), and NPY5R (Y5). The said receptor family belongs to the class of G - protein - coupled receptors (GPCRs) that are expressed in the CNS, particularly in the hypothalamic region. The receptors NPY1R - NPY5R exhibit both appetite - suppressing effects (NPY2R, NPY4R) and appetite - promoting effects (NPY5R, NPY1R). The two main forms of peptide YY are PYY 1-36 and PYY 3-36 . PYY 1-36 is proportional to the energy intake and is released post - prandially from intestinal L - cells, and a part of it is cleaved to PYY 3-36 . PYY 3-36 is the main circulating form of PPY and is a relatively selective Y2 receptor agonist. PYY 1-36 and PYY 3-36 inhibit gastric acid secretion, gastrointestinal transit, and food intake. Food intake is inhibited via both the stimulatory effect on Y2 receptors in vagal afferent neurons and the interaction with Y2 receptors in the hypothalamus, which is consistent with the ability of PYY to increase access to the brain via circumventricular organs such as the area postrema and the subfornical organ. Furthermore, it is known that the blood PPY concentration in obese people is lower than that in healthy people. Therefore, NPY2R and / or NPY4R agonists hold potential in the treatment of obesity.

[0004] Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinopromoting polypeptide (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 from 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 insulinopromoting activity (i.e., stimulate insulin release) and feeding suppressive activity. GIP acts via the GIP receptor and is also known to have glucose-dependent insulinopromoting activity, although its effect on feeding is somewhat unclear. GLP-1 receptor / GIP receptor coagonist peptides have been reported to exhibit more potent blood glucose-lowering and weight-reducing effects than GLP-1 receptor agonists alone. Therefore, research efforts have been undertaken to develop GLP-1 / GIP receptor coagonists for the treatment of obesity and / or diabetes, based on the structures of natural glucagon, GIP, or GLP-1.

[0005] The most notable effect of GLP-1 agonists is their ability to stimulate glucose-dependent insulin secretion 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 higher than fasting levels. Importantly, this does not affect the glucagon response to hypoglycemia, making GLP-1 agonists safer antidiabetic drugs compared to insulin, with a significantly lower incidence of hypoglycemia. In June 2021, the GLP-1 agonist semaglutide was approved by the FDA for chronic weight management in obese or overweight adults with at least one weight-related condition (e.g., hypertension, type 2 diabetes, or high cholesterol). As anti-obesity drugs, GLP-1 agonists act 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 gastric motility, thereby collectively increasing satiety. As a result, patients with diabetes treated with GLP-1 receptor agonists often experience beneficial weight loss in addition to their blood glucose control.

[0006] However, despite years of efforts, the number of patients with overweight and obesity is still increasing. The first-line treatment for patients with overweight and obesity includes diet and exercise, but often they are not sufficiently effective. The second-line treatment options are bariatric surgery and pharmacotherapy. The available pharmacological treatments seem to lack efficacy and / or safety, and only a limited number of approved treatments such as semaglutide are available in the United States and Europe. Therefore, there is still a high medical need for more effective and safe treatment options. Future obesity treatments can benefit by considering the biological roles of PYY, GIP or GLP-1 and targeting GLP1-R, GIPR and NPY2R simultaneously. In fact, recent research efforts in the obesity field have aimed to develop hybrid polypeptides as triple agonists for these receptors (see, for example, EP3467106 A1). Hybrid polypeptides are highly desirable compared to combination therapies using individual polypeptides for several reasons. First, hybrid polypeptides are easier to formulate into a single dosage unit compared to a mixture of different polypeptides. This is mainly because different peptides can have different physicochemical properties at a given pH, such as isoelectric point, solubility or chemical stability, meaning that a formulation developed for one polypeptide may not be optimal or compatible for a different polypeptide. Thus, combination therapies using individual polypeptides may require individual dosage units. Second, hybrid polypeptides can be manufactured more cheaply and the regulatory approval burden is also reduced compared to individual polypeptides.

[0007] The present invention aims to provide a hybrid polypeptide that stimulates all of the receptors GLP1-R, GIPR and NPY2R, for example, to provide an improved treatment for obesity, diabetes and / or metabolic syndrome. Furthermore, it is an object of the present invention to provide a triple agonist that is soluble at or around physiological pH (e.g., pH 7). A further object of the present invention is to provide a triple agonist that has a long-term effect in the body, i.e., a long in vivo half-life. A further object of the present invention is to provide a triple agonist that stimulates all of the GLP1-R, GIPR, and NPY2R receptors and is soluble at or around physiological pH (e.g., pH 7). A further object of the present invention is to provide a triple agonist that stimulates all of the GLP1-R, GIPR, and NPY2R receptors, is soluble at or around physiological pH (e.g., pH 7), and has a long-lasting effect in the body. A further object of the present invention is to provide a triple agonist that exhibits superior selectivity for GLP1-R, GIPR, and NPY2R receptors compared to other incretins or related receptors. For example, the agonists of the present invention may not activate other receptors of the NPY receptor family (e.g., NPY1, NPY4, or NPY5 receptors), and / or GLP-2 or glucagon receptors.

[0008] Summary of the Invention In a first aspect, the present invention provides polypeptides having the general structure of formula (I), or pharmaceutically acceptable salts thereof. Z1-Z2-Z3 (I) (In the formula, Z1 is a hybrid polypeptide that provides GIPR agonism and GLP1R agonism, comprising the amino acid sequence Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK (SEQ ID NO: 306), or derivatives thereof having one, two, or three substitutions; Z2 is a linker; Z3 is a polypeptide that provides an hY2R agonism, including the amino acid sequence ASLRHYYNWLTRQRY (SEQ ID NO: 307), or its derivatives having one, two, three, four, or five substitutions.

[0009] In a second aspect, the present invention provides polypeptides comprising the general structure of formula (I) or pharmaceutically acceptable salts thereof. Z1-Z2-Z3 (Sequence ID: 647) (I) (In the formula, Z1 has the 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 A GIP / GLP1 hybrid polypeptide containing -K (SEQ ID NO: 646), where X3 is selected as E or D; X 10 If selected as Y or L; X 13 is selected as Aib or L; X 15 is selected as E, D, or A; X 16 is selected as K, E, D, Aib, G, LysAc, A, L, S, Q, or R; X 17 is selected as Q, E, K, or A; X 19 is selected as Q or E; X 20 is selected as Aib, D-Asp, or D-Arg; X 21 is selected as A, E, or K; X 23 is selected as V or I; X 24 is selected as E or Q; X 25 is selected as W or Y; X 27 is I or L; Z2 has the amino acid sequence GGX 31 -X 32 -X 33 -X 34 A linker consisting of X 31 is selected as P, G, or Q; X 32 is selected as S, E, or R; X 33 is selected as S, E, Y, or T; X 34is selected as G, P, Y, or A; Z3 is an 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 A polypeptide containing X 35 is selected as A, Q, I, V, E, or L; X 36 is selected as S, E, T, D, or L; X 37 is selected as L, Aib, V, D-Leu, I or Tle; X 38 is selected as R, L, or Aib; X 39 is selected as H, Aib, D-His or Tle; X 41 is selected as L, Y, Aib, I or Tle; X 42 is selected as N or Aib; X 43 is selected as W, H, L, R, or Aib; X 44 is selected as L, Aib, D-Arg, D-Asp, or Tle; X 46 is selected as R, hArg, or D-Arg; X 47 is selected as Q, bh-Gln, or NMeQ; X 48 is selected as R or NMeR;X 49 (These are selected as Y, Tle, Chg, D-Tyr, and Phg.)

[0010] In a third aspect, the present invention relates to a polypeptide according to the first or second aspect for use as a pharmaceutical. In a fourth aspect, the present invention relates to a method for treating a disease, disorder and / or symptom selected from the list consisting of excessive body weight, obesity, type 1 and type 2 diabetes, eating disorders, hyperlipidemia, metabolic syndrome, NAFLD / NASH, and / or cardiovascular disease, the method comprising administering a therapeutically effective amount of the polypeptide or a pharmaceutically acceptable salt thereof of the first or second aspect to an individual in need thereof.

[0011] Terms, definitions, and conventions Terms not specifically defined herein should be given the meanings that a person skilled in the art would assign to them, taking into account the disclosure and context. However, where used herein, unless otherwise specified, the following terms shall have the meanings indicated and the following conventions shall be observed. amino acid According to the present invention, unless otherwise specified, all amino acids are L-amino acids (L-stereoisomers, native amino acids). In this context, substitutions in analogs / derivatives may be substitutions with native and unnatural amino acids, including L- and D-stereoisomers. Substitutions in derivatives may be conservative substitutions with conservative amino acids. The group of conservative amino acids can be defined as follows: G, A, V, L, I, P (aliphatic or cyclic), S, C, T, M (containing hydroxyl or sulfur) F, Y, W (aromatic) H, K, R (basic) D, E, N, Q (acids or amides)

[0012] Common non-natural amino acids include: NMeG (N-methylglycine, also known as NMeGly, MeGly, or sarcosine), NMeP (N-methyl-L-proline, also known as NMePro, or (S)-1-methylpyrrolidine-2-carboxylic acid), Dpr (L-2,3-diaminopropionic acid), Aib (2-aminoisobutyric acid), NMeQ (N-methylglutamine, also known as NMeGln or MeGln), NMeAla (N-methylalanine, also known as NMeA or MeAla), and (S)-2-amino-3-methylglycine. Examples include Cha (also called L-cyclohexylalanine), meaning lohexylpropanoic acid; Tle (also called L-2-(tert-butyl)glycine), meaning amino acid (S)-2-amino-3,3-dimethylbutanoic acid; 1-Nal (also called 3-(1-naphthyl)-L-alanine), meaning amino acid (S)-2-amino-3-(naphthalene-1-yl)propanoic acid; Pip (also called L-pipecolic acid), meaning amino acid (S)-piperidine-2-carboxylic acid; Nip (also called L-nipecotinic acid), meaning amino acid (S)-piperidine-3-carboxylic acid; Nle (also called L-norleucine), meaning amino acid (2S)-2-aminohexanoic acid; and Phe(4F) (also called 4-fluoro-L-phenylalanine), meaning amino acid (S)-2-amino-3-(4-fluorophenyl)propanoic acid.

[0013] Salts and pharmaceutically acceptable salts According to the present invention, the polypeptide or its derivative may be in the form of a salt. According to the present invention, polypeptides or derivatives thereof may be in the form of pharmaceutically acceptable salts. Therefore, pharmaceutically acceptable salts are intended to include any salt commonly used in peptide formulations. Such salts include both acid addition salts and basic salts, examples of which can be found in Remington's Pharmaceutical Sciences, 17th edition, etc. Similarly, polypeptides or pharmaceutically acceptable salts may be in the form of solvates (e.g., hydrates).

[0014] Compound Nomenclature Compounds are represented using Boehringer Ingelheim Line Notation (BILN), a human-readable method for describing complex peptides (Fox et al, J. Chem. Inf. Model. 2022, 62, 17, 3942-3947). In BILN, chains are constructed from monomers (e.g., A for alanine, Aib for isobutyric acid), and two monomers are linked by a hyphen "-". Different chains are separated by a dot ".", and the relationship between chains is explicitly defined in parentheses after the monomer. These parentheses include the link ID number and the R group number; for example, K(1,3) represents a lysine residue linked to another monomer having the link ID number "1" via its R"3"- group (ε-amino group). For example, 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) (where C20DA represents 19-carboxynonadecanoyl and gGlu([γE]) represents L-γ-glutamyl) binds to C20DA via its amino group, and to the amino group of the next gGlu via its γ-carboxyl group, and this is repeated four times, resulting in a total of six gGlu residues, and then binds to the ε-amino group of lysine (eLys) via the last γ-carboxyl group, and to the ε-amino group of lysine (K) via the carboxyl group, completely defining the following structure: [ka] The structure is disclosed in sequence number 412.

[0015] Lipidation In this context, lipidation refers to the covalent attachment of a lipid (L), such as C18DA (octadecanedioic acid), C20DA (icosanedioic acid) or other half-life extension moieties, to the hybrid polypeptide of the present invention, optionally via a linker / spacer (-(Y-) 1-8 ). The linker / spacer may consist of one or more covalently bonded monomers commonly used in the art, such as [γE], [OEG] or [AHX] shown below.

Chemical formula

[0016] The lipid (L) is a linker / spacer (-(Y-) 1-8) can be bonded via esters, ethers, sulfonyl esters, thioesters, amides, amines, triazoles, or sulfonamides, preferably via amides or esters. Therefore, preferably, lipid (L) will be understood to contain acyl groups, sulfonyl groups, alkynes, azides, N atoms, O atoms, or S atoms, which form a part of the ester, sulfonyl ester, thioester, triazole, amide, amine, or sulfonamide. Preferably, the acyl group or O or N atom in the lipophilic substituent (L) is a linker / spacer (-(Y-) 1-8 It forms a part of an amide or ester having ). Similarly, linker / spacer (-(Y-) 1-8 (If present) the linker / spacer (-(Y-) is linked to the amino acid residue of the hybrid polypeptide of the present invention via an ester, sulfonyl ester, thioester, amide, amine, or sulfonamide. Therefore, preferably, a linker / spacer (-(Y-) 1-8 (If present) it will be understood to include an acyl group, a sulfonyl group, an N atom, an O atom, or an S atom, which form part of an ester, sulfonyl ester, thioester, amide, amine, or sulfonamide. Preferably, a linker (-(Y-) 1-8 The acyl group, or the O or N atom in ), forms part of an amide or ester having an amino acid residue.

[0017] The lipophilic substituent (L) may include a hydrocarbon chain having 10 to 24 carbon atoms, for example, 14 to 22 carbon atoms, for example, 16 to 20 carbon atoms. Preferably, it has at least 14 carbon atoms, and preferably 20 or fewer carbon atoms. For example, the hydrocarbon chain may contain 14, 15, 16, 17, 18, 19, or 20 carbon atoms. The hydrocarbon chain may be linear or branched, and may be saturated or unsaturated. Furthermore, it may include a functional group at the end of the hydrocarbon chain, for example, a carboxylic acid group, a sulfonic acid group, or a tetrazole group. From the above discussion, the hydrocarbon chain may preferably be part of the linkage to the amino acid residue of the hybrid polypeptide of the present invention, or a linker (-(Y-) 1-8It will also be understood that the hydrocarbon chain may be substituted with a site (e.g., an acyl group, a sulfonyl group, an N atom, an O atom, or an S atom) that forms part of the bond to the linker / spacer. Most preferably, the hydrocarbon chain is substituted with an acyl group (for bonding to the linker / spacer), and thus the hydrocarbon chain may be part of an alkanoyl group, e.g., dodecanoyl, 2-butyloctanoyl, tetradecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, or eicosaenoyl group. The other end of these hydrocarbon chains, with one end substituted with an acyl group, may be further functionalized with a carboxylic acid group. Examples of functionalized hydrocarbon chains (e.g., lipophilic substituent L) are 15-carboxyl-pentadecanoyl (abbreviated as C16DA), 17-carboxy-heptadecanoyl (abbreviated as C18DA), and 19-carboxy-nonadecanoyl (abbreviated as C20DA). Preferred lipids or lipid / linkers in this disclosure 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][γE]-, C18DA[γE][γE][γE][γE][γE]-, C18DA[γE][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][γ E][γE]-, C20DA[γE][γE][γE][γE][γE][γE]-, C20DA[γE][γE][γE][γE][γE][γE][γE]-, C1 8DA[eLys], C18DA[E][E][E][E][E][eLys]-(SEQ ID NO: 635), C18DA[E][E][E][E][E][E][eLys ]-(SEQ ID NO: 643), 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[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][γE][OEG][OEG]-, C20DA[OEG][OEG]-, C20DA[E][E][E][E][OEG][OEG]-(SEQ ID NO: 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][OEG][eLys]-、C18DA[γE][γE][OEG][eLys]-、C18DA[γE][γE][OEG][eLys]-、C18DA[γE][γE][OEG][eLys]-、C18DA[γE][γE][OEG][eLys]- ]-、C18DA[γE][γE][γE][γE][OEG][eLys]-、C18DA[γE][γE][γE][γE][γE][γE][OEG][eLys]-、C20DA[OEG][eLys]-、C20DA[γE][γE][OEG][eLys]-、C20DA[γE][γE][OEG][eLys]-、C20DA[γE][γE][γE][OEG][eLys]-、C20DA[γE][γE][γE][OEG][eLys]-、C20DA[γE][γE][γE][γE][OEG][eLys]-、C20DA[γE][γE][γE][γE][OEG][eLys]-、C20DA[ 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][OEG][OEG][eLys]-、C18DA[γE][γE][γE][γE][OEG][OEG][eLys]-、C20DA[OEG][OEG][eLys]-、C20DA[γE][ EG][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][γE][AHX]-、C20DA[AHX]、C20DA[γE][AHX]-、C20DA[γE][γE][AHX]-, C20DA[γE][γE][γE][AHX]-, C20DA[γE][γE][γE][γE][γE][AHX]-, C20DA[γE][γE][γE][γE][γE][AHX]-, or C20DA[γE][γE][γE][γE][γE][γE][AHX]-. Preferably, the polypeptide is amino acid position X, 28 Lipid addition occurs at the lysine (K) residue.

[0018] N- and C-terminuses In this context, polypeptides are generally amidated at the C-terminus (-CONH2), as is common with natural peptides. However, polypeptides of the present invention may have a free carboxylic acid (-COOH) or other post-translational modifications, such as a methyl ester (-COOMe). In a very preferred embodiment of the present invention, the polypeptide is amidated at the C-terminus. Polypeptides of the present invention may have a free amine (-NH2) and may be N-acetylated (-NHCOR), N-methylated (-NHCH3 or -N(CH3)2), deamidated, or N-lipid-added at the N-terminus.

[0019] Pharmaceutical composition In this context, it should be understood that the polypeptide of the present invention, or a pharmaceutically acceptable salt thereof, may be in the form of a pharmaceutical composition. The pharmaceutical composition may comprise a pharmaceutically acceptable carrier and / or one or more excipients. The pharmaceutical composition (i.e., formulation) may include, but is not limited to, tablets, pills, capsules, emulsifiers, suspending agents, sustained-release formulations, solutions, or lyophilized powders intended to be dissolved before administration. In some embodiments, the formulation may be a depot formulation providing a slow release. It should be understood that various routes of administration may be used based 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, parenteral administration (intravenous (IV), subcutaneous (SC), intradermal (ID), and intramuscular (IM)), or inhalation. In a preferred embodiment of the present invention, the route of administration is parenteral administration. In a more preferred embodiment, the route of administration is subcutaneous. Peptide therapies are typically provided as pre-filled, ready-to-use liquid formulations in syringes. Dosage has been limited in these peptide formulations for subcutaneous administration. Therefore, excellent solubility of the peptide at or around physiological pH (e.g., pH 7) is required for administration in ready-to-use syringes.

[0020] Detailed description of the invention In a first aspect, the present invention provides a polypeptide having the general structure of formula (I), or a salt thereof, or a pharmaceutically acceptable salt thereof. Z1-Z2-Z3 (I) (In the formula, Z1 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; Z2 is a linker; Z3 is a polypeptide containing, or comprising, the amino acid sequence ASLRHYYNWLTRQRY (SEQ ID NO: 307), or its derivatives having one, two, three, four, or five amino acid substitutions. The compounds of the present invention bind to and / or activate GLP-1, GIP, and hY2 (NPY2) receptors.

[0021] Linker Z2 Peptide fragments Z1 and Z3 are linked via linker Z2. It should be understood that Z1 and Z3 can be linked by various linkers, for example, those commonly used in the field of fusion proteins. Preferably, the linker contains or consists of a short peptide comprising 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 comprises 6 amino acid residues (i.e., amino acid X 29 -X 34 ) consists of. In a more preferred embodiment, Z2 is the amino acid sequence GGPSEG (Sequence ID: 311, i.e., amino acid X 29 -X 34 ) is a derivative thereof having or containing the same, or having one, two, three or four amino acid substitutions. Preferably, the one, two, three or four amino acid substitutions in Z2 are at any position X 31 , X 32 , X 33 or X 34 It is present in (i.e., in the amino acid sequence PSEG (SEQ ID NO: 644)). Therefore, the Z2 derivative is a Z2 peptide analog of the amino acid sequence (SEQ ID NO: 311) having one or more amino acid substitutions compared to SEQ ID NO: 311. In a very preferred embodiment (Z2-Emb1), Z2 (i.e., amino acid X) 29 -X 34 ) is the amino acid sequence GGX 31 X 32X 33 X 34 A derivative thereof having, containing, or having one amino acid substitution, where X 31 is selected as P, G, or Q; X 32 is selected as S, E, or R; X 33 is selected as S, E, or Y, or preferably S, E, Y, or T; X 34 This is selected as G, P, Y, or A. In a more very preferred embodiment, Z2 has one of the following embodiments of Z2 (e.g., Z2-Emb2, Z2-Emb3) in a second aspect of the present invention.

[0022] Hybrid polypeptide Z1 Z1 (i.e., amino acids X1-X) 28 ) is a GIP / GLP1 hybrid polypeptide containing the amino acid sequence Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK (SEQ ID NO: 306), or consisting thereof, 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 chosen as the reference sequence. Table 1 (see [Table 1-1] and subsequent tables) summarizes the number of substitutions in Z1, the position of the substituted Z1, and examples of the substituted amino acids compared to the reference (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 27It was found to be tolerant of substitutions. Therefore, in a preferred embodiment, one, two, or three substitutions in the derivative of Z1 are permitted at any 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 It exists in [location]. Preferably, the derivative of Z1 has one or two substitutions. Most preferably, the derivative of Z1 has one substitution. Therefore, the Z1 derivative is a Z1 peptide analog of the amino acid sequence (SEQ ID NO: 306) having one or more amino acid substitutions compared to SEQ ID NO: 306. In a very preferred embodiment, the substitution in the derivative of Z1 is selected as follows: X3 is selected as D; X 10 is selected as L; X1 is selected as L; X 15 is selected as D or A; X 16 is selected as E, D, Aib, G, LysAc, A, L, S, Q, or R; X 17 is selected as E, K, or A; X 19 is selected as E; X 20 is selected as D-Asp or D-Arg;X 21 is selected as E, or preferably E or K; X 23 is selected as I; X 24 Q is selected; X 25 is selected as Y; X 27 This is selected as L.

[0023] Z1 may consist of or contain the amino acid sequence Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK (Sequence ID: 306), or any amino acid positions X3, X 10 , X 13 , X 15 , X16 , X 17 , X 19 , X 21 , X 23 , X 24 , X 25 or X 27 The derivatives may have one, two, or three amino acid substitutions, where the substitutions are selected as follows: X3 is selected as D; X 10 is selected as L; X 13 is selected as L; X 15 is selected as D; X 16 is selected as E, D, G, A, S, Q, or R; X 17 is selected as E or A; X 19 is selected as E; X 21 is selected as E or K; X 23 is selected as I; X 24 Q is selected; X 25 is selected as Y; X 27 This is selected as L. Z1 may consist of or contain the amino acid sequence Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK (Sequence ID: 306), or any amino acid positions X3, X 10 , X 13 , X 15 , X 16 , X 17 , X 21 , X 23 , X 24 or X 25 The derivatives may have one, two, or three amino acid substitutions, where the substitutions are selected as follows: X3 is selected as D; X 10 is selected as L; X 13 is selected as L; X 15 is selected as D; X 16 is selected as E, D, G, A, S, Q, or R; X 17 is selected as E or A; X 21 is selected as E; X 23 is selected as I; X 24 Q is selected; X25 This is selected as Y. Z1 may consist of or contain the amino acid sequence Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK (Sequence ID: 306), or any amino acid position X 21 or X 24 The derivatives may have one or two, preferably one, amino acid substitutions, where the substitution is selected as follows: X 21 is selected as A or E; X 24 E or Q is selected.

[0024] Polypeptide Z3 Z3 (i.e., amino acid X) 35 -X 49 This polypeptide provides an hY2R agonism containing or consisting of the amino acid sequence ASLRHYYNWLTRQRY (SEQ ID NO: 307), or its derivatives having one, two, three, four, or five amino acid substitutions. The sequence ASLRHYYNWLTRQRY (SEQ ID NO: 307) (i.e., Z3 in SEQ ID NO: 286) was chosen as the reference sequence. Table 1 (see Table 2-1 and subsequent tables) summarizes the number of substitutions at Z3, the possible positions of Z3 substitution, and examples of substituted amino acids compared to the reference (i.e., SEQ ID NO: 286). As shown in Table 1, 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 It was found to be tolerant of substitutions. Therefore, in a preferred embodiment, one, two, three, four, or five substitutions in the derivative of Z3 are permitted at any 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 It is present in [location]. In a preferred embodiment, Z3 has one, two, or three substitutions. More preferably, Z3 has one or two substitutions. Most preferably, Z3 has one 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: 236) having one or more amino acid substitutions compared to SEQ ID NO: 307.

[0025] In a very preferred embodiment, the substitution in the derivative of Z3 is selected as follows: X 35 is selected as Q, I, V, E, or L; X 36 is selected as E, T, D, or L; X 37 is selected as Aib, V, D-Leu or I, or preferably Aib, V, D-Leu, I or Tle; X 38 is selected as L or Aib; X 39 Selected as Aib, D-His or Tle; X 41 is selected as L, Aib, I or Tle; X 42 is selected as Aib;X 43 is selected as H, L, R, or Aib; X 44 is selected as Aib, D-Arg, or D-Asp, or preferably Aib, D-Arg, D-Asp, or Tle; X 46 is selected as hArg or D-Arg; X 47 is selected as bh-Gln or NMeQ;X 48 is selected as NMeR;X 49 This is selected as Tle, Chg, D-Tyr, or Phg. Z3 may consist of or contain the amino acid sequence ASLRHYYNWLTRQRY (Sequence ID: 307), or any amino acid position X 35 , X 36 , X 37 , X 38 , X 39 , X 41 , X 44 , X 47 Or X 48 The derivative may have one, two, or three amino acid substitutions, where the substitutions are selected as follows: X 35 is selected as Q, I, V, E, or L; X 36 is selected as T; X 37 is selected as Aib, V, I, or Tle; X 38 is selected as Aib;X 39 is selected as Tle;X 41 is selected as I, L, or Tle; X 44 is selected as Tle;X 47 is selected as NMeQ;X 48 This is selected as NMeR. Z3 may consist of or contain the amino acid sequence ASLRHYYNWLTRQRY (SEQ ID NO: 307), or any amino acid position X 35 , X 37 , X 47 Or X 48 The derivative may have one or two, preferably one, amino acid substitutions, where the substitution is selected as follows: X 35 Q and V are selected; X 37 is selected as I; X 47 is selected as NMeQ;X 48 This is selected as NMeR. Overall, polypeptides Z1-Z2-Z3 of any embodiment disclosed in the present invention, in the first aspect of the present invention, preferably have 0, 1, 2, 3, 4, 5, or 6 amino acid substitutions, more preferably have 0, 1, 2, 3, or 4 amino acid substitutions, and very preferably have 0, 1, 2, or 3 substitutions, compared to SEQ ID NO: 286.

[0026] In a second aspect, the present invention provides a polypeptide having the general structure of formula (I), or a salt thereof, or a pharmaceutically acceptable salt thereof. Z1-Z2-Z3 (Sequence ID: 647) (I) (In the formula, Z1 has the 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) is included in or consists of a GIP / GLP1 hybrid polypeptide, or a derivative thereof having one amino acid substitution, where X3 is selected as E or D; X 10 If selected as Y or L; X 13 is selected as Aib or L; X 15 is selected as E, D, or A; X 16 is selected as K, E, D, Aib, G, LysAc, A, L, S, Q, or R; X 17 is selected as Q, E, K, or A; X 19 is selected as Q or E; X 20 is selected as Aib, D-Asp, or D-Arg; X 21 is selected as A, E, or K; X 23 is selected as V or I; X 24 is selected as E or Q; X 25is selected as W or Y; X 27 is I or L; Z2 has the amino acid sequence GGX 31 -X 32 -X 33 -X 34 A linker containing or consisting of, or a derivative thereof having one amino acid substitution, where X 31 is selected as P, G, or Q; X 32 is selected as S, E, or R; X 33 is selected as S, E, Y, or T; X 34 This is selected as G, P, Y, or A. Z3 is an 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 A polypeptide containing or consisting thereof, or a derivative thereof having one amino acid substitution, where X 35 is selected as A, Q, I, V, E, or L; X 36 is selected as S, E, T, D, or L; X 37 is selected as L, Aib, V, D-Leu, I or Tle; X 38 is selected as R, L, or Aib; X 39 is selected as H, Aib, D-His or Tle; X 41 is selected as Y, L, Aib, I, or Tle; X 42 is selected as N or Aib; X 43 is selected as W, H, L, R, or Aib; X 44 is selected as L, Aib, D-Arg, D-Asp, or Tle; X 46 is selected as R, hArg, or D-Arg; X 47 is selected as Q, bh-Gln, or NMeQ; X 48is selected as R or NMeR;X 49 (These are selected as Y, Tle, Chg, D-Tyr, and Phg.)

[0027] Preferred amino acids in Z1 In a preferred embodiment (Z1-Emb1), X3 is selected as E or D; X 10 is selected as Y or L; X 13 is selected as Aib or L; X 15 is selected as E or D; X 16 is selected as K, E, D, G, A, S, Q, or R; X 17 is selected as Q, E, or A; X 19 is selected as E or Q; X 20 It was selected as Aib; X 21 is selected as A, E, or K; X 23 is selected as V or I; X 24 is selected as E or Q; X 25 is selected as W or Y; X 27 is selected as I or L; Alternatively, Z1 is a derivative of it that has one amino acid substitution.

[0028] In a preferred embodiment (Z1-Emb2), X3 is selected as E or D; X 10 is selected as Y or L; X 13 is selected as Aib or L; X 15 is selected as E or D; X 16 is selected as K, E, D, G, A, S, Q, or R; X 17 is selected as Q, E, or A; X 19 Q is selected; X 20 It was selected as Aib; X 21 is selected as A or E; X 23 is selected as V or I; X 24 is selected as E or Q; X 25 is selected as W or Y; X 27 is I; Alternatively, Z1 is a derivative of it that has one amino acid substitution.

[0029] In a preferred embodiment (Z1-Emb3), X3 is selected as E; X 10 Y is selected; X 13 It was selected as Aib; X 15 E is selected; X 16 is selected as K; X 17 Q is selected; X 19 Q is selected; X 20 It was selected as Aib; X 21 is selected as A or E; X 23 V is selected; X 24 is selected as E or Q; X 25 is selected as W; X 27 is I; Alternatively, Z1 is a derivative of it that has one amino acid substitution.

[0030] In a preferred embodiment, X3 in Z1 is selected as E. In a preferred embodiment, X 10is selected as Y. In a preferred embodiment, X in Z1 13 is selected as Aib. In a preferred embodiment, X in Z1 15 is selected as E. In a preferred embodiment, X in Z1 16 is selected as K. In a preferred embodiment, X in Z1 17 is selected as Q. In a preferred embodiment, X in Z1 19 is selected as Q. In a preferred embodiment, X in Z1 20 is selected as Aib. In a preferred embodiment, X in Z1 21 is selected as A. In a preferred embodiment, X in Z1 23 is selected as V. In a preferred embodiment, X in Z1 24 is selected as E. In a preferred embodiment, X in Z1 25 is selected as W. In a preferred embodiment, X in Z1 27 It is selected as I. In a very preferred embodiment, X3 in Z1 is selected as E; X in Z1 10 is selected as Y; X in Z1 13 is selected as Aib. In a very preferred embodiment, X in Z1 15 is selected as E; X in Z1 16 is selected as K; X in Z1 17 is selected as Q. In a very preferred embodiment, X in Z1 19 is selected as Q; X in Z1 20 is selected as Aib; X in Z1 21 is selected as A. In a very preferred embodiment, X in Z1 23 is selected as V; X in Z1 24 is selected as E; X in Z1 25 is selected as W; X in Z1 27 It is selected as I.

[0031] Preferred amino acids in Z2 In a preferred embodiment (Z2-Emb1), Z2 is the amino acid sequence GGX 31 X 32 X 33 X 34 A derivative thereof containing, consisting of, or having one amino acid substitution, where X 31 is selected as P, G, or Q; X 32 is selected as S, E, or R; X 33 is selected as S, E, Y, or T; X 34 This is selected as G, P, Y, or A. In the preferred embodiment (Z2-Emb2), Z2 is the amino acid sequence GGX 31 -X 32 -X 33 -X 34 A derivative thereof containing, consisting of, or having one amino acid substitution, where X 31 is selected as P or Q; X 32 is selected as S or E; X 33 is selected as S, E, Y, or T; X 34 This is selected as G, P, Y, or A. In a very 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 is a derivative thereof having one amino acid substitution. In a preferred embodiment, X in Z2 31 is selected as P. In a preferred embodiment, X in Z2 32 is selected as S. In a preferred embodiment, X in Z2 33 is selected as S. In a preferred embodiment, X in Z2 34 It is selected as G.

[0032] In a further embodiment (Z2-Emb4), Z2 is GGPEEG (sequence number: 313), GGPEEP (sequence number: 314), GGPESG (sequence number: 315), GGPESP (sequence number: 316), GGPSEG (sequence number: 311), GGPSEP (sequence number: 317), GGPSEY (sequence number: 318), GGPSSA (sequence number: 319), GGPSSG (sequence number: 320), GGPSSP (sequence number: 321), GGPSSY (sequence number: 313), GGPSSA (sequence number: 319), GGPSSG (sequence number: 320), GGPSSP (sequence number: 321), GGPSSY (sequence number: 313), GGPSSG (sequence number: 320), GGPSSP (sequence number: 321), GGPSSY (sequence number: 313), GGPSSG (sequence number: 315), GGPSSP (sequence number: 316), GGPSEG (sequence number: 311), GGPSEP (sequence number: 317), GGPSEY (sequence number: 318), GGPSSA (sequence number: 319 Selected from the group consisting of (Sequence No.: 322), GGPSTG (Sequence No.: 323), GGPSYG (Sequence No.: 324), GGQSSG (Sequence No.: 325), GGGSEY (Sequence No.: 648), GGPEYY (Sequence No.: 649), GGPRSG (Sequence No.: 650), GGPRYY (Sequence No.: 651), GGPSYY (Sequence No.: 652), GGQRSY (Sequence No.: 653), GGQRYY (Sequence No.: 654), and GGQSSY (Sequence No.: 655). In a further embodiment (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).

[0033] In a further embodiment (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). In a further embodiment (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).

[0034] Preferred amino acids in Z3 In a further embodiment (Z3-Emb1), X 35 However, these are selected as A, E, I, L, Q, and V; X 36 is selected as S or T; X 37 Aib, I, L, Tle, and V are selected; X 38 Aib or R is selected; X 39 is selected as H or Tle; X 41 is selected as I, L, Tle, or Y; X 42 N is selected; X 43 is selected as W; X 44is selected as L or Tle; X 46 R is selected; X 47 is selected as NMeQ or Q; X 48 is selected as NMeR or R; X 49 Y is selected; Alternatively, Z3 is a derivative of it that has one amino acid substitution.

[0035] In a preferred embodiment (Z3-Emb2), X 35 is selected as A, Q, or V; X 36 S is selected; X 37 is selected as I or L; X 38 R is selected; X 39 is selected as H; X 41 Y is selected; X 42 N is selected; X 43 is selected as W; X 44 is selected as L; X 46 R is selected; X 47 is selected as Q or NMeQ; X 48 is selected as R or NMeR; X 49 Y is selected; Alternatively, Z3 is a derivative of it that has one amino acid substitution.

[0036] In a preferred embodiment, X in Z3 35 However, it is selected as A. In a preferred embodiment, X in Z3 36 However, it is selected as S. In a preferred embodiment, X in Z3 37However, it is selected as L. In a preferred embodiment, X in Z3 38 However, R is selected. In a preferred embodiment, X in Z3 39 However, it is selected as H. In a preferred embodiment, X in Z3 41 However, it is selected as Y. In a preferred embodiment, X in Z3 42 However, N is selected. In a preferred embodiment, X in Z3 43 However, it is selected as W. In a preferred embodiment, X in Z3 44 However, it is selected as L. In a preferred embodiment, X in Z3 46 However, R is selected. In a preferred embodiment, X in Z3 47 However, it is selected as Q. In a preferred embodiment, X in Z3 48 However, R is selected. In a preferred embodiment, X in Z3 49 However, it is selected as Y.

[0037] In a very preferred embodiment, X 35 X 36 X 37 X 38 X 39 is selected as ASLRH (Sequence ID: 645). In a very preferred embodiment, X 41 X 42 X 43 X 44 This is selected as YNWL (Sequence ID: 326). In a very preferred embodiment, X 46 X 47 X 48 X 49 This is selected as RQRY (sequence number: 327). It should be understood that any second aspect of the present invention and / or any related embodiment disclosed herein may be dependent on any first aspect of the present invention and / or any related embodiment disclosed herein. It should be understood that one or more embodiments of the first or second aspect of the present invention describing preferred amino acids at position Z1 may be combined with one or more embodiments describing preferred amino acids at positions Z2 and / or Z3, and vice versa. Thus, any combination of one or more embodiments referred to under “Preferred Amino Acids at Z1” may be combined with one or more embodiments referred to under “Preferred Amino Acids at Z2” and / or “Preferred Amino Acids at Z3” and vice versa. Any such combination of embodiments should be understood as a direct and explicit part of this disclosure.

[0038] With regard to a second aspect of the present invention, an example of a combination of the embodiments mentioned above is: The second embodiment is 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; These are Z1-Emb3, Z2-Emb3, and Z3-Emb2.

[0039] Preferred lipids / linkers A polypeptide according to the first and / or second aspect of the present invention preferably has a lysine (K) residue at amino acid position X 28 In the lysine (K) residue in, the general formula is LY 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 -Y 7 -Y 8 The structure (i.e., lipid / linker) can be lipid-added, where L is a lipid selected from 17-carboxy-heptadecanoyl (simply C18DA) and 19-carboxy-nonadecanoyl (simply C20DA), and furthermore, each Y1 ~Y 8 However, independently, it does not exist, or it is selected from [γE], [E], [OEG], [eLys], or [AHX]. Preferably, the lipid / linker is of the general formula LY 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 -Y 7 -Y 8 It has the structure, where L is a lipid selected from C18DA or C20DA, and each Y 1 ~Y 8 However, independently, they do not exist, or are selected from [γE], [E], [OEG], [eLys] or [AHX], and each Y 1 ~Y 3 However, [γE] or each Y 1 ~Y 3 However, [E] and Y 4 However, each Y is selected from [γE], [E], or [OEG]. 5 ~Y 8 However, independently, it does not exist, or it is selected from [γE], [E], [OEG], [eLys], or [AHX]. Preferably, the lipid / linker is of the general formula LY 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 -Y 7 -Y 8 It has the structure, where L is C20DA, and each Y 1 ~Y 8 However, independently, they do not exist, or are selected from [γE], [E], [OEG], or [eLys], and each Y 1 ~Y 4 However, [γE] or each Y 1 ~Y 4 However, [E] and Y 5 However, each Y is selected from [γE], [E], [OEG], or [eLys]. 6 ~Y 8 However, independently, it either does not exist or is selected from [γE], [E], [OEG], or [eLys].

[0040] The polypeptide of the present invention is, for example, an amino acid at position X 28 Lipid addition occurs at the lysine (K) residue in the molecule, and the lipid / linker is C18DA[E][E][E][E]-(SEQ ID: 640), C18DA[E][E][E][E][E]-(SEQ ID: 636), C18DA[E][E][E][E][E][E]-(SEQ ID: 637), 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[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[E][E][E][E][E][eLys]-(SEQ ID: 635), C18DA[E][E][E][E][E][E][eLys]-(SEQ ID: 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: 639), 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[E][E][E][OEG][OEG]-, C18DA[E][E][E][E][OEG][OEG]-(SEQ ID: 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 ID: 638), C20DA[γE][γE][γE][OEG][OEG]-, C20DA[γE][γE][γE][γE][OEG][OEG]-,C20DA[γE][γE][γE][γE][γE][OEG][OEG]-, C18DA[γE][γE][γE][OEG]-, C18DA[γE][γE][γE][γE][OEG]-, C18DA[γE][γE][γ E][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][eLy Selected from the group consisting of s]-, 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][γE][AHX]- or C20DA[γE][γE][γE][γE][γE][γE][AHX]-.

[0041] The polypeptide of the present invention is, for example, an amino acid at position X 28 Lipid addition occurs at the lysine (K) residue in the molecule, and the lipid / linker is 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]-, C20DA[γE][γE][γE][γE][γE][γE][γE][eLys]-, C20DA[γE][γE][γE][γE][γE][eLy s][eLys]-, C20DA[E][E][E][E][OEG][OEG]-(SEQ ID NO: 638), C20DA[γE][γE][γE][γE][OEG][OEG]-, C2 0DA[γE][γE][γE][γE][γE][OEG][OEG]-, C20DA[γE][γE][γE][γE][OEG]-, C20DA[γE][γE][γE][γE][ The group is selected from the following: γE][OEG]-, C20DA[γE][γE][γE][γE][γE][γE][OEG]-, C20DA[γE][γE][γE][γE][OEG][e Lys]-, C20DA[γE][γE][γE][γE][γE][OEG][e Lys]-, C20DA[γE][γE][γE][γE][OEG][OEG][e Lys]-.

[0042] The triple agonist of the present invention is generally soluble around pH 7. Several methods for measuring solubility exist that 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. In some embodiments, the solubility of the compound of the present invention is 1.0 mg / ml or higher at around pH 7. In some embodiments, the solubility of the compound of the present invention is greater than 3.0 mg / ml around pH 7. In some embodiments, the solubility of the compound of the present invention is greater than 5.0 mg / ml around pH 7. In some embodiments, the solubility of the compounds of the present invention is 6.0 mg / ml or higher, 7.0 mg / ml or higher, 8.0 mg / ml or higher, or 9.0 mg / ml or higher at around pH 7.

[0043] The hybrid polypeptide of the present invention can stimulate hGLP1R, GIPR, and hNPY2R in the presence of human serum albumin, a major protein present in human plasma (see Table 3). The activity of the peptide of the present invention in the presence of human plasma is an essential requirement for a promising compound that may be useful in treating the disclosed diseases. Those skilled in the art will know of appropriate assay methods, and examples are provided below. For example, for the peptide of the present invention, EC of hGLP1R, GIPR, and hNPY2R in the presence of 100% human plasma (100% hP) 50 The values ​​were evaluated by the assay described in Example 1 below. In some embodiments of the peptide of the present invention, EC against hGLP1R100%hP and GIPR100%hP 50 This is less than 100 nM (for example, from 0.01 nM to 100 nM), and the EC is less than 100 nM than hNPY2R100% hP. 50 This range is less than 1000 nM (for example, from 0.01 nM to 1000 nM). In some embodiments of the peptide of the present invention, EC against hGLP1R100%hP and GIPR100%hP 50 It is less than 30 nM (for example, from 0.01 nM to 50 nM), and the EC relative to hNPY2R100%hP 50 This range is less than 300 nM (for example, from 0.01 nM to 300 nM). In some embodiments of the peptide of the present invention, EC against hGLP1R100%hP and GIPR100%hP 50 It is less than 10 nM (for example, from 0.01 nM to 10 nM), and the EC relative to hNPY2R100%hP 50 This range is less than 100 nM (for example, from 0.01 nM to 100 nM).

[0044] In preferred embodiments of the peptide of the present invention, EC is applied to hGLP1R100%hP and GIPR100%hP. 50 It is less than 10 nM (for example, from 0.01 nM to 10 nM), and the EC relative to hNPY2R100%hP 50 The concentration is less than 100 nM (for example, between 0.01 nM and 100 nM), and the solubility is 1.0 mg / ml or higher around pH 7. In some embodiments, the peptides of the present invention have advantageous pharmacokinetic properties. In this regard, the in vivo half-life of the peptides of the present invention may be longer than 6 hours, longer than 8 hours, or longer than 10 hours in mice (NMRI mice, see measurements described in Example 3). In preferred embodiments of the peptide of the present invention, EC is applied to hGLP1R100%hP and GIPR100%hP. 50 It is less than 10 nM (for example, from 0.01 nM to 10 nM), and the EC relative to hNPY2R100%hP 50 Its concentration is less than 100 nM (e.g., between 0.01 nM and 100 nM), its solubility is 1.0 mg / ml or higher around pH 7, and its in vivo half-life is longer than 8 hours.

[0045] In a third aspect, the present invention provides polypeptides for use as pharmaceuticals. Since the Y2 receptor has an appetite-suppressing effect, polypeptides having Y2 agonist activity may be useful in treating symptoms associated with eating disorders, obesity (e.g., simple obesity or symptomatic obesity), and / or diabetes. Furthermore, the gastrointestinal hormones GLP-1 and GIP (called incretins) promote insulin secretion from the pancreas. Since incretins are deeply involved in glucose metabolism, polypeptides having GLP-1 receptor agonist activity and GIP receptor agonist activity may be useful in treating symptoms associated with glucose metabolism disorders, including diabetes and obesity. Accordingly, the polypeptides of the present invention may have an appetite-suppressing effect and / or a weight-reducing effect. In preferred embodiments, the present invention treats excessive weight (overweight), obesity. (e.g., simple obesity (chronic weight management) or symptomatic obesity), insulin resistance, diabetes (e.g., type 1 or type 2 diabetes) or prediabetes, eating disorders, hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, hyper-LDL cholesterolemia, low HDL cholesterolemia, postprandial hyperlipidemia), metabolic syndrome (three of the following five conditions: abdominal obesity, hypertension, hyperglycemia, high serum triglycerides and low serum high-density lipoprotein (HDL)), liver disease, e.g., metabolic-related fatty liver disease (MAFLD), non-alcoholic fatty liver disease (N). The present invention provides polypeptides for use in the prevention, treatment and / or remission of diseases, disorders, or symptoms selected from a list consisting of AFLD, non-alcoholic steatohepatitis (NASH), portal hypertension; cardiovascular diseases (e.g., hypertension, arteriosclerosis, stroke, or heart failure); kidney diseases (e.g., diabetic nephropathy (DKD) and chronic kidney disease (CKD)); and neurodegenerative diseases (Alzheimer's disease or Parkinson's disease), but also selected from a list consisting of other obesity-related diseases (e.g., osteoporosis, sleep apnea, obesity-associated cancer, and obesity-associated asthma).Examples of symptomatic obesity include endocrine obesity (e.g., Cushing's syndrome, hypothyroidism, insulinoma, obese type 2 diabetes, pseudohypoparathyroidism, hypogonadism, and associated 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-Beadle syndrome), and drug-induced obesity (e.g., steroid-induced obesity, phenothiazine-induced obesity, insulin-induced obesity, sulfonylurea-induced obesity, beta-blocker-induced obesity). The polypeptides of the present invention may also be used for the prevention of obesity, or for the prevention or reversal of comorbidities of obesity and / or obesity, such as type 2 diabetes, hypertension, NAFLD, NASH, DKD, CKD, sleep apnea, obesity-related cancer, or obesity-related asthma.

[0046] In a fourth aspect, the present invention provides a method for the treatment of a disease, disorder and / or symptom, the method comprising administering a therapeutically effective amount of a polypeptide or a pharmaceutically acceptable salt thereof of any aspect and embodiment disclosed herein to a person in need thereof. Preferably, the disease, disorder and / or symptom is selected from the list consisting of excessive weight, obesity, diabetes (type 1 or 2) or prediabetes, eating disorders, hyperlipidemia, metabolic syndrome, NAFLD, NASH, and / or cardiovascular disease. Most preferably, the disease, disorder and / or symptom is obesity, prediabetes and / or diabetes (type 1 or 2). Furthermore, the present invention provides a method for binding to and / or activating GLP-1, GIP, and hNPY2 receptors in a human being who requires such a method, the method comprising administering a therapeutically effective amount of a polypeptide or a pharmaceutically acceptable salt thereof of any aspect and embodiment disclosed herein.

[0047] Similarly, the present invention relates to the use of polypeptides or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for the treatment of diseases, disorders and / or symptoms of any aspect and embodiment disclosed herein. The typical weekly dose range for polypeptides with the general structure of formula (I) is 0.01 to 100 mg in humans (subcutaneous administration). The polypeptide of the present invention can be administered subcutaneously using a suitable device, such as a pre-filled, ready-to-use syringe, pen injector, or auto-injector. The actual effective pharmacopoeia or therapeutic dose usually depends on factors known to those skilled in the art, such as the patient's age and weight, the route of administration, and the severity of the disease. In any case, the compound is administered in a dose and manner that allows for the delivery of a pharmaceutically effective amount based on the patient's specific symptoms. [Examples]

[0048] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19

[0049] Table 2-1 Table 2-2 Table 2-3 Table 2-4 Table 2-5 Table 2-6 Table 2-7 Table 2-8 [Table 2-9] [Table 2-10]

[0050] General procedure for solid-phase synthesis of peptides All peptides were synthesized by standard Fmoc-based solid-phase peptide chemistry on Tentagel S RAM resin (filled at 0.23–0.25 mmol / g, bead size 90 μm) supplied by Iris Biotech GmbH or Rapp Polymere GmbH. The following protected amino acids were used: 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, Fm oc-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, the L-form of the amino acid building block was used. Modular half-life extension sites were assembled by solid-phase peptide synthesis (SPPS) using protected building blocks, such 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.

[0051] The 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, and 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. Peptide organization was performed by stepwise chain extension toward the N-terminus of each sequence, starting from the C-terminus and continuing until reaching the N-terminal amino acid. After deprotection of the side chain of branched amino acids, e.g., Lys(Dde), organization of the half-life extension site was performed. The peptide was obtained as a TFA salt by cleavage / deprotection or by HPLC purification. The trifluoroacetate can be exchanged by common procedures (e.g., resin-ion exchange procedures), as disclosed, for example, in Roux, St. et al. J. Pept. Sci. 2008; 14: 354-359.

[0052] Synthesis method 1 (S01) Peptides were synthesized on a 0.25 mmol scale on Tentagel S RAM resin using a CEM Liberty Blue Peptide Synthesizer via microwave-assisted solid-phase peptide synthesis (SPPS) with the Fmoc strategy. The stoichiometry and concentrations for the peptide coupling reaction were 4 equivalents of well-protected amino acids in DMF (0.2 mol / 1 ml, 5 ml), 4 equivalents of oxima in DMF (1 mol / l, 1 ml), and 8 equivalents of DIC in DMF (1 mol / l, 2 ml). Reaction times and temperatures varied for each amino acid. Single coupling at 90°C for 4 minutes was used for all standard amino acids, except for those mentioned below. Single coupling at 75°C for 20 minutes was used for Fmoc-Aib-OH, with the amino acid after Aib being coupled twice. Double coupling at 90°C for 4 minutes was used for Fmoc-Arg(Pbf)-OH, C18DA(tBu), C20DA(tBu), Fmoc-OEG-OH, FmocNMeArg(Pbf)-OH, and Fmoc-NMeGln(Trt)-OH. The amino acids after NMeArg and NMeGln were coupled twice. The last eight standard amino acids in the main chain were coupled at 90°C for 8 minutes. The capping process was carried out at 65°C for 5 minutes using 20% ​​acetic anhydride in DMF (10 ml) before and after the coupling of Fmoc-Glu-OtBu, and before the coupling of C18DA(tBu) and C20DA(tBu). αFmoc deprotection was performed using 10% piperidine / DMF (10 ml) at 90°C for 1 minute. Deprotection of the Lys(Dde)- moiety was performed using 5% hydrazine hydrate in DMF (10 ml) at 90°C for 3 minutes, and this deprotection was repeated twice. The raw material was washed with DCM on the resin and dried before cleavage. Cleavage and deprotection from the resin were performed using a mixture of 95% TFA / water (10 ml) and triisopropylsilane (250 μl) at 40°C for 45 minutes. The crude peptide was precipitated with cold tert. butyl methyl ether, dissolved in 50% acetonitrile / water, and purified by preparative HPLC.

[0053] Synthesis method 2 (S02) Peptides were synthesized by SPPS on a 0.2 mmol scale using MultiSynTech SYRO. Standard amino acid coupling was achieved by using 4 equivalents (0.5 mol / l) of well-protected amino acids dissolved in 0.5 mol / l oxima-DMF solution and 4.5 equivalents (1 mol / l) of DIC in DMF. Fmoc-Phe-OH was dissolved in 0.5 mol / l oxima-NMP, and 4 equivalents were used for coupling (0.5 mol / l). The coupling time for the first 23 amino acids starting from the C-terminus was 15 minutes at 75°C (Cys and His were coupled at 50°C). Further extension was performed by double coupling (15 minutes x 2 at 75°C). Deprotection of the Lys(Mtt)- site was selectively performed using hexafluoroisopropanol (10 minutes x 10, 10 ml at room temperature). The deprotected lysine intermediate was derivatized by double coupling of 4 equivalents of appropriate linker building blocks (Fmoc-OEG-OEG-OH, Fmoc-Glu-OtBu, Boc-Lys(Fmoc)-OH, C18DA(tBu), C20DA(tBu)) at 75°C for 15 minutes. αFmoc deprotection was performed at 45°C for 3 minutes using 40% piperidine in 4 ml of NMP, followed by 15 minutes using 20% ​​piperidine in 4 ml of NMP. The appropriately protected Fmoc-Asp, Fmoc-Cys, and Fmoc-His intermediates were deprotected at room temperature. The peptides were cleaved from the resin and the side chains were deprotected by adding 15 ml of TFA / DODT / TES / water (95:2:1:2) and allowing it to run at room temperature for 4 hours or at 45°C for 60 minutes. The peptides were precipitated with cold diethyl ether, dissolved in acetonitrile / water, and purified by preparative HPLC (purification method 3, P02).

[0054] Purification method 1 (P01) Crude peptides were 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, diode array detector G7115A, mass spectrometer G6135B, and fraction collector G7158B. A Waters Luna Prep C8(3) column (100 Å, 10 μm, 300 g, self-packed steel column) was used as the stationary phase. The mobile phase was flowed at 150 ml / min at 40°C with a gradient of buffer A (ACN) and buffer (H2O + 0.1% TFA) as listed in the table below. Appropriate fractions were pooled and lyophilized. The final product was characterized by analytical HPLC-MS (U046_001 and U046_006).

[0055] [Table 3]

[0056] Purification method 2 (P02) Crude peptides were dissolved in DMF / acetonitrile / water and purified by reverse-phase chromatography using a GILSON preparative HPLC system equipped with a preparative pump AP-MOD (maximum flow rate: 200 ml / min), a diode array detector ECOM Flash 10, and a fraction collector GILSON GX 281. The stationary phase was a Phenomenex LUNA C8 10 μm preparative column (50 × 250 mm). The peptides were eluted at 40°C at a flow rate of 120 ml / min using a focus gradient with water (eluent A) and acetonitrile (eluent B); the adjusting agent solution was added in "at-column dilution" mode to maintain a constant amount of 0.1% TFA in the mobile phase. Homogeneous fractions were pooled and lyophilized. The final products were characterized by HPLC-MS (U046_001 and U046_006).

[0057] [Table 4]

[0058] Purification method 3 (P03) Crude peptides were purified by reverse-phase HPLC using a Waters preparative HPLC system equipped with a C8 column (Reprosil Gold 200 Å, 5 μm, 40 mm × 250 mm), a preparative pump (Waters 2545), a UV / VIS detector (Waters 2489), and a Waters fraction collector III. The mobile phase was flowed at a flow rate of 50 ml / min at room temperature with a gradient of buffer A (0.1% TFA in H2O) and buffer B (0.1% TFA in ACN, gradient: 35-45% B over 20 minutes). Appropriate fractions were analyzed, pooled, and lyophilized. The final product was characterized by analytical ULC-MS (A02).

[0059] Analysis method 1 (A01-A / B) The purity and mass of the peptides were estimated by analytical HPLC-MS using a Kinetex C8 column (4.6 mm × 150 mm, 2.6 μm, Phenomenex) and an Agilent 1260 HPLC system equipped with a G6135 mass detector. The analysis was performed by gradient elution at 40°C using buffer A (0.3% TFA in H2O) and buffer B (0.24% TFA in ACN). Details of the gradient and flow rate are summarized in the table below. Retention time and mass were recorded. The purity of the peptide (relative peak area at 214 nm) was in the range of 80 to 99%, preferably exceeding 95%.

[0060] [Table 5]

[0061] [Table 6]

[0062] Analysis method 2 (A02-A / B) The purity and mass of the peptides were measured by analytical HPLC-MS using a Kinetex C8 column (Phenomenex, 100 Å, 2.6 μm, 4.6 mm × 150 mm) and a Waters Acquity HPLC system equipped with a 3100 mass detector. The analysis was performed by gradient elution at 40°C using buffer A (0.3% TFA in H2O) and buffer B (0.3% TFA in ACN). Details of the gradient and flow rate are summarized in the table below. Retention time and mass were recorded.

[0063] [Table 7]

[0064] [Table 8]

[0065] List of abbreviations ACN: Acetonitrile AHX: 6-aminohexanoic acid Aib: Amino-isobutyl acid aMeF: α-methyl-L-phenylalanine bh-Gln: β-homo-L-glutamine Boc:tert-butoxycarbonyl Chg: Cyclohexyl-glycine C18DA(tBu):18-(tert-butoxy)-18-oxooctadecanoic acid C20DA(tBu):20-(tert-butoxy)-20-oxoicosanoic acid D-Arg: D-arginine D-Asp: D-aspartic acid DCM: Dichloromethane DIC: Diisopropylcarbodiimide DIPEA: Diisopropylethylamine Dde:(4,4-dimethyl-2,6-dioxocyclohexa-1-ylidene)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-epsilon-L-lysine Fmoc:9H-Fluorene-9-ylmethoxycarbonyl Fmoc-Ahx:6-{[(9H-fluoren-9-ylmethoxy)carbonyl]aminohexanoic 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-fluorene-9-ylmethoxycarbonyl-amino)ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetic acid gGlu:C-gamma-L-glutamate hArg: Homo-L-arginine HTRF: Uniform time-resolved fluorescence IBMX:3-Isobutyl-1-methylxanthine Iva: 2-amino-2-methylbutyrate iVal: 3-methylbutanoyl(isovalerianoyl) MRT: Average residence time Mtt:4-methyl-trityl NMeR: N-methyl-L-arginine NMeQ: N-methyl-L-glutamine NMeY:N-methyl-L-tyrosine NMP:1-methylpyrrolidine-2-one Oxyma: 2-Cyano-2-(hydroxyimino)ethyl ester 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 Sarcosine: N-methylglycine SPPS: Solid-phase peptide synthesis tBu:tert-butyl Tle:L-tert-butylglycine Trt: Trichil TRX: Tranexamic acid, trans-4-(aminomethyl)cyclohexane-1-carboxylic acid TES: Triethylsilane TFA: Trifluoroacetic acid

[0066] The following compounds were synthesized. All compounds were obtained as TFA salts: compound 2 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGIELRHFLNHLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Allocation number: 328) MW (calculated): 6869.8 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:35.8 minutes; m / 3: m / 4:1718.1 m / 5: Compound 3 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGQRSYASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Allocation number: 329) MW (calculated): 7106.0 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.7min;m / 3:2370.2 m / 4:1777.9 m / 5: 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)(Allocation number: 330) MW (calculated): 6736.5Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:34.0 minutes; m / 3: m / 4:1684.9 m / 5:

[0067] 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)(Allocation number: 331) MW (calculated): 6900.7Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:34.8 minutes; m / 3: m / 4:1726.0 m / 5: Compound 6 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGQRYYASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 332) MW (calculated): 7182.1 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:8.0 min;m / 3:2395.5 m / 4:1797.0 m / 5: Compound 7 Y-Aib-EGTFTSDYSI-Aib-LEEEAQ-Aib-AFVQWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys-eLys(1,2)(array number: 333) MW (calculated): 6900.7Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:35.9 minutes; m / 3: m / 4:1725.9 m / 5: Compound 8 Y-Aib-EGTFTSDYSI-Aib-LEEQAQ-Aib-AFVQWLIK(1,3)-GGPSSGQSLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Allocation number: 334) MW (calculated): 6957.7 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.5min;m / 3:2320.3 m / 4:1740.7 m / 5:

[0068] Compound 9 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSYVSIRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 335) MW (calculated): 7034.9 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.7min;m / 3:2346.7 m / 4:1760.1 m / 5: Compound 10 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSPES-Aib-RHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eK (array number: 336) MW (calculated): 6970.8 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:6.1 points;m / 3:2324.9 m / 4:1743.9 m / 5: Compound 11 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPESPASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(Allocation number: 337) MW (calculated): 6724.6 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.8 points;m / 3:2242.2 m / 4:1681.8 m / 5: Compound 12 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPESPASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu(1,2) (Allocation number: 338) MW (calculated): 6696.5Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.1 points;m / 3:2232.7 m / 4:1674.9 m / 5:

[0069] 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)(Allocation number: 339) MW (calculated): 6814.6 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:33.6 minutes; m / 3: m / 4:1704.5 m / 5: Compound 14 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPRYYASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 340) MW (calculated): 7151.1 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.2 points;m / 3:2385.6 m / 4:1789.2 m / 5: Compound 15 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSSYVSLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 341) MW (calculated): 7033.9 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.6 points;m / 3:2346.2 m / 4:1759.9 m / 5: 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)(array number: 342) MW (calculated): 6915.7 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:38.2 minutes; m / 3: m / 4:1729.7 m / 5:

[0070] 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)(array number: 343) MW (calculated): 6749.6 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:35.1 minutes; m / 3: m / 4:1688.1 m / 5: 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)(Allocation number: 344) MW (calculated): 6764.6 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:34.3 minutes; m / 3: m / 4:1691.9 m / 5: Compound 19 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSYYVSLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 345) MW (calculated): 7110.0 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.6 points;m / 3:2370.9 m / 4:1778.2 m / 5: Compound 20 Y-Aib-EGTFTSDYSI-Aib-LAAAAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Allocation number: 346) MW (calculated): 6728.5Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:39.8 minutes; m / 3: m / 4:1682.9 m / 5:

[0071] 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)(Allocation number: 347) MW (calculated): 6900.7Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:35.0 minutes; m / 3: m / 4:1725.9 m / 5: Compound 22 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGQSSYASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(colocation number: 348) MW (calculated): 7036.9 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.2 points;m / 3:2347.4 m / 4:1760.7 m / 5: Compound 23 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPEYYASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 349) MW (calculated): 6994.9 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.4 points;m / 3:2331.8 m / 4:1749.4 m / 5: 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)(array number: 350) MW (calculated): 6915.7 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:36.6 minutes; m / 3: m / 4:1723.2 m / 5:

[0072] Compound 25 Y-Aib-EGTFTSDYSI-Aib-LEAAKQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 351) MW (calculated): 6843.7 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:37.2 minutes; m / 3: m / 4:1711.7 m / 5: 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)(Sequence ID:352) MW (calculated): 6886.7Da Synthesis and purification methods: S01; P01 LCMS:A01-B;Rt:34.3min;m / 3: m / 4:1722.4 m / 5: compound 27 [ka] The structure is disclosed in sequence number 353. Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGVSIRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Sequence ID: 353) MW (calculated): 6928.8Da Synthesis and purification methods: S02; P03 LCMS:A02-A;Rt:7.3 min;m / 3:2311.6 m / 4:1733.8 m / 5: compound 28 [ka] The structure is disclosed in sequence number 354. Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVQWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(Sequence ID: 354) MW (calculated): 6829.6Da Synthesis method and purification method: S01; P02 LCMS:A01-A;Rt:13.3 minutes;m / 3: m / 4:1708.0 m / 5:

[0073] Compound 29 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPESGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(array number: 355) MW (calculated): 6684.5Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.7min;m / 3:2228.8 m / 4:1672.0 m / 5: Compound 30 Y-Aib-EGTFTSDYSI-Aib-LEEQAQ-Aib-AFVQWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 356) MW (calculated): 6900.7Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:36.2 minutes; m / 3: m / 4:1725.9 m / 5: Compound 31 Y-Aib-EGTFTSDYSI-Aib-LEEQAQ-Aib-AFVEWLIK(1,3)-GGPSSGQSLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Allocation number: 357) MW (calculated): 6958.7 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.6 points;m / 3:2320.8 m / 4:1740.7 m / 5: Compound 32 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPESGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(Allocation number: 358) MW (calculated): 6974.8 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.7 points;m / 3:2325.7 m / 4:1744.4 m / 5:

[0074] Compound 33 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSAVSLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 359) MW (calculated): 6942.8 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.5min;m / 3:2316.3 m / 4:1737.1 m / 5: Compound 34 Y-Aib-EGTFTSDYSI-Aib-LEEQAQ-Aib-AFVQWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 360) MW (calculated): 6771.6 Da Synthesis method and purification method: S01; P01 LCMS:A01-B; Rt:36.4 minutes; m / 3: m / 4:1693.6 m / 5: Compound 35 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSSGESLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eK (array number: 361) MW (calculated): 6957.8 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:6.2 points;m / 3:2320.5 m / 4:1740.4 m / 5: Compound 36 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVQWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(array number: 362) MW (calculated): 6990.8 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.6 points;m / 3:2331.2 m / 4:1748.3 m / 5:

[0075] Compound 37 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPESGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 363) MW (calculated): 6941.8 Da Synthesis method and refining method: S01; L20 LCMS:A01-A;Rt:7.2 minutes;m / 3:2314.9 m / 4:1736.3 m / 5: 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)(array number: 364) MW (calculated): 6900.7Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:6.1 points;m / 3:2301.4 m / 4:1726.2 m / 5: 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)(Allocation number: 365) MW (calculated): 6886.7 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:34.4 minutes; m / 3: m / 4:1722.3 m / 5: Compound 40 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSYVSLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 366) MW (calculated): 7034.9 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.5min;m / 3:2345.5 m / 4:1759.4 m / 5:

[0076] Compound 41 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSPQSLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 367) MW (calculated): 6997.8 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:10.4 minutes;m / 3:2333.6 m / 4:1750.6 m / 5: Compound 42 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEYVSIRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 368) MW (calculated): 7076.9 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.7min;m / 3:2360.0 m / 4:1770.6 m / 5: Compound 43 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVQWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 369) MW (calculated): 7086.9 Da Synthesis method and purification method: S01; P02 LCMS:A01-A;Rt:12.3 minutes;m / 3: m / 4:1772.6 m / 5: 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)(array number: 370) MW (calculated): 6929.7 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:6.0 points;m / 3:2311.2 m / 4:1733.2 m / 5:

[0077] Compound 45 Y-Aib-EGTFTSDYSI-Aib-LEEQAQ-Aib-AFVQWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-OEG-eLys(1,2)(Allocation number: 371) MW (calculated): 6916.7 Da Synthesis method and purification method: S01; P01 LCMS:A01-B; Rt:36.2 minutes; m / 3: m / 4:1729.8 m / 5: Compound 46 Y-Aib-EGTFTSDYSI-Aib-LEKEAQ-Aib-KFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 372) MW (calculated): 6958.8Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:34.6 minutes; m / 3: m / 4:1740.5 m / 5: Compound 47 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSSGVSLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 373) MW (calculated): 6927.8 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:10.7 minutes;m / 3:2310.9 m / 4:1733.2 m / 5: Compound 48 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEPQSIRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 374) MW (calculated): 7039.9Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:10.1 points;m / 3:2347.9 m / 4:1761.1 m / 5:

[0078] 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)(array number: 375) MW (calculated): 6930.7 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:6.1 points;m / 3:2311.3 m / 4:1733.7 m / 5: Compound 50 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSYESLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2) (Allocation number: 376) MW (calculated): 7064.9 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.4 minutes;m / 3:2356.2 m / 4:1767.5 m / 5: Compound 51 Y-Aib-EGTFTSDYSI-Aib-LEKQAE-Aib-AFVQWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 377) MW (calculated): 6872.7 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:5.7min;m / 3:2291.8 m / 4:1719.6 m / 5: Compound 52 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPESGASLRHYYNWLTRQRY-NH2.C18DA-EEEE-OEG-OEG(1,2)(array number: 378) MW (calculated): 6817.6 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:10.3 minutes;m / 3:2273.8 m / 4:1705.5 m / 5:

[0079] Compound 53 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPESGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(array number: 379) MW (calculated): 6656.4 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.9 points;m / 3:2219.5 m / 4:1664.9 m / 5: Compound 54 Y-Aib-EGTFTSDYSI-Aib-LEKQAE-Aib-AFVQWLIK(1,3)-GGPSEPASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Allocation number: 380) MW (calculated): 6696.5Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:5.9 points;m / 3:2232.8 m / 4:1675.3 m / 5: Compound 55 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPESGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(Allocation number: 381) MW (calculated): 6946.8 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.1 points;m / 3:2316.4 m / 4:1737.6 m / 5: Compound 56 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVEWLIK(1,3)-GGPSSPASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(array number: 382) MW (calculated): 6874.7 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.2 points;m / 3:2292.4 m / 4:1719.8 m / 5:

[0080] Compound 57 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPEEPASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(array number: 383) MW (calculated): 6899.7 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.1 points;m / 3:2300.8 m / 4:1725.9 m / 5: Compound 58 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPESGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(array number: 384) MW (calculated): 6817.6 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:10.0 points;m / 3:2273.4 m / 4:1705.5 m / 5: Compound 59 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSYYASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 385) MW (calculated): 6952.9 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt: min;m / 3:2318.5 m / 4:1738.9 m / 5: Compound 60 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPESGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 386) MW (calculated): 6784.6 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:9.2 points;m / 3:2262.5 m / 4:1697.3 m / 5:

[0081] Compound 61 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPESGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 387) MW (calculated): 6812.7 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.4 points;m / 3:2271.8 m / 4:1704.2 m / 5: Compound 62 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPRYYASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 388) MW (calculated): 7152.1Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:35.2 minutes; m / 3: m / 4:1788.8 m / 5: Compound 63 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPESGASLRHYYNWLTRQRY-NH2.C18DA-EEEEE-eLys(1,2) (each with allocation numbers 389 and び635) MW (calculated): 6784.6 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:9.6 points;m / 3:2262.4 m / 4:1697.1 m / 5: Compound 64 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPESPASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(Allocation number: 390) MW (calculated): 6858.7Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.1 points;m / 3:2286.9 m / 4:1715.2 m / 5:

[0082] Compound 65 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGGSEYVSLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(array number: 391) MW (calculated): 6908.7Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.4 points;m / 3:2345.9 m / 4:1760.1 m / 5: Compound 66 Y-Aib-EGTFTSDYSI-Aib-LEEEAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 392) MW (calculated): 6902.7 Da Synthesis method and purification method: S01; P02 LCMS:A01-A;Rt:14.1 minutes;m / 3: m / 4:1726.5 m / 5: Compound 67 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPEEPASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 393) MW (calculated): 6894.8 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.1 points;m / 3:2298.9 m / 4:1724.2 m / 5: 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)(array number: 394) MW (calculated): 6842.7 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:34.3 minutes; m / 3: m / 4:1711.4 m / 5:

[0083] Compound 69 Y-Aib-EGTFTSDYSI-Aib-LEKEKQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 395) MW (calculated): 6958.8Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:33.8 minutes; m / 3: m / 4:1740.4 m / 5: Compound 70 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPESPASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 396) MW (calculated): 6853.7 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.3 minutes;m / 3:2284.9 m / 4:1714.4 m / 5: 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)(Allocation number: 397) MW (calculated): 6914.8 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:34.7 minutes; m / 3: m / 4:1729.4 m / 5: Compound 72 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGADLRHYLNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 398) MW (calculated): 6878.7 Da Synthesis method and purification method: S01; P01 LCMS:A01-B; Rt:36.2 minutes; m / 3: m / 4:1720.4 m / 5:

[0084] Compound 73 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSPESLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Allocation number: 399) MW (calculated): 6998.8Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:6.3min;m / 3:2334.1 m / 4:1751.0 m / 5: 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)(Allocation number: 400) MW (calculated): 6872.7 Da Synthesis method and purification method: S01; P01 LCMS:A01-B; Rt:34.3 minutes; m / 3: m / 4:1718.8 m / 5: Compound 75 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSYYVSLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 401) MW (calculated): 6981.9 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.6 points;m / 3:2328.1 m / 4:1746.1 m / 5: 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)(Allocation number: 402) MW (calculated): 6794.6 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:34.9 minutes; m / 3: m / 4:1699.4 m / 5:

[0085] Compound 77 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPEEPASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(array number: 403) MW (calculated): 6927.8 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.8 points;m / 3:2310.2 m / 4:1733.1 m / 5: Compound 78 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEYVSLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 404) MW (calculated): 7076.0 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.4 points;m / 3:2358.9 m / 4:1769.7 m / 5: Compound 79 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNL-Aib-TRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 405) MW (calculated): 6799.6 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:34.9 minutes; m / 3: m / 4:1700.6 m / 5: Compound 80 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSYYVSLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 406) MW (calculated): 7111.0 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:9.7 points;m / 3:2370.9 m / 4:1778.5 m / 5:

[0086] Compound 81 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVEWLIK(1,3)-GGPESGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-OEG-OEG(1,2)(array number: 407) MW (calculated): 6747.5 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:6.1 points;m / 3:2250.8 m / 4:1688.3 m / 5: Compound 82 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPESPASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(Allocation number: 408) MW (calculated): 6886.7 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:11.4 points;m / 3:2296.2 m / 4:1722.4 m / 5: Compound 83

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[0087] compound 85 [ka] The structure is disclosed in sequence number 411. Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTR-NMeQ-RY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 411) MW (calculated): 6914.8 Da Synthesis method and purification method: S01; P02 LCMS:A01-A;Rt:12.7 minutes;m / 3: m / 4: m / 5:1383.8 Compound 86 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYLNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 412) MW (calculated): 6850.7 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:35.9 minutes; m / 3: m / 4:1713.5 m / 5: Compound 87 Y-Aib-DGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 413) MW (calculated): 6886.7 Da Synthesis method and purification method: S01; P01 LCMS:A01-B; Rt:35.4 minutes; m / 3: m / 4:1722.4 m / 5: Compound 88 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 414) MW (calculated): 7087.9 Da Synthesis method and purification method: S01; P02 LCMS:A01-A;Rt:12.4 minutes;m / 3: m / 4:1772.7 m / 5:

[0088] Compound 89 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPEEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 415) MW (calculated): 6983.8Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:10.6 minutes;m / 3:2328.9 m / 4:1746.9 m / 5: Compound 90 Y-Aib-EGTFTSDYSI-Aib-LEDQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 416) MW (calculated): 6887.6 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:36.3 minutes; m / 3: m / 4:1722.7 m / 5: Compound 91 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGATLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Allocation number: 417) MW (calculated): 6914.8 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.4 points;m / 3:2306.6 m / 4:1730.1 m / 5: Compound 92 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Allocation number: 418) MW (calculated): 7028.9Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.3min;m / 3:2343.6 m / 4:1758.1 m / 5:

[0089] Compound 93 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEYESLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Allocation number: 419) MW (calculated): 7106.9 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:10.8 points;m / 3:2370.5 m / 4:1777.8 m / 5: Compound 94 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGISLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 420) MW (calculated): 6942.8 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:11.1 points;m / 3:2315.9 m / 4:1737.1 m / 5: Compound 95 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSPASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Allocation number: 421) MW (calculated): 6940.8 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:34.8 minutes; m / 3: m / 4:1735.9 m / 5: Compound 96 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGVSLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 422) MW (calculated): 6928.8Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.3 minutes;m / 3:2310.1 m / 4:1732.7 m / 5:

[0090] Compound 97 Y-Aib-EGTFTSDYSI-Aib-LEEQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 423) MW (calculated): 6643.4 Da Synthesis method and purification method: S01; P01 LCMS:A01-B; Rt:36.9 minutes; m / 3: m / 4:1661.5 m / 5: Compound 98 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSAASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 424) MW (calculated): 6914.8 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:11.0 points;m / 3:2306.3 m / 4:1730.1 m / 5: Compound 99 Y-Aib-EGTFTSDYSI-Aib-LEGQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 425) MW (calculated): 6829.6 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:36.8 minutes; m / 3: m / 4:1708.1 m / 5: Compound 100 Y-Aib-EGTFTSDYSI-Aib-LEEQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG-eLys(1,2)(array number: 426) MW (calculated): 6933.8 Da Synthesis method and purification method: S01; P01 LCMS:A01-B; Rt:36.5 minutes; m / 3: m / 4:1734.0 m / 5:

[0091] Compound 101 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEPASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 427) MW (calculated): 6981.8 Da Synthesis method and refining method: S01; L20 LCMS:A01-B; Rt:7.4 minutes; m / 3:2328.2 m / 4:1746.3 m / 5: Compound 102 Y-Aib-EGTFTSDYSI-Aib-LEAQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 428) MW (calculated): 6843.6 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:37.5 minutes; m / 3: m / 4: m / 5:1369.4 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)(array number: 429) MW (calculated): 6900.7Da Synthesis method and purification method: S01; P01 LCMS:A01-B; Rt:34.9 minutes; m / 3: m / 4: m / 5:1380.9 Compound 104 Y-Aib-EGTFTSDYSILLEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 430) MW (calculated): 6928.8Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:35.4 minutes; m / 3: m / 4:1732.9 m / 5:

[0092] Compound 105 Y-Aib-EGTFTSDYSI-Aib-LEEQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys-eLys(1,2)(Allocation number: 431) MW (calculated): 6900.7Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:35.9 minutes; m / 3: m / 4:1725.9 m / 5: Compound 106 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYINWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 432) MW (calculated): 6850.7 Da Synthesis method and purification method: S01; P01 LCMS:A01-B; Rt:35.9 minutes; m / 3: m / 4: m / 5:1370.8 Compound 107 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGSLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Allocation number: 433) MW (calculated): 6942.8 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:35.7 minutes; m / 3: m / 4:1736.4 m / 5: Compound 108 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPEEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 434) MW (calculated): 6854.7 Da Synthesis method and purification method: S01; P02 LCMS:A01-A;Rt:12.9 minutes;m / 3: m / 4:1714.4 m / 5:

[0093] Compound 109 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLLK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 435) MW (calculated): 6900.7Da Synthesis method and purification method: S01; P01 LCMS:A01-B; Rt:35.2 minutes; m / 3: m / 4:1725.9 m / 5: Compound 110 Y-Aib-EGTFTSDYSI-Aib-LEEQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-OEG-eLys(1,2)(array number: 436) MW (calculated): 6917.7 Da Synthesis method and purification method: S01; P01 LCMS:A01-B; Rt:36.5 minutes; m / 3: m / 4:1730.1 m / 5: Compound 111 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEPASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(array number: 437) MW (calculated): 7014.9 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:9.8 points;m / 3:2339.5 m / 4:1754.9 m / 5: Compound 112 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(array number: 438) MW (calculated): 6932.8 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.8 points;m / 3:2312.2 m / 4:1734.1 m / 5:

[0094] Compound 113 Y-Aib-EGTFTSDLSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Allocation number: 439) MW (calculated): 6891.8 Da Synthesis method and purification method: S01; P02 LCMS:A01-A;Rt:13.7 minutes;m / 3: m / 4:1723.7 m / 5: Compound 114 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGVSLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 440) MW (calculated): 6969.8 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.3 minutes;m / 3:2323.6 m / 4:1743.1 m / 5: 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)(Allocation number: 441) MW (calculated): 6955.8 Da Synthesis method and purification method: S01; P02 LCMS:A01-A;Rt:12.8 minutes;m / 3: m / 4:1739.6 m / 5: Compound 116 Y-Aib-EGTFTSDYSI-Aib-LEEQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 442) MW (calculated): 6901.7Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:36.7 minutes; m / 3: m / 4:1726.2 m / 5:

[0095] Compound 117 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASVRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 443) MW (calculated): 6886.7 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.2 points;m / 3:2297.3 m / 4:1722.9 m / 5: 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)(array number: 444) MW (calculated): 6872.7 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:34.5 minutes; m / 3: m / 4:1718.9 m / 5: 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)(array number: 445) MW (calculated): 6876.7 Da Synthesis method and purification method: S01; P01 LCMS:A01-B; Rt:36.0 minutes; m / 3: m / 4: m / 5:1376.1 Compound 120 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSPASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(array number: 446) MW (calculated): 6973.8 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.9 points;m / 3:2325.1 m / 4:1744.6 m / 5:

[0096] Compound 121 Y-Aib-EGTFTSDYSI-Aib-LESQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 447) MW (calculated): 6859.6 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:39.8 minutes; m / 3: m / 4:1715.6 m / 5: Compound 122 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEPESLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Allocation number: 448) MW (calculated): 7040.9 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:9.3 points;m / 3:2347.9 m / 4:1761.4 m / 5: Compound 123 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGQSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 449) MW (calculated): 6931.7 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:10.9 points;m / 3:2312.0 m / 4:1732.4 m / 5: Compound 124 Y-Aib-EGTFTSDYSI-Aib-LEQQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Allocation number: 450) MW (calculated): 6900.7Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:36.0 minutes; m / 3: m / 4: m / 5:1381.0

[0097] Compound 125 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRYYNWLTRQ-NMeR-Y-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Allocation number: 451) MW (calculated): 6955.8 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:35.5 minutes; m / 3: m / 4:1739.8 m / 5: Compound 126 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSYASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Allocation number: 452) MW (calculated): 7006.9Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:34.7 minutes; m / 3: m / 4:1752.5 m / 5: Compound 127 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGESLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Allocation number: 453) MW (calculated): 6958.8Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.3 minutes;m / 3:2320.8 m / 4:1740.8 m / 5: Compound 128 Y-Aib-EGTFTSDYSI-Aib-LDKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Allocation number: 454) MW (calculated): 6886.7 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:34.9 minutes; m / 3: m / 4:1722.3 m / 5:

[0098] 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)(array number: 455) MW (calculated): 6829.6 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:36.0 minutes; m / 3: m / 4:1708.2 m / 5: Compound 130 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFIEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 456) MW (calculated): 6914.8 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:35.4 minutes; m / 3: m / 4:1729.3 m / 5: Compound 131 Y-Aib-EGTFTSDYSI-Aib-LERQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Allocation number: 457) MW (calculated): 6928.7 Da Synthesis method and purification method: S01; P01 LCMS:A01-B; Rt:35.4 points; m / 3: m / 4: m / 5:1386.5 Compound 132 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASIRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 458) MW (calculated): 6900.7Da Synthesis method and purification method: S02; P03 LCMS:A02-A; Rt:7.3 minutes;m / 3:2301.5 m / 4:1726.6 m / 5:

[0099] 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)(array number: 459) MW (calculated): 6851.7 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:36.0 minutes; m / 3: m / 4:1713.4 m / 5: Compound 134 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGQSIRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 460) MW (calculated): 6999.8Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.1 points;m / 3:2334.4 m / 4:1750.9 m / 5: Compound 135 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEYLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 461) MW (calculated): 6877.7 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:34.2 minutes; m / 3: m / 4:1720.1 m / 5: Compound 136 Y-Aib-EGTFTSDYSI-Aib-LEKAAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 462) MW (calculated): 6843.7 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:36.1 minutes; m / 3: m / 4:1711.7 m / 5:

[0100] 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)(array number: 463) MW (calculated): 6900.7Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:35.4 minutes; m / 3: m / 4:1725.9 m / 5: Compound 138 Y-Aib-EGTFTSDYSI-Aib-LEKQAE-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 464) MW (calculated): 6785.6 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.0 points;m / 3:2262.8 m / 4:1697.6 m / 5: Compound 139 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-AHX(1,2)(array number: 465) MW (calculated): 6856.7 Da Synthesis method and purification method: S02; P03 LCMS:A02-A; Rt:7.1 points;m / 3:2286.8 m / 4:1713.0 m / 5: Compound 140 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSPASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(Allocation number: 466) MW (calculated): 6945.8 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.3 points;m / 3:2316.6 m / 4:1737.6 m / 5:

[0101] Compound 141 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(array number: 467) MW (calculated): 6714.5Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:9.8 points;m / 3:2239.3 m / 4:1679.7 m / 5: Compound 142 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEPASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(array number: 468) MW (calculated): 6986.8Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.0 points;m / 3:2329.8 m / 4:1747.6 m / 5: Compound 143 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPEEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 469) MW (calculated): 6826.7 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:6.8 points;m / 3:2276.4 m / 4:1707.7 m / 5: Compound 144 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPEEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-OEG-OEG(1,2)(Allocation number: 470) MW (calculated): 6730.6 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:10.2 minutes;m / 3:2244.5 m / 4:1683.6 m / 5:

[0102] Compound 145 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(array number: 471) MW (calculated): 6834.6 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:9.8 points;m / 3:2279.3 m / 4:1709.6 m / 5: Compound 146 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPEEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(array number: 472) MW (calculated): 6859.7 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:10.0 points;m / 3:2287.7 m / 4:1716.0 m / 5: Compound 147 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(array number: 473) MW (calculated): 6743.5Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.1 points;m / 3:2248.8 m / 4:1686.9 m / 5: Compound 148 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEPASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 474) MW (calculated): 6824.7 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:6.8 points;m / 3:2275.9 m / 4:1707.1 m / 5:

[0103] Compound 149 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPEEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Allocation number: 475) MW (calculated): 6955.8 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:9.2 points;m / 3:2319.9 m / 4:1740.0 m / 5: Compound 150 Y-Aib-EGTFTSDYSI-Aib-LEKQAE-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(array number: 476) MW (calculated): 6777.6 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:6.2 points;m / 3:2260.5 m / 4:1695.4 m / 5: Compound 151 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(colocation number: 477) MW (calculated): 6843.6 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:6.9 points;m / 3:2281.9 m / 4:1711.8 m / 5: Compound 152 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPESGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 478) MW (calculated): 6785.6 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:6.9 points;m / 3:2263.3 m / 4:1697.4 m / 5:

[0104] Compound 153 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 479) MW (calculated): 6971.8 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:7.5min;m / 3:2325.0 m / 4:1743.9 m / 5: Compound 154 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 480) MW (calculated): 6842.7Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:8.9 points;m / 3:2282.1 m / 4:1711.6 m / 5: Compound 155 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPEEGASLRHYYNWLTRQRY-NH2.C18DA-EEEEE-eLys(1,2)(each allocated number 481 and び635) MW (calculated): 6826.7Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:9.6 points;m / 3:2276.8 m / 4:1707.6 m / 5: Compound 156 Y-Aib-EGTFTSDYSI-Aib-LEKQAE-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(array number: 482) MW (calculated): 6818.6 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.3min;m / 3:2273.6 m / 4:1705.4 m / 5:

[0105] Compound 157 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-EEE-OEG-OEG(1,2)(array number: 483) MW (calculated): 6688.5Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.1 points;m / 3:2249.8 m / 4:1687.8 m / 5:6746.5 Compound 158 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSPASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(array number: 484) MW (calculated): 6816.7Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.4 points;m / 3:2273.2 m / 4:1705.2 m / 5: Compound 159 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 485) MW (calculated): 6801.6Da Synthesis method and purification method: S02; P03 LCMS:A02-A; Rt:6.6 points;m / 3:2268.2 m / 4:1701.4 m / 5: Compound 160 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-OEG-OEG(1,2)(array number: 486) MW (calculated): 6746.6 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:9.8 points;m / 3:2249.8 m / 4:1687.6 m / 5:

[0106] Compound 161 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPEEPASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(array number: 487) MW (calculated): 6900.7Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.2 points;m / 3:2301.2 m / 4:1726.2 m / 5: Compound 162 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPEEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-AHX(1,2)(array number: 488) MW (calculated): 6811.6 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:8.8 points;m / 3:2271.5 m / 4:1704.1 m / 5: Compound 163 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPESGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(array number: 489) MW (calculated): 6818.6 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.2 points;m / 3:2273.8 m / 4:1705.6 m / 5: Compound 164 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-AHX(1,2)(Allocation number: 490) MW (calculated): 6956.8 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:8.2 points;m / 3:2319.5 m / 4:1740.3 m / 5:

[0107] Compound 165 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEPASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(array number: 491) MW (calculated): 6885.8 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:10.8 minutes;m / 3:2295.9 m / 4:1722.1 m / 5: Compound 166 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPESGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-OEG-OEG(1,2)(array number: 492) MW (calculated): 6689.5Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:6.2 points;m / 3:2231.0 m / 4:1673.6 m / 5: Compound 167 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(array number: 493) MW (calculated): 6904.7 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.1 min;m / 3:2302.7 m / 4:1727.3 m / 5: Compound 168 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPRSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Allocation number: 494) MW (calculated): 6969.8 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:9.9 points;m / 3:2324.9 m / 4:1743.5 m / 5:

[0108] Compound 169 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEPASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 495) MW (calculated): 6853.7 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.2 points;m / 3:2285.1 m / 4:1714.0 m / 5: Compound 170 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 496) MW (calculated): 6871.7 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:6.7 points;m / 3:2291.8 m / 4:1719.1 m / 5: Compound 171 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-OEG-OEG(1,2)(array number: 497) MW (calculated): 6705.5Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:10.1 minutes;m / 3:2236.5 m / 4:1677.6 m / 5: Compound 172 Y-Aib-EGTFTSDLSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Allocation number: 498) MW (calculated): 6850.7 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:36.4 minutes; m / 3: m / 4:1713.4 m / 5:

[0109] Compound 173 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEPASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(array number: 499) MW (calculated): 6857.7 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:10.0 points;m / 3:2286.9 m / 4:1715.5 m / 5: Compound 174 Y-Aib-EGTFTSDYSI-Aib-LEKQAE-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Allocation number: 500) MW (calculated): 6656.5Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:5.9 points;m / 3:2220.1 m / 4:1665.7 m / 5: Compound 175 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSPASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(array number: 501) MW (calculated): 6844.7Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:8.0 points;m / 3:2282.2 m / 4:1712.2 m / 5: Compound 176 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-EEEEE(1,2)(each allocated number is 502 and び636) MW (calculated): 6714.5Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.1 points;m / 3:2239.9 m / 4:1679.8 m / 5:

[0110] Compound 177 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPEEGASLRHYYNWLTRQRY-NH2.C18DA-EEEE-OEG-OEG(1,2)(each arrangement number is 503 and び634) MW (calculated): 6859.7Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:10.3 minutes;m / 3:2287.1 m / 4:1716.0 m / 5: Compound 178 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSPASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(Allocation number: 504) MW (calculated): 6683.5Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.7min;m / 3:2228.3 m / 4:1671.5 m / 5: Compound 179 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-EEEEEE(1,2)(each with serial numbers 505 and び637) MW (calculated): 6843.6 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:10.0 points;m / 3:2282.2 m / 4:1711.8 m / 5: Compound 180 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSPASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(Allocation number: 506) MW (calculated): 6655.5Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.1 points;m / 3:2218.6 m / 4:1664.3 m / 5:

[0111] Compound 181 Y-Aib-EGTFTSDYSI-Aib-LEEQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 507) MW (calculated): 6772.6 Da Synthesis method and purification method: S01; P01 LCMS:A01-B; Rt:36.8 minutes; m / 3: m / 4:1693.8 m / 5: 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)(array number: 508) MW (calculated): 6848.7 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:36.1 minutes; m / 3: m / 4:1712.9 m / 5: Compound 183 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSYASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 509) MW (calculated): 6877.7 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.4 points;m / 3:2293.2 m / 4:1720.3 m / 5: 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)(array number: 510) MW (calculated): 6822.7 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:35.2 minutes; m / 3: m / 4:1706.5 m / 5:

[0112] Compound 185 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(colocation number: 511) MW (calculated): 6871.6 Da Synthesis method and purification method: S01; P02 LCMS:A01-A;Rt:13.3 minutes;m / 3: m / 4:1718.7 m / 5: 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)(Allocation number: 512) MW (calculated): 6955.8 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:35.0 minutes; m / 3: m / 4:1739.6 m / 5: Compound 187 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Allocation number: 513) MW (calculated): 6930.7 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:8.6 points;m / 3:2311.2 m / 4:1733.4 m / 5: Compound 188 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPEEGASLRHYYNWLTRQRY-NH2.C18DA-EEE-OEG-OEG(1,2)(array number: 514) MW (calculated): 6730.6 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:10.5 minutes;m / 3:2243.9 m / 4:1683.6 m / 5:

[0113] Compound 189 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEYASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 515) MW (calculated): 6918.8 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.3 minutes;m / 3:2306.7 m / 4:1730.5 m / 5: 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)(array number: 516) MW (calculated): 6943.8 Da Synthesis method and purification method: S01; P01 LCMS:A01-B; Rt:34.1 minutes; m / 3: m / 4:1736.6 m / 5: Compound 191 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQR-Tle-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 517) MW (calculated): 6850.7 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:35.4 minutes; m / 3: m / 4:1713.4 m / 5: 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)(array number: 518) MW (calculated): 6942.8 Da Synthesis method and purification method: S01; P01 LCMS:A01-B; Rt:37.0 minutes; m / 3: m / 4:1736.3 m / 5:

[0114] Compound 193 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPEEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(array number: 519) MW (calculated): 6887.7Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:6.6 points;m / 3:2297.1 m / 4:1723.5 m / 5: Compound 194 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu(1,2)(array number: 520) MW (calculated): 6613.4 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.7 points;m / 3:2205.7 m / 4:1654.4 m / 5: Compound 195 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNLLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 521) MW (calculated): 6827.7Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:35.0 minutes; m / 3: m / 4:1707.7 m / 5: Compound 196 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPEEGASLRHYYNWLTRQRY-NH2.C18DA-EEEEEE-eLys(1,2) (each allocated number 522 and び643) MW (calculated): 6955.8 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:9.4 points;m / 3:2319.1 m / 4:1739.8 m / 5:

[0115] Compound 197 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGALLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 523) MW (calculated): 6927.8 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:36.7 minutes; m / 3: m / 4:1732.4 m / 5: Compound 198 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(array number: 524) MW (calculated): 6830.6 Da Synthesis method and purification method: S01; P02 LCMS:A01-A;Rt:13.4 minutes;m / 3: m / 4:1708.3 m / 5: 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)(array number: 525) MW (calculated): 6857.7 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:38.5 minutes; m / 3: m / 4:1715.2 m / 5: Compound 200 Y-Aib-EGTFTSDYSI-Aib-LEKQAE-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 526) MW (calculated): 6813.7 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:6.5 minutes;m / 3:2272.0 m / 4:1704.7 m / 5:

[0116] Compound 201 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(array number: 527) MW (calculated): 6963.7 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:6.9 points;m / 3:2322.1 m / 4:1742.1 m / 5: Compound 202 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu(1,2)(array number: 528) MW (calculated): 6585.4 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:9.9 points;m / 3:2196.5 m / 4:1647.5 m / 5: Compound 203 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSYYASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 529) MW (calculated): 6953.8 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.5min;m / 3:2318.6 m / 4:1739.0 m / 5: 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)(array number: 530) MW (calculated): 6902.7 Da Synthesis method and purification method: S01; P01 LCMS:A01-B; Rt:34.6 minutes; m / 3: m / 4:1726.4 m / 5:

[0117] Compound 205 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(array number: 531) MW (calculated): 6862.7 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.8 points;m / 3:2288.4 m / 4:1716.7 m / 5: Compound 206 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPEEPASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(array number: 532) MW (calculated): 6928.8Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.9 points;m / 3:2310.6 m / 4:1733.1 m / 5: Compound 207 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Allocation number: 533) MW (calculated): 7128.9 Da Synthesis method and purification method: S01; P02 LCMS:A01-A;Rt:12.4 minutes;m / 3: m / 4:1783.0 m / 5: 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)(Allocation number: 534) MW (calculated): 6914.8 Da Synthesis method and purification method: S01; P01 LCMS:A01-B; Rt:35.1 minutes; m / 3: m / 4:1729.5 m / 5:

[0118] Compound 209 Y-Aib-EGTFTSDYSI-Aib-LELQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 535) MW (calculated): 6885.7 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:39.6 minutes; m / 3: m / 4:1722.1 m / 5: Compound 210 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLLHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Allocation number: 536) MW (calculated): 6857.7 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:37.1 minutes; m / 3: m / 4:1715.2 m / 5: Compound 211 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-DAsp-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Allocation number: 537) MW (calculated): 6930.7 Da Synthesis method and purification method: S01; P01 LCMS:A01-B; Rt:35.1 minutes; m / 3: m / 4:1733.4 m / 5: Compound 212 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGVSLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(array number: 538) MW (calculated): 6800.6Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:11.7 minutes;m / 3:2268.3 m / 4:1701.3 m / 5:

[0119] 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)(array number: 539) MW (calculated): 6871.7 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:36.5 minutes; m / 3: m / 4:1718.6 m / 5: Compound 214 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQR-DTyr-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 540) MW (calculated): 6900.7Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:34.8 minutes; m / 3: m / 4:1725.8 m / 5: Compound 215 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 541) MW (calculated): 6958.8Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:6.1 points;m / 3:2320.6 m / 4:1740.7 m / 5: Compound 216 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-DArg-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 542) MW (calculated): 6971.8 Da Synthesis method and purification method: S01; P01 LCMS:A01-B; Rt:34.0 minutes; m / 3: m / 4:1743.7 m / 5:

[0120] Compound 217 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEYVSLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 543) MW (calculated): 7076.9 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.5min;m / 3:2359.6 m / 4:1769.8 m / 5: 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)(array number: 544) MW (calculated): 6799.6 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:35.0 minutes; m / 3: m / 4:1700.6 m / 5: Compound 219 Y-Aib-EGTFTSDYSI-Aib-LEKQAE-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(array number: 545) MW (calculated): 6846.7 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:11.7 minutes;m / 3:2283.3 m / 4:1712.5 m / 5: Compound 220

change

[0121] compound 221 [ka] The structure is disclosed in sequence number 547. Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Sequence ID: 547) MW (calculated): 6900.7Da Synthesis and purification methods: S01; P02 LCMS:A01-A;Rt:12.8 min;m / 3: m / 4:1725.9 m / 5 compound 222 [ka] The structure is disclosed in sequence number 548. Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTR-NMeQ-RY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Sequence ID: 548) MW (calculated): 6956.8Da Synthesis and purification methods: S01; P02 LCMS:A01-A;Rt:12.7min;m / 3: m / 4:1740.0 m / 5: compound 223 [ka] The structure is disclosed by sequence number: 549. Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(Sequence ID: 549) MW (calculated): 6813.6Da Synthesis and purification methods: S01; L20 LCMS:A01-A;Rt:6.7 min;m / 3:2272.1 m / 4:1704.5 m / 5: compound 224 [ka] The structure is disclosed in sequence number 550. Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Sequence ID: 550) MW (calculated): 7070.9Da Synthesis method and purification method: S01; P02 LCMS: A01 - B; Rt: 34.4 minutes; m / z: m / 4: m / 5: 1415.0

[0122] Compound 225 [Chemical formula] The structure discloses SEQ ID NO: 551. Y - Aib - E - G - T - F - T - S - D - Y - S - I - Aib - L - E - K - Q - A - Q - Aib - A - F - V - E - W - L - I - K(1,3) - G - G - P - S - S - G - A - S - L - R - H - Y - Y - N - W - L - T - R - Q - R - Y - NH2.C20DA - gGlu - gGlu - gGlu - gGlu - gGlu - gGlu - gGlu - eLys(1,2) (SEQ ID NO: 551) MW (calculated): 7029.8 Da Synthesis method and purification method: S01; P02 LCMS: A01 - A; Rt: 12.6 minutes; m / z: m / 4: 1758.2 m / 5: Compound 226 Y - Aib - E - G - T - F - T - S - D - Y - S - I - Aib - L - E - K - Q - A - Q - Aib - A - F - V - E - W - L - I - K(1,3) - G - G - P - S - E - P - A - S - L - R - H - Y - Y - N - W - L - T - R - Q - R - Y - NH2.C20DA - gGlu - gGlu - gGlu - gGlu - OEG - OEG(1,2) (SEQ ID NO: 552) MW (calculated): 6886.7 Da Synthesis method and purification method: S02; P03 LCMS: A02 - B; Rt: 11.6 minutes; m / z: 2296.6 m / 4: 1722.6 m / 5: Compound 227 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGQSLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Allocation number: 553) MW (calculated): 6999.8Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:10.2 minutes;m / 3:2334.1 m / 4:1750.9 m / 5: Compound 228 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(Allocation number: 554) MW (calculated): 6974.8 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.7min;m / 3:2326.1 m / 4:1744.6 m / 5:

[0123] Compound 229 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(array number: 555) MW (calculated): 6933.8 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.8 points;m / 3:2312.1 m / 4:1734.4 m / 5: Compound 230 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPEEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 556) MW (calculated): 6855.7 Da Synthesis method and purification method: S01; P02 LCMS:A01-A;Rt:13.0 minutes;m / 3: m / 4:1714.6 m / 5: Compound 231 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFIEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(array number: 557) MW (calculated): 6860.7 Da Synthesis method and purification method: S01; P02 LCMS:A01-A;Rt:13.7 minutes;m / 3: m / 4:1716.0 m / 5: Compound 232 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSYGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Allocation number: 558) MW (calculated): 6976.8 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.4 points;m / 3:2326.8 m / 4:1745.9 m / 5:

[0124] Compound 233 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEPASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 559) MW (calculated): 6982.8Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:34.6 minutes; m / 3: m / 4:1746.4 m / 5: Compound 234 Y-Aib-EGTFTSDLSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Allocation number: 560) MW (calculated): 6892.8 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:36.4 minutes; m / 3: m / 4:1723.9 m / 5: Compound 235 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(array number: 561) MW (calculated): 6772.6 Da Synthesis method and refining method: S01; L20 LCMS:A01-A;Rt:6.7 points;m / 3:2259.1 m / 4:1694.4 m / 5: Compound 236 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRYYNWLTRQ-NMeR-Y-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Allocation number: 562) MW (calculated): 6956.8 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:35.7 minutes; m / 3: m / 4:1739.9 m / 5:

[0125] Compound 237 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGESLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Allocation number: 563) MW (calculated): 7000.8Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:6.2 points;m / 3:2334.9 m / 4:1751.3 m / 5: Compound 238 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(array number: 564) MW (calculated): 6643.4 Da Synthesis method and purification method: S01; P02 LCMS:A01-A;Rt:13.7 minutes;m / 3: m / 4:1661.6 m / 5: Compound 239 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-EEEE-OEG-OEG(1,2)(each arrangement number is 565 and び638) MW (calculated): 6845.7Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.9 points;m / 3:2283.0 m / 4:1712.3 m / 5: Compound 240 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-EEEEE-eLys(1,2)(each allocation number is 566 and び639) MW (calculated): 6812.7Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.5 minutes;m / 3:2272.1 m / 4:1704.2 m / 5:

[0126] Compound 241 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGVSLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 567) MW (calculated): 6970.8Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.3min;m / 3:2323.8 m / 4:1743.4 m / 5: Compound 242 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 568) MW (calculated): 6812.7 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:10.6 minutes;m / 3:2272.0 m / 4:1704.2 m / 5: Compound 243 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(array number: 569) MW (calculated): 6684.5Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.8 points;m / 3:2228.7 m / 4:1672.1 m / 5: Compound 244 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSTGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Allocation number: 570) MW (calculated): 6914.8 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:10.8 minutes;m / 3:2306.2 m / 4:1729.9 m / 5:

[0127] Compound 245 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-AHX(1,2)(Allocation number: 571) MW (calculated): 6898.7 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:8.6 points;m / 3:2300.5 m / 4:1725.9 m / 5: Compound 246 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(Allocation number: 572) MW (calculated): 6946.8 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.0 points;m / 3:2316.7 m / 4:1737.6 m / 5: Compound 247 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFIEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu(1,2)(array number: 573) MW (calculated): 6542.3Da Synthesis method and purification method: S01; P02 LCMS:A01-A;Rt:12.7 minutes;m / 3: m / 4:1636.4 m / 5: Compound 248 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPEEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-OEG-OEG(1,2)(array number: 574) MW (calculated): 6731.5Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.3min;m / 3:2245.0 m / 4:1684.0 m / 5:

[0128] Compound 249 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-EEEEEE-eLys(1,2) (each with allocation numbers 575 and び643) MW (calculated): 6913.7 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:6.8 points;m / 3:2305.4 m / 4:1729.5 m / 5: Compound 250 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(array number: 576) MW (calculated): 6656.4 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.0 points;m / 3:2219.5 m / 4:1664.9 m / 5: Compound 251 Y-Aib-EGTFTSDYSI-Aib-LEKQAE-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(array number: 577) MW (calculated): 6819.6 Da Synthesis method and refining method: S01; L20 LCMS:A01-A;Rt:6.2 points;m / 3:2274.4 m / 4:1705.9 m / 5: Compound 252 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(colocation number: 578) MW (calculated): 6785.6 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:9.8 points;m / 3:2263.0 m / 4:1697.4 m / 5:

[0129] Compound 253 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(array number: 579) MW (calculated): 6615.4 Da Synthesis method and purification method: S01; P02 LCMS:A01-A;Rt:12.4 minutes;m / 3: m / 4:1654.7 m / 5: Compound 254 Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-E-W-L-I-K(1,3)-G-G-P-S-S-G-A-S-L-R-H-Y-Y-N-W-L-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(SEQ ID NO: 580) MW (Calculated): 6776.6 Da Synthesis method and purification method: S02; P03 LCMS: A02-A; Rt: 7.2 min; m / z: 2259.7 m / z4: 1695.0 m / z5: Compound 255

Chemical Structure

[0130] Compound 257 Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-Q-W-L-I-K(1,3)-G-G-P-S-E-G-A-S-L-R-H-Y-Y-N-W-L-T-R-Q-R-Y-NH2.C18DA-E-E-E-E-E(1,2)(SEQ ID Nos: 583 and 636) MW (calculated): 6656.4 Da Synthesis method and purification method: S02; P03 LCMS: A02-B; Rt: 10.4 min; m / z: 2220.0 m / z4: 1665.3 m / z5: [[ID=​​​​​​​​​​​​​​​​​​​​​​​​LCMS:A02-A;Rt:6.8 points;m / 3:2291.5 m / 4:1719.2 m / 5: Compound 260 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-AHX(1,2)(array number: 586) MW (calculated): 6728.5Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.3 minutes;m / 3:2243.7 m / 4:1683.2 m / 5:

[0131] Compound 261 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSSGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(array number: 587) MW (calculated): 6905.7 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.1 points;m / 3:2303.4 m / 4:1727.7 m / 5: Compound 262 Y-Aib-EGTFTSDYSI-Aib-LEKQAE-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu(1,2)(array number: 588) MW (calculated): 6529.3 Da Synthesis method and purification method: S01; P02 LCMS:A01-A;Rt:12.9 minutes;m / 3: m / 4:1633.1 m / 5: Compound 263 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEPASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 589) MW (calculated): 6825.7 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:12.5 minutes;m / 3:2275.8 m / 4:1707.2 m / 5: Compound 264 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-EEEEEE(1,2)(each arrangement number is 590 and び637) MW (calculated): 6785.6 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:10.3 minutes;m / 3:2263.0 m / 4:1697.4 m / 5:

[0132] Compound 265

change

[0133] Compound 269 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(array number: 595) MW (calculated): 6845.7 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.7 points;m / 3:2282.5 m / 4:1712.3 m / 5: Compound 270 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVQWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(array number: 596) MW (calculated): 6817.6 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:10.1 minutes;m / 3:2273.8 m / 4:1705.2 m / 5: Compound 271 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu(1,2)(array number: 597) MW (calculated): 6614.4 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.8 points;m / 3:2205.7 m / 4:1654.6 m / 5: Compound 272 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPEEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu(1,2)(array number: 598) MW (calculated): 6570.3 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.4 points;m / 3:2191.6 m / 4:1644.1 m / 5:

[0134] Compound 273 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-OEG-OEG(1,2)(array number: 599) MW (calculated): 6775.6 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.8 points;m / 3:2259.7 m / 4:1694.9 m / 5: Compound 274 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-OEG(1,2)(array number: 600) MW (calculated): 6602.4Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:8.9 points;m / 3:2201.8 m / 4:1651.7 m / 5: Compound 275 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 601) MW (calculated): 7000.8Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.3 minutes;m / 3:2335.4 m / 4:1751.1 m / 5: Compound 276 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu(1,2)(array number: 602) MW (calculated): 6586.3 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.1 points;m / 3:2196.1 m / 4:1647.5 m / 5:

[0135] 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)(Allocation number: 603) MW (calculated): 6956.8 Da Synthesis method and purification method: S01; P02 LCMS:A01-B; Rt:35.1 minutes; m / 3: m / 4:1740.0 m / 5: Compound 278 Y-Aib-EGTFTSDYSI-Aib-LEKQAE-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(array number: 604) MW (calculated): 6847.7 Da Synthesis method and purification method: S01; P02 LCMS:A01-A;Rt:13.8 minutes;m / 3: m / 4:1712.7 m / 5: Compound 279 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-EFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-AHX(1,2)(array number: 605) MW (calculated): 6957.7 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:8.4 points;m / 3:2320.4 m / 4:1741.0 m / 5: Compound 280 Y-Aib-EGTFTSDYSI-Aib-LEKQAE-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu(1,2)(array number: 606) MW (calculated): 6557.3 Da Synthesis method and purification method: S01; P02 LCMS:A01-A;Rt:14.1 minutes;m / 3: m / 4:1640.2 m / 5:

[0136] Compound 281 Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-Q-W-L-I-K(1,3)-G-G-P-S-E-G-A-S-L-R-H-Y-Y-N-W-L-T-R-Q-R-Y-NH2.C18DA-E-E-E-E(1,2)(SEQ ID Nos: 607 and 640) MW (calculated): 6527.3 Da Synthesis method and purification method: S02; P03 LCMS: A02-A; Rt: 7.3 min; m / z: 2177.4 m / z: 1632.6 m / z: Compound 282 Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-E-F-V-E-W-L-I-K(1,3)-G-G-P-S-E-G-A-S-L-R-H-Y-Y-N-W-L-T-R-Q-R-Y-NH2.C18DA-gGlu-OEG-OEG(1,2)(SEQ ID No: 608) MW (calculated): 6489.3 Da Synthesis method and purification method: S02; P03 LCMS: A02-A; Rt: 7.5 min; m / z: 2163.1 m / z: 1623.1 m / z: Compound 283 Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-I-E-W-L-I-K(1,3)-G-G-P-S-E-G-A-S-L-R-H-Y-Y-N-W-L-T-R-Q-R-Y-NH2.C20DA-gGlu-gGlu-gGlu-gGlu(1,2)(SEQ ID No: 609) MW (calculated): 6570.4 Da Synthesis method and purification method: S01; P02 LCMS: A01-A; Rt: 14.0 min; m / z: m / z: 1643.5 m / z: Compound 284

Chemical Structure

[0137] compound 285 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPEEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Sequence ID: 611) MW (calculated): 6984.8Da Synthesis and purification methods: S02; P03 LCMS:A02-B;Rt:10.7 min;m / 3:2329.3 m / 4:1747.2 m / 5: compound 286 [ka] The structure is disclosed in sequence number 612. Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Sequence ID: 612) MW (calculated): 6942.8Da Synthesis and purification methods: S01; P02 LCMS:A01-A;Rt:12.7 minutes;m / 3:2315.4 m / 4:1736.7 m / 5: Compound 287 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2)(array number: 613) MW (calculated): 6846.7 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.9 points;m / 3:2283.2 m / 4:1712.5 m / 5: Compound 288 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 614) MW (calculated): 7071.9 Da Synthesis method and purification method: S01; P02 LCMS:A01-A;Rt:12.9 minutes;m / 3: m / 4:1768.6 m / 5:

[0138] Compound 289 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(array number: 615) MW (calculated): 6685.5Da Synthesis method and purification method: S01; P02 LCMS:A01-A;Rt:13.6 minutes;m / 3: m / 4:1672.2 m / 5: Compound 290 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 616) MW (calculated): 6813.7 Da Synthesis method and purification method: S01; P02 LCMS:A01-A;Rt:13.0 points;m / 3: m / 4: m / 5:1363.6 Compound 291 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-EEEE(1,2)(each arrangement number is 617 and び640) MW (calculated): 6657.4 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:10.6 minutes;m / 3:2117.4 m / 4:1633.3 m / 5: Compound 292 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(array number: 618) MW (calculated): 6657.4 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:10.6 points;m / 3:2220.6 m / 4:1665.5 m / 5:

[0139] Compound 293 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(Allocation number: 619) MW (calculated): 6914.7 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:6.8 points;m / 3:2306.3 m / 4:1729.9 m / 5: Compound 294 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu(1,2)(array number: 620) MW (calculated): 6528.3Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:10.5 minutes;m / 3:2177.2 m / 4:1633.1 m / 5: Compound 295 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2)(array number: 621) MW (calculated): 6785.6 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:9.4 points;m / 3:2262.9 m / 4:1697.4 m / 5: Compound 296 Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-E-W-L-I-K(1,3)-G-G-P-S-E-G-A-S-L-R-H-Y-Y-N-W-L-T-R-Q-R-Y-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(SEQ ID NO: 622) MW (calculated): 6786.5 Da Synthesis method and purification method: S02; P03 LCMS: A02-B; Rt: 10.1 min; m / z: 2263.2 m / z4: 1697.7 m / z5:

[0140] Compound 297

Chemical Structure

[0141] Compound 301 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-AHX(1,2)(array number: 627) MW (calculated): 6798.6 Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:10.4 minutes;m / 3:2267.1 m / 4:1700.9 m / 5: Compound 302 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-EEEEEE(1,2)(each arrangement number is 628 and び637) MW (calculated): 6786.5Da Synthesis method and purification method: S02; P03 LCMS:A02-B;Rt:10.5 minutes;m / 3:2263.1 m / 4:1697.6 m / 5: Compound 303 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-AHX(1,2)(Allocation number: 629) MW (calculated): 6899.7 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.2 minutes;m / 3:2301.3 m / 4:1726.1 m / 5: Compound 304 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-AHX(1,2)(array number: 630) MW (calculated): 6770.6 Da Synthesis method and purification method: S02; P03 LCMS:A02-A;Rt:7.2 points;m / 3:2258.0 m / 4:1694.0 m / 5:

[0142] Compound 305 Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK(1,3)-GGPSEGASLRHYYNWLTRQRY-NH2.C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu(1,2)(Sequence ID: 631) MW (calculated): 6814.6Da Synthesis and purification methods: S01; P02 LCMS:A01-B;Rt:35.5min;m / 3: m / 4: m / 5:1363.7 Literature 1 NMeY-Aib-EGT-aMeF-TSDK(1,3)-SI-Aib-LEKQRQ-Iva-EFVRHLLNK-Aib-TRQRY-NH2.C16A-GGGG(1,2) (Sequence numbers 632 and 641 respectively) Example 41 of EP3467106 Solubility:<1mg / ml (pH7) Literature 2 NMeY-Aib-EGT-aMeF-TSDK(1,3)-SI-Aib-LEKQRQ-Iva-EFVRHLLNK-Aib-TRQRY-NH2.C18DA-GGGG(1,2)(Sequence IDs 633 and 642) Example 42 of EP3467106 Solubility:<1mg / ml (pH7)

[0143] Examples The following examples illustrate specific embodiments of the present invention. Unless otherwise described in particular, the following examples were carried out using standard methods that are well known and customary to those skilled in the art.

[0144] Example 1: hGLP1R / hGIPR / hNPY2R CreLuc assay in 0.5% and 100% plasma CHO and HEK-293 recombinant cell lines express the luciferase reporter gene under the control of the cAMP responsive factor (CRE). As a second recombinant protein, GLP-1 and NPY2 receptors were expressed in HEK cells, and the GIP receptor was expressed in CHO cells. Stimulation of these recombinant cells with an agonist causes an increase in intracellular cAMP levels. In the presence of cAMP, the transcription factor CRE-binding protein (CREB) binds to CRE and CREB-binding protein (CBP), inducing transcription of the luciferase reporter gene. The peptide, serially diluted with 100% DMSO, was transferred to a 384-well assay plate using acoustic dispensing with Labcyte ECHO, along with 5 μl of pre-dispensed assay buffer (1×HBSS, 20 mM HEPES, pH 7.4, with 0.5% human plasma added). Cryopreserved transgenic reporter gene cells were thawed in assay buffer. 20 μl (10,000 cells / well) of peptide was added to a plate and incubated in a humidified incubator at 37°C for 4 hours. After incubation, the assay plate was equilibrated to room temperature, 25 μl of Bright-Glo® luciferase was added, and the plate was incubated at room temperature for 10 minutes. Luminescence was then analyzed (using an Envision Reader). The concentration response of the compound was evaluated at eight different peptide concentrations (covering four decades). EC50 values ​​were calculated by nonlinear regression using a concentration-response sigmoid curve with a variable slope. The same assay was performed in the presence of 100% plasma without the addition of any additional buffer components.

[0145] The results are summarized in Table 3 below. [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4] [Table 9-5] [Table 9-6] [Table 9-7]

[0146] Example 2: Solubility The peptide (as TFA-salt) was weighed using a filter unit (Mini-UniPrep Syringeless Filter 0.45 μm, Whatman PVDF), and 0.1 M phosphate buffer at pH 7 was added to obtain a final peptide concentration of 10 mg / mL. The peptide was dissolved by shaking the filter unit horizontally at 600 rpm for 2 hours at room temperature. The sample was then filtered to remove any insoluble particles. The control was prepared by weighing the corresponding peptide solid material 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 of ​​the sample was compared to the control, and solubility was calculated based on the ratio. The pH was measured and recorded for each sample.

[0147] Example 3: Mouse PK Pharmacokinetic parameters of peptides were measured after intravenous administration to NMRI mice. Male NMRI mice weighing 30g to 40g were obtained from Janvier Laboratories (France). Mice were housed in standard cages with appropriate access to standard food and water on a 12:12 light-dark cycle. Each test peptide was dissolved in 50mM phosphate buffer (pH 7.4) / 3.5% mannitol. Intravenous administration of 30–60 nmol / kg was performed via the anal vein. Blood samples were collected sequentially from conscious mice at various time points up to 56 hours post-administration into EDTA-containing vials via the saphenous vein. Plasma was then prepared by centrifugation at approximately 5000 rpm for 5 minutes and stored at -20°C until quantification of peptide plasma levels by liquid chromatography-mass spectrometry (LC-MS). Individual plasma concentration-time profiles were analyzed using a non-compartmental approach, and the resulting pharmacokinetic parameters were calculated. The mean mouse residence time (MRT) of the GGY peptide of the present invention was measured and summarized in Table 4 below.

[0148] [Table 10]

[0149] Example 4: Effects of sudden food intake in normal NMRI mice Three-week-old male NMRI mice were obtained from Janvier (Janvier Labs, France) or Charles River (Charles River Research Models & Services Germany GmbH). After delivery, the animals were microchipmed (Datamars, Slim Microchip T-SL) for individual identification. Four mice were housed in each cage under a 12 / 12 light-dark cycle, with the lights turned off at 3 PM. Room temperature was maintained at 21°C ± 1°C and humidity at 60% ± 20%. Mice were given access to standard rodent feed (KLIBA Nafag 3040 or Altromin 1324, Brogaarden, Denmark) and tap water as needed. Five days prior to the start of the experiment, the animals were finally transferred to the MBRose (Denmark) HM2 system (a system for real-time monitoring of feeding and drinking) to allow for adaptation to the experimental conditions. Each animal was uniquely identified using a microchip; each individual animal was identified by its own microchip via an antenna as it entered and exited the food passage. Randomization of mice (n=8; youngest 6 weeks old) for each test group was based on food intake (median over the past 3 days (24-hour intervals)) and body weight immediately prior to the start of the experiment. A vehicle (50 mM phosphate buffer at pH 7.4 containing 3.5% mannitol) was included in each experiment. To ensure that each animal had the same nutritional standards, access to food was blocked 8 hours before the dark period. A single subcutaneous dose of the test peptide was administered to the animals 1 hour before the dark period. Food intake was reported hourly for a 24-hour period. The food intake was normalized relative to the average food intake of the vehicle group. The values ​​are summarized in Table 5 below.

[0150] [Table 11]

[0151] Item A 1. A polypeptide having the general structure of formula (I), or a pharmaceutically acceptable salt thereof. Z1-Z2-Z3 (Sequence ID: 647) (I) (In the formula, Z1 has the 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 A hybrid polypeptide containing -K (SEQ ID NO: 646), where X3 is selected as E or D; X 10If selected as Y or L; X 13 Aib or L is selected; X 15 is selected as E, D, or A; X 16 is selected as K, E, D, Aib, G, LysAc, A, L, S, Q, or R; X 17 is selected as Q, E, K, or A; X 19 is selected as Q or E; X 20 Aib, D-Asp, or D-Arg is selected; X 21 is selected as A, E, or K; X 23 is selected as V or I; X 24 is selected as E or Q; X 25 is selected as W or Y; X 27 is I or L, or Z1 is a derivative thereof having one amino acid substitution; Z2 has the amino acid sequence GGX 31 -X 32 -X 33 -X 34 A linker that includes, where X 31 is selected as P, G, or Q; X 32 is selected as S, E, or R; X 33 is selected as S, E, Y, or T; X 34 is selected as G, P, Y, or A; or Z2 is a derivative thereof having one amino acid substitution; Z3 is an 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 A polypeptide containing X 35 is selected as A, Q, I, V, E, or L; X 36 is selected as S, E, T, D, or L; X 37is selected as L, Aib, V, D-Leu, I, or Tle; X 38 is selected as R, L, or Aib; X 39 is selected as H, Aib, D-His, or Tle; X 41 is selected as Y, L, Aib, I, or Tle; X 42 is selected as N or Aib; X 43 is selected as W, H, L, R, or Aib; X 44 is selected as L, Aib, D-Arg, D-Asp, or Tle; X 46 is selected as R, hArg, or D-Arg; X 47 is selected as Q, bh-Gln, or NMeQ; X 48 is selected as R or NMeR; X 49 (The selected derivatives are Y, Tle, Chg, D-Tyr, Phg, or Z3 is a derivative having one amino acid substitution.) 2. The polypeptide described in Item 1, in which X3 in Z1 is selected as E. 3. X in Z1 10 However, the polypeptide described in item 1 or 2 is selected as Y. 4. X in Z1 13 However, the polypeptide listed in any one of items 1 to 3 is selected as Aib. 5. X in Z1 15 However, the polypeptide listed in any one of items 1 through 4 is selected as E. 6. X in Z1 16 However, the polypeptide selected as K is one of the items listed in items 1 through 5. 7. X in Z1 17 However, the polypeptide listed in one of items 1 through 6 is selected as Q. 8.X in Z1 19 However, the polypeptide listed in one of items 1 through 7 is selected as Q. 9. X in Z1 20However, the polypeptide listed in any one of items 1 through 8 is selected as Aib. 10. X in Z1 21 However, the polypeptide described in any one of items 1 to 9, selected as A or E, preferably as A. 11. X in Z1 23 However, the polypeptide listed in one of items 1 through 10 is selected as V. 12. X in Z1 24 However, the polypeptide described in any one of items 1 to 11 is selected as E or Q, preferably as E. 13. X in Z1 25 However, the polypeptide listed in one of items 1 through 12 is selected as W. 14. X in Z1 27 However, the polypeptide listed in one of items 1 through 13 is selected as I. 15. X in Z2 31 However, the polypeptide selected as P is one of the items 1 through 14. 16. X in Z2 32 However, the polypeptide listed in one of items 1 through 15 is selected as S. 17. X in Z2 33 However, the polypeptide described in any one of items 1 to 16 is selected as E or S, preferably as S. 18. X in Z2 34 However, the polypeptide listed in any one of items 1 through 17 is selected as G. 19. X in Z3 35 However, the polypeptide described in any one of items 1 to 18 is selected as A, Q, or V, preferably as A. 20. X in Z3 36 However, the polypeptide listed in one of items 1 through 19 is selected as S. 21. X in Z3 37However, the polypeptide described in any one of items 1 to 20 is selected as I or L, preferably as L. 22. X in Z3 38 However, the polypeptide selected as R is one of the items listed in Item 1 to 21. 23. X in Z3 39 However, the polypeptide listed in any one of items 1 through 22 is selected as H. 24. X in Z3 41 However, the polypeptide listed in one of items 1 through 23 is selected as Y. 25. X in Z3 42 However, the polypeptide listed in one of items 1 through 24 is selected as N. 26. X in Z3 43 However, the polypeptide listed in any one of items 1 through 25 is selected as W. 27. X in Z3 44 However, the polypeptide listed in any one of items 1 through 26 is selected as L. 28. X in Z3 46 However, the polypeptide selected as R is one of the polypeptides listed in any one of items 1 through 27. 29. X in Z3 47 However, the polypeptide described in any one of items 1 to 28 is selected as Q or NMeQ, preferably as Q. 30. X in Z3 48 However, the polypeptide described in any one of items 1 to 29 is selected as R or NMeQ, preferably as R. 31. X in Z3 49 However, the polypeptide listed in one of items 1 through 30 is selected as Y. 32.X 35 X 36 X 37 X 38 X 39 However, the polypeptide listed in any one of items 1 to 31 is selected as ASLRH (Sequence ID: 645). 33.X 41X 42 X 43 X 44 However, the polypeptide listed in any one of items 1 through 32 is selected as YNWL (Sequence ID: 326). 34.X 46 X 47 X 48 X 49 However, the polypeptide listed in one of items 1 through 33 is selected as RQRY (sequence number: 327). 35. A polypeptide according to any one of items 1 to 34, wherein the polypeptide can bind to and / or activate GLP-1, GIP, and hY2 (hNPY2) receptors.

[0152] Item B 1. A polypeptide having the general structure of formula (I), or a pharmaceutically acceptable salt thereof. Z1-Z2-Z3(I) (In the formula, Z1 is a hybrid polypeptide containing the amino acid sequence Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK (SEQ ID NO: 306), or a derivative thereof having one, two, or three substitutions; Z2 is a linker; Z3 is a polypeptide containing the amino acid sequence ASLRHYYNWLTRQRY (SEQ ID NO: 307), or a derivative thereof having one, two, three, four, or five substitutions. 2. The polypeptide according to claim 1, wherein the linker consists of 1 to 10 amino acid residues. 3. The polypeptide according to claim 1 or 2, wherein Z2 has the amino acid sequence GGPSEG (SEQ ID NO: 311) or a derivative thereof having one, two, three, or four amino acid substitutions. 4. In Z2, one, two, three, or four amino acid substitutions occur at position X 31 , X 32 , X 33 or X 34The polypeptide according to claim 3, which is present in any of the following. 5.Z2 is the amino acid sequence GGX 31 X 32 X 33 X 34 It has, here, X 31 However, it is selected as P, G, or Q; X 32 However, it is selected as S, E, or R; X 33 However, it is selected as S, E, or Y; X 34 The polypeptide according to any one of claims 1 to 4, wherein Z2 is selected as G, P, Y, or A; or Z2 is a derivative thereof having one amino acid substitution. 6. One, two, or three substitutions in the derivative of Z1 result in 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 A polypeptide according to any one of claims 1 to 5, which is present in any of the following. 7. One, two, three, four, or five substitutions in derivatives of Z3 result in 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 A polypeptide according to any one of claims 1 to 6, which is present in any of the following. 8. The polypeptide according to any one of claims 1 to 7, wherein the derivative of Z3 has one, two, or three substitutions, preferably one or two substitutions, most preferably one substitution. 9. The polypeptide according to any one of claims 1 to 8, wherein the derivative of Z1 has one or two substitutions, preferably one substitution. 10. In derivatives of Z1, the substitutions are selected as follows: X3 is selected as D; X 10 is selected as L; X 13 is selected as L; X 15 is selected as D or A; X 16 is selected as E, D, Aib, G, LysAc, A, L, S, Q, or R; X 17 is selected as E, K, or A; X 19 is selected as E; X 20 is selected as D-Asp or D-Arg;X 21 is selected as E; X 23 is selected as I; X 24 Q is selected; X 25 is selected as Y; X 27 A polypeptide according to any one of claims 1 to 9, wherein L is selected. 11. In derivatives of Z3, the substitution is selected as follows: X 35 is selected as Q, I, V, E, or L; X 36 is selected as E, T, D, or L; X 37 is selected as Aib, V, D-Leu, or I; X 38 is selected as L or Aib; X 39 Selected as Aib, D-His or Tle; X 41 is selected as L, Aib, I or Tle; X 42 is selected as Aib;X 43 is selected as H, L, R, or Aib; X 44 is selected as Aib, D-Arg, or D-Asp; X 46 is selected as hArg or D-Arg; X 47 is selected as bh-Gln or NMeQ;X 48 is selected as NMeR;X 49 The polypeptide according to any one of claims 1 to 10, wherein is selected as Tle, Chg, D-Tyr, or Phg. 12. The polypeptide is lipid-added at a lysine (K) residue, preferably at amino acid position X 28 A poipeptide according to any one of claims 1 to 11, wherein lipid addition is performed at the lysine (K) residue in [the specified part of the product]. 13. A polypeptide according to any one of claims 1 to 12, wherein the polypeptide has the general formula LY 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 -Y 7 -Y 8 The structure is modified by lipid addition, where L is a lipid selected from C18DA or C20DA, and furthermore, each Y 1 ~Y 8 However, polypeptides that are either non-existent or selected from [γE], [OEG], [eLys], or [AHX] independently. 14.C18DA、C18DA[γE]-、C18DA[γE][γE]-、C18DA[γE][γE][γE]-、C18 DA[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、C20 DA[γE]-、C20DA[γE][γE]-、C20DA[γE][γE][γE]-、C20DA[γE][γE][γE][γ E]-、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][eLy s]-、C18DA[γE][γE][eLys]-、C18DA[γE][γE][γE][eLys]-、C18DA[γE][γ E][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][γ E][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]-、C20 DA[OEG][OEG]-、C20DA[γE][OEG][OEG]-、C20DA[γE][γE][OEG][OEG]-、C 20DA[γE][γE][γE][OEG][OEG]-、C20DA[γE][γE][γE][γE][OEG][OEG]-、C20DA[γE][γE][γE][γE][γE][OEG][OEG]-、C18DA[OEG]-、C18DA[γE][γE][OEG]-、C18DA[γE][γE][OEG]-、C18DA[γE][γE][γE][OEG]-、C18DA[γE][γE][γE][γE][OEG]-、C18DA[γE][γE][γE][γE][OEG]-、C18DA[γE][γE][γE][γE][γE][OEG]-、C18DA[γE][γE][γE][γE][γE][OEG]-、C20DA[OEG]-、C20DA[OEG]-、C20DA[OG ][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][OEG]-、C18DA[OEG][eLys]-、C18DA[γE][γE][OEG][eLys]-、C18DA[γE][γE][γE][γE][OEG][eLys]- [OEG][eLys]-、C18DA[γE][γE][γE][γE][γE][OEG][eLys]-、C20DA[OEG][eLys]-、C20DA[γE][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][OEG][eLys]-、C20DA[γE][γE][γE][γE][OEG][eLys]-、C18DA[OEG][OEG][eLys]-、C18 DA[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[γE][OEG][OEG][oEG][eLys]-、C20DA[γE][γE][OEG][OEG][eLys]-、C20DA[γE][γE][OEG][OEG][oEG][eLys]-、C20DA[γE][γE][OEG][OEG][eLys]-、C20DA[γE][γE][OEG][OEG][eLys]-、C20DA[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][γE][AHX]-, A polypeptide according to any one of claims 1 to 13, selected from the list consisting of C20DA[AHX], C20DA[γE][AHX]-, C20DA[γE][γE][AHX]-, C20DA[γE][γE][γE][γE][AHX]-, C20DA[γE][γE][γE][γE][γE][AHX]-, C20DA[γE][γE][γE][γE][γE][γE][AHX]-, C20DA[γE][γE][γE][γE][γE][γE][AHX]-. 15. A polypeptide according to any one of claims 1 to 14, selected from the group consisting of compound 1 to compound 305.

[0153] Item C 1. A polypeptide having the general structure of formula (I), or a salt thereof or a pharmaceutically acceptable salt thereof. Z1-Z2-Z3(I) (In the formula, Z1 consists of or contains 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, or a hybrid polypeptide X1-X. 28 and; Z2 consists of or contains peptide X, which has the amino acid sequence GGPSEG (SEQ ID NO: 311), or a derivative thereof having one, two, three, or four amino acid substitutions. 29 -X 34 and; Z3 consists of or contains the amino acid sequence ASLRHYYNWLTRQRY (SEQ ID NO: 307), or a derivative thereof having one, two, three, four, or five amino acid substitutions, or a polypeptide X. 35 -X 49 and; Preferably, Z1-Z2-Z3 has 0, 1, 2, 3, 4, 5, or 6 amino acid substitutions. 2. Polypeptides described in Item 1, Z1 consists of or contains the amino acid sequence Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK (Sequence ID: 306), or any 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 A derivative thereof having one, two, or three amino acid substitutions, wherein the substitutions are selected as follows: X3 is selected as D; X 10 is selected as L; X 13 is selected as L; X 15 is selected as D or A; X 16 is selected as E, D, Aib, G, LysAc, A, L, S, Q, or R; X 17 is selected as E, K, or A; X 19 is selected as E; X 20 is selected as D-Asp or D-Arg;X 21 is selected as E or K; X 23 is selected as I; X 24 Q is selected; X 25 is selected as Y; X 27 is selected as L; Z2 has the amino acid sequence GGX 31 X 32 X33 X 34 It consists of or includes, where X 31 is selected as P, G, or Q; X 32 is selected as S, E, or R; X 33 is selected as S, E, Y, or T; X 34 is selected as G, P, Y, or A; Z3 consists of or contains the amino acid sequence ASLRHYYNWLTRQRY (SEQ ID NO: 307), or any 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 The derivative having one, two, three, four, or five substitutions, wherein the substitutions are selected as follows: X 35 is selected as Q, I, V, E, or L; X 36 is selected as E, T, D, or L; X 37 is selected as Aib, V, D-Leu, I or Tle; X 38 is selected as L or Aib; X 39 Selected as Aib, D-His or Tle; X 41 is selected as L, Aib, I or Tle; X 42 is selected as Aib;X 43 is selected as H, L, R, or Aib; X 44 is selected as Aib, D-Arg, D-Asp, or Tle; X 46 is selected as hArg or D-Arg; X 47 is selected as bh-Gln or NMeQ;X 48 is selected as NMeR;X 49 Polypeptides selected as Tle, Chg, D-Tyr, and Phg. 3. Polypeptides described in item 1 or 2, Z1 consists of or contains the amino acid sequence Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK (Sequence ID: 306), or any 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 The derivative having one, two or three amino acid substitutions, wherein the substitutions are selected as follows: X3 is selected as D; X 10 is selected as L; X 13 is selected as L; X 15 is selected as D; X 16 is selected as E, D, G, A, S, Q, or R; X 17 is selected as E or A; X 19 is selected as E; X 21 is selected as E or K; X 23 is selected as I; X 24 Q is selected; X 25 is selected as Y; X 27 is selected as L; Z2 has the amino acid sequence GGX 31 -X 32 -X 33 -X 34 It consists of or includes, where X 31 is selected as P or Q; X 32 is selected as S or E; X 33 is selected as S, E, Y, or T; X 34 is selected as G, P, Y, or A; Z3 consists of or contains the amino acid sequence ASLRHYYNWLTRQRY (SEQ ID NO: 307), or any 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 The derivative having one, two, or three substitutions, wherein the substitutions are selected as follows: X 35 is selected as Q, I, V, E, or L; X 36 is selected as T; X 37 is selected as Aib, V, I, or Tle; X 38 is selected as Aib;X 39 is selected as Tle;X 41 is selected as I, L, or Tle; X 44 is selected as Tle;X 47 is selected as NMeQ;X 48 The polypeptide selected as NMeR. 4. A polypeptide described in any one of items 1 to 3, Z1 consists of or contains the amino acid sequence Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK (Sequence ID: 306), or any amino acid positions X3, X 10 , X 13 , X 15 , X 16 , X 17 , X 21 , X 23 , X 24 or X 25 The derivative having one, two or three substitutions, wherein the substitutions are selected as follows: X3 is selected as D; X 10 is selected as L; X 13 is selected as L; X 15 is selected as D; X 16 is selected as E, D, G, A, S, Q, or R; X 17 is selected as E or A; X 21 is selected as E; X 23is selected as I; X 24 Q is selected; X 25 Y is selected; Z2 has the amino acid sequence GGX 31 -X 32 -X 33 -X 34 It consists of or includes, where X 31 is selected as P or Q; X 32 is selected as S or E; X 33 is selected as S, E, Y, or T; X 34 is selected as G, P, Y, or A; Z3 consists of or contains the amino acid sequence ASLRHYYNWLTRQRY (SEQ ID NO: 307), or any amino acid position X 35 , X 36 , X 37 , X 38 , X 39 , X 41 , X 44 , X 47 , X 48 or X 49 The derivative having one or two amino acid substitutions, wherein the substitutions are selected as follows: X 35 is selected as Q, I, V, E, or L; X 36 is selected as T; X 37 is selected as Aib, V, I, or Tle; X 38 is selected as Aib;X 39 is selected as Tle;X 41 is selected as I, L, or Tle; X 44 is selected as Tle;X 47 is selected as NMeQ;X 48 The polypeptide selected as NMeR. 5. A polypeptide described in any one of items 1 to 4, Z1 consists of or contains the amino acid sequence Y-Aib-EGTFTSDYSI-Aib-LEKQAQ-Aib-AFVEWLIK (Sequence ID: 306), or any amino acid position X21 or X 24 The derivative having one or two, preferably one amino acid substitution, the substitution being selected as follows: X 21 is selected as A or E; X 24 is selected as E or Q; Z2 consists of or contains the amino acid sequence GGPSEG (SEQ ID NO: 311) or GGPSSG (SEQ ID NO: 320); Z3 consists of or contains the amino acid sequence ASLRHYYNWLTRQRY (SEQ ID NO: 307), or any amino acid position X 35 , X 37 , X 47 or X 48 The derivative having one or two, preferably one amino acid substitution, wherein the substitution is selected as follows: X 35 Q and V are selected; X 37 is selected as I; X 47 is selected as NMeQ;X 48 The polypeptide selected as NMeR.

Claims

1. A polypeptide of the general structure of formula (I) or a salt thereof. Z1-Z2-Z3(I) (Sequence number: 647) (In the formula, Z1 is a hybrid polypeptide consisting of the amino acid sequence Y - Aib - X 3 -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), where X 3 is selected as E; X 10 is selected as Y; X 13 is selected as Aib; X 15 is selected as E; X 16 is selected as K; X 17 is selected as Q; X 19 is selected as Q; X 20 is selected as Aib; X 21 is selected as A or E; X<了 23 is selected as V; X 24 is selected as E or Q; X 25 is selected as W; X 27 is I; Z2 has the amino acid sequence G-G-X 31 -X 32 -X 33 -X 34 A linker consisting of X 31 is selected as P, G, or Q; X 32 is selected as S, E, or R; X 33 is selected as S, E, Y, or T; X 34 is selected as G, P, Y, or A; Z3 is an 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 It is a polypeptide consisting of X 35 is selected as A, Q, or V; X 36 is selected as S; X 37 is selected as I or L; X 38 is selected as R; X 39 is selected as H; X 41 Y is selected; X 42 is selected as N; X 43 is selected as W; X 44 is selected as L; X 46 is selected as R; X 47 is selected as Q or NMeq; X 48 is selected as R or NMeeR; X 49 (This is selected as Y.)

2. Z2 has the amino acid sequence G-G-X 31 -X 32 -X 33 -X 34 It consists of, and here, X 31 is selected as P or Q; X 32 is selected as S or E; X 33 is selected as S, E, Y, or T; X 34 The polypeptide or salt thereof according to claim 1, wherein is selected as G, P, Y, or A.

3. The polypeptide or salt thereof according to claim 1, wherein 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), GGPSSTG (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).

4. In Z1, X 3 is selected as E; X 10 Y is selected; X 13 is selected as Aib; X 15 is selected as E; X 16 is selected as K; X 17 Q is selected; X 19 Q is selected; X 20 is selected as Aib; X 21 is selected as A or E; X 23 is selected as V; X 24 is selected as E or Q; X 25 is selected as W; X 27 is I; Z2 consists of the amino acid sequence GGPSEG (SEQ ID NO: 311) or GGPSSG (SEQ ID NO: 320); In Z3, X 35 is selected as A, Q or V; X 36 is selected as S; X 37 is selected as I or L; X 38 is selected as R; X 39 is selected as H; X 41 is selected as Y; X 42 is selected as N; X 43 is selected as W; X 44 is selected as L; X 46 is selected as R; X 47 is selected as Q or NMeQ; X 48 is selected as R or NMeR; X 49 is selected as Y, the polypeptide according to claim 1 or a salt thereof.

5. The polypeptide according to claim 1 or a salt thereof, wherein Z2 consists of the amino acid sequence GGPSEG (SEQ ID NO: 311).

6. The polypeptide according to claim 1 or a salt thereof, wherein Z2 consists of the amino acid sequence GGPSSG (SEQ ID NO: 320).

7. Polypeptide, amino acid position X 28 The polypeptide or salt thereof according to claim 1, wherein lipid addition is performed at the lysine (K) residue in the polypeptide.

8. The polypeptide is lipid-modified by the structure of general formula L-Y 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 -Y 7 -Y 8 , where L is a lipid selected from 17-carboxy-heptadecanoyl (C18DA) or 19-carboxy-nonadecanoyl (C20DA), and each Y 1 ~Y 8 is independently absent or selected from [γE], [E], [OEG], [eLys] or [AHX], the polypeptide according to claim 7 or a salt thereof.

9. Polypeptide, general formula L-Y 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 -Y 7 -Y 8 The structure is lipid-added, where L is a lipid selected from 17-carboxyheptadecanoyl (C18DA) or 19-carboxynonadecanoyl (C20DA), and each Y 1 ~Y 8 However, independently, it does not exist, or it is selected from [γE], [E], [OEG], [eLys] or [AHX], and each Y 1 ~Y 3 is [γE], or each Y 1 ~Y 3 [E] and Y 4 is selected from [γE], [E], or [OEG], and each Y 5 ~Y 8 The polypeptide or salt thereof according to claim 7, wherein independently, it does not exist or is selected from [γE], [E], [OEG], [eLys], or [AHX]. 【10】 [#]||[|[|]_______________]| [##|[|[][]_______________] [#]||[|[|][[][]_____________] [#]、||#|[|[γ][][γ][!!!!!!verage [[γ][][_γ][[_γ][|[γ]]、|[#]!|[_γ] [[γ][][γ][[[γ][][γ]][#γ#]、![[]]!!!!!4E! [[γ][[][γ][][_γ][][_γ][]!!] [[γ][|[γ][[_γ]||[|]|_[γ][[]][_γ]] [[γ][][γ][[]||!][||@[S][[!!!!ES [|[γ][|[γ]|[||[]|、|[|[γ]][[γ][[] [|[γ][|[γ][[_γ]]、|[#|[[][]] [|||] [||||_]_____________________________________________________________ ______________________________________________________________________________________ [#]#]、[#]|[#γ][[][][][][]][\]!! [#]、|[#][|[γ][][γ][|[γ][[]] [|]||||[γ][[][_γ][[]][_γ][[]] [_γ][]|||||[[]][[]][[]] [||]______________________________________________________________________________________________ [|[γ]|[||||]||、|[||[|[γ][][|] [[]][|_γ][|[|]]|、|||___[__]_[__] [|[γ]|[[γ][][_γ][[]]__、!!!!! [γ|] [[γ][[][_γ][][γ][[][_γ][][[]] [|]__、|[*][|[_γ][[_γ][][γ][[][_γ]] |_________、|_________________________________________ [[#]|||||[][][][]]_____| [#]_____________________________________________________________ γ|[||||||[|||]、|[|][|[γ][[][[]][]] [[γ]|[#|]||||[#][|][|][_]] γ||[γ]|[|||[][|||||||] [[]][|][|]___________________________________________________________________ The [#|[γ][|[γ][[][][][]][!!!]C20DA [γE] [γE] [γE] [γE] [γE] [OEG] [OEG] -, C18DA [γE] [γE] [γE] [OEG] -, C18DA [γE] [γE] [γE] [γE] [OEG] -, C18DA [γE] [γE] [γE] [γ E] [γE] [OEG] -, C18DA [γE] [γE] [γE] [γE] [γE] [γE] [OEG] -, C20DA [γE] [γE] [γE] [OEG] -, C20DA [γE] [γE] [γE] [γE] [OEG] -, C20DA [γ E] [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] [OE G] [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] The polypeptide or salt thereof according to claim 7, which is lipid-added by a structure selected from the group consisting of [AHX]-, C18DA[γE][γE][γE][γE][γE][γE][AHX]-, C18DA[γE][γE][γE][γE][γE][γE][γE][AHX]-, C20DA[γE][γE][γE][γE][γE][γE][AHX]-, or C20DA[γE][γE][γE][γE][γE][γE][γE][AHX]-.

11. The polypeptide according to claim 1 or a salt thereof, which is amidated at the C-terminus.

12. The polypeptide according to claim 1, selected from the group consisting of compounds listed in the following table. Table 1

13. The polypeptide according to claim 12, which is a pharmaceutically acceptable salt form.

14. The polypeptide according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the polypeptide is Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-E-W-L-I-K(1,3)-G-G-P-S-S-G-V-S-I-R-H-Y-Y-N-W-L-T-R-Q-R-Y-NH2. C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2) (SEQ ID NO: 353).

15. The polypeptide according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the polypeptide is Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-E-W-L-I-K(1,3)-G-G-P-S-S-G-A-S-L-R-H-Y-Y-N-W-L-T-R-NMeQ-R-Y-NH2. C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2) (SEQ ID NO: 411).

16. The polypeptide according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the polypeptide is Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-E-F-V-E-W-L-I-K(1,3)-G-G-P-S-S-G-A-S-L-R-H-Y-Y-N-W-L-T-R-Q-R-Y-NH2. C18DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2) (Sequence ID: 471).

17. The polypeptide according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the polypeptide is Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-Q-W-L-I-K(1,3)-G-G-P-S-E-G-A-S-L-R-H-Y-Y-N-W-L-T-R-Q-R-Y-NH2. C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2) (SEQ ID NO: 546).

18. The polypeptide according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the polypeptide is Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-E-W-L-I-K(1,3)-G-G-P-S-S-G-A-S-L-R-H-Y-Y-N-W-L-T-R-Q-R-Y-NH2. C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2) (SEQ ID NO: 547).

19. The polypeptide according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the polypeptide is Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-E-W-L-I-K(1,3)-G-G-P-S-E-G-A-S-L-R-H-Y-Y-N-W-L-T-R-NMeQ-R-Y-NH2. C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2) (SEQ ID NO: 548).

20. The polypeptide according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the polypeptide is Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-Q-W-L-I-K(1,3)-G-G-P-S-E-G-A-S-L-R-H-Y-Y-N-W-L-T-R-Q-R-Y-NH2. C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2) (SEQ ID NO: 550).

21. The polypeptide according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the polypeptide is Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-E-W-L-I-K(1,3)-G-G-P-S-S-G-A-S-L-R-H-Y-Y-N-W-L-T-R-Q-R-Y-NH2. C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2) (SEQ ID NO: 551).

22. The polypeptide according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the polypeptide is Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-E-W-L-I-K(1,3)-G-G-P-S-S-G-A-S-L-R-H-Y-Y-N-W-L-T-R-Q-R-Y-NH2. C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2) (SEQ ID NO: 585).

23. The polypeptide according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the polypeptide is Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-Q-W-L-I-K(1,3)-G-G-P-S-E-G-A-S-L-R-H-Y-Y-N-W-L-T-R-Q-R-Y-NH2. C18DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2) (SEQ ID NO: 591).

24. The polypeptide according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the polypeptide is Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-E-W-L-I-K(1,3)-G-G-P-S-E-G-A-S-L-R-H-Y-Y-N-W-L-T-R-Q-R-Y-NH2. C20DA-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-gGlu-eLys(1,2) (SEQ ID NO: 612).

25. The polypeptide according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the polypeptide is Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-E-W-L-I-K(1,3)-G-G-P-S-E-G-A-S-L-R-H-Y-Y-N-W-L-T-R-Q-R-Y-NH2. C18DA-gGlu-gGlu-gGlu-gGlu-OEG-OEG(1,2) (Sequence ID: 623).

26. A pharmaceutical composition comprising a polypeptide according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof.

27. A pharmaceutical composition comprising a polypeptide or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 25, together with one or more pharmaceutically acceptable carriers and / or excipients.

28. Overweight, chronic weight management, obesity, symptomatic obesity, eating disorders; Insulin resistance, diabetes, type 1 diabetes, type 2 diabetes, prediabetes; Endocrine obesity: Cushing's syndrome, hypothyroidism, insulinoma, obese type 2 diabetes, pseudohypoparathyroidism, 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-Beadle syndrome; Drug-induced obesity: steroid-induced obesity, phenothiazine-induced obesity, insulin-induced obesity, sulfonylurea-induced obesity, beta-blocker-induced obesity; Comorbidities of obesity and / or being overweight: associated type 2 diabetes, associated hypertension, associated non-alcoholic fatty liver disease (NAFLD), associated non-alcoholic steatohepatitis (NASH), associated diabetic nephropathy (DKD), associated chronic kidney disease (CKD), associated osteoporosis, associated sleep apnea, associated cancer, associated asthma; Hyperlipidemia: hypertriglyceridemia, hypercholesterolemia, hyperLDL cholesterolemia, hypoHDL cholesterolemia, postprandial hyperlipidemia; Metabolic syndrome: abdominal obesity, high blood pressure, high blood sugar, 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, arteriosclerosis, stroke, heart failure; Kidney disease: Diabetic nephropathy (DKD), chronic kidney disease (CKD); Neurodegenerative diseases: Alzheimer's disease, Parkinson's disease; A pharmaceutical composition comprising a polypeptide according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, for use in a method of treating and / or preventing a disease.

29. Use of a polypeptide or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 25 for the manufacture of a pharmaceutical composition.

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