GLP-1, GIP and GCG receptor tri-agonist and application thereof

Abstract

The invention relates to a GLP-1-, GIP and GCG receptor tri-agonist and application thereof. According to the present invention, the corresponding compounds have the agonist effect on the human glucagon-like peptide-KGhiagon-likepfoptimal-l (GLP-1) receptor, the human glucose-dependent insulinotropic polypeptide (Glucose-dedentin sublinotropic polypeptide, GIP) receptor, and the human glucagon (Glucagon, GCG) receptor, and can be used for prevention and / or treatment of metabolic disorder related diseases or symptoms.

Description

GLP-1, GIP and GCG receptor triagonists and their applications Technical Field

[0001] The present disclosure belongs to the field of biomedicine, and specifically relates to a compound that has an agonist effect on the human glucagon-like peptide-1 (GLP-1) receptor, the human glucose-dependent insulinotropic polypeptide (GIP) receptor, and the human glucagon (GCG) receptor, and can be used to prevent or treat diseases or conditions related to metabolic disorders. Background Art

[0002] Glucagon-like peptide-1 (GLP-1) is a gastrointestinal regulatory polypeptide consisting of 30 or 31 amino acid residues. GLP-1 secretion is primarily regulated by the L-cells of the small intestine based on nutrient absorption and fluctuating blood glucose levels. After food ingestion, L-cells in the small intestine secrete large amounts of GLP-1 to enhance pancreatic endocrine function. GLP-1 peptides primarily achieve their physiological functions of controlling blood glucose and reducing appetite by activating GLP-1 receptors located on the cell membrane. The mechanism by which GLP-1 regulates blood glucose levels is primarily through activation of GLP-1 receptors located on pancreatic β-cells, thereby promoting insulin biosynthesis and secretion. Furthermore, GLP-1 peptides can inhibit glucagon secretion, gastric emptying, and food intake in the presence of high blood glucose levels and enhance glucose degradation through specific neural mechanisms. Notably, the physiological function of GLP-1 peptides in promoting insulin secretion is controlled by plasma glucose concentration. Therefore, compared with other diabetes treatments, GLP-1 peptides are less likely to cause severe and prolonged hypoglycemia. Furthermore, literature reports indicate that GLP-1 peptides and their analogs directly promote the growth, differentiation, and proliferation of beta cells in experimental animals, suggesting that they can protect pancreatic islets, slow the progression of diabetes, and inhibit beta cell apoptosis. GLP-1 peptides also have the potential to inhibit gastrin and food-stimulated gastric acid secretion, suggesting that these properties may also protect against peptic ulcers. GLP-1 peptides can also activate GLP-1 receptors in the brain's central nervous system, thereby enhancing satiety, reducing food intake, and achieving the physiological effects of maintaining or reducing body weight. Therefore, the broad range of mechanisms of action and physiological functions of GLP-1 peptides and their analogs suggest that they are ideal therapeutic agents for non-insulin-dependent diabetes mellitus and obese-type diabetes.

[0003] Glucose-dependent insulinotropic peptide (GIP) and GLP-1 peptides are both incretins that play a key physiological role in blood glucose metabolism. GIP is primarily composed of 42 amino acid residues and is secreted by K cells in the duodenum and adjacent jejunum in response to plasma glucose levels. GIP peptides exert their physiological effects by binding to GIP receptors located in pancreatic β cells, adipose tissue, and the central nervous system. Similar to GLP-1 peptides, GIP peptides stimulate insulin secretion from pancreatic β cells, thereby lowering plasma glucose concentrations, and protect β cells, thereby controlling glucose metabolism. Furthermore, GIP peptides have physiological functions by activating GIP receptors in adipose tissue, thereby promoting fat metabolism. Interestingly, intracerebroventricular injection of GIP peptides into mice reduces food intake and body weight, suggesting that GIP peptides may have specific physiological functions in reducing body weight. Research has shown that the incretin function of GIP peptides is significantly reduced in patients with non-insulin-dependent diabetes, resulting in a lack or loss of incretin effects. Studies have shown that the inhibitory effect of GIP peptides produced by these diabetic patients is significantly reduced when blood sugar levels return to normal.

[0004] Glucagon (GCG) is secreted by pancreatic α cells and primarily acts on glucagon receptors in the liver to elevate blood glucose levels. In addition to increasing blood glucose levels, recent studies have shown that glucagon can promote fat and amino acid metabolism, increase energy expenditure, suppress appetite, and so on. Therefore, activation of the glucagon receptor also has the potential to treat metabolic diseases such as obesity and non-alcoholic steatohepatitis. When glucagon receptor activation is combined with activation of GLP-1 and GIP receptors, it can have unparalleled efficacy in treating metabolic diseases. Currently, no triple agonist products for GLP-1, GIP, and GCG receptors have been approved for marketing.

[0005] The present disclosure provides compounds that have agonist effects on the human GLP-1 receptor, the human GIP receptor, and the human GCG receptor. Furthermore, some of the compounds disclosed herein have a stronger weight loss effect than other triple agonists known in the art. Finally, some of the compounds disclosed herein have extremely high plasma stability and good drugability.

[0006] Summary of the Invention

[0007] The purpose of the present disclosure is to provide a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a GLP-1 / GIP / GCG receptor triagonist, a pharmaceutical composition, medical uses, and a method for treating a disease.

[0008] In one aspect, the present disclosure provides a compound comprising a polypeptide sequence.

[0009] In yet another aspect, the present disclosure provides a compound comprising a polypeptide sequence and a substituent, wherein the substituent is linked to an amino acid residue in the polypeptide sequence, for example, through a functional group on an amino acid side chain.

[0010] Compound represented by formula (I)

[0011] In some embodiments, a compound represented by formula (I) or a pharmaceutically acceptable salt thereof is provided:

[0012] R1-X1-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-X 10 -Ser-X 12 -X 13 -X 14 -Glu-X 16 -X 17 -X 18 -X 19 -X 20 -X 21 -Phe-Val-Glu-Trp-Leu-X 27 -X 28 -X 29 -ZX 40 -R2 (SEQ ID NO: 145) (I);

[0013] wherein R1 is hydrogen, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu, and R2 is -NH2 or -OH;

[0014] X1, X2, X3, X 10 、X 12 、X 13 、X 14 、X 16 、X 17 、X 18 、X 19 、X 20 、X 21 、X 27 、X 28 、X 29 , Z, X 40 Each is independently selected from any natural amino acid, non-natural amino acid, or a peptide segment consisting of natural amino acids and / or non-natural amino acids.

[0015] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0016] R1 is hydrogen, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu, R2 is -NH2 or -OH;

[0017] X1 is an amino acid residue selected from Tyr or His;

[0018] X2 is an amino acid residue of Aib;

[0019] X3 is an amino acid residue selected from Gln or His;

[0020] X 10 an amino acid residue selected from Leu or Tyr;

[0021] X 12 an amino acid residue selected from Lys, alpha-methyl-Lys or Ile;

[0022] X 13 an amino acid residue selected from Aib, Ile, Leu, Tyr, alpha-methyl-Tyr or alpha-methyl-Leu;

[0023] X 14 an amino acid residue selected from Leu or alpha-methyl-Leu;

[0024] X 16 an amino acid residue selected from Glu, Lys, or Y1;

[0025] X 17 an amino acid residue selected from Glu, Arg, homoArg, Ile, Lys, Gln, alpha-methyl-Lys, or Y1;

[0026] X 18 an amino acid residue selected from Ala or Aib;

[0027] X 19 an amino acid residue selected from Ala or Gln;

[0028] X 20 an amino acid residue selected from Gln, Aib, isovaline, alpha-methyl-Ser, 1-aminocyclopropane-1-carboxylic acid or 1-aminocyclobutane-1-carboxylic acid;

[0029] X 21 an amino acid residue selected from Glu or Y1;

[0030] X 27an amino acid residue selected from Ile or Leu;

[0031] X 28 an amino acid residue selected from Ala or Glu;

[0032] X 29 an amino acid residue selected from Gly or D-Glu;

[0033] X 40 an amino acid residue selected from Lys, Y1 or absent;

[0034] Z is selected from Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 146), Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 147), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 148) or Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 149);

[0035] Y1 is a Lys, Orn, Dap, Dab or Cys residue whose side chain is linked to a substituent.

[0036] In some embodiments, X 16 、X 17 and X 21 The amino acid at at least one position is Y1.

[0037] In some embodiments, X 16 In some embodiments, X 17 is Y1.

[0038] In some embodiments, the present disclosure provides a compound represented by the following formula (Ia) or a pharmaceutically acceptable salt thereof:

[0039] R1-X1-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-X 10 -Ser-X 12 -X 13 -X 14 -Glu-Y1-X 17 -X 18 -X 19 -X20-Glu-Phe-Val-Glu-Trp-Leu-X 27 -X 28 -X 29 -ZX 40-R2 (SEQ ID NO: 151)

[0040] (Ia);

[0041] wherein R1 is hydrogen, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu, and R2 is -NH2 or -OH;

[0042] X1 is an amino acid residue selected from Tyr or His;

[0043] X2 is an amino acid residue of Aib;

[0044] X3 is an amino acid residue selected from Gln or His;

[0045] X 10 an amino acid residue selected from Leu or Tyr;

[0046] X 12 an amino acid residue selected from Lys, alpha-methyl-Lys or Ile;

[0047] X 13 an amino acid residue selected from Aib, Ile, Leu, Tyr, alpha-methyl-Tyr or alpha-methyl-Leu;

[0048] X 14 an amino acid residue selected from Leu or alpha-methyl-Leu;

[0049] X 17 an amino acid residue selected from Glu, Arg, homoArg, Ile, Lys, Gln or alpha-methyl-Lys;

[0050] X 18 an amino acid residue selected from Ala or Aib;

[0051] X 19 an amino acid residue selected from Ala or Gln;

[0052] X 20 an amino acid residue selected from Gln, Aib, isovaline, alpha-methyl-Ser, 1-aminocyclopropane-1-carboxylic acid or 1-aminocyclobutane-1-carboxylic acid;

[0053] X 27 an amino acid residue selected from Ile or Leu;

[0054] X 28 an amino acid residue selected from Ala or Glu;

[0055] X 29 an amino acid residue selected from Gly or D-Glu;

[0056] X 40 an amino acid residue selected from Lys or absent;

[0057] Z is selected from Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 146), Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 147), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 148) or Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 149).

[0058] Y1 is a Lys, Orn, Dap, Dab or Cys residue whose side chain is linked to a substituent.

[0059] In some embodiments, in the compound of formula (Ia), R1 is hydrogen.

[0060] In some embodiments, in the compound represented by formula (Ia), R2 is -NH2 or -OH.

[0061] In some embodiments, in the compound of formula (Ia), R2 is -NH2.

[0062] In some embodiments, in the compound of formula (Ia), Z is Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 146).

[0063] In some embodiments, the compound represented by formula (Ia), X 40 It doesn't exist.

[0064] In some embodiments, in the compound represented by formula (Ia), Y1 is a Lys residue whose side chain is linked to a substituent.

[0065] In some embodiments, the present disclosure provides a compound represented by the following formula (Ib) or a pharmaceutically acceptable salt thereof:

[0066] R1-X1-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-X 10 -Ser-X 12 -X 13 -X 14 -Glu-Y1-X 17 -X 18 -X 19-X20-Glu-Phe-Val-Glu-Trp-Leu-X 27 -X 28 -X 29 -Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-R2 (SEQ ID NO: 150)

[0067] (Ib);

[0068] wherein R1 is hydrogen, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu, and R2 is -NH2 or -OH;

[0069] X1 is an amino acid residue selected from Tyr or His;

[0070] X2 is an amino acid residue of Aib;

[0071] X3 is an amino acid residue selected from Gln or His;

[0072] X 10 an amino acid residue selected from Leu or Tyr;

[0073] X 12 an amino acid residue selected from Lys, alpha-methyl-Lys or Ile;

[0074] X 13 an amino acid residue selected from Aib, Ile, Leu, Tyr, alpha-methyl-Tyr or alpha-methyl-Leu;

[0075] X 14 an amino acid residue selected from Leu or alpha-methyl-Leu;

[0076] X 17 an amino acid residue selected from Ile, Lys, Gln or alpha-methyl-Lys;

[0077] X 18 an amino acid residue selected from Ala or Aib;

[0078] X 19 an amino acid residue selected from Ala or Gln;

[0079] X 20 an amino acid residue selected from Gln, Aib, isovaline, alpha-methyl-Ser, 1-aminocyclopropane-1-carboxylic acid or 1-aminocyclobutane-1-carboxylic acid;

[0080] X 27 an amino acid residue selected from Ile or Leu;

[0081] X 28 an amino acid residue selected from Ala or Glu;

[0082] X 29 an amino acid residue selected from Gly or D-Glu;

[0083] Y1 is a Lys, Orn, Dap, Dab or Cys residue whose side chain is linked to a substituent.

[0084] In some embodiments, in the compound of formula (Ib), R1 is hydrogen.

[0085] In some embodiments, in the compound represented by formula (Ib), R2 is -NH2 or -OH.

[0086] In some embodiments, in the compound of formula (Ib), R2 is -NH2.

[0087] In some embodiments, in the compound represented by formula (Ib), Y1 is a Lys residue whose side chain is linked to a substituent.

[0088] In some embodiments, in the compound of any of the foregoing structures, X1, X2, and X3 are selected from any of the following:

[0089] X1 is His, X2 is Aib, and X3 is His;

[0090] X1 is Tyr, X2 is Aib, and X3 is Gln; or

[0091] X1 is His, X2 is Aib, and X3 is Gln.

[0092] In some embodiments, the compound of any of the structures shown above,

[0093] X1 is His, X2 is Aib, and X3 is His; or

[0094] X1 is His, X2 is Aib, and X3 is Gln.

[0095] In some embodiments, in the compound of any of the aforementioned structures, X1, X2 and X3 are His, Aib and His, respectively.

[0096] In some embodiments, the compound of any of the above structures, wherein X 17 is a Lys residue.

[0097] In some embodiments, X 17 、X 18 、X 19 and X 20 Select any of the following:

[0098] X 17 Lys, X 18 Ala, X 19 Ala, and X 20 for Gln;

[0099] X 17 Lys, X 18 Ala, X 19 Ala, and X 20 is alpha-methyl-Ser;

[0100] X 17 Lys, X 18 Ala, X 19 Ala, and X 20 isovaline;

[0101] X 17 Lys, X 18 Ala, X 19 Ala, and X 20 is 1-aminocyclopropane-1-carboxylic acid;

[0102] X 17 Lys, X 18 Ala, X 19 Ala, and X 20 is 1-aminocyclobutane-1-carboxylic acid;

[0103] X 17 Lys, X 18 Ala, X 19 Ala, and X 20 for Aib;

[0104] X 17 Lys, X 18 Aib, X 19 Ala, and X 20 is Gln; and

[0105] X 17 Lys, X 18 Ala, X 19 Gln, and X 20 For Gln.

[0106] In some embodiments, the compound of any of the above structures, wherein X 17 In some embodiments, X 17 、X 18 、X 19 and X 20 Select any of the following:

[0107] X 17 Gln, X 18 Ala, X 19 Ala, and X 20 for Gln;

[0108] X 17 Gln, X 18 Ala, X 19 Ala, and X 20 isovaline;

[0109] X 17 Gln, X 18 Ala, X 19 Ala, and X 20 is 1-aminocyclopropane-1-carboxylic acid; and

[0110] X 17 Gln, X 18 Ala, X 19 Ala, and X 20 It is 1-aminocyclobutane-1-carboxylic acid.

[0111] In some embodiments, the compound of any of the above structures, wherein X 17 It is alpha-methyl-Lys.

[0112] In some embodiments, X 17 、X 18 、X 19 and X 20 In some embodiments, the compound of any one of the foregoing structures, wherein X 17 In some embodiments, X 17 、X 18 、X 19 and X 20 They are Ile, Ala, Ala and Gln respectively.

[0113] In some embodiments, as in any of the above compounds, X 12 is an Ile residue.

[0114] In some embodiments, X 12 、X 13 and X 14 Select any of the following:

[0115] X 12 Ile, X 13 Leu, and X 14is Leu; or

[0116] X 12 Ile, X 13 alpha-methyl-Leu, and X 14 For Leu.

[0117] In some embodiments, the compound of any of the above structures, wherein X 12 is a Lys residue.

[0118] In some embodiments, X 12 、X 13 and X 14 Select any of the following:

[0119] X 12 Lys, X 13 is alpha-methyl-Tyr, and X 14 for Leu;

[0120] X 12 Lys, X 13 For Aib, and X 14 for Leu;

[0121] X 12 Lys, X 13 Tyr, and X 14 is alpha-methyl-Leu; and

[0122] X 12 Lys, X 13 Tyr, and X 14 For Leu.

[0123] In some embodiments, the compound of any of the above structures, wherein X 12 is an alpha-methyl-Lys residue.

[0124] In some embodiments, X 12 、X 13 and X 14 Select any of the following:

[0125] X 12 alpha-methyl-Lys, X 13 Tyr, and X 14 for Leu;

[0126] X 12 alpha-methyl-Lys, X 13 Leu, and X 14 Leu; and

[0127] X12 alpha-methyl-Lys, X 13 Ile, and X 14 For Leu.

[0128] In some embodiments, the compound of any of the above structures, wherein X1 to X 29 Select from any of the following groups:

[0129] (i) X1, X2, and X3 are selected from any one of the following:

[0130] X1 is His, X2 is Aib, and X3 is His;

[0131] X1 is His, X2 is Aib, and X3 is Gln; or

[0132] X1 is Tyr, X2 is Aib, and X3 is Gln;

[0133] X 10 an amino acid residue selected from Leu or Tyr,

[0134] X 12 an amino acid residue selected from Lys, alpha-methyl-Lys or Ile,

[0135] X 13 an amino acid residue selected from the group consisting of Aib, Ile, Leu, Tyr, alpha-methyl-Tyr or alpha-methyl-Leu,

[0136] X 14 an amino acid residue selected from Leu or alpha-methyl-Leu,

[0137] X 16 It's Y1.

[0138] X 17 an amino acid residue selected from Lys,

[0139] X 18 an amino acid residue selected from Ala or Aib,

[0140] X 19 an amino acid residue selected from Ala or Gln,

[0141] X 20 an amino acid residue selected from the group consisting of Gln, Aib, isovaline, alpha-methyl-Ser, 1-aminocyclopropane-1-carboxylic acid or 1-aminocyclobutane-1-carboxylic acid,

[0142] X 27 an amino acid residue selected from Ile or Leu,

[0143] X 28 An amino acid residue selected from Ala or Glu, X 29 an amino acid residue selected from Gly or D-Glu;

[0144] In some embodiments,

[0145] X1 is His, X2 is Aib, and X3 is His; or

[0146] X1 is His, X2 is Aib, and X3 is Gln;

[0147] (ii) X1, X2, and X3 are selected from any one of the following:

[0148] X1 is His, X2 is Aib, and X3 is His;

[0149] X1 is His, X2 is Aib, and X3 is Gln; or

[0150] X1 is Tyr, X2 is Aib, and X3 is Gln;

[0151] X 10 an amino acid residue selected from Leu or Tyr,

[0152] X 12 an amino acid residue selected from Lys, alpha-methyl-Lys or Ile,

[0153] X 13 an amino acid residue selected from the group consisting of Aib, Ile, Leu, Tyr, alpha-methyl-Tyr or alpha-methyl-Leu,

[0154] X 14 an amino acid residue selected from Leu or alpha-methyl-Leu,

[0155] X 16 It is Y1, X 17 an amino acid residue selected from Lys,

[0156] X 18 an amino acid residue selected from Ala or Aib,

[0157] X 19 an amino acid residue selected from Ala or Gln,

[0158] X 20 an amino acid residue selected from Gln,

[0159] X 27 an amino acid residue selected from Ile or Leu,

[0160] X 28an amino acid residue selected from Ala or Glu,

[0161] X 29 an amino acid residue selected from Gly or D-Glu;

[0162] (iii) X1, X2, and X3 are selected from any one of the following:

[0163] X1 is His, X2 is Aib, and X3 is His;

[0164] X1 is His, X2 is Aib, and X3 is Gln; or

[0165] X1 is Tyr, X2 is Aib, and X3 is Gln;

[0166] X 10 an amino acid residue selected from Leu or Tyr,

[0167] X 12 an amino acid residue selected from alpha-methyl-Lys or Ile,

[0168] X 13 an amino acid residue selected from Ile, Leu or alpha-methyl-Leu,

[0169] X 14 an amino acid residue selected from Leu or alpha-methyl-Leu,

[0170] X 16 It is Y1, X 17 an amino acid residue selected from Lys,

[0171] X 18 an amino acid residue selected from Ala,

[0172] X 19 an amino acid residue selected from Ala,

[0173] X 20 an amino acid residue selected from the group consisting of Aib, isovaline, alpha-methyl-Ser, 1-aminocyclopropane-1-carboxylic acid or 1-aminocyclobutane-1-carboxylic acid,

[0174] X 27 an amino acid residue selected from Ile or Leu,

[0175] X 28 an amino acid residue selected from Ala or Glu,

[0176] X 29 an amino acid residue selected from Gly or D-Glu;

[0177] In some embodiments,

[0178] X1 is His, X2 is Aib, and X3 is His; or

[0179] X1 is His, X2 is Aib, and X3 is Gln;

[0180] (iv) X1 is His;

[0181] X2 is Aib;

[0182] X3 is His;

[0183] X 10 an amino acid residue selected from Tyr,

[0184] X 12 an amino acid residue selected from Lys or alpha-methyl-Lys,

[0185] X 13 an amino acid residue selected from Tyr,

[0186] X 14 an amino acid residue selected from Leu or alpha-methyl-Leu,

[0187] X 16 It is Y1, X 17 an amino acid residue selected from Lys,

[0188] X 18 an amino acid residue selected from Ala or Aib,

[0189] X 19 an amino acid residue selected from Ala or Gln,

[0190] X 20 an amino acid residue selected from Gln,

[0191] X 27 an amino acid residue selected from Ile or Leu,

[0192] X 28 an amino acid residue selected from Ala or Glu,

[0193] X 29 an amino acid residue selected from Gly;

[0194] (v) X1 is His;

[0195] X2 is Aib;

[0196] X3 is His or Gln;

[0197] X 10 an amino acid residue selected from Leu or Tyr,

[0198] X 12 an amino acid residue selected from Ile,

[0199] X 13 an amino acid residue selected from alpha-methyl-Leu,

[0200] X 14 an amino acid residue selected from Leu,

[0201] X 16 It is Y1, X 17 an amino acid residue selected from Lys,

[0202] X 18 an amino acid residue selected from Ala,

[0203] X 19 an amino acid residue selected from Ala,

[0204] X 20 an amino acid residue selected from Gln, Aib, 1-aminocyclobutane-1-carboxylic acid or isovaline,

[0205] X 27 an amino acid residue selected from Leu,

[0206] X 28 an amino acid residue selected from Ala,

[0207] X 29 an amino acid residue selected from Gly or D-Glu;

[0208] (vi) X1, X2, and X3 are selected from any one of the following:

[0209] X1 is His, X2 is Aib, and X3 is His;

[0210] X1 is His, X2 is Aib, and X3 is Gln; or

[0211] X1 is Tyr, X2 is Aib, and X3 is Gln;

[0212] X 10 an amino acid residue selected from Leu or Tyr,

[0213] X 12 an amino acid residue selected from alpha-methyl-Lys or Ile,

[0214] X 13 an amino acid residue selected from Leu;

[0215] X 14 an amino acid residue selected from Leu,

[0216] X 16 It is Y1, X 17 an amino acid residue selected from Ile, Lys or Gln,

[0217] X 18 an amino acid residue selected from Ala,

[0218] X 19 an amino acid residue selected from Ala,

[0219] X 20 an amino acid residue selected from the group consisting of Gln, Aib, isovaline, alpha-methyl-Ser, 1-aminocyclopropane-1-carboxylic acid or 1-aminocyclobutane-1-carboxylic acid,

[0220] X 27 an amino acid residue selected from Ile or Leu,

[0221] X 28 an amino acid residue selected from Ala or Glu,

[0222] X 29 an amino acid residue selected from Gly or D-Glu;

[0223] In some embodiments,

[0224] X1 is His, X2 is Aib, and X3 is His; or

[0225] X1 is His, X2 is Aib, and X3 is Gln;

[0226] (vii) X1 is His;

[0227] X2 is Aib;

[0228] X3 is His;

[0229] X 10 an amino acid residue selected from Tyr,

[0230] X 12 an amino acid residue selected from Lys,

[0231] X 13 an amino acid residue selected from alpha-methyl-Tyr or Aib;

[0232] X 14 an amino acid residue selected from Leu,

[0233] X 16 It's Y1.

[0234] X 17 an amino acid residue selected from Lys,

[0235] X 18 an amino acid residue selected from Ala,

[0236] X 19 an amino acid residue selected from Ala,

[0237] X 20 an amino acid residue selected from Gln,

[0238] X 27 an amino acid residue selected from Leu,

[0239] X 28 an amino acid residue selected from Ala,

[0240] X 29 an amino acid residue selected from Gly;

[0241] (viii) X1, X2, and X3 are selected from any one of the following:

[0242] X1 is His, X2 is Aib, and X3 is His; or

[0243] X1 is Tyr, X2 is Aib, and X3 is Gln;

[0244] X 10 an amino acid residue selected from Leu or Tyr,

[0245] X 12 an amino acid residue selected from alpha-methyl-Lys,

[0246] X 13 an amino acid residue selected from Ile;

[0247] X 14 an amino acid residue selected from Leu,

[0248] X 16 It's Y1.

[0249] X 17 an amino acid residue selected from Lys,

[0250] X 18 an amino acid residue selected from Ala,

[0251] X 19 an amino acid residue selected from Ala,

[0252] X 20 an amino acid residue selected from Gln or isovaline,

[0253] X 27 an amino acid residue selected from Leu or Ile,

[0254] X 28 an amino acid residue selected from Ala or Glu,

[0255] X 29 an amino acid residue selected from Gly;

[0256] In some embodiments, X1 is His, X2 is Aib, and X3 is His;

[0257] (ix) X1 is His;

[0258] X2 is Aib;

[0259] X3 is His;

[0260] X 10 an amino acid residue selected from Leu or Tyr,

[0261] X 12 an amino acid residue selected from Lys, alpha-methyl-Lys or Ile,

[0262] X 13 an amino acid residue selected from Ile, Leu, or Tyr,

[0263] X 14 an amino acid residue selected from Leu,

[0264] X 16 It is Y1, X 17 an amino acid residue selected from Ile, Gln or alpha-methyl-Lys,

[0265] X 18 an amino acid residue selected from Ala,

[0266] X 19 an amino acid residue selected from Ala,

[0267] X 20 an amino acid residue selected from Gln, isovaline, 1-aminocyclopropane-1-carboxylic acid or 1-aminocyclobutane-1-carboxylic acid,

[0268] X 27 an amino acid residue selected from Leu,

[0269] X 28 an amino acid residue selected from Ala,

[0270] X 29 an amino acid residue selected from Gly or D-Glu;

[0271] (x) X1 is His;

[0272] X2 is Aib;

[0273] X3 is His;

[0274] X 10 an amino acid residue selected from Leu or Tyr,

[0275] X 12 an amino acid residue selected from alpha-methyl-Lys or Ile,

[0276] X 13 an amino acid residue selected from Ile or Leu,

[0277] X 14 an amino acid residue selected from Leu,

[0278] X 16 It's Y1.

[0279] X 17 an amino acid residue selected from Gln,

[0280] X 18 an amino acid residue selected from Ala,

[0281] X 19 an amino acid residue selected from Ala,

[0282] X 20 an amino acid residue selected from Gln, isovaline, 1-aminocyclopropane-1-carboxylic acid or 1-aminocyclobutane-1-carboxylic acid,

[0283] X 27 an amino acid residue selected from Leu,

[0284] X 28 an amino acid residue selected from Ala,

[0285] X 29 an amino acid residue selected from Gly or D-Glu;

[0286] (xi) X1 is His;

[0287] X2 is Aib;

[0288] X3 is His;

[0289] X 10 an amino acid residue selected from Tyr,

[0290] X 12 an amino acid residue selected from Lys or alpha-methyl-Lys,

[0291] X 13 an amino acid residue selected from Leu or Tyr,

[0292] X 14 an amino acid residue selected from Leu,

[0293] X 16 It's Y1.

[0294] X 17 an amino acid residue selected from Ile or alpha-methyl-Lys,

[0295] X 18 an amino acid residue selected from Ala,

[0296] X 19 an amino acid residue selected from Ala,

[0297] X 20 an amino acid residue selected from Gln,

[0298] X 27 an amino acid residue selected from Leu,

[0299] X 28 an amino acid residue selected from Ala,

[0300] X 29 An amino acid residue selected from Gly.

[0301] In some embodiments, the amino acid combination as shown in any one of (i) to (xi) above, wherein Z is selected from Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 146), Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 147), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 148), or Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 149). In some embodiments, Z is Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 146).

[0302] In some embodiments, as shown in any one of the above (i) to (xi), wherein X 40 In some embodiments, X 40 It doesn't exist.

[0303] In some embodiments, the amino acid combination as shown in any one of the above (i) to (xi), wherein Y1 is a Lys, Orn, Dap, Dab or Cys residue whose side chain is connected to a substituent. In some embodiments, Y1 is a Lys residue whose side chain is connected to a substituent.

[0304] In some embodiments, in the amino acid combination as shown in any of the above (i) to (xi), R1 is hydrogen, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl, or pGlu, and R2 is -NH2 or -OH. In some embodiments, R1 is hydrogen, R2 is -NH2 or -OH. In some embodiments, R1 is hydrogen, R2 is -NH2.

[0305] In some embodiments, the compound represented by Formula (I), Formula (Ia) or Formula (Ib) comprises (or is) any of the following polypeptide sequences:

[0306] Table 1

[0307] In Table 1, αK is alpha-methyl-Lys, αY is alpha-methyl-Tyr, αL is alpha-methyl-Leu, Iva is isovaline, e is D-Glu, Aib is α-aminoisobutyric acid, Ac3c is 1-aminocyclopropane-1-carboxylic acid, and Ac4c is 1-aminocyclobutane-1-carboxylic acid.

[0308] In some embodiments, the compound of any of the aforementioned structures further comprises a substituent. In some embodiments, the substituent is linked to an amino acid residue at any position. In some embodiments, the substituent is covalently linked to the side chain of the amino acid residue. For example, the substituent is covalently linked to the ε-amino group of a Lys residue.

[0309] In some embodiments, the substituent comprises the structure shown below: -Z1-Z2.

[0310] In some embodiments, Z2 comprises (or is) C 12 -C 32 Fatty acids. For example, C 12 -C 32 Examples of fatty acids include, but are not limited to, palmitic acid (hexadecanoic acid) (C 16 Monoacid), hexadecanedioic acid (C 16 Diacid), pearl fatty acid (heptadecanoic acid) (C 17 monoacid), heptadecanedioic acid (C 17 Diacid), stearic acid (C 18 Monoacid), octadecanedioic acid (C 18diacid), nonadecanoic acid (nonadecanoic acid) (C 19 Monoacid), nonadecanedioic acid (C 19 Diacid), arachidic acid (eicosanoic acid) (C 20 monoacid), eicosanedioic acid (C 20 dicarboxylic acid), eicosanoic acid (eicosanoic acid) (C 21 Monoacid), heneicosane dioic acid (C 21 dicarboxylic acid), behenic acid (behenic acid) (C 22 monoacid), docosanoic acid (C 22 diacids), including their branched and substituted derivatives.

[0311] In some embodiments, Z1 can have an amino acid, an aminopolyethylene glycol, or a blend thereof.

[0312] In some embodiments, Z1 comprises (or is) 0-10 (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid residues independently selected from Gly, Glu, γGlu, OEG.

[0313] Exemplarily, when the linker includes at least one amino acid, the amino acid may be 1 to 4 Glu or γGlu amino acid residues. In some embodiments, the linker may include one or two Glu or γGlu amino acid residues, including their D forms. For example, the linker may include one or two γGlu amino acid residues. Alternatively, the linker may include 1 to 4 amino acid residues (e.g., Glu or γGlu amino acids) used in combination with OEG.

[0314] For example, the linker can be a combination of 1 to 4 Glu or γGlu amino acids and 1 to 4 OEG. In other cases, the linker can be a combination of 1 or 2 γGlu amino acids and 1 or 2 OEG.

[0315] As described in the present disclosure, the amino acid residue of "OEG" is [2-(2-amino-ethoxy)-ethoxy]-acetyl. Specifically, its structure is shown below:

[0316] As described in this disclosure, the structure of the "γGlu" amino acid residue is shown below:

[0317] As described in the present disclosure, "pGlu" is polyglutamic acid, and its structure is Glu-(Glu)d-Glu. Exemplarily, the molecular weight of pGlu is 700,000-2,000,000 units (e.g., 100 units).

[0318] In some embodiments, Z1 comprises the structure shown below: -(OEG) a -(γGlu)b -; wherein a is any integer between 0 and 4 (e.g., 0, 1, 2, 3, or 4), and b is any integer between 1 and 2 (e.g., 0, 1, or 2). In some specific embodiments, a is 1, 2, or 3, and b is 1 or 2. In some specific embodiments, a is 2 or 3, and b is 1 or 2. In some specific embodiments, a is 2, and b is 1 or 2. In some specific embodiments, a is 2, and b is 1.

[0319] In some embodiments, Z2 comprises the structure shown below: -CO-(CH2) c -COOH, c is any integer between 10 and 30 (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30). In some specific embodiments, c is any integer between 16 and 20 (e.g., 16, 17, 18, 19, 20). In some specific embodiments, c is 16, 18 or 20. In some specific embodiments, c is 16 or 18.

[0320] In some embodiments, the substituent has the structure shown below {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γGlu) b -CO-(CH2) c -COOH;

[0321] wherein a is any integer between 0 and 4 (e.g., 0, 1, 2, 3, or 4), b is any integer between 1 and 2 (e.g., 1 or 2), and c is any integer between 10 and 30 (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30).

[0322] In some specific embodiments, a is 1, 2 or 3, b is 1 or 2, and c is any integer from 16 to 20 (e.g., 16, 17, 18, 19, 20).

[0323] In some specific embodiments, a is 2 or 3, b is 1 or 2, and c is 16, 18 or 20.

[0324] In some specific embodiments, a is 2, b is 1 or 2, and c is 16, 18 or 20.

[0325] In some specific embodiments, a is 2, b is 1 or 2, and c is 16 or 18.

[0326] In some specific embodiments, a is 2, b is 1, and c is 16 or 18.

[0327] In some specific embodiments, the substituent has the following structure:

[0328] In some embodiments, the compound of any of the aforementioned structures, X 16 、X 21 and X 40 are each independently selected from Y1.

[0329] In some embodiments, Y1 is a Lys, Orn, Dap, Dab or Cys residue of a side chain-linked substituent. In some embodiments, the substituent has the structure: -Z1-Z2, wherein Z1 comprises 0-10 amino acid residues independently selected from Gly, Glu, γGlu, OEG, and Z2 is selected from C 12-32 of fatty acids.

[0330] In some embodiments, Z1 comprises (or is) the structure shown below: -(OEG) a -(γGlu) b -; wherein a is any integer between 0 and 4 (e.g., 0, 1, 2, 3, or 4), and b is any integer between 1 and 2 (e.g., 1 or 2). In some embodiments, Z2 comprises (or is) the structure shown below: -CO-(CH2) c -COOH, c is any integer between 10 and 30 (e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30).

[0331] In some embodiments, the substituent comprises (or is) the structure shown below: {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γGlu) b -CO-(CH2) c -COOH;

[0332] Wherein, a is any integer between 0 and 4, b is any integer between 1 and 2, and c is any integer between 10 and 30. In some specific embodiments, a is 1, 2 or 3, b is 1 or 2, and c is any integer between 16 and 20 (e.g., 16, 17, 18, 19, 20). In some specific embodiments, a is 2 or 3, b is 1 or 2, and c is 16, 18 or 20. In some specific embodiments, a is 2, b is 1 or 2, and c is 16, 18 or 20. In some specific embodiments, a is 2, b is 1 or 2, and c is 16 or 18. In some specific embodiments, a is 2, b is 1, and c is 16 or 18.

[0333] In some embodiments, Y1 is a Lys residue having a side chain-linked substituent covalently linked to the epsilon-amino group of the Lys residue via an amide bond.

[0334] In some embodiments, Y1 is K(-OEG-OEG-γGlu-C(O)-(CH2) 16 -COOH), K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH), or K(-OEG-OEG-γGlu-C(O)-(CH2) 20 -COOH).

[0335] Among them, K(-OEG-OEG-γGlu-C(O)-(CH2) 16 -COOH) has the structure shown below:

[0336] K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH) has the structure shown below:

[0337] In some embodiments, Y1 has the structure shown below:

[0338] In some embodiments, the compound has a structure as shown in the following formula (I) or a pharmaceutically acceptable salt thereof,

[0339] R1-X1-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-X 10 -Ser-X 12 -X 13 -X 14 -Glu-X 16 -X 17 -X 18 -X 19 -X 20 -X 21 -Phe-Val-Glu-Trp-Leu-X 27 -X 28 -X 29 -ZX 40 -R2 (SEQ ID NO: 145)

[0340] (I);

[0341] in:

[0342] R1 is hydrogen, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu,

[0343] R2 is -NH2 or -OH;

[0344] X1 is an amino acid residue selected from Tyr or His;

[0345] X2 is an amino acid residue of Aib;

[0346] X3 is an amino acid residue selected from Gln or His;

[0347] X 10 an amino acid residue selected from Leu or Tyr;

[0348] X 12 an amino acid residue selected from Lys, alpha-methyl-Lys or Ile;

[0349] X 13 an amino acid residue selected from Aib, Ile, Leu, Tyr, alpha-methyl-Tyr or alpha-methyl-Leu;

[0350] X 14 an amino acid residue selected from Leu or alpha-methyl-Leu;

[0351] X 16 an amino acid residue selected from Glu, Lys, or Y1;

[0352] X 17 an amino acid residue selected from Glu, Arg, homoArg, Ile, Lys, Gln, alpha-methyl-Lys, or Y1;

[0353] X 18 an amino acid residue selected from Ala or Aib;

[0354] X 19 an amino acid residue selected from Ala or Gln;

[0355] X 20 an amino acid residue selected from Gln, Aib, isovaline, alpha-methyl-Ser, 1-aminocyclopropane-1-carboxylic acid or 1-aminocyclobutane-1-carboxylic acid;

[0356] X 21 an amino acid residue selected from Glu or Y1;

[0357] X 27 an amino acid residue selected from Ile or Leu;

[0358] X 28 an amino acid residue selected from Ala or Glu;

[0359] X29 an amino acid residue selected from Gly or D-Glu;

[0360] X 40 an amino acid residue selected from Lys, Y1 or absent;

[0361] Z is selected from Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 146), Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 147), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 148) or Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 149).

[0362] Y1 is a Lys, Orn, Dap, Dab or Cys residue connected to a side chain substituent, the structure of which is as follows: -Z1-Z2, wherein Z1 comprises 0-10 amino acid residues independently selected from Gly, Glu, γGlu, OEG, and Z2 is selected from C 12-32 In some embodiments, Z1 comprises (or is) the structure shown below: -(OEG) a -(γGlu) b -; wherein a is any integer between 0 and 4, and b is any integer between 1 and 2. In some embodiments, Z2 comprises (or is) the structure shown below: -CO-(CH2) c -COOH, c is any integer between 10 and 30.

[0363] In some embodiments, the structure of the substituent is as follows:

[0364] {[2-(2-Amino-ethoxy)-ethoxy]-acetyl} a -(γGlu) b -CO-(CH2) c -COOH;

[0365] Wherein, a is any integer between 0 and 4, b is any integer between 1 and 2, and c is any integer between 10 and 30. In some specific embodiments, a is 1, 2 or 3, b is 1 or 2, and c is any integer between 16 and 20 (e.g., 16, 17, 18, 19, 20). In some specific embodiments, a is 2 or 3, b is 1 or 2, and c is 16, 18 or 20. In some specific embodiments, a is 2, b is 1 or 2, and c is 16, 18 or 20. In some specific embodiments, a is 2, b is 1 or 2, and c is 16 or 18. In some specific embodiments, a is 2, b is 1, and c is 16 or 18.

[0366] In some embodiments, Y1 is a Lys residue with a side chain attached substituent, said substituent being covalently attached to the ε-amino group of said Lys residue via an amide bond. In some embodiments, Y1 is K(-OEG-OEG-γGlu-C(O)-(CH2) 16 -COOH), K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH) or K(-OEG-OEG-γGlu-C(O)-(CH2) 20 -COOH).

[0367] In some embodiments, the group has the structure shown below:

[0368] In some embodiments, X 16 、X 17 and X 21 In some embodiments, the amino acid at least one position in the 16 is Y1.

[0369] In some embodiments, the present disclosure provides a compound represented by the following formula (Ia) or a pharmaceutically acceptable salt thereof:

[0370] R1-X1-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-X 10 -Ser-X 12 -X 13 -X 14 -Glu-Y1-X 17 -X 18 -X 19 -X20-Glu-Phe-Val-Glu-Trp-Leu-X 27 -X 28 -X 29 -ZX 40 -R2 (SEQ ID NO: 151)

[0371] (Ia);

[0372] wherein R1 is hydrogen, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu,

[0373] R2 is -NH2 or -OH;

[0374] X1 is an amino acid residue selected from Tyr or His;

[0375] X2 is an amino acid residue of Aib;

[0376] X3 is an amino acid residue selected from Gln or His;

[0377] X 10 an amino acid residue selected from Leu or Tyr;

[0378] X 12 an amino acid residue selected from Lys, alpha-methyl-Lys or Ile;

[0379] X 13 an amino acid residue selected from Aib, Ile, Leu, Tyr, alpha-methyl-Tyr or alpha-methyl-Leu;

[0380] X 14 an amino acid residue selected from Leu or alpha-methyl-Leu;

[0381] X 17 an amino acid residue selected from Glu, Arg, homoArg, Ile, Lys, Gln or alpha-methyl-Lys;

[0382] X 18 an amino acid residue selected from Ala or Aib;

[0383] X 19 an amino acid residue selected from Ala or Gln;

[0384] X 20 an amino acid residue selected from Gln, Aib, isovaline, alpha-methyl-Ser, 1-aminocyclopropane-1-carboxylic acid or 1-aminocyclobutane-1-carboxylic acid;

[0385] X 27 an amino acid residue selected from Ile or Leu;

[0386] X 28 an amino acid residue selected from Ala or Glu;

[0387] X 29 an amino acid residue selected from Gly or D-Glu;

[0388] X 40 an amino acid residue selected from Lys or absent;

[0389] Z is selected from Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 146), Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 147), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 148) or Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 149);

[0390] Y1 is a Lys, Orn, Dap, Dab or Cys residue connected to a side chain substituent, the structure of which is as follows: -Z1-Z2, wherein Z1 comprises 0-10 amino acid residues independently selected from Gly, Glu, γGlu, OEG ([2-(2-amino-ethoxy)-ethoxy]-acetyl), and Z2 is selected from C 12-32 In some embodiments, Z1 comprises (or is) the structure shown below: -(OEG) a -(γGlu) b -; wherein a is any integer between 0 and 4, and b is any integer between 1 and 2. In some embodiments, Z2 comprises (or is) the structure shown below: -CO-(CH2) c -COOH, c is any integer between 10 and 30.

[0391] In some embodiments, the structure of the substituent is as follows:

[0392] {[2-(2-Amino-ethoxy)-ethoxy]-acetyl} a -(γGlu) b -CO-(CH2) c -COOH;

[0393] Wherein, a is any integer between 0 and 4, b is any integer between 1 and 2, and c is any integer between 10 and 30. In some specific embodiments, a is 1, 2 or 3, b is 1 or 2, and c is any integer between 16 and 20 (e.g., 16, 17, 18, 19, 20). In some specific embodiments, a is 2 or 3, b is 1 or 2, and c is 16, 18 or 20. In some specific embodiments, a is 2, b is 1 or 2, and c is 16, 18 or 20. In some specific embodiments, a is 2, b is 1 or 2, and c is 16 or 18. In some specific embodiments, a is 2, b is 1, and c is 16 or 18.

[0394] In some embodiments, Y1 is a Lys residue with a side chain attached substituent, said substituent being covalently attached to the ε-amino group of said Lys residue via an amide bond. In some embodiments, Y1 is K(-OEG-OEG-γGlu-C(O)-(CH2) 16 -COOH), K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH) or K(-OEG-OEG-γGlu-C(O)-(CH2) 20 -COOH).

[0395] In some embodiments, Y1 has the structure shown below:

[0396] In some embodiments, R1 is hydrogen.

[0397] In some embodiments, R2 is -NH2 or -OH.

[0398] In some embodiments, R2 is -NH2.

[0399] In some embodiments, Z is Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 146).

[0400] In some embodiments, X 40 It doesn't exist.

[0401] In some embodiments, Y1 is a Lys residue whose side chain is linked to a substituent.

[0402] In some embodiments, the present disclosure provides a compound represented by the following formula (Ib) or a pharmaceutically acceptable salt thereof:

[0403] R1-X1-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-X 10 -Ser-X12 -X 13 -X 14 -Glu-Y1-X 17 -X 18 -X 19 -X20-Glu-Phe-Val-Glu-Trp-Leu-X 27 -X 28 -X 29 -Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-R2 (SEQ ID NO: 150)

[0404] (Ib);

[0405] wherein R1 is hydrogen,

[0406] R2 is -NH2 or -OH;

[0407] X1 is an amino acid residue selected from Tyr or His;

[0408] X2 is an amino acid residue of Aib;

[0409] X3 is an amino acid residue selected from Gln or His;

[0410] X 10 an amino acid residue selected from Leu or Tyr;

[0411] X 12 an amino acid residue selected from Lys, alpha-methyl-Lys or Ile;

[0412] X 13 an amino acid residue selected from Aib, Ile, Leu, Tyr, alpha-methyl-Tyr or alpha-methyl-Leu;

[0413] X 14 an amino acid residue selected from Leu or alpha-methyl-Leu;

[0414] X 17 an amino acid residue selected from Ile, Lys, Gln or alpha-methyl-Lys;

[0415] X 18 an amino acid residue selected from Ala or Aib;

[0416] X 19 an amino acid residue selected from Ala or Gln;

[0417] X 20an amino acid residue selected from Gln, Aib, isovaline, alpha-methyl-Ser, 1-aminocyclopropane-1-carboxylic acid or 1-aminocyclobutane-1-carboxylic acid;

[0418] X 27 an amino acid residue selected from Ile or Leu;

[0419] X 28 an amino acid residue selected from Ala or Glu;

[0420] X 29 an amino acid residue selected from Gly or D-Glu;

[0421] Y1 is a Lys residue of a side chain-linked substituent, the structure of which is as follows: -Z1-Z2, wherein Z1 comprises 0-10 amino acid residues independently selected from Gly, Glu, γGlu, OEG, and Z2 is selected from C 12-32 In some embodiments, Z1 comprises (or is) the structure shown below: -(OEG) a -(γGlu) b -; wherein a is any integer between 0 and 4, and b is any integer between 1 and 2. In some embodiments, Z2 comprises (or is) the structure shown below: -CO-(CH2) c -COOH, c is any integer between 10 and 30.

[0422] In some embodiments, the structure of the substituent is as follows:

[0423] {[2-(2-Amino-ethoxy)-ethoxy]-acetyl} a -(γGlu) b -CO-(CH2) c -COOH;

[0424] Wherein, a is any integer between 0 and 4, b is any integer between 1 and 2, and c is any integer between 10 and 30.

[0425] In some specific embodiments, a is 1, 2 or 3, b is 1 or 2, and c is any integer from 16 to 20 (e.g., 16, 17, 18, 19, 20). In some specific embodiments, a is 2 or 3, b is 1 or 2, and c is 16, 18 or 20. In some specific embodiments, a is 2, b is 1 or 2, and c is 16, 18 or 20. In some specific embodiments, a is 2, b is 1 or 2, and c is 16 or 18. In some specific embodiments, a is 2, b is 1, and c is 16 or 18.

[0426] In some embodiments, the substituent is covalently linked to the ε-amino group of the Lys residue via an amide bond. In some embodiments, Y1 is K(-OEG-OEG-γGlu-C(O)-(CH2) 16 -COOH), K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH) or K(-OEG-OEG-γGlu-C(O)-(CH2) 20 -COOH).

[0427] In some embodiments, Y1 has the structure shown below:

[0428] In some embodiments, in the compound of any of the foregoing structures, Y1 has the structure shown below:

[0429] In some embodiments, the compound of any of the foregoing structures, wherein X1, X2 and X3 are selected from any of the following:

[0430] X1 is His, X2 is Aib, and X3 is His;

[0431] X1 is Tyr, X2 is Aib, and X3 is Gln; or

[0432] X1 is His, X2 is Aib, and X3 is Gln.

[0433] In some embodiments, in the compound of any of the foregoing structures, X1, X2, and X3 are selected from the group consisting of:

[0434] X1 is His, X2 is Aib, and X3 is His; or

[0435] X1 is His, X2 is Aib, and X3 is Gln.

[0436] In some embodiments, in the compound of any of the aforementioned structures, X1, X2 and X3 are His, Aib and His, respectively.

[0437] In some embodiments, the compound of any of the above structures, wherein X 17 is a Lys residue.

[0438] In some embodiments, X 17 、X 18 、X 19 and X 20 Select any of the following:

[0439] X 17 Lys, X18 Ala, X 19 Ala, and X 20 for Gln;

[0440] X 17 Lys, X 18 Ala, X 19 Ala, and X 20 is alpha-methyl-Ser;

[0441] X 17 Lys, X 18 Ala, X 19 Ala, and X 20 isovaline;

[0442] X 17 Lys, X 18 Ala, X 19 Ala, and X 20 is 1-aminocyclopropane-1-carboxylic acid;

[0443] X 17 Lys, X 18 Ala, X 19 Ala, and X 20 is 1-aminocyclobutane-1-carboxylic acid;

[0444] X 17 Lys, X 18 Ala, X 19 Ala, and X 20 for Aib;

[0445] X 17 Lys, X 18 Aib, X 19 Ala, and X 20 is Gln; and

[0446] X 17 Lys, X 18 Ala, X 19 Gln, and X 20 For Gln.

[0447] In some embodiments, the compound of any of the above structures, wherein X 17 In some embodiments, X 17 、X 18 、X 19 and X 20 Select any of the following:

[0448] X 17 Gln, X18 Ala, X 19 Ala, and X 20 for Gln;

[0449] X 17 Gln, X 18 Ala, X 19 Ala, and X 20 isovaline;

[0450] X 17 Gln, X 18 Ala, X 19 Ala, and X 20 is 1-aminocyclopropane-1-carboxylic acid; and

[0451] X 17 Gln, X 18 Ala, X 19 Ala, and X 20 It is 1-aminocyclobutane-1-carboxylic acid.

[0452] In some embodiments, the compound of any of the above structures, wherein X 17 It is alpha-methyl-Lys.

[0453] In some embodiments, X 17 、X 18 、X 19 and X 20 They are alpha-methyl-Lys, Ala, Ala and Gln respectively.

[0454] In some embodiments, the compound of any of the above structures, wherein X 17 In some embodiments, X 17 、X 18 、X 19 and X 20 They are Ile, Ala, Ala and Gln respectively.

[0455] In some embodiments, as in any of the above compounds, X 12 is an Ile residue.

[0456] In some embodiments, X 12 、X 13 and X 14 Select any of the following:

[0457] X 12 Ile, X 13 Leu, and X 14 is Leu; or

[0458] X 12 Ile, X 13 alpha-methyl-Leu, and X 14 For Leu.

[0459] In some embodiments, the compound of any of the above structures, wherein X 12 is a Lys residue.

[0460] In some embodiments, X 12 、X 13 and X 14 Select any of the following:

[0461] X 12 Lys, X 13 is alpha-methyl-Tyr, and X 14 for Leu;

[0462] X 12 Lys, X 13 For Aib, and X 14 for Leu;

[0463] X 12 Lys, X 13 Tyr, and X 14 is alpha-methyl-Leu; and

[0464] X 12 Lys, X 13 Tyr, and X 14 For Leu.

[0465] In some embodiments, the compound of any of the above structures, wherein X 12 is an alpha-methyl-Lys residue.

[0466] In some embodiments, X 12 、X 13 and X 14 Select any of the following:

[0467] X 12 alpha-methyl-Lys, X 13 Tyr, and X 14 for Leu;

[0468] X 12 alpha-methyl-Lys, X 13 Leu, and X 14 is Leu; or

[0469] X 12 alpha-methyl-Lys, X13 Ile, and X 14 For Leu.

[0470] In some embodiments, the compound of any of the above structures, wherein X1 to X 29 An amino acid combination selected from any one of the above (i) to (xi).

[0471] In some embodiments, Z is selected from Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 146), Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 147), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 148), or Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 149). In some embodiments, Z is Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 146). In some embodiments, X 40 In some embodiments, X 40 In some embodiments, R1 is hydrogen, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl, or pGlu, and R2 is -NH2 or -OH. In some embodiments, R1 is hydrogen, and R2 is -NH2 or -OH. In some embodiments, Y1 is a Lys, Orn, Dap, Dab, or Cys residue with a side chain attached to a substituent having the structure shown below:

[0472] {[2-(2-Amino-ethoxy)-ethoxy]-acetyl} a -(γGlu) b -CO-(CH2) c -COOH;

[0473] Wherein, a is any integer between 0 and 4, b is any integer between 1 and 2, and c is any integer between 10 and 30. In some specific embodiments, a is 1, 2 or 3, b is 1 or 2, and c is any integer between 16 and 20 (e.g., 16, 17, 18, 19, 20). In some specific embodiments, a is 2 or 3, b is 1 or 2, and c is 16, 18 or 20. In some specific embodiments, a is 2, b is 1 or 2, and c is 16, 18 or 20. In some specific embodiments, a is 2, b is 1 or 2, and c is 16 or 18. In some specific embodiments, a is 2, b is 1, and c is 16 or 18.

[0474] In some embodiments, the substituent is covalently linked to the ε-amino group of the Lys residue via an amide bond. In some embodiments, Y1 is K(-OEG-OEG-γGlu-C(O)-(CH2) 16 -COOH) or K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH), wherein Y1 has the structure shown below:

[0475] In some embodiments, the compound comprises (or is) a structure as shown in any one of the following:

[0476] Table 2. Examples of compound sequence structures

[0477] In Table 2 , αK is alpha-methyl-Lys, αY is alpha-methyl-Tyr, αL is alpha-methyl-Leu, Iva is isovaline, e is D-Glu, Aib is α-aminoisobutyric acid, Ac3c is 1-aminocyclopropane-1-carboxylic acid, and Ac4c is 1-aminocyclobutane-1-carboxylic acid;

[0478] Y1 is a Lys, Orn, Dap, Dab or Cys residue connected to a side chain substituent, the structure of which is as follows: -Z1-Z2, wherein Z1 comprises 0-10 amino acid residues independently selected from Gly, Glu, γGlu, OEG, and Z2 is selected from C 12-32 In some embodiments, Z1 comprises (or is) the structure shown below: -(OEG) a -(γGlu) b -; wherein a is any integer between 0 and 4, and b is any integer between 1 and 2. In some embodiments, Z2 comprises (or is) the structure shown below: -CO-(CH2) c -COOH, c is any integer between 10 and 30.

[0479] In some embodiments, the structure of the substituent is as follows:

[0480] {[2-(2-Amino-ethoxy)-ethoxy]-acetyl} a -(γGlu) b -CO-(CH2) c -COOH;

[0481] Wherein, a is any integer between 0 and 4, b is any integer between 1 and 2, and c is any integer between 10 and 30. In some specific embodiments, a is 1, 2 or 3, b is 1 or 2, and c is any integer between 16 and 20 (e.g., 16, 17, 18, 19, 20). In some specific embodiments, a is 2 or 3, b is 1 or 2, and c is 16, 18 or 20. In some specific embodiments, a is 2, b is 1 or 2, and c is 16, 18 or 20. In some specific embodiments, a is 2, b is 1 or 2, and c is 16 or 18. In some specific embodiments, a is 2, b is 1, and c is 16 or 18.

[0482] In some embodiments, the substituent is covalently linked to the ε-amino group of the Lys residue via an amide bond. In some embodiments, Y1 is K(-OEG-OEG-γGlu-C(O)-(CH2) 16 -COOH), K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH) or K(-OEG-OEG-γGlu-C(O)-(CH2) 20 -COOH).

[0483] In some embodiments, Y1 has the structure shown below:

[0484] In some more specific embodiments, the structure of Y1 is:

[0485] As mentioned above, αK, also known as alpha-methyl-Lys, refers to Lys substituted with an α-methyl group. αY, also known as alpha-methyl-Tyr, refers to Tyr substituted with an α-methyl group. αL, also known as alpha-methyl-Leu, refers to Leu substituted with an α-methyl group. Iva is isovaline. e is D-Glu, the D-type of Glu. Aib is α-aminoisobutyric acid. Ac3c is 1-aminocyclopropane-1-carboxylic acid, and Ac4c is 1-aminocyclobutane-1-carboxylic acid.

[0486] In some embodiments, the compound comprises (or is) any of the following structures:

[0487] Table 3

[0488] In Table 3, αK is alpha-methyl-Lys, αY is alpha-methyl-Tyr, αL is alpha-methyl-Leu, Iva is isovaline, e is D-Glu, Aib is α-aminoisobutyric acid, Ac3c is 1-aminocyclopropane-1-carboxylic acid, Ac4c is 1-aminocyclobutane-1-carboxylic acid, and OEG is [2-(2-amino-ethoxy)-ethoxy]-acetyl.

[0489] An exemplary structural formula is as follows:

[0490] In some embodiments, the present disclosure provides a pharmaceutically acceptable salt or solvate of any of the aforementioned compounds. In some embodiments, the compounds of any structure in the present disclosure are amphiphilic compounds, and those skilled in the art can react with acidic or basic compounds to form salts using known techniques, or form solvates using techniques known in the art. For example, a solvate is a complex with a defined stoichiometry formed between a compound, a pharmaceutically acceptable salt, and a solvent (including but not limited to water).

[0491] In some embodiments, the present disclosure provides compounds comprising (or being) the polypeptide sequence of any of the aforementioned compounds.

[0492] In some embodiments, the compounds of any structure disclosed herein have agonist activity at at least one of the following receptors: GLP-1 receptor, GIP receptor, GCG receptor.

[0493] In some embodiments, compounds of any structure disclosed herein have agonist activity at the GLP-1 receptor (GLP-1-R). In some embodiments, compounds of any of the foregoing structures have agonist activity at the GIP (GIP-R) receptor. In some embodiments, compounds of any of the foregoing structures have agonist activity at the GCG (GCG-R) receptor.

[0494] In some embodiments, the compounds of any structure disclosed herein have agonist activity at the GLP-1 receptor, the GIP receptor, and the GCG receptor. In some embodiments, any compound of Compound 1 to Compound 48 disclosed herein has agonist activity at the GLP-1 receptor, the GIP receptor, and the GCG receptor.

[0495] In some embodiments, compounds of any structure disclosed herein can activate GLP-1 receptors, GIP receptors, and / or GCG receptors. In some embodiments, any compound of Compound 1 to Compound 48 disclosed herein can activate GLP-1 receptors, GIP receptors, and / or GCG receptors.

[0496] In some embodiments, compounds of any structure in the present disclosure can activate the GLP-1 receptor, the GIP receptor, and the GCG receptor. In some embodiments, any compound of Compound 1 to Compound 48 in the present disclosure can activate the GLP-1 receptor, the GIP receptor, and the GCG receptor.

[0497] As used herein and with reference to one or more of the GIP, GLP-1 or GCG receptors, "activity," "activation," "activation," and the like refers to assays known in the art, such as those provided in the Examples of this disclosure.

[0498] In some embodiments, activity in in vitro assays can also be used as a measure of compound activity. 50 The EC value can be used as a numerical measure of the potency of an agonist at a given receptor. 50 The EC value is a measure of the concentration of a compound required to achieve half of its maximal activity in a particular assay. In some embodiments of the present disclosure, for example, when evaluated using the assays described in the Test Examples, the EC 50 GLP-1-R and / or EC 50 GIP-R and / or EC 50 GCG-R is less than 10.0 nM, less than 8.0 nM, less than 5.0 nM, less than 3.0 nM, less than 1.0 nM, less than 0.9 nM, less than 0.8 nM, less than 0.7 nM, less than 0.6 nM, less than 0.5 nM, less than 0.4 nM, less than 0.3 nM, less than 0.2 nM, less than 0.1 nM, less than 0.09 nM, less than 0.08 nM, less than 0. 07 nM, less than 0.06 nM, less than 0.05 nM, less than 0.04 nM, less than 0.03 nM, less than 0.02 nM, less than 0.01 nM, less than 0.009 nM, less than 0.008 nM, less than 0.007 nM, less than 0.006 nM, less than 0.005 nM, less than 0.004 nM, less than 0.003 nM or less than 0.002 nM.

[0499] In some embodiments, compounds of any structure disclosed herein have enhanced weight loss efficacy. For example, any of Compounds 1 to 48 disclosed herein have enhanced weight loss efficacy in DIO mice, DIO rats, and / or db / db mice. In some embodiments, compounds of any structure disclosed herein have enhanced weight loss efficacy compared to LY3437943.

[0500] In some embodiments, the compounds of the present disclosure have good safety. For example, after administration to DIO mice, the compounds of the present disclosure (e.g., compound 16 or compound 17) reduce the body weight of DIO mice to more than 80% of the body weight of mice on a normal diet (chow). In some embodiments, the compounds of the present disclosure have an increased dosing window. For example, compared with LY3437943, there is an increased dosing window. In some embodiments, the compounds of the present disclosure have an increased maximum safe dose. For example, the maximum safe dose of the compounds of the present disclosure is at least 1 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, etc., that of LY3437943.

[0501] In some embodiments, the compounds of the present disclosure reduce liver weight, perirenal fat weight, inguinal fat, and / or epididymal fat. For example, compounds 1 through 48 of the present disclosure reduce liver weight, perirenal fat weight, inguinal fat, and / or epididymal fat in the DIO mouse model described in Example 4 or the DIO rat model described in Example 5.

[0502] In some embodiments, the compounds of the present disclosure reduce alanine aminotransferase (ALT), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), serum triglycerides (TG), and / or serum total cholesterol (TC) in a subject. For example, the compounds described in Compounds 1 to 48 of the present disclosure reduce ALT, HDL, LDL, serum TG, and / or serum TC in the DIO mouse model described in Example 4, or the DIO rat model described in Example 5.

[0503] In some embodiments, compounds of any structure disclosed herein have improved solubility. In some embodiments, any of compounds 1 to 48 disclosed herein have improved solubility. In some embodiments, compounds 17 and 18 disclosed herein have a solubility in a solvent of ≥ 20 mg / mL.

[0504] In some embodiments, compounds of any structure disclosed herein have improved chemical and / or physical stability. In some embodiments, any of compounds 1 to 48 disclosed herein have improved chemical and / or physical stability. In some embodiments, compounds 17 and 18 disclosed herein, after being dissolved in a solvent, remain clear and transparent after incubation at 25 degrees for 28 days.

[0505] In some embodiments, the compounds of any structure disclosed herein have improved pharmacokinetic properties. In some embodiments, any compound of Compound 1 to Compound 48 disclosed herein has improved pharmacokinetic properties.

[0506] The pharmacokinetic parameters of the compounds disclosed herein can be determined using existing assays in the art. For example, area under the curve (AUC), clearance (CL), half-life (T 1 / 2 In some embodiments, the pharmacokinetic properties of the compound to the drug are detected using the method provided in the examples of the present disclosure.

[0507] In some embodiments, compounds of any structure disclosed herein have an extended half-life, for example, compared to native GLP-1, GIP, or GCG. In some embodiments, any compound of Compound 1 to Compound 48 disclosed herein has an extended half-life. Illustratively, the half-life of the compounds of the present disclosure is ≥ 30 min, 40 min, 45 min, 50 min, 1 h, 1.5 h, 1.8 h, 2 h, 2.2 h, 2.5 h, 2.8 h, 3.0 h, 3.2 h, 3.5 h, 3.8 h, 4.0 h, 4.2 h, 4.5 h, 4.8 h, 5.0 h, 5.2 h, 5.5 h, 5.8 h, 6.0 h, 6.2 h, 6.5 h, 6.8 h, 7.0 h, 7.2 h, 7.5 h, 7.8 h, 8.0 h, 8.2 h, 8.5 h, 8.8 h, 9.0 h, 9.2 h, 9.5 h, 9.8 h, 10.0 h, 10.2 h, 10.5 h, 10.8 h, 11.0 h, 12. 1.2h, 11.5h, 11.8h, 12.0h, 12.2h, 12.5h, 12.8h, 13.0h, 13.2h, 13.5h, 13.8h, 14.0h, 14.2h, 14.5h, 14.8h, 15.0h, 15.2h, 15.5h, 15.8h, 16.0h, 16.5h, 16.0h, 17.0h, 17.5h, 18.0h, 18.5h, 19.0h, 19.5h, 20.0h, 25h, 30h, 40h, 50h, 60h, 70h, 80h, 90h, 100h, 120h, 150h, 200h, etc. (including any range between the above point values).

[0508] In some embodiments, the compounds provided herein are derivatives of GLP-1 analogs that have agonist activity at human GIP and GCG receptors, and have triple agonist effects on human GLP-1 receptors, human GIP receptors, and human GCG receptors. In some embodiments, some compounds of the present disclosure have a stronger weight loss effect than other triple agonists in the art. In some embodiments, some compounds of the present disclosure have extremely high plasma stability.

[0509] GLP-1 / GIP / GCG receptor triagonist

[0510] In some embodiments, the present disclosure provides a GLP-1 / GIP / GCG receptor triagonist comprising a compound having any of the aforementioned structures or a pharmaceutically acceptable salt thereof.

[0511] In some embodiments, the GLP-1 / GIP / GCG receptor triple agonist has agonist activity on the GLP-1 receptor, the GIP receptor, and the GCG receptor.

[0512] In some embodiments, the GLP-1 / GIP / GCG receptor tri-agonist can activate the GLP-1 receptor, the GIP receptor, and / or the GCG receptor.

[0513] In some embodiments, the GLP-1 / GIP / GCG receptor triple agonist is capable of activating the GLP-1 receptor, the GIP receptor, and the GCG receptor.

[0514] In some embodiments, activity in in vitro assays can also be used as a measure of compound activity. 50 The EC value can be used as a numerical measure of the potency of an agonist at a given receptor. 50 The EC value is a measure of the concentration of a compound required to achieve half of its maximal activity in a particular assay. In some embodiments of the present disclosure, for example, when evaluated using the assays described in the Test Examples, the EC 50 GLP-1-R and / or EC 50 GIP-R and / or EC 50 GCG-R is less than 10.0 nM, less than 8.0 nM, less than 5.0 nM, less than 3.0 nM, less than 1.0 nM, less than 0.9 nM, less than 0.8 nM, less than 0.7 nM, less than 0.6 nM, less than 0.5 nM, less than 0.4 nM, less than 0.3 nM, less than 0.2 nM, less than 0.1 nM, less than 0.09 nM, less than 0.08 nM, less than 0. 07 nM, less than 0.06 nM, less than 0.05 nM, less than 0.04 nM, less than 0.03 nM, less than 0.02 nM, less than 0.01 nM, less than 0.009 nM, less than 0.008 nM, less than 0.007 nM, less than 0.006 nM, less than 0.005 nM, less than 0.004 nM, less than 0.003 nM or less than 0.002 nM.

[0515] In some embodiments, the GLP-1 / GIP / GCG receptor triagonist has improved solubility.

[0516] In some embodiments, the GLP-1 / GIP / GCG receptor triagonist has improved chemical and / or physical stability.

[0517] In some embodiments, the GLP-1 / GIP / GCG receptor triagonist has improved pharmacokinetic properties.

[0518] The pharmacokinetic parameters of the compounds disclosed herein can be determined using existing assays in the art. For example, area under the curve (AUC), clearance (CL), half-life (T 1 / 2 In some embodiments, the pharmacokinetic properties of the compound to the drug are detected using the method provided in the examples of the present disclosure.

[0519] In some embodiments, the GLP-1 / GIP / GCG receptor triagonist has an extended half-life. For example, compared to native GLP-1, GIP or GCG. In some embodiments, any one of Compounds 1 to 48 in the present disclosure has an extended half-life. Exemplarily, the half-life of the compounds in the present disclosure is ≥30 min, 40 min, 45 min, 50 min, 1 h, 1.5 h, 1.8 h, 2 h, 2.2 h, 2.5 h, 2.8 h, 3.0 h, 3.2 h, 3.5 h, 3.8 h, 4.0 h, 4.2 h, 4.5 h, 4.8 h, 5.0 h, 5.2 h, 5.5 h, 5.8 h, 6.0 h, 6.2 h, 6.5 h, 6.8 h, 7.0 h, 7.2 h, 7.5 h, 7.8 h, 8.0 h, 8.2 h , 8.5h, 8.8h, 9.0h, 9.2h, 9.5h, 9.8h, 10.0h, 10.2h, 10.5h, 10.8h, 11.0h, 11.2h, 11.5h, 11.8h, 12.0h, 12.2h , 12.5h, 12.8h, 13.0h, 13.2h, 13.5h, 13.8h, 14.0h, 14.2h, 14.5h, 14.8h, 15.0h, 15.2h, 15.5h, 15.8h, 16.0h, 16.5h, 16.0h, 17.0h, 17.5h, 18.0h, 18.5h, 19.0h, 19.5h, 20.0h, 25h, 30h, 40h, 50h, 60h, 70h, 80h, 90h, 100h, 120h, 150h, 200h, etc. (including any range between the above point values).

[0520] Pharmaceutical composition

[0521] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of any of the aforementioned structures or a pharmaceutically acceptable salt or solvate thereof, or any of the aforementioned GLP-1 / GIP / GCG receptor triagonists.

[0522] In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient or pharmaceutical carrier.

[0523] In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt or solvate thereof, or a GLP-1 / GIP / GCG receptor triagonist. In some embodiments, the pharmaceutical composition may contain 0.01 to 99% by weight of the aforementioned compound, or a pharmaceutically acceptable salt or solvate thereof, per unit dose, or the amount of the aforementioned compound, or a pharmaceutically acceptable salt or solvate thereof, per unit dose is 0.1-2000 mg, and in some embodiments, 1-1000 mg.

[0524] Medical uses and treatments

[0525] In another aspect, the present disclosure provides use of the aforementioned compound or a pharmaceutically acceptable salt thereof, a GLP-1 / GIP / GCG receptor triagonist, or a pharmaceutical composition as a medicament.

[0526] In some embodiments, the present disclosure provides use of the aforementioned compound or a pharmaceutically acceptable salt thereof, a GLP-1 / GIP / GCG receptor triagonist, or a pharmaceutical composition in the preparation of a medicament for preventing and / or treating a disease or condition associated with a metabolic disorder.

[0527] In some embodiments, the metabolic disorder-related disease or condition comprises diabetes, diabetes-related conditions, obesity, obesity-related conditions, weight management, metabolic dysfunction-associated steatotic liver disease (MASLD).

[0528] In some embodiments, the present disclosure provides a method for preventing or treating a disease, comprising administering the aforementioned compound or a pharmaceutically acceptable salt thereof, a GLP-1 / GIP / GCG receptor triagonist, or a pharmaceutical composition to a subject in need thereof.

[0529] In some embodiments, the present disclosure also provides a method for preventing and / or treating a disease or condition related to metabolic disorders, comprising administering the aforementioned compound or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0530] In some embodiments, the metabolic disorder-related disease or condition comprises diabetes, diabetes-related conditions, obesity, obesity-related conditions, weight management, metabolic dysfunction-related fatty liver disease.

[0531] In some embodiments, the present disclosure provides any of the following uses of the aforementioned compound or a pharmaceutically acceptable salt thereof, a triagonist, or a pharmaceutical composition:

[0532] (i) preventing and / or treating eating disorders, such as obesity, for example, by reducing food intake, increasing energy expenditure, reducing body weight, suppressing appetite, or inducing satiety;

[0533] (ii) Weight maintenance following successful weight loss (whether drug-induced or diet and exercise--that is, preventing weight gain following successful weight loss.

[0534] (iii) prevention and / or treatment of all forms of diabetes.

[0535] (iv) Delaying or preventing the progression of diabetes.

[0536] In some embodiments, the present disclosure provides any of the following uses of the aforementioned compound or a pharmaceutically acceptable salt thereof, a triagonist, or a pharmaceutical composition:

[0537] (1) Used to activate GLP-1 receptor, GIP receptor and GCG receptor,

[0538] (2) preparing drugs for activating GLP-1 receptors, GIP receptors and GCG receptors,

[0539] (3) As a drug for the prevention and / or treatment of diseases,

[0540] (4) preparing medicines for preventing and / or treating diseases,

[0541] (5) for preventing and / or treating diseases or conditions related to metabolic disorders,

[0542] (6) Preparation of drugs for preventing and / or treating diseases or conditions related to metabolic disorders.

[0543] In some embodiments, the metabolic disorder-related disease or condition comprises diabetes, diabetes-related conditions, obesity, weight management, metabolic dysfunction-related fatty liver disease.

[0544] Preparation method

[0545] In another aspect, the present disclosure provides a method for preparing the aforementioned compound or a pharmaceutically acceptable salt thereof, or a GLP-1 / GIP / GCG receptor triagonist.

[0546] In some embodiments, the method is a chemical synthesis method.

[0547] In some embodiments, the method further comprises the step of purifying or isolating the compound or a pharmaceutically acceptable salt thereof, or the GLP-1 / GIP / GCG receptor triagonist.

[0548] In some embodiments, the chemical synthesis method is solid phase synthesis. In some embodiments, the compounds, triagonists, or fragments thereof described herein can be produced by classical peptide synthesis, such as solid phase synthesis using t-Boc or Fmoc chemistry, or other established techniques, see, for example, Greene and Wuts, "Protective Groups in Organic Synthesis", John Wiley & Sons, 1999, Florencio Zaragoza, "Organic Synthesis on solid Phase", Wiley-VCH Verlag GmbH, 2000, and "Fmoc Solid Phase Peptide Synthesis", edited by WC Chan and PD White, Oxford University Press, 2000. In some embodiments, the method for preparing the compound or GLP-1 / GIP / GCG receptor triagonist includes a solid phase peptide synthesis step.

[0549] In some embodiments, the compounds or GLP-1 / GIP / GCG receptor triagonists as described herein can be produced by recombinant methods, i.e., by culturing host cells that contain a DNA sequence encoding a compound or GLP-1 / GIP / GCG receptor triagonist peptide sequence and are capable of expressing the peptide in a suitable nutrient medium under conditions that allow expression of the peptide. Non-limiting examples of host cells suitable for expressing peptides are: Escherichia coli, Saccharomyces cerevisiae, and mammalian BHK or CHO cell lines.

[0550] As a non-limiting example, the compounds and derivatives provided in the present disclosure are obtained by the Fmoc-tBu solid-phase synthesis method, and the synthesis carrier is Rink-amide MBHA (Xi'an Lanxiao Technology) resin. The α-amino group of the amino acid derivatives used in the synthesis process is protected by the Fmoc group (fluorenylcarbonyl), and the side chains of the amino acids are selected from the following protecting groups according to the different functional groups: for example, the cysteine ​​side chain thiol, glutamine side chain amide, and histidine side chain imidazole group are protected by Trt (trityl), the arginine side chain guanidinium group is protected by Pbf (2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl), the tryptophan side chain indole group and the lysine side chain amino group are protected by Boc (tert-butyloxycarbonyl), the threonine side chain hydroxyl group, tyrosine side chain phenol group, and serine side chain hydroxyl group are protected by t-Bu (tert-butyl), and the glutamic acid and aspartic acid side chain carboxyl groups are protected by OtBu (tert-butyl ester), etc. During the synthesis process, the carboxyl group of the C-terminal amino acid residue of the peptide is first condensed onto the high-molecular-weight, insoluble Rink-amide MBHA resin via an amide bond. The Fmoc protecting group on the α-amino group is then removed using a 20% 4-methylpiperidine-in-dimethylformamide (DMF) solution. The solid support is then reacted with the next amino acid derivative in the sequence in excess to form an amide bond, extending the peptide chain. The condensation → wash → deprotection → wash → next amino acid condensation cycle is repeated to achieve the desired peptide chain length. Finally, the peptide is cleaved from the solid support by reacting with a mixture of trifluoroacetic acid: water: triisopropylsilane (90:5:5, v:v:v) and the resin. The crude peptide derivative is then precipitated with methyl tert-butyl ether to yield a solid crude product. The crude peptide solid is then dissolved in an acetonitrile / water mixture containing 0.1% trifluoroacetic acid and purified using a C-18 reverse-phase preparative chromatography column to obtain pure peptides and their derivatives.

[0551] Specific implementation plans

[0552] The technical solutions of the present disclosure are further described by the following non-limiting embodiments:

[0553] 1. A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:

[0554] R1-X1-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-X 10 -Ser-X 12 -X 13 -X 14 -Glu-X 16 -X 17 -X 18 -X 19 -X 20 -X 21-Phe-Val-Glu-Trp-Leu-X 27 -X 28 -X 29 -ZX 40 -R2 (SEQ ID NO: 145) (I);

[0555] wherein R1 is hydrogen, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu, and R2 is -NH2 or -OH;

[0556] X1 is an amino acid residue selected from Tyr or His;

[0557] X2 is an amino acid residue of Aib;

[0558] X3 is an amino acid residue selected from Gln or His;

[0559] X 10 an amino acid residue selected from Leu or Tyr;

[0560] X 12 an amino acid residue selected from Lys, alpha-methyl-Lys or Ile;

[0561] X 13 an amino acid residue selected from Aib, Ile, Leu, Tyr, alpha-methyl-Tyr or alpha-methyl-Leu;

[0562] X 14 an amino acid residue selected from Leu or alpha-methyl-Leu;

[0563] X 16 an amino acid residue selected from Glu, Lys, or Y1;

[0564] X 17 an amino acid residue selected from Glu, Arg, homoArg, Ile, Lys, Gln, alpha-methyl-Lys, or Y1;

[0565] X 18 an amino acid residue selected from Ala or Aib;

[0566] X 19 an amino acid residue selected from Ala or Gln;

[0567] X 20 an amino acid residue selected from Gln, Aib, isovaline, alpha-methyl-Ser, 1-aminocyclopropane-1-carboxylic acid or 1-aminocyclobutane-1-carboxylic acid;

[0568] X 21an amino acid residue selected from Glu or Y1;

[0569] X 27 an amino acid residue selected from Ile or Leu;

[0570] X 28 an amino acid residue selected from Ala or Glu;

[0571] X 29 an amino acid residue selected from Gly or D-Glu;

[0572] X 40 an amino acid residue selected from Lys, Y1 or absent;

[0573] Z is selected from Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 146), Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 147), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 148) or Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 149);

[0574] Y1 is a Lys, Orn, Dap, Dab or Cys residue whose side chain is linked to a substituent.

[0575] 2. The compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, which is a compound represented by the following formula (Ia) or a pharmaceutically acceptable salt thereof:

[0576] R1-X1-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-X 10 -Ser-X 12 -X 13 -X 14 -Glu-Y1-X 17 -X 18 -X 19 -X20-Glu-Phe-Val-Glu-Trp-Leu-X 27 -X 28 -X 29 -ZX 40 -R2

[0577] (Ia);

[0578] wherein R1 is hydrogen, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu, and R2 is -NH2 or -OH;

[0579] X1 is an amino acid residue selected from Tyr or His;

[0580] X2 is an amino acid residue of Aib;

[0581] X3 is an amino acid residue selected from Gln or His;

[0582] X 10 an amino acid residue selected from Leu or Tyr;

[0583] X 12 an amino acid residue selected from Lys, alpha-methyl-Lys or Ile;

[0584] X 13 an amino acid residue selected from Aib, Ile, Leu, Tyr, alpha-methyl-Tyr or alpha-methyl-Leu;

[0585] X 14 an amino acid residue selected from Leu or alpha-methyl-Leu;

[0586] X 17 an amino acid residue selected from Glu, Arg, homoArg, Ile, Lys, Gln or alpha-methyl-Lys;

[0587] X 18 an amino acid residue selected from Ala or Aib;

[0588] X 19 an amino acid residue selected from Ala or Gln;

[0589] X 20 an amino acid residue selected from Gln, Aib, isovaline, alpha-methyl-Ser, 1-aminocyclopropane-1-carboxylic acid or 1-aminocyclobutane-1-carboxylic acid;

[0590] X 27 an amino acid residue selected from Ile or Leu;

[0591] X 28 an amino acid residue selected from Ala or Glu;

[0592] X 29 an amino acid residue selected from Gly or D-Glu;

[0593] X 40 an amino acid residue selected from Lys or absent;

[0594] Z is selected from Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 146), Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 147), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 148) or Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 149);

[0595] Y1 is a Lys, Orn, Dap, Dab or Cys residue whose side chain is linked to a substituent.

[0596] 3. The compound according to Embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, which is a compound represented by the following formula (Ib) or a pharmaceutically acceptable salt thereof:

[0597] R1-X1-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-X 10 -Ser-X 12 -X 13 -X 14 -Glu-Y1-X 17 -X 18 -X 19 -X20-Glu-Phe-Val-Glu-Trp-Leu-X 27 -X 28 -X 29 -Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-R2 (SEQ ID NO: 150)

[0598] (Ib);

[0599] wherein R1 is hydrogen, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu, and R2 is -NH2 or -OH;

[0600] X1 is an amino acid residue selected from Tyr or His;

[0601] X2 is an amino acid residue of Aib;

[0602] X3 is an amino acid residue selected from Gln or His;

[0603] X 10 an amino acid residue selected from Leu or Tyr;

[0604] X 12an amino acid residue selected from Lys, alpha-methyl-Lys or Ile;

[0605] X 13 an amino acid residue selected from Aib, Ile, Leu, Tyr, alpha-methyl-Tyr or alpha-methyl-Leu;

[0606] X 14 an amino acid residue selected from Leu or alpha-methyl-Leu;

[0607] X 17 an amino acid residue selected from Ile, Lys, Gln or alpha-methyl-Lys;

[0608] X 18 an amino acid residue selected from Ala or Aib;

[0609] X 19 an amino acid residue selected from Ala or Gln;

[0610] X 20 an amino acid residue selected from Gln, Aib, isovaline, alpha-methyl-Ser, 1-aminocyclopropane-1-carboxylic acid or 1-aminocyclobutane-1-carboxylic acid;

[0611] X 27 an amino acid residue selected from Ile or Leu;

[0612] X 28 an amino acid residue selected from Ala or Glu;

[0613] X 29 an amino acid residue selected from Gly or D-Glu;

[0614] Y1 is a Lys, Orn, Dap, Dab or Cys residue whose side chain is linked to a substituent.

[0615] 4. The compound according to any one of embodiments 1-3, or a pharmaceutically acceptable salt thereof, wherein X1, X2 and X3 are selected from any one of the following:

[0616] X1 is His, X2 is Aib, and X3 is His;

[0617] X1 is Tyr, X2 is Aib, and X3 is Gln; or

[0618] X1 is His, X2 is Aib, and X3 is Gln.

[0619] 5. The compound according to any one of embodiments 1-3, or a pharmaceutically acceptable salt thereof, wherein X1 is His, X2 is Aib, and X3 is His; or

[0620] X1 is His, X2 is Aib, and X3 is Gln.

[0621] 6. The compound according to any one of embodiments 1-3, or a pharmaceutically acceptable salt thereof, wherein X1 is His, X2 is Aib, and X3 is His.

[0622] 7. The compound according to any one of embodiments 1-6 or a pharmaceutically acceptable salt thereof, wherein X 17 is a Lys residue.

[0623] 8. The compound according to any one of embodiments 1-6 or a pharmaceutically acceptable salt thereof, wherein X 17 is a Gln residue.

[0624] 9. The compound according to any one of embodiments 1-6 or a pharmaceutically acceptable salt thereof, wherein X 17 is an alpha-methyl-Lys residue.

[0625] 10. The compound according to any one of embodiments 1-6, or a pharmaceutically acceptable salt thereof, wherein X 17 is an Ile residue.

[0626] 11. The compound according to any one of embodiments 1-10, or a pharmaceutically acceptable salt thereof, wherein X 18 is an Ala residue.

[0627] 12. The compound according to any one of embodiments 1-11, or a pharmaceutically acceptable salt thereof, wherein X 19 is an Ala residue.

[0628] 13. The compound according to any one of embodiments 1-12, or a pharmaceutically acceptable salt thereof, wherein X 20 is a Gln residue.

[0629] 14. The compound according to any one of embodiments 1-12, or a pharmaceutically acceptable salt thereof, wherein X 20 is the Aib residue.

[0630] 15. The compound according to any one of embodiments 1-12, or a pharmaceutically acceptable salt thereof, wherein X 20 Isovaline residue.

[0631] 16. The compound according to any one of embodiments 1-12, or a pharmaceutically acceptable salt thereof, wherein X 20is an alpha-methyl-Ser residue.

[0632] 17. The compound according to any one of embodiments 1-12, or a pharmaceutically acceptable salt thereof, wherein X 20 It is the residue of 1-aminocyclobutane-1-carboxylic acid.

[0633] 18. The compound according to any one of embodiments 1-12, or a pharmaceutically acceptable salt thereof, wherein X 20 It is a 1-aminocyclopropane-1-carboxylic acid residue.

[0634] 19. The compound according to any one of embodiments 1-6, or a pharmaceutically acceptable salt thereof, wherein X 17 、X 18 、X 19 and X 20 Select any of the following:

[0635] X 17 Lys, X 18 Ala, X 19 Ala, and X 20 for Gln;

[0636] X 17 Lys, X 18 Ala, X 19 Ala, and X 20 is alpha-methyl-Ser;

[0637] X 17 Lys, X 18 Ala, X 19 Ala, and X 20 isovaline;

[0638] X 17 Lys, X 18 Ala, X 19 Ala, and X 20 is 1-aminocyclopropane-1-carboxylic acid;

[0639] X 17 Lys, X 18 Ala, X 19 Ala, and X 20 is 1-aminocyclobutane-1-carboxylic acid;

[0640] X 17 Lys, X 18 Ala, X 19 Ala, and X 20 for Aib;

[0641] X17 Lys, X 18 Aib, X 19 Ala, and X 20 for Gln;

[0642] X 17 Lys, X 18 Ala, X 19 Gln, and X 20 for Gln;

[0643] X 17 Gln, X 18 Ala, X 19 Ala, and X 20 for Gln;

[0644] X 17 Gln, X 18 Ala, X 19 Ala, and X 20 isovaline;

[0645] X 17 Gln, X 18 Ala, X 19 Ala, and X 20 is 1-aminocyclopropane-1-carboxylic acid;

[0646] X 17 Gln, X 18 Ala, X 19 Ala, and X 20 is 1-aminocyclobutane-1-carboxylic acid;

[0647] X 17 alpha-methyl-Lys, X 18 Ala, X 19 Ala, and X 20 is Gln; or

[0648] X 17 Ile, X 18 Ala, X 19 Ala, and X 20 For Gln.

[0649] 20. The compound according to any one of embodiments 1-19, or a pharmaceutically acceptable salt thereof, wherein X 12 is an alpha-methyl-Lys residue.

[0650] 21. The compound according to any one of embodiments 1-19, or a pharmaceutically acceptable salt thereof, wherein X 12 is an Ile residue.

[0651] 22. The compound according to any one of embodiments 1-19, or a pharmaceutically acceptable salt thereof, wherein X 12 is a Lys residue.

[0652] 23. The compound according to any one of embodiments 1-22, or a pharmaceutically acceptable salt thereof, wherein X 13 is a Leu residue.

[0653] 24. The compound according to any one of embodiments 1-22, or a pharmaceutically acceptable salt thereof, wherein X 13 is an alpha-methyl-Leu residue.

[0654] 25. The compound according to any one of embodiments 1-22, or a pharmaceutically acceptable salt thereof, wherein X 13 is an Ile residue.

[0655] 26. The compound according to any one of embodiments 1-22, or a pharmaceutically acceptable salt thereof, wherein X 13 is a Tyr residue.

[0656] 27. The compound according to any one of embodiments 1-22, or a pharmaceutically acceptable salt thereof, wherein X 13 is the Aib residue.

[0657] 28. The compound according to any one of embodiments 1-22, or a pharmaceutically acceptable salt thereof, wherein X 13 is an alpha-methyl-Tyr residue.

[0658] 29. The compound according to any one of embodiments 1-22, or a pharmaceutically acceptable salt thereof, wherein X 14 is a Leu residue.

[0659] 30. The compound according to any one of embodiments 1-22, or a pharmaceutically acceptable salt thereof, wherein X 14 is an alpha-methyl-Leu residue.

[0660] 31. The compound according to any one of embodiments 1-19, or a pharmaceutically acceptable salt thereof, wherein X 12 、X 13 and X 14 Select any of the following:

[0661] X 12 Ile, X 13 Leu, and X 14 for Leu;

[0662] X 12Ile, X 13 alpha-methyl-Leu, and X 14 for Leu;

[0663] X 12 Lys, X 13 is alpha-methyl-Tyr, and X 14 for Leu;

[0664] X 12 Lys, X 13 For Aib, and X 14 for Leu;

[0665] X 12 Lys, X 13 Tyr, and X 14 is alpha-methyl-Leu;

[0666] X 12 Lys, X 13 Tyr, and X 14 for Leu;

[0667] X 12 alpha-methyl-Lys, X 13 Tyr, and X 14 for Leu;

[0668] X 12 alpha-methyl-Lys, X 13 Leu, and X 14 is Leu; or

[0669] X 12 alpha-methyl-Lys, X 13 Ile, and X 14 For Leu;.

[0670] 32. The compound according to any one of embodiments 1-31, or a pharmaceutically acceptable salt thereof, wherein X 27 is an Ile residue.

[0671] 33. The compound according to any one of embodiments 1-31, or a pharmaceutically acceptable salt thereof, wherein X 27 is a Leu residue.

[0672] 34. The compound according to any one of embodiments 1-33, or a pharmaceutically acceptable salt thereof, wherein X 28 is an Ala residue.

[0673] 35. The compound according to any one of embodiments 1-33, or a pharmaceutically acceptable salt thereof, wherein X28 is a Glu residue.

[0674] 36. The compound according to any one of embodiments 1-35, or a pharmaceutically acceptable salt thereof, wherein X 29 is a Gly residue.

[0675] 37. The compound according to any one of embodiments 1-35, or a pharmaceutically acceptable salt thereof, wherein X 29 It is a D-Glu residue.

[0676] 38. The compound according to any one of Embodiments 1-37 or a pharmaceutically acceptable salt thereof, which is a compound represented by the following formula (Ib) or a pharmaceutically acceptable salt thereof:

[0677] R1-X1-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-X 10 -Ser-X 12 -X 13 -X 14 -Glu-Y1-X 17 -X 18 -X 19 -X20-Glu-Phe-Val-Glu-Trp-Leu-X 27 -X 28 -X 29 -Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-R2 (SEQ ID NO: 150)

[0678] (Ib);

[0679] wherein R1 is hydrogen, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu, and R2 is -NH2 or -OH;

[0680] X1, X2 and X3 are selected from any of the following:

[0681] X1 is His, X2 is Aib, and X3 is His;

[0682] X1 is Tyr, X2 is Aib, and X3 is Gln; or

[0683] X1 is His, X2 is Aib, and X3 is Gln;

[0684] X 10 an amino acid residue selected from Leu or Tyr;

[0685] X 12 an amino acid residue selected from Lys, alpha-methyl-Lys or Ile;

[0686] X 13 an amino acid residue selected from Aib, Ile, Leu, Tyr, alpha-methyl-Tyr or alpha-methyl-Leu;

[0687] X 14 an amino acid residue selected from Leu or alpha-methyl-Leu;

[0688] X 17 an amino acid residue selected from Lys;

[0689] X 18 an amino acid residue selected from Ala or Aib;

[0690] X 19 an amino acid residue selected from Ala or Gln;

[0691] X 20 an amino acid residue selected from Gln, Aib, isovaline, alpha-methyl-Ser, 1-aminocyclopropane-1-carboxylic acid or 1-aminocyclobutane-1-carboxylic acid;

[0692] X 27 an amino acid residue selected from Ile or Leu;

[0693] X 28 an amino acid residue selected from Ala or Glu;

[0694] X 29 an amino acid residue selected from Gly or D-Glu;

[0695] Y1 is a Lys, Orn, Dap, Dab or Cys residue whose side chain is linked to a substituent.

[0696] 39. The compound according to embodiment 38, or a pharmaceutically acceptable salt thereof, wherein:

[0697] X1 is His, X2 is Aib, and X3 is His; or

[0698] X1 is His, X2 is Aib, and X3 is Gln.

[0699] 40. The compound according to embodiment 38 or 39, or a pharmaceutically acceptable salt thereof, wherein:

[0700] X1 is His, X2 is Aib, and X3 is His; or

[0701] X1 is His, X2 is Aib, and X3 is Gln;

[0702] X 10an amino acid residue selected from Leu or Tyr,

[0703] X 12 an amino acid residue selected from Lys, alpha-methyl-Lys or Ile,

[0704] X 13 an amino acid residue selected from the group consisting of Aib, Ile, Leu, Tyr, alpha-methyl-Tyr or alpha-methyl-Leu,

[0705] X 14 an amino acid residue selected from Leu or alpha-methyl-Leu,

[0706] X 17 an amino acid residue selected from Lys,

[0707] X 18 an amino acid residue selected from Ala or Aib,

[0708] X 19 an amino acid residue selected from Ala or Gln,

[0709] X 20 an amino acid residue selected from Gln,

[0710] X 27 an amino acid residue selected from Ile or Leu,

[0711] X 28 an amino acid residue selected from Ala or Glu,

[0712] X 29 An amino acid residue selected from Gly or D-Glu.

[0713] 41. The compound according to any one of embodiments 38-40, or a pharmaceutically acceptable salt thereof, wherein:

[0714] X1 is His,

[0715] X2 is Aib,

[0716] X3 is His,

[0717] X 10 is the amino acid residue of Tyr,

[0718] X 12 an amino acid residue selected from Lys or alpha-methyl-Lys,

[0719] X 13 an amino acid residue selected from Aib, Ile or alpha-methyl-Tyr,

[0720] X14 is an amino acid residue of Leu,

[0721] X 17 is the amino acid residue of Lys,

[0722] X 18 is the amino acid residue of Ala,

[0723] X 19 is the amino acid residue of Ala,

[0724] X 20 is the amino acid residue of Gln,

[0725] X 27 is an amino acid residue of Leu,

[0726] X 28 is the amino acid residue of Ala,

[0727] X 29 It is the amino acid residue of Gly.

[0728] 42. The compound according to any one of embodiments 38-40, or a pharmaceutically acceptable salt thereof, wherein:

[0729] X1 is His,

[0730] X2 is Aib,

[0731] X3 is His or Gln,

[0732] X 10 an amino acid residue selected from Leu or Tyr,

[0733] X 12 an amino acid residue selected from alpha-methyl-Lys or Ile,

[0734] X 13 is an amino acid residue of Leu,

[0735] X 14 is an amino acid residue of Leu,

[0736] X 17 is the amino acid residue of Lys,

[0737] X 18 is the amino acid residue of Ala,

[0738] X 19 is the amino acid residue of Ala,

[0739] X 20 is the amino acid residue of Gln,

[0740] X27 is an amino acid residue of Leu,

[0741] X 28 is the amino acid residue of Ala,

[0742] X 29 It is an amino acid residue of Gly or D-Glu.

[0743] 43. The compound according to any one of embodiments 38-40, or a pharmaceutically acceptable salt thereof, wherein:

[0744] X1 is His,

[0745] X2 is Aib,

[0746] X3 is His or Gln,

[0747] X 10 an amino acid residue selected from Leu or Tyr,

[0748] X 12 is an amino acid residue of Ile,

[0749] X 13 is an amino acid residue of alpha-methyl-Leu,

[0750] X 14 is an amino acid residue of Leu,

[0751] X 17 is the amino acid residue of Lys,

[0752] X 18 is the amino acid residue of Ala,

[0753] X 19 is the amino acid residue of Ala,

[0754] X 20 is the amino acid residue of Gln,

[0755] X 27 is an amino acid residue of Leu,

[0756] X 28 is the amino acid residue of Ala,

[0757] X 29 It is an amino acid residue of Gly or D-Glu.

[0758] 44. The compound of embodiment 38 or 39, or a pharmaceutically acceptable salt thereof, wherein:

[0759] X1, X2, and X3 are selected from any one of the following:

[0760] X1 is His, X2 is Aib, and X3 is His;

[0761] X1 is His, X2 is Aib, and X3 is Gln; or

[0762] X1 is Tyr, X2 is Aib, and X3 is Gln;

[0763] X 10 an amino acid residue selected from Leu or Tyr,

[0764] X 12 an amino acid residue selected from alpha-methyl-Lys or Ile,

[0765] X 13 an amino acid residue selected from Ile, Leu or alpha-methyl-Leu,

[0766] X 14 is selected from Leu amino acid residues,

[0767] X 17 an amino acid residue selected from Lys,

[0768] X 18 an amino acid residue selected from Ala,

[0769] X 19 an amino acid residue selected from Ala,

[0770] X 20 is selected from the group consisting of Aib, isovaline, alpha-methyl-Ser, 1-aminocyclopropane-1-carboxylic acid or 1-aminocyclobutane-1-carboxylic acid amino acid residues,

[0771] X 27 an amino acid residue selected from Ile or Leu,

[0772] X 28 an amino acid residue selected from Ala or Glu,

[0773] X 29 An amino acid residue selected from Gly or D-Glu.

[0774] 45. The compound of embodiment 44, or a pharmaceutically acceptable salt thereof, wherein:

[0775] X1 is His,

[0776] X2 is Aib,

[0777] X3 is His or Gln,

[0778] X 10an amino acid residue selected from Leu or Tyr,

[0779] X 12 is an amino acid residue of Ile,

[0780] X 13 an amino acid residue selected from alpha-methyl-Leu,

[0781] X 14 an amino acid residue selected from Leu,

[0782] X 17 an amino acid residue selected from Lys,

[0783] X 18 an amino acid residue selected from Ala,

[0784] X 19 an amino acid residue selected from Ala,

[0785] X 20 an amino acid residue selected from Aib or isovaline,

[0786] X 27 an amino acid residue selected from Leu,

[0787] X 28 an amino acid residue selected from Ala,

[0788] X 29 An amino acid residue selected from Gly.

[0789] 46. ​​The compound of embodiment 44, or a pharmaceutically acceptable salt thereof, wherein:

[0790] X1-X2-X3 is selected from His-Aib-His, His-Aib-Gln or Tyr-Aib-Gln,

[0791] X 10 an amino acid residue selected from Leu or Tyr,

[0792] X 12 an amino acid residue selected from alpha-methyl-Lys or Ile,

[0793] X 13 an amino acid residue selected from Leu,

[0794] X 14 an amino acid residue selected from Leu,

[0795] X 17 an amino acid residue selected from Lys,

[0796] X 18an amino acid residue selected from Ala,

[0797] X 19 an amino acid residue selected from Ala,

[0798] X 20 is selected from the group consisting of Aib, isovaline, alpha-methyl-Ser, 1-aminocyclopropane-1-carboxylic acid or 1-aminocyclobutane-1-carboxylic acid amino acid residues,

[0799] X 27 an amino acid residue selected from Ile or Leu,

[0800] X 28 an amino acid residue selected from Ala or Glu,

[0801] X 29 An amino acid residue selected from Gly or D-Glu.

[0802] 47. The compound of embodiment 44, or a pharmaceutically acceptable salt thereof, wherein:

[0803] X1, X2, and X3 are selected from any one of the following:

[0804] X1 is His, X2 is Aib, and X3 is His; or

[0805] X1 is Tyr, X2 is Aib, and X3 is Gln;

[0806] X 10 an amino acid residue selected from Leu or Tyr,

[0807] X 12 an amino acid residue selected from alpha-methyl-Lys,

[0808] X 13 an amino acid residue selected from Ile,

[0809] X 14 an amino acid residue selected from Leu,

[0810] X 17 an amino acid residue selected from Lys,

[0811] X 18 an amino acid residue selected from Ala,

[0812] X 19 an amino acid residue selected from Ala,

[0813] X 20 an amino acid residue selected from the group consisting of isovaline,

[0814] X 27an amino acid residue selected from Ile or Leu,

[0815] X 28 an amino acid residue selected from Ala or Glu,

[0816] X 29 An amino acid residue selected from Gly.

[0817] 48. A compound according to any one of embodiments 44-47, or a pharmaceutically acceptable salt thereof, wherein: X1 is His; X2 is Aib; X3 is His or Gln.

[0818] 49. The compound according to any one of embodiments 1-37, or a pharmaceutically acceptable salt thereof, comprising a compound represented by the following formula (Ib) or a pharmaceutically acceptable salt thereof:

[0819] R1-X1-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-X 10 -Ser-X 12 -X 13 -X 14 -Glu-Y1-X 17 -X 18 -X 19 -X20-Glu-Phe-Val-Glu-Trp-Leu-X 27 -X 28 -X 29 -Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-R2 (SEQ ID NO: 150)

[0820] (Ib);

[0821] wherein R1 is hydrogen, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu, and R2 is -NH2 or -OH;

[0822] X1 is His;

[0823] X2 is Aib;

[0824] X3 is His;

[0825] X 10 an amino acid residue selected from Tyr;

[0826] X 12 an amino acid residue selected from Lys or alpha-methyl-Lys;

[0827] X 13 an amino acid residue selected from Tyr;

[0828] X 14 an amino acid residue selected from Leu or alpha-methyl-Leu;

[0829] X 17 an amino acid residue selected from Lys;

[0830] X 18 an amino acid residue selected from Ala or Aib;

[0831] X 19 an amino acid residue selected from Ala or Gln;

[0832] X 20 an amino acid residue selected from Gln;

[0833] X 27 an amino acid residue selected from Ile or Leu;

[0834] X 28 an amino acid residue selected from Ala or Glu;

[0835] X 29 an amino acid residue selected from Gly;

[0836] Y1 is a Lys, Orn, Dap, Dab or Cys residue whose side chain is linked to a substituent.

[0837] 50. The compound according to embodiment 49 or a pharmaceutically acceptable salt thereof, wherein X 18 An amino acid residue selected from Ala.

[0838] 51. The compound according to embodiment 49 or a pharmaceutically acceptable salt thereof, wherein X 19 An amino acid residue selected from Ala.

[0839] 52. The compound according to any one of Embodiments 1-37 or a pharmaceutically acceptable salt thereof, which is a compound represented by the following formula (Ib) or a pharmaceutically acceptable salt thereof:

[0840] R1-X1-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-X 10 -Ser-X 12 -X 13 -X 14 -Glu-Y1-X 17 -X 18 -X 19 -X20-Glu-Phe-Val-Glu-Trp-Leu-X 27 -X 28 -X 29-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-R2 (SEQ ID NO: 150) (Ib);

[0841] wherein R1 is hydrogen, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu, and R2 is -NH2 or -OH;

[0842] X1 is His;

[0843] X2 is Aib;

[0844] X3 is His;

[0845] X 10 an amino acid residue selected from Leu or Tyr;

[0846] X 12 an amino acid residue selected from Ile;

[0847] X 13 an amino acid residue selected from alpha-methyl-Leu;

[0848] X 14 an amino acid residue selected from Leu;

[0849] X 17 an amino acid residue selected from Lys;

[0850] X 18 an amino acid residue selected from Ala;

[0851] X 19 an amino acid residue selected from Ala;

[0852] X 20 an amino acid residue selected from Gln, Aib, 1-aminocyclobutane-1-carboxylic acid or isovaline;

[0853] X 27 an amino acid residue selected from Leu;

[0854] X 28 an amino acid residue selected from Ala;

[0855] X 29 an amino acid residue selected from Gly or D-Glu;

[0856] Y1 is a Lys, Orn, Dap, Dab or Cys residue whose side chain is linked to a substituent.

[0857] 53. The compound according to any one of Embodiments 1-37 or a pharmaceutically acceptable salt thereof, which is a compound represented by the following formula (Ib) or a pharmaceutically acceptable salt thereof:

[0858] R1-X1-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-X 10 -Ser-X 12 -X 13 -X 14 -Glu-Y1-X 17 -X 18 -X 19 -X20-Glu-Phe-Val-Glu-Trp-Leu-X 27 -X 28 -X 29 -Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-R2 (SEQ ID NO: 150)

[0859] (Ib);

[0860] wherein R1 is hydrogen, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu, and R2 is -NH2 or -OH;

[0861] X1, X2, and X3 are selected from any one of the following:

[0862] X1 is His, X2 is Aib, and X3 is His;

[0863] X1 is His, X2 is Aib, and X3 is Gln; or

[0864] X1 is Tyr, X2 is Aib, and X3 is Gln;

[0865] X 10 an amino acid residue selected from Leu or Tyr;

[0866] X 12 an amino acid residue selected from alpha-methyl-Lys or Ile;

[0867] X 13 an amino acid residue selected from Leu;

[0868] X 14 an amino acid residue selected from Leu;

[0869] X 17 an amino acid residue selected from Lys;

[0870] X 18 an amino acid residue selected from Ala;

[0871] X 19 an amino acid residue selected from Ala;

[0872] X 20 an amino acid residue selected from Gln, Aib, isovaline, alpha-methyl-Ser, 1-aminocyclopropane-1-carboxylic acid or 1-aminocyclobutane-1-carboxylic acid;

[0873] X 27 an amino acid residue selected from Ile or Leu;

[0874] X 28 an amino acid residue selected from Ala or Glu;

[0875] X 29 an amino acid residue selected from Gly or D-Glu;

[0876] Y1 is a Lys, Orn, Dap, Dab or Cys residue whose side chain is linked to a substituent.

[0877] 54. The compound according to embodiment 53, or a pharmaceutically acceptable salt thereof, wherein X 20 is selected from Gln residues.

[0878] 55. The compound according to embodiment 53, or a pharmaceutically acceptable salt thereof, wherein X 20 An amino acid residue selected from Aib, isovaline, alpha-methyl-Ser, 1-aminocyclopropane-1-carboxylic acid or 1-aminocyclobutane-1-carboxylic acid.

[0879] 56. The compound according to embodiment 53, or a pharmaceutically acceptable salt thereof, wherein X 20 An amino acid residue selected from isovaline.

[0880] 57. The compound according to embodiment 53, or a pharmaceutically acceptable salt thereof, wherein X 20 An amino acid residue selected from 1-aminocyclopropane-1-carboxylic acid.

[0881] 58. The compound according to embodiment 53, or a pharmaceutically acceptable salt thereof, wherein X 20 An amino acid residue selected from 1-aminocyclobutane-1-carboxylic acid.

[0882] 59. The compound according to any one of embodiments 53-58, or a pharmaceutically acceptable salt thereof, wherein X1 is His, X2 is Aib, and X3 is His or Gln.

[0883] 60. The compound according to any one of embodiments 1-37, or a pharmaceutically acceptable salt thereof, comprising a compound represented by the following formula (Ib) or a pharmaceutically acceptable salt thereof:

[0884] R1-X1-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-X 10 -Ser-X 12 -X 13 -X 14 -Glu-Y1-X 17 -X 18 -X 19 -X20-Glu-Phe-Val-Glu-Trp-Leu-X 27 -X 28 -X 29 -Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-R2 (SEQ ID NO: 150) (Ib);

[0885] wherein R1 is hydrogen, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu, and R2 is -NH2 or -OH;

[0886] X1 is His,

[0887] X2 is Aib,

[0888] X3 is His,

[0889] X 10 an amino acid residue selected from Tyr,

[0890] X 12 an amino acid residue selected from Lys,

[0891] X 13 an amino acid residue selected from alpha-methyl-Tyr or Aib;

[0892] X 14 an amino acid residue selected from Leu,

[0893] X 17 an amino acid residue selected from Lys,

[0894] X 18 an amino acid residue selected from Ala,

[0895] X 19 an amino acid residue selected from Ala,

[0896] X 20 an amino acid residue selected from Gln,

[0897] X 27 an amino acid residue selected from Leu,

[0898] X 28 an amino acid residue selected from Ala,

[0899] X 29 an amino acid residue selected from Gly;

[0900] Y1 is a Lys, Orn, Dap, Dab or Cys residue whose side chain is linked to a substituent.

[0901] 61. The compound according to any one of embodiments 1-37, or a pharmaceutically acceptable salt thereof, comprising a compound represented by the following formula (Ib) or a pharmaceutically acceptable salt thereof:

[0902] R1-X1-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-X 10 -Ser-X 12 -X 13 -X 14 -Glu-Y1-X 17 -X 18 -X 19 -X20-Glu-Phe-Val-Glu-Trp-Leu-X 27 -X 28 -X 29 -Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-R2 (SEQ ID NO: 150)

[0903] (Ib);

[0904] wherein R1 is hydrogen, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu, and R2 is -NH2 or -OH;

[0905] X1, X2, and X3 are selected from any one of the following:

[0906] X1 is His, X2 is Aib, and X3 is His; or

[0907] X1 is Tyr, X2 is Aib, and X3 is Gln;

[0908] X 10 an amino acid residue selected from Leu or Tyr,

[0909] X 12 an amino acid residue selected from alpha-methyl-Lys,

[0910] X 13 an amino acid residue selected from Ile;

[0911] X 14 an amino acid residue selected from Leu,

[0912] X17 an amino acid residue selected from Lys,

[0913] X 18 an amino acid residue selected from Ala,

[0914] X 19 an amino acid residue selected from Ala,

[0915] X 20 an amino acid residue selected from Gln or isovaline,

[0916] X 27 an amino acid residue selected from Leu or Ile,

[0917] X 28 an amino acid residue selected from Ala or Glu,

[0918] X 29 an amino acid residue selected from Gly;

[0919] Y1 is a Lys, Orn, Dap, Dab or Cys residue whose side chain is linked to a substituent.

[0920] 62. The compound of embodiment 61, or a pharmaceutically acceptable salt thereof, wherein X1-X2-X3 is His-Aib-His.

[0921] 63. The compound according to any one of embodiments 1-37 or a pharmaceutically acceptable salt thereof, which is a compound represented by the following formula (Ib) or a pharmaceutically acceptable salt thereof:

[0922] R1-X1-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-X 10 -Ser-X 12 -X 13 -X 14 -Glu-Y1-X 17 -X 18 -X 19 -X20-Glu-Phe-Val-Glu-Trp-Leu-X 27 -X 28 -X 29 -Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-R2 (SEQ ID NO: 150) (Ib);

[0923] wherein R1 is hydrogen, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu, and R2 is -NH2 or -OH;

[0924] X1 is His,

[0925] X2 is Aib,

[0926] X3 is His,

[0927] X 10 an amino acid residue selected from Leu or Tyr,

[0928] X 12 an amino acid residue selected from Lys, alpha-methyl-Lys or Ile,

[0929] X 13 an amino acid residue selected from Ile, Leu, or Tyr,

[0930] X 14 an amino acid residue selected from Leu,

[0931] X 17 an amino acid residue selected from Ile, Gln or alpha-methyl-Lys,

[0932] X 18 an amino acid residue selected from Ala,

[0933] X 19 an amino acid residue selected from Ala,

[0934] X 20 an amino acid residue selected from Gln, isovaline, 1-aminocyclopropane-1-carboxylic acid or 1-aminocyclobutane-1-carboxylic acid,

[0935] X 27 an amino acid residue selected from Leu,

[0936] X 28 an amino acid residue selected from Ala,

[0937] X 29 an amino acid residue selected from Gly or D-Glu;

[0938] Y1 is a Lys, Orn, Dap, Dab or Cys residue whose side chain is linked to a substituent.

[0939] 64. The compound of embodiment 63, or a pharmaceutically acceptable salt thereof, wherein:

[0940] X1 is His,

[0941] X2 is Aib,

[0942] X3 is His,

[0943] X 10 an amino acid residue selected from Leu or Tyr,

[0944] X 12 an amino acid residue selected from alpha-methyl-Lys or Ile,

[0945] X 13 an amino acid residue selected from Ile or Leu,

[0946] X 14 an amino acid residue selected from Leu,

[0947] X 17 an amino acid residue selected from Gln,

[0948] X 18 an amino acid residue selected from Ala,

[0949] X 19 an amino acid residue selected from Ala,

[0950] X 20 an amino acid residue selected from Gln, isovaline, 1-aminocyclopropane-1-carboxylic acid or 1-aminocyclobutane-1-carboxylic acid,

[0951] X 27 an amino acid residue selected from Leu,

[0952] X 28 an amino acid residue selected from Ala,

[0953] X 29 An amino acid residue selected from Gly or D-Glu.

[0954] 65. The compound of embodiment 63, or a pharmaceutically acceptable salt thereof, wherein:

[0955] X1 is His,

[0956] X2 is Aib,

[0957] X3 is His,

[0958] X 10 an amino acid residue selected from Tyr,

[0959] X 12 an amino acid residue selected from Lys or alpha-methyl-Lys,

[0960] X 13 an amino acid residue selected from Leu or Tyr,

[0961] X 14 an amino acid residue selected from Leu,

[0962] X 17an amino acid residue selected from Ile or alpha-methyl-Lys,

[0963] X 18 an amino acid residue selected from Ala,

[0964] X 19 an amino acid residue selected from Ala,

[0965] X 20 an amino acid residue selected from Gln,

[0966] X 27 an amino acid residue selected from Leu,

[0967] X 28 an amino acid residue selected from Ala,

[0968] X 29 An amino acid residue selected from Gly.

[0969] 66. The compound according to any one of embodiments 63-65, or a pharmaceutically acceptable salt thereof, wherein: X 20 An amino acid residue selected from Gln.

[0970] 67. The compound according to any one of embodiments 63-64, or a pharmaceutically acceptable salt thereof, wherein: X 20 An amino acid residue selected from isovaline, 1-aminocyclopropane-1-carboxylic acid or 1-aminocyclobutane-1-carboxylic acid.

[0971] 68. A compound according to any one of embodiments 1-74, or a pharmaceutically acceptable salt thereof, wherein Y1 is a Lys residue to which a side chain substituent is covalently linked to the ε-amino group of the Lys residue via an amide bond.

[0972] 69. The compound according to any one of embodiments 1-68 or a pharmaceutically acceptable salt thereof, wherein the structure of the substituent is as follows:

[0973] {[2-(2-Amino-ethoxy)-ethoxy]-acetyl} a -(γGlu) b -CO-(CH2) c -COOH;

[0974] Wherein, a is any integer between 0 and 4, b is any integer between 1 and 2, and c is any integer between 10 and 30.

[0975] 70. The compound of embodiment 69, or a pharmaceutically acceptable salt thereof, wherein: a is 1, 2 or 3, b is 1 or 2, and c is 16-20.

[0976] 71. The compound of embodiment 69, or a pharmaceutically acceptable salt thereof, wherein: a is 2 or 3, b is 1 or 2, and c is 16-20.

[0977] 72. The compound of embodiment 69, or a pharmaceutically acceptable salt thereof, wherein: a is 2 or 3, b is 1 or 2, and c is 16, 18, or 20.

[0978] 73. The compound of embodiment 69, or a pharmaceutically acceptable salt thereof, wherein: a is 2, b is 1 or 2, and c is 16, 18, or 20.

[0979] 74. The compound of embodiment 69, or a pharmaceutically acceptable salt thereof, wherein: a is 2, b is 1 or 2, and c is 16 or 18.

[0980] 75. The compound of embodiment 69, or a pharmaceutically acceptable salt thereof, wherein: a is 2, b is 1, and c is 16 or 18.

[0981] 76. The compound according to any one of embodiments 1-75, or a pharmaceutically acceptable salt thereof, wherein:

[0982] Y1 is K(-OEG-OEG-γGlu-C(O)-(CH2) 16 -COOH) or K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH), which has the structure shown below:

[0983] 77. The compound according to any one of embodiments 1-76, or a pharmaceutically acceptable salt thereof, wherein Y1 is

[0984] 78. The compound according to any one of embodiments 1-77, or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen.

[0985] 79. A compound according to any one of embodiments 1-78, or a pharmaceutically acceptable salt thereof, wherein R2 is -NH2 or -OH.

[0986] 80. The compound of embodiment 79, or a pharmaceutically acceptable salt thereof, wherein R2 is -NH2.

[0987] 81. The compound according to any one of embodiments 1-80 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from any one of Compound 1 to Compound 48.

[0988] 82. The compound according to any one of embodiments 1-81 or a pharmaceutically acceptable salt thereof, wherein the compound has triple agonist activity at the GLP-1 receptor, the GIP receptor and the GCG receptor.

[0989] 83. The compound according to any one of embodiments 1-81, or a pharmaceutically acceptable salt thereof, wherein the compound has an extended half-life.

[0990] 84. The compound according to any one of embodiments 1-81, or a pharmaceutically acceptable salt thereof, wherein the compound has improved solubility, physical stability and / or chemical stability.

[0991] 85. A compound according to any one of embodiments 1-84, or a pharmaceutically acceptable salt or solvate thereof.

[0992] 86. A triple agonist of the GLP-1 / GIP / GCG receptor, comprising a compound according to any one of embodiments 1-84 or a pharmaceutically acceptable salt thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0993] FIG1 shows the results of body weight changes (%) at different times (days) in diet-induced obese (DIO) mice after subcutaneous injection of compounds.

[0994] FIG2 shows the results of changes in body weight (g) over time in diet-induced obese (DIO) mice after subcutaneous injection of the compound of the present disclosure.

[0995] FIG3 shows the results of changes in body weight (g) over time in diet-induced obese (DIO) rats after subcutaneous injection of the compound.

[0996] FIG4 shows the results of body weight changes (%) in diet-induced obese (DIO) rats at different times (days) after subcutaneous injection of the compound.

[0997] FIG5 is a graph showing the time course of daily food intake in diet-induced obese (DIO) rats after subcutaneous injection of the compound.

[0998] FIG6 is a graph showing the cumulative food intake over time in diet-induced obese (DIO) rats after subcutaneous injection of the compound.

[0999] Detailed Description of the Invention

[1000] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[1001] In the context of the present disclosure, Greek letters may be represented by their symbols or corresponding written names, for example: α = alpha; β = beta; ε = epsilon; γ = gamma; ω = omega; and so on.

[1002] The term "compound" is used herein to refer to a molecular entity and, therefore, a "compound" may have different structural elements in addition to the minimum elements defined for each compound or group of compounds. Thus, a compound may be a peptide or a derivative thereof, as long as the compound contains the defined structural and / or functional elements.

[1003] The term "polypeptide" refers to a sequence of two or more amino acids. A "polypeptide" may also include amino acid extensions at the N-terminal and / or C-terminal positions and / or truncations at the N-terminal and / or C-terminal positions. Generally, amino acid residues may be represented by their full names, their single-letter codes, and / or their three-letter codes. These three representations are fully equivalent.

[1004] In the context of the present disclosure, "polypeptide", "compound", and "polypeptide compound" are used interchangeably.

[1005] Amino acids are molecules containing an amino group and a carboxylic acid group and optionally one or more additional groups often called side chains.

[1006] The term "amino acid" includes proteinogenic (or natural) amino acids (including the 20 standard amino acids) and non-proteinogenic (or non-natural) amino acids. Proteinogenic amino acids are amino acids that are naturally incorporated into proteins. Standard amino acids are amino acids encoded by the genetic code. Non-proteinogenic amino acids are either not present in proteins or are not produced by standard cellular mechanisms (e.g., they may have undergone post-translational modification). Non-limiting examples of non-proteinogenic amino acids are Aib (α-aminoisobutyric acid or 2-aminoisobutyric acid), norleucine (Nle), norvaline, and the D-isomers of proteinogenic amino acids. D-Ala is D-alanine, -αL- is a leucine modified by methylation at the alpha position, αS is a serine modified by methylation at the alpha position, αK is a lysine modified by methylation at the alpha position, etc.

[1007] “Natural amino acids” refer to the 20 common amino acids (i.e., alanine (A), cysteine ​​(C), aspartic acid (D), glutamic acid (E), phenylalanine (F), glycine (G), histidine (H), isoleucine (I), lysine (K), leucine (L), methionine (M), asparagine (N), proline (P), glutamine (Q), arginine (R), serine (S), threonine (T), valine (V), tryptophan (W) and tyrosine (Y).

[1008] "Non-natural amino acids" refer to amino acids that are not naturally encoded or found in the genetic code of any organism. They can be, for example, purely synthetic compounds. Examples of non-natural amino acids include, but are not limited to, hydroxyproline, γ-carboxyglutamate, O-phosphoserine, azetidine carboxylic acid, 2-aminoadipic acid, 3-aminoadipic acid, β-alanine, aminopropionic acid, 2-aminobutyric acid, 4-aminobutyric acid, 6-aminohexanoic acid, 2-aminoheptanoic acid, 2-aminoisobutyric acid, 3-aminoisobutyric acid, 2-aminopimelic acid, tert-butylglycine, 2,4-diaminoisobutyric acid (Dap), desmosine, 2,2'-diaminopimelic acid, 2,3-diaminopropionic acid (Dab), N-ethylglycine, N-methylglycine, N- The present invention also includes ethylasparagine, homoproline, hydroxylysine, allo-hydroxylysine, 3-hydroxyproline, 4-hydroxyproline, isodesmosine, alloisoleucine, N-methylalanine, N-methylglycine, N-methylisoleucine, N-methylpentylglycine, N-methylvaline, naphthylalanine, norvaline, norleucine, ornithine (Orn), D-ornithine, D-arginine, p-aminophenylalanine, pentylglycine, pipecolic acid, and thioproline. In addition, the present invention also includes natural or non-natural amino acids in which the C-terminal carboxyl group, N-terminal amino group, and / or their side chain functional groups are chemically modified.

[1009] The term agonist is defined as a substance that activates the receptor type in question, for example, the term GLP-1 / GIP / GCG triple agonist as used in the context of this disclosure refers to a substance or ligand that can activate the GLP-1 receptor, the GIP receptor and the GCG receptor simultaneously.

[1010] The term "native GLP-1" refers to a peptide comprising the human GLP-1 (7-36 or 7-37) sequence, the term "native GIP" refers to a peptide comprising the human GIP (1-42) sequence, and the term "native GCG" refers to a peptide comprising the human GCG (1-29) sequence. The terms "GLP-1," "GIP," or "GCG," unless otherwise specified, refer to native GLP-1, native GIP, or native GCG, respectively.

[1011] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched-chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups. Methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl are preferred.

[1012] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[1013] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[1014] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[1015] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that are safe and effective when used in mammals and have the desired biological activity.

[1016] "Administer," "apply," and "treat" as applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, refer to the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with an animal, human, subject, cell, tissue, organ, or biological fluid, for example, therapeutic, pharmacokinetics, diagnostic, research, and experimental procedures. Treatment of cells includes contact of an agent with a cell, as well as contact of an agent with a fluid, wherein the fluid is in contact with the cell. "Administer," "apply," and "treat" also mean the in vitro and ex vivo treatment of, for example, a cell, by an agent, a diagnostic, a binding composition, or by another cell. When applied to humans, veterinary medicine, or research subjects, it refers to therapeutic treatment, prophylactic or preventative measures, research, and diagnostic applications.

[1017] "Treatment" means administering to a subject, for internal or external use, a therapeutic agent, such as a binding protein or a pharmaceutical composition thereof, comprising any of the present disclosure as a therapeutic agent, to a subject who has, is suspected of having, or is predisposed to having one or more metabolic-related diseases or symptoms thereof, and for which the therapeutic agent is known to have a therapeutic effect. Typically, the therapeutic agent is administered to the treated subject or population in an amount effective to alleviate one or more disease symptoms, either by inducing regression of such symptoms or inhibiting the progression of such symptoms to any clinically measurable degree. The amount of therapeutic agent effective to alleviate any specific disease symptom (also referred to as a "therapeutically effective amount") may vary according to a variety of factors, such as the disease state, age, and weight of the subject, and the ability of the drug to produce the desired therapeutic effect in the subject. Whether the disease symptoms have been alleviated can be evaluated by any clinical test method commonly used by a physician or other health care professional to evaluate the severity or progression of the symptoms. Although an embodiment of the present disclosure (e.g., a method of treatment or article of manufacture) may not be effective in alleviating the symptoms of the target disease in a certain subject, it should alleviate the symptoms of the target disease in a statistically significant number of subjects as determined by any statistical test known in the art, such as Student's t-test, chi-square test, U test according to Mann and Whitney, Kruskal-Wallis test (H test), Jonckheere-Terpstra test, and Wilcoxon test.

[1018] An "effective amount" encompasses an amount sufficient to ameliorate or prevent the symptoms or conditions of a medical condition. An effective amount also refers to an amount sufficient to permit or facilitate diagnosis. The effective amount for a subject may vary depending on factors such as the condition to be treated, the subject's overall health, the route and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or dosage regimen that avoids significant side effects or toxic effects. The subject of the present disclosure may be an animal or a human subject.

[1019] "Pharmaceutically acceptable carriers, diluents or excipients" include any material that, when combined with an active ingredient, allows the ingredient to retain biological activity and does not have the intended therapeutic purpose. Examples include, but are not limited to, any standard pharmaceutical carrier, such as phosphate-buffered saline solution, water, emulsions such as oil / water emulsions, and various types of wetting agents. In some embodiments, the diluent for aerosol or parenteral administration is phosphate-buffered saline (PBS) or physiological (0.9%) saline. Compositions comprising such carriers are formulated by well-known conventional methods (see, for example, Remington's Pharmaceutical Sciences, 18th edition, A. Gennaro, ed., Mack Publishing Co., Easton, PA, 1990; and R Remington, The Science and Practice of Pharmacy 20th edition Mack Publishing, 2000).

[1020] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. "And / or" should be taken as specifically disclosing that each of the two specified features or components has or does not have the other. Thus, the term "and / or" as used in phrases such as "A and / or B" in this disclosure includes "A and B," "A or B," "A" (alone), and "B" (alone). Unless the context clearly requires otherwise, throughout the specification and claims, the words "comprising," "having," "including," etc. should be understood to have an inclusive sense, rather than an exclusive or exhaustive sense; that is, the sense of "including but not limited to."

[1021] A "subject," "patient," of the present disclosure can be a mammal, including a human or a non-human mammal, such as a non-human primate (e.g., an ape, Old World monkey, or New World monkey), a livestock animal (e.g., a cow or pig), a companion animal (e.g., a dog or cat), or an experimental animal such as a rodent (e.g., a mouse or rat). DETAILED DESCRIPTION

[1022] In order to illustrate the present invention in more detail, this specification provides the following specific embodiments, but the embodiments of the present invention are not limited thereto.

[1023] Example 1. Preparation of target compound

[1024] Experimental reagents

[1025] Table 4

[1026] 2. Experimental instruments

[1027] Table 5

[1028] 3.1 Chemical Synthesis of Compound No. 0100

[1029] Compound 0100 was synthesized using the fluorenylmethoxycarbonyl (Fmoc) / tert-butyl (t-Bu) synthesis method on a Prelude-X fully automated peptide synthesizer. Rink-amide MBHA resin with a degree of substitution of 0.54 mmole / g was used as the resin. The amino acid modification site was Fmoc-L-Lys(Mtt)-OH, and the N-terminal amino acid was Boc-L-His(Trt)-OH. Prior to the amino acid condensation step, the Fmoc group was removed using a 20% 4-methylpiperidine solution in DMF (two reactions, 8 minutes each). All standard amino acid condensations used an equimolar ratio of Fmoc amino acid, HATU, and two equivalents of 4-methylmorpholine at 10 times the theoretical peptide loading, and the condensation was performed at room temperature for 25 minutes. The exception was coupling to Cα-methylated amino acids, which required two or three condensations, each 60 minutes, to ensure complete condensation. After the peptide-resin extension was completed, the resin peptide was washed with dichloromethane, and a hexafluoroisopropanol / dichloromethane mixture (30% hexafluoroisopropanol, 10 mL) was added. The mixture was shaken at room temperature for 45 minutes and then removed from the vacuum. A hexafluoroisopropanol / dichloromethane mixture (30%, 10 mL) was added again and shaken at room temperature for 45 minutes before removal from the vacuum. After the reaction, the resin was washed three times with DMF. Additional coupling / deprotection cycles for lysine side chain extension were performed using an Fmoc / tBu solid-phase synthesis strategy on the same peptide synthesizer, involving Fmoc-AEEA-OH (twice), Fmoc-L-Glu-OtBu (once), and mono-tert-butyl eicosanedioate (once). Condensation was performed using an equimolar ratio of Fmoc amino acid, HATU, and 2 equivalents of 4-methylmorpholine at a 10-fold excess of the theoretical peptide loading for 25 minutes at room temperature. The exception was the coupling of mono-tert-butyl eicosanedioate, which required condensation at room temperature for at least 3 hours to ensure complete condensation.

[1030] After synthesis, the resulting resin peptide was washed three times with DMF and then DCM, followed by vacuum drying. 10 mL of freshly prepared cleavage buffer (trifluoroacetic acid: triisopropylsilane: water = 90:5:5, v:v:v) was added and the mixture was shaken at room temperature for 3-4 hours. After the reaction, the resin was filtered and washed twice with trifluoroacetic acid. The combined filtrates were then added with a large amount of methyl tert-butyl ether to precipitate the crude peptide solid. The supernatant was removed by centrifugation to obtain the crude peptide, compound number 0100. The crude peptide was dissolved in a 20% acetic acid / water mixture, filtered through a 0.22 μm membrane, and separated using a WATERS Prep150 LC reverse-phase HPLC system with mobile phases A (0.1% trifluoroacetic acid, 10% acetonitrile, aqueous solution) and B (0.1% trifluoroacetic acid, 90% acetonitrile, aqueous solution). The chromatographic column used was an X-SELECT OBD C-18 (WATERS) reverse-phase column. During purification, the detection wavelength was set at 220 nm and the flow rate was 15-20 mL / min. The relevant fractions were collected and lyophilized to obtain the pure peptide of compound number 0100 in a yield of approximately 16%. The purity and identity of the pure peptide were confirmed by analytical ultra-high performance liquid chromatography and liquid chromatography / mass spectrometry, with a purity of 94.83% and a measured molecular weight of 4934.5.

[1031] 3.2 Chemical Synthesis of Other Compounds in the Disclosure

[1032] The remaining compounds were synthesized using the experimental protocol for compound 0100, where the N-terminal amino acid could be selected as Boc-L-Tyr(tBu)-OH or Boc-L-His(Trt)-OH depending on the sequence. The purity and molecular weight of the compounds were determined by analytical ultra-high performance liquid chromatography and liquid chromatography / mass spectrometry, as shown in Table 6 below:

[1033] Table 6 Purity and molecular weight of compounds

[1034] Example 2. Detection of the agonist activity of the compound at human glucagon-like peptide-1 receptor (GLP-1R), human glucose-dependent insulinotropic polypeptide receptor (GIPR) and human glucagon receptor (GCGR)

[1035] The purpose of this example is to detect the agonist activity of the test compound at human glucagon-like peptide-1 receptor, human glucose-dependent insulinotropic polypeptide receptor and human glucagon receptor.

[1036] 2.1 Experimental methods:

[1037] Functional activity was determined in a CHO-K1 clonal cell line expressing GIPR, GLP-1R, and GCGR. Peptides were diluted (8-10 spots, 10-fold dilution) in a 10 μL assay volume in DMEM / F12 (HyClone, SH30023.01) supplemented with 5% FBS (fetal bovine serum, Gibco, 10099141), 0.1% Casein (Sigma, C4765), and 0.25 mM IBMX (Selleck, S5836). Recipient cells (5000 cells / well) were added to an SV 96-well plate (Cisbio, 66PL96025) and incubated with the formulated peptides at 37°C for 30 minutes. The resulting increase in intracellular cAMP was quantified using the cAMP-GS dynamic HTRF assay kit (Cisbio, 62AM4PEJ). Briefly, intracellular cAMP levels were detected by adding cAMP-d2 conjugate in cell lysis buffer, followed by the addition of antibody anti-cAMP-Eu cryptate (also in cell lysis buffer). The resulting competition assay was incubated at room temperature for at least 60 minutes and then detected using a Tecan Infinite FPlex instrument with excitation at 320 nm and emission at 665 nm and 620 nm. The measured data (emission at 665 nm / 620 nm * 10000) is inversely proportional to the amount of cAMP present and is converted to cAMP content per well using a cAMP standard curve.

[1038] The amount of cAMP generated in each well was converted into a percentage of the maximum response observed with human GLP-1(7-36)-NH2, human GCG(1-29), or human GIP(1-42)-NH2 (purchased from Sigma). Relative EC values ​​were derived by nonlinear regression analysis using the percentage of maximum response versus the concentration of added peptide. 50 The values ​​were fitted to a four-parameter logarithmic equation. Specific data are shown in Tables 7-1 to 7-8 below. For the LY3437943 molecule, see Example 12 of WO2019 / 125938, which is incorporated herein by reference in its entirety.

[1039] Table 7-1

[1040] Table 7-2

[1041] Table 7-3

[1042] Table 7-4

[1043] Table 7-5

[1044] Table 7-6

[1045] Table 7-7

[1046] Table 7-8

[1047] From the above results, it can be seen that the polypeptide molecules provided by the present disclosure have good agonist activities of GLP-1R, GIPR and GCGR.

[1048] Example 3. Pharmacokinetic properties of the compounds in mice

[1049] Male C57 mice were used as test animals, and the target compounds were injected intravenously once to detect the pharmacokinetic characteristics of the compounds in C57 mice (plasma).

[1050] 3.1 Test method:

[1051] Male C57 mice weighing approximately 25 g and aged 4-6 weeks were used. A peptide compound solution was prepared using 1× PBS solution and administered intravenously at a dose of 200 nmol / kg. Three animals were administered each compound. Blood was collected at 5 min, 15 min, 0.5 h, 1 h, 2 h, 4 h, 6 h, 24 h, 48 h, and 72 h after the infusion, 60 μL each, and transferred to a centrifuge tube containing EDTA-K2 anticoagulant. Whole blood samples were centrifuged at 4000 g for 5 min at 4°C to separate plasma, which was then stored frozen at -80°C.

[1052] Sample pretreatment method: Take 30 μL of plasma sample, add 120 μL of 0.1% formic acid methanol solution containing 1 ng / mL internal standard verapamil, vortex for 5 minutes, centrifuge at 10000 rpm for 10 minutes, take 70 μL of supernatant, add 70 μL of water, mix well, and analyze by LC-MS instrument.

[1053] LC-MS analysis method: (1) Chromatographic conditions: Mobile phases A and B were 0.1% formic acid in water and 0.1% formic acid in acetonitrile, respectively; gradient elution mode; flow rate 0.5 mL / min; injection volume 10 μL; chromatographic column: nanomicro Unisil C18aq (4.6 mm × 150 mm, 5 μm); column temperature: 40°C. (2) Mass spectrometry conditions: Mass spectrometry was performed using an electrospray ionization source (ESI), positive ion analysis mode, and multiple reaction monitoring (MRM) scanning.

[1054] SCIEX OS (Version 2.1.6) software was used for data processing to quantify blood drug concentration data, and PKSolver (Version 2.0) software was used to calculate pharmacokinetic parameters.

[1055] 3.2 Test results

[1056] Table 8. Comparison of pharmacokinetic parameters of compounds (200 nmol / kg) administered to mice

[1057] From the above results, it can be seen that the polypeptide molecules in the present disclosure have a longer half-life.

[1058] Example 4. Evaluation of the in vivo efficacy of compounds in a diet-induced obesity (DIO) mouse model

[1059] This example uses a DIO mouse model induced by a high-fat diet to evaluate the effects and improvements of subcutaneous injection of some of the compounds disclosed herein on obesity and diabetes-related indicators in DIO mice.

[1060] 4.1 Experimental Methods: Male C57BL / 6J mice (23-24 weeks old, purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd.) were induced to high-fat diet and fed a 60% high-fat diet (RD D12492) until they reached a body weight of 45-50 g to establish the DIO model. Following a week of acclimatization, the animals were randomly divided into groups based on body weight and administered subcutaneously via the neck with vehicle (model group), LY3437943, compound 15, compound 16, compound 17, and compound 18. Compounds were administered at a dose of 10 nmol / kg once daily for 24 days, with each group containing five DIO mice. According to the experimental design, each mouse was weighed and recorded daily at 3:00 PM or before dosing. The mean body weight for each group was calculated, and weight changes over time were plotted. Following the conclusion of the experiment, fat tissue and other internal organs were removed from the mice and weighed.

[1061] 4.2 Experimental Results: Figure 1 shows the weight change (%) of DIO mice at different times (days) after subcutaneous injection of the compounds. The weight change (%) refers to the percentage of weight loss after injection. For example, the weight change (%) on day 15 refers to the percentage of weight loss between day 1 and day 15 after injection. Compared to the vehicle-treated group, LY3437943 and compounds 15, 16, 17, and 18 of the present disclosure all significantly reduced the weight of DIO mice. At the endpoint of the experiment, the weight loss in the LY3437943 group was 30.4%, the weight loss in the compound 15 group was 50.2%, the weight loss in the compound 16 group was 36.6%, the weight loss in the compound 17 group was 30.7%, and the weight loss in the compound 18 group was 52.1%. Compound 17 significantly reduced the weight of DIO mice from day 5 to day 15 compared to the LY3437943 group.

[1062] The changes in body weight (g) over time in DIO mice after subcutaneous injection of the compounds are shown in Figure 2 . LY3437943 and compounds 15, 16, 17, and 18 can significantly reduce the body weight of DIO mice, and the final body weight of mice injected with compounds 16 and 17 can be maintained at a level above 80% of the body weight of mice on a normal diet (Chow), indicating good safety.

[1063] Example 5. Evaluation of the in vivo efficacy of compounds in a diet-induced obesity (DIO) rat model

[1064] 5.1. Experimental Purpose

[1065] In this study, a DIO rat model was established using a 45% high-fat diet (HFD) to evaluate the effects of compounds on obesity-related indicators in DIO rats.

[1066] 5.2 Experimental methods

[1067] After one week of animal adaptation, all rats were randomly divided into two groups, namely, a normal group and a model group. Then, the rats in the model group were fed 45% HFD (Medicine: MD12032), and the rats in the normal group were fed normal food. The body weight of the rats was measured once a week to monitor the modeling status.

[1068] DIO rats fed a high-fat diet for 37 weeks were weighed. Seventy-five DIO rats (approximately 1100 g) and eight rats fed a normal chow diet (approximately 800 g) were selected and housed individually in individual cages. Each cage was provided with approximately 100 g of feed, which was changed every 48 hours. A sham dose pilot study was then initiated. Subcutaneous acupuncture was performed in the neck at 4:00 PM daily for nine days. Body weight was measured before each acupuncture session, and the effects of the sham dose on body weight were observed. A graph of body weight changes over time was plotted, and the formal dosing experiment began after body weight stabilized.

[1069] After sham dose pre-test screening, 6 Chow diet rats (weighing approximately 800g) and 30 HFD rats (weighing approximately 1100g) were selected for subsequent dosing experiments. The 6 Chow diet rats served as the control group (Naive group), and the remaining HFD rats were randomly divided into 6 groups according to body weight, including the model group (Model group), LY3437943 group, 0120 low-dose group, 0120 high-dose group, 0125 low-dose group, and 0125 high-dose group, with 5 rats in each group. All rats were housed in single cages during the experiment. The compound was dissolved in PBS solution with a pH of 7.4. On the day of grouping (Day 1), the rats in each group were given drugs by subcutaneous injection in the neck according to their body weight, and the drug was administered once a day (QD). See Table 9 for details. Starting on Day 15 (D15), the LY3437943 dose was adjusted from 1 nmol / kg to 10 nmol / kg, and the doses for the 0120 and 0125 low-dose groups were adjusted from 0.3 nmol / kg to 3 nmol / kg. Body weight was measured daily at 3:00 PM or before dosing, and a graph of body weight changes over time was plotted. Food intake: From Days 1 to 7, the dose was measured daily at 3:00 PM or before dosing; from Days 8 to 40, the dose was measured every three days at 3:00 PM or before dosing. A graph of daily food intake / cumulative food intake over time was plotted.

[1070] Table 9. Experimental group and medication information

[1071] 5.3 Test results

[1072] Figures 3 and 4 show the results of rat body weight. Before dose adjustment, the model group showed a significant increase in body weight compared to the control group (Naive group). Compared to the model group, the rats in the compound 16 (1 nmol / kg) and compound 17 (1 nmol / kg) groups showed a trend of decreasing body weight. After the LY3437943 dose was adjusted from 1 nmol / kg to 10 nmol / kg, the compound 16 dose from 0.3 nmol / kg to 3 nmol / kg, and the compound 17 dose from 0.3 nmol / kg to 3 nmol / kg, the body weight of the rats in each group began to decrease rapidly. The body weight of the rats in the LY3437943 (10 nmol / kg) group decreased by 29.4% at the end of the study; the rats in the compound 16 (3 nmol / kg) group decreased by 30.2%; and the rats in the compound 17 (3 nmol / kg) group decreased by 33.2% at the end of the study.

[1073] As shown in Figures 5 and 6, before dose adjustment, the 24-h food intake and cumulative food intake of each drug-treated group were basically equivalent to those of the model group; after dose adjustment, compared with the model group, the 24-h food intake and cumulative food intake of rats in the LY3437943 (10 nmol / kg) group, the compound 16 (3 nmol / kg) group, and the compound 17 (3 nmol / kg) group were significantly reduced. At the same time, the 24-h food intake gradually decreased with the extension of the drug administration time; during the entire drug administration period (before and after dose adjustment), the cumulative food intake of each drug-treated group was 273.8±15.0 g in the LY3437943 (10 nmol / kg) group, with a body weight loss of 29.4%; the cumulative food intake of the compound 16 (3 nmol / kg) group was 258.8±23.5 g, with a body weight loss of 30.2%; the cumulative food intake of the compound 17 (3 nmol / kg) group was 224.5±25.8 g, with a body weight loss of 33.2%.

Claims

1. A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof: R1-X1-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-X 10 -Ser-X 12 -X 13 -X 14 -Glu-X 16 -X 17 -X 18 -X 19 -X 20 -X 21 -Phe-Val-Glu-Trp-Leu-X 27 -X 28 -X 29 -ZX 40 -R2 (SEQ ID NO: 145) (I); in, R1 is hydrogen, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu, R2 is -NH2 or -OH; X1, X2, X3, X 10 , X 12 , X 13 , X 14 , X 16 , X 17 , X 18 , X 19 , X 20 , X 21 , X 27 , X 28 , X 29 , Z, X 40 Each is independently selected from any natural amino acid, non-natural amino acid or a peptide segment consisting of natural amino acids and / or non-natural amino acids.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R1 is hydrogen, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu, R2 is -NH2 or -OH; X1 is an amino acid residue selected from Tyr or His; X2 is the amino acid residue of Aib; X3 is an amino acid residue selected from Gln or His; X 10 an amino acid residue selected from Leu or Tyr; X 12 an amino acid residue selected from Lys, alpha-methyl-Lys or Ile; X 13 an amino acid residue selected from Aib, Ile, Leu, Tyr, alpha-methyl-Tyr or alpha-methyl-Leu; X 14 an amino acid residue selected from Leu or alpha-methyl-Leu; X 16 An amino acid residue selected from Glu, Lys or Y1; X 17 An amino acid residue selected from Glu, Arg, homoarginine (homoArg), Ile, Lys, Gln, alpha-methyl-Lys or Y1; X 18 an amino acid residue selected from Ala or Aib; X 19 an amino acid residue selected from Ala or Gln; X 20 An amino acid residue selected from Gln, Aib, isovaline, alpha-methyl-Ser, 1-aminocyclopropane-1-carboxylic acid (Ac3c) or 1-aminocyclobutane-1-carboxylic acid (Ac4c); X 21 An amino acid residue selected from Glu or Y1; X 27 an amino acid residue selected from Ile or Leu; X 28 an amino acid residue selected from Ala or Glu; X 29 An amino acid residue selected from Gly or D-Glu; X 40 An amino acid residue selected from Lys, Y1 or absent; Z is selected from Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 146), Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 147), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO: 148) or Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO: 149); Y1 is a Lys, Orn, Dap, Dab or Cys residue having a side chain linked to a substituent.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, which is a compound represented by the following formula (Ib) or a pharmaceutically acceptable salt thereof: R1-X1-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-X 10 -Ser-X 12 -X 13 -X 14 -Glu-Y1-X 17 -X 18 -X 19 -X20-Glu-Phe-Val-Glu-Trp-Leu-X 27 -X 28 -X 29 -Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-R2 (SEQ ID NO: 150) (Ib); in, R1 is hydrogen, R2 is -NH2 or -OH; X1 is an amino acid residue selected from Tyr or His; X2 is the amino acid residue of Aib; X3 is an amino acid residue selected from Gln or His; X 10 an amino acid residue selected from Leu or Tyr; X 12 an amino acid residue selected from Lys, alpha-methyl-Lys or Ile; X 13 an amino acid residue selected from Aib, Ile, Leu, Tyr, alpha-methyl-Tyr or alpha-methyl-Leu; X 14 an amino acid residue selected from Leu or alpha-methyl-Leu; X 17 An amino acid residue selected from Ile, Lys, Gln or alpha-methyl-Lys; X 18 an amino acid residue selected from Ala or Aib; X 19 an amino acid residue selected from Ala or Gln; X 20 an amino acid residue selected from the group consisting of Gln, Aib, isovaline, alpha-methyl-Ser, 1-aminocyclopropane-1-carboxylic acid or 1-aminocyclobutane-1-carboxylic acid; X 27 an amino acid residue selected from Ile or Leu; X 28 an amino acid residue selected from Ala or Glu; X 29 An amino acid residue selected from Gly or D-Glu; Y1 is a Lys residue whose side chain is linked to a substituent.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein: X1, X2 and X3 are selected from any of the following: X1 is His, X2 is Aib, and X3 is His; X1 is Tyr, X2 is Aib, and X3 is Gln; or X1 is His, X2 is Aib, and X3 is Gln; Preferably, X1 is His, X2 is Aib, and X3 is His; or X1 is His, X2 is Aib, and X3 is Gln; More preferably, X1 is His, X2 is Aib, and X3 is His.

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein X 17 is an amino acid residue of Ile, Lys, Gln or alpha-methyl-Lys; Preferably, X 17 , X 18 , X 19 and X 20 Select from any of the following: X 17 Lys, X 18 Ala, X 19 Ala, and X 20 for Gln; X 17 Lys, X 18 Ala, X 19 Ala, and X 20 is alpha-methyl-Ser; X 17 Lys, X 18 Ala, X 19 Ala, and X 20 isovaline; X 17 Lys, X 18 Ala, X 19 for Ala, and X 20 is 1-aminocyclopropane-1-carboxylic acid; X 17 Lys, X 18 Ala, X 19 for Ala, and X 20 is 1-aminocyclobutane-1-carboxylic acid; X 17 Lys, X 18 Ala, X 19 for Ala, and X 20 for Aib; X 17 Lys, X 18 Aib, X 19 for Ala, and X 20 for Gln; X 17 Lys, X 18 Ala, X 19 is Gln, and X 20 for Gln; X 17 Gln, X 18 Ala, X 19 Ala, and X 20 for Gln; X 17 Gln, X 18 Ala, X 19 Ala, and X 20 isovaline; X 17 Gln, X 18 Ala, X 19 Ala, and X 20 is 1-aminocyclopropane-1-carboxylic acid; X 17 Gln, X 18 Ala, X 19 Ala, and X 20 is 1-aminocyclobutane-1-carboxylic acid; X 17 alpha-methyl-Lys, X 18 Ala, X 19 Ala, and X 20 is Gln; or X 17 Ile, X 18 Ala, X 19 for Ala, and X 20 For Gln.

6. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein: X 12 , X 13 and X 14 Select from any of the following: X 12 Ile, X 13 Leu, and X 14 for Leu; X 12 Ile, X 13 is alpha-methyl-Leu, and X 14 for Leu; X 12 Lys, X 13 is alpha-methyl-Tyr, and X 14 for Leu; X 12 Lys, X 13 for Aib, and X 14 for Leu; X 12 Lys, X 13 Tyr, and X 14 is alpha-methyl-Leu; X 12 Lys, X 13 Tyr, and X 14 for Leu; X 12 alpha-methyl-Lys, X 13 Tyr, and X 14 for Leu; X 12 alpha-methyl-Lys, X 13 Leu, and X 14 is Leu; or X 12 alpha-methyl-Lys, X 13 for Ile, and X 14 For Leu.

7. The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, which is a compound represented by the following formula (Ib) or a pharmaceutically acceptable salt thereof: R1-X1-X2-X3-Gly-Thr-Phe-Thr-Ser-Asp-X 10 -Ser-X 12 -X 13 -X 14 -Glu-Y1-X 17 -X 18 -X 19 -X20-Glu-Phe-Val-Glu-Trp-Leu-X 27 -X 28 -X 29 -Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-R2 (SEQ ID NO: 150) (Ib); in, R1 is hydrogen, R2 is -NH2 or -OH; X1 is His; X2 is Aib; X3 is His or Gln; X 10 an amino acid residue selected from Leu or Tyr; X 12 an amino acid residue selected from Lys, alpha-methyl-Lys or Ile; X 13 an amino acid residue selected from Aib, Ile, Leu, Tyr, alpha-methyl-Tyr or alpha-methyl-Leu; X 14 an amino acid residue selected from Leu or alpha-methyl-Leu; X 17 An amino acid residue selected from Ile, Lys, Gln or alpha-methyl-Lys; X 18 an amino acid residue selected from Ala or Aib; X 19 an amino acid residue selected from Ala or Gln; X 20 an amino acid residue selected from the group consisting of Gln, Aib, isovaline, alpha-methyl-Ser, 1-aminocyclopropane-1-carboxylic acid or 1-aminocyclobutane-1-carboxylic acid; X 27 an amino acid residue selected from Ile or Leu; X 28 an amino acid residue selected from Ala or Glu; X 29 An amino acid residue selected from Gly or D-Glu; Y1 is a Lys residue with a side chain attached to the substituent; Preferably, X 17 , X 18 , X 19 and X 20 Select from any of the following: X 17 Lys, X 18 Ala, X 19 Ala, and X 20 for Gln; X 17 Lys, X 18 Ala, X 19 for Ala, and X 20 is alpha-methyl-Ser; X 17 Lys, X 18 Ala, X 19 Ala, and X 20 isovaline; X 17 Lys, X 18 Ala, X 19 for Ala, and X 20 is 1-aminocyclopropane-1-carboxylic acid; X 17 Lys, X 18 Ala, X 19 for Ala, and X 20 is 1-aminocyclobutane-1-carboxylic acid; X 17 Lys, X 18 Ala, X 19 Ala, and X 20 for Aib; X 17 Lys, X 18 Aib, X 19 for Ala, and X 20 for Gln; X 17 Lys, X 18 Ala, X 19 is Gln, and X 20 for Gln; X 17 Gln, X 18 Ala, X 19 Ala, and X 20 for Gln; X 17 Gln, X 18 Ala, X 19 Ala, and X 20 isovaline; X 17 Gln, X 18 Ala, X 19 Ala, and X 20 is 1-aminocyclopropane-1-carboxylic acid; X 17 Gln, X 18 Ala, X 19 for Ala, and X 20 is 1-aminocyclobutane-1-carboxylic acid; X 17 alpha-methyl-Lys, X 18 Ala, X 19 for Ala, and X 20 is Gln; or X 17 Ile, X 18 Ala, X 19 for Ala, and X 20 For Gln: Preferably, X 12 , X 13 and X 14 Select from any of the following: X 12 Ile, X 13 Leu, and X 14 for Leu; X 12 Ile, X 13 is alpha-methyl-Leu, and X 14 for Leu; X 12 Lys, X 13 is alpha-methyl-Tyr, and X 14 for Leu; X 12 Lys, X 13 for Aib, and X 14 for Leu; X 12 Lys, X 13 Tyr, and X 14 is alpha-methyl-Leu; X 12 Lys, X 13 Tyr, and X 14 for Leu; X 12 alpha-methyl-Lys, X 13 Tyr, and X 14 for Leu; X 12 alpha-methyl-Lys, X 13 Leu, and X 14 is Leu; or X 12 alpha-methyl-Lys, X 13 for Ile, and X 14 For Leu.

8. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein: X1 to X 29 Select from any of the following groups: (i) X1, X2, and X3 are selected from any of the following: X1 is His, X2 is Aib, and X3 is His; X1 is His, X2 is Aib, and X3 is Gln; or X1 is Tyr, X2 is Aib, and X3 is Gln; X 10 an amino acid residue selected from Leu or Tyr; X 12 an amino acid residue selected from Lys, alpha-methyl-Lys or Ile; X 13 an amino acid residue selected from Aib, Ile, Leu, Tyr, alpha-methyl-Tyr or alpha-methyl-Leu; X 14 an amino acid residue selected from Leu or alpha-methyl-Leu; X 16 is Y1; X 17 an amino acid residue selected from Lys; X 18 an amino acid residue selected from Ala or Aib; X 19 an amino acid residue selected from Ala or Gln; X 20 is selected from Gln, Aib, isovaline, alpha-methyl-Ser, 1-aminocyclopropane-1-carboxylic acid or 1- amino acid residue of aminocyclobutane-1-carboxylic acid; X 27 an amino acid residue selected from Ile or Leu; X 28 an amino acid residue selected from Ala or Glu; and X 29 An amino acid residue selected from Gly or D-Glu; (ii) X1, X2, and X3 are selected from any of the following: X1 is His, X2 is Aib, and X3 is His; X1 is His, X2 is Aib, and X3 is Gln; or X1 is Tyr, X2 is Aib, and X3 is Gln; X 10 an amino acid residue selected from Leu or Tyr; X 12 an amino acid residue selected from Lys, alpha-methyl-Lys or Ile; X 13 an amino acid residue selected from Aib, Ile, Leu, Tyr, alpha-methyl-Tyr or alpha-methyl-Leu; X 14 an amino acid residue selected from Leu or alpha-methyl-Leu; X 16 is Y1; X 17 an amino acid residue selected from Lys; X 18 an amino acid residue selected from Ala or Aib; X 19 an amino acid residue selected from Ala or Gln; X 20 an amino acid residue selected from Gln; X 27 an amino acid residue selected from Ile or Leu; X 28 an amino acid residue selected from Ala or Glu; and X 29 An amino acid residue selected from Gly or D-Glu; (iii) X1, X2, and X3 are selected from any of the following: X1 is His, X2 is Aib, and X3 is His; X1 is His, X2 is Aib, and X3 is Gln; or X1 is Tyr, X2 is Aib, and X3 is Gln; X 10 an amino acid residue selected from Leu or Tyr; X 12 an amino acid residue selected from alpha-methyl-Lys or Ile; X 13 an amino acid residue selected from Ile, Leu or alpha-methyl-Leu; X 14 an amino acid residue selected from Leu or alpha-methyl-Leu; X 16 It is Y1, X 17 an amino acid residue selected from Lys; X 18 an amino acid residue selected from Ala; X 19 an amino acid residue selected from Ala; X 20 an amino acid residue selected from Aib, isovaline, alpha-methyl-Ser, 1-aminocyclopropane-1-carboxylic acid or 1-aminocyclobutane-1-carboxylic acid; X 27 an amino acid residue selected from Ile or Leu; X 28 an amino acid residue selected from Ala or Glu; and X 29 An amino acid residue selected from Gly or D-Glu; (iv) X1 is His; X2 is Aib; X3 is His; X 10 an amino acid residue selected from Tyr; X 12 an amino acid residue selected from Lys or alpha-methyl-Lys; X 13 an amino acid residue selected from Tyr; X 14 an amino acid residue selected from Leu or alpha-methyl-Leu; X 16 is Y1; X 17 an amino acid residue selected from Lys; X 18 an amino acid residue selected from Ala or Aib; X 19 an amino acid residue selected from Ala or Gln; X 20 an amino acid residue selected from Gln; X 27 an amino acid residue selected from Ile or Leu; X 28 an amino acid residue selected from Ala or Glu; and X 29 an amino acid residue selected from Gly; (v) X1 is His; X2 is Aib; X3 is His or Gln; X 10 an amino acid residue selected from Leu or Tyr; X 12 an amino acid residue selected from Ile; X 13 an amino acid residue selected from alpha-methyl-Leu; X 14 an amino acid residue selected from Leu; X 16 is Y1; X 17 an amino acid residue selected from Lys; X 18 an amino acid residue selected from Ala; X 19 an amino acid residue selected from Ala; X 20 An amino acid residue selected from Gln, Aib, 1-aminocyclobutane-1-carboxylic acid or isovaline; X 27 an amino acid residue selected from Leu; X 28 an amino acid residue selected from Ala; and X 29 An amino acid residue selected from Gly or D-Glu; (vi) X1, X2, and X3 are selected from any of the following: X1 is His, X2 is Aib, and X3 is His; X1 is His, X2 is Aib, and X3 is Gln; or X1 is Tyr, X2 is Aib, and X3 is Gln; X 10 an amino acid residue selected from Leu or Tyr; X 12 an amino acid residue selected from alpha-methyl-Lys or Ile; X 13 an amino acid residue selected from Leu; X 14 an amino acid residue selected from Leu; X 16 is Y1; X 17 an amino acid residue selected from Ile, Lys or Gln; X 18 an amino acid residue selected from Ala; X 19 an amino acid residue selected from Ala; X 20 an amino acid residue selected from the group consisting of Gln, Aib, isovaline, alpha-methyl-Ser, 1-aminocyclopropane-1-carboxylic acid or 1-aminocyclobutane-1-carboxylic acid; X 27 an amino acid residue selected from Ile or Leu; X 28 an amino acid residue selected from Ala or Glu; and X 29 An amino acid residue selected from Gly or D-Glu; (vii) X1 is His; X2 is Aib; X3 is His; X 10 an amino acid residue selected from Tyr; X 12 an amino acid residue selected from Lys; X 13 an amino acid residue selected from alpha-methyl-Tyr or Aib; X 14 an amino acid residue selected from Leu; X 16 is Y1; X 17 an amino acid residue selected from Lys; X 18 an amino acid residue selected from Ala; X 19 an amino acid residue selected from Ala; X 20 an amino acid residue selected from Gln; X 27 an amino acid residue selected from Leu; X 28 an amino acid residue selected from Ala; and X 29 an amino acid residue selected from Gly; (viii) X1, X2, and X3 are selected from any of the following: X1 is His, X2 is Aib, and X3 is His; or X1 is Tyr, X2 is Aib, and X3 is Gln; X 10 an amino acid residue selected from Leu or Tyr; X 12 an amino acid residue selected from alpha-methyl-Lys; X 13 an amino acid residue selected from Ile; X 14 an amino acid residue selected from Leu; X 16 is Y1; X 17 an amino acid residue selected from Lys; X 18 an amino acid residue selected from Ala; X 19 an amino acid residue selected from Ala; X 20 an amino acid residue selected from Gln or isovaline; X 27 an amino acid residue selected from Leu or Ile; X 28 an amino acid residue selected from Ala or Glu; and X 29 an amino acid residue selected from Gly; (ix) X1 is His; X2 is Aib; X3 is His; X 10 an amino acid residue selected from Leu or Tyr; X 12 an amino acid residue selected from Lys, alpha-methyl-Lys or Ile; X 13 an amino acid residue selected from Ile, Leu, or Tyr; X 14 an amino acid residue selected from Leu; X 16 is Y1; X 17 an amino acid residue selected from Ile, Gln or alpha-methyl-Lys; X 18 an amino acid residue selected from Ala; X 19 an amino acid residue selected from Ala; X 20 An amino acid residue selected from Gln, isovaline, 1-aminocyclopropane-1-carboxylic acid or 1-aminocyclobutane-1-carboxylic acid; X 27 an amino acid residue selected from Leu; X 28 an amino acid residue selected from Ala; and X 29 An amino acid residue selected from Gly or D-Glu; (x) X1 is His; X2 is Aib; X3 is His; X 10 an amino acid residue selected from Leu or Tyr; X 12 an amino acid residue selected from alpha-methyl-Lys or Ile; X 13 an amino acid residue selected from Ile or Leu; X 14 an amino acid residue selected from Leu; X 16 is Y1; X 17 an amino acid residue selected from Gln; X 18 an amino acid residue selected from Ala; X 19 an amino acid residue selected from Ala; X 20 An amino acid residue selected from Gln, isovaline, 1-aminocyclopropane-1-carboxylic acid or 1-aminocyclobutane-1-carboxylic acid; X 27 an amino acid residue selected from Leu; X 28 an amino acid residue selected from Ala; and X 29 An amino acid residue selected from Gly or D-Glu; (xi) X1 is His; X2 is Aib; X3 is His; X 10 an amino acid residue selected from Tyr; X 12 an amino acid residue selected from Lys or alpha-methyl-Lys; X 13 an amino acid residue selected from Leu or Tyr; X 14 an amino acid residue selected from Leu; X 16 It is Y1, X 17 an amino acid residue selected from Ile or alpha-methyl-Lys; X 18 an amino acid residue selected from Ala; X 19 an amino acid residue selected from Ala; X 20 an amino acid residue selected from Gln; X 27 an amino acid residue selected from Leu; X 28 an amino acid residue selected from Ala; and X 29 An amino acid residue selected from Gly.

9. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, which comprises or is any of the following polypeptide sequences: H-Aib-HGTFTSDYS-αK-YLEEKAAQEFVEWLLAGGPSSGAPPPS-NH2 (SEQ ID NO: 1); H-Aib-HGTFTSDYS-αK-YLEKKAAQEFVEWLLAGGPSSGAPPPS-NH2 (SEQ ID NO: 2); H-Aib-HGTFTSDYSK-αY-LEKKAAQEFVEWLLAGGPSSGAPPPS-NH2 (SEQ ID NO: 3); H-Aib-HGTFTSDYSK-Aib-LEKKAAQEFVEWLLAGGPSSGAPPPS-NH2 (SEQ ID NO: 4); H-Aib-HGTFTSDYSKY-αL-EKKAAQEFVEWLLAGGPSSGAPPPS-NH2 (SEQ ID NO: 5); H-Aib-HGTFTSDYSKYLEK-αK-AAQEFVEWLLAGGPSSGAPPPS-NH2 (SEQ ID NO: 6); H-Aib-HGTFTSDYSKYLEKK-Aib-AQEFVEWLLAGPGPSSGAPPPS-NH2 (SEQ ID NO: 7); H-Aib-HGTFTSDYS-αK-YLEKKAAQEFVEWLIAGGPSSGAPPPS-NH2 (SEQ ID NO: 8); H-Aib-HGTFTSDYS-αK-LLEKKAAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:9); H-Aib-HGTFTSDYS-αK-YLEKKAQQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:10); Y-Aib-QGTFTSDYS-αK-LLEKKAAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:11); H-Aib-HGTFTSDYS-αK-YLEKKAAQEFVEWLIEGGPSSGAPPPS-NH2(SEQ ID NO:12); H-Aib-HGTFTSDYS-αK-LLEKQAAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:13); H-Aib-HGTFTSDYS-αK-LLEKIAAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:14); H-Aib-HGTFTSDYS-αK-ILEKKAAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:15); H-Aib-HGTFTSDYSILLEKKAAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:16); H-Aib-HGTFTSDYSI-αL-LEKKAAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:17); H-Aib-HGTFTSDYS-αK-LLEKKAA-αS-EFVEWLIEGGPSSGAPPPS-NH2(SEQ ID NO:18); Y-Aib-QGTFTSDYS-αK-LLEKKAA-Iva-EFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:19); H-Aib-HGTFTSDYS-αK-LLEKQAA-Iva-EFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:20); Y-Aib-QGTFTSDYS-αK-ILEKKAA-Iva-EFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:21); H-Aib-HGTFTSDYS-αK-ILEKQAA-Iva-EFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:22); H-Aib-HGTFTSDYS-αK-LLEKKAA-Iva-EFVEWLIEGGPSSGAPPPS-NH2(SEQ ID NO:23); <h2 style=";text-align:left;direction:ltr">H-Aib-HGTFTSDYS-αK-ILEKKAA-Iva-EFVEWLIEGGPSSGAPPPS-NH2(SEQ ID NO:24); <h2 style=";text-align:left;direction:ltr"> H-Aib-HGTFTSDLS-αK-LLEKKAA-Iva-EFVEWLIEGGPSSGAPPPS-NH2(SEQ ID NO:25); <h2 style=";text-align:left;direction:ltr"> H-Aib-HGTFTSDLS-αK-ILEKKAA-Iva-EFVEWLIEGGPSSGAPPPS-NH2(SEQ ID NO:26); <h2 style=";text-align:left;direction:ltr"> H-Aib-HGTFTSDYSILLEKKAA-Iva-EFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:27); <h2 style=";text-align:left;direction:ltr"> H-Aib-HGTFTSDLSILLEKKAA-Iva-EFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:28); <h2 style=";text-align:left;direction:ltr"> H-Aib-HGTFTSDYSI-αL-LEKKAA-Iva-EFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:29); <h2 style=";text-align:left;direction:ltr"> H-Aib-HGTFTSDLSI-αL-LEKKAA-Iva-EFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:30); <h2 style=";text-align:left;direction:ltr"> H-Aib-HGTFTSDYSI-αL-LEKKAAQEFVEWLLAeGPSSGAPPPS-NH2(SEQ ID NO:31); <h2 style=";text-align:left;direction:ltr"> H-Aib-HGTFTSDLSI-αL-LEKKAA-Ac4c-EFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:32); <h2 style=";text-align:left;direction:ltr"> H-Aib-HGTFTSDLSI-αL-LEKKAAQEFVEWLLAeGPSSGAPPPS-NH2(SEQ ID NO:33); <h2 style=";text-align:left;direction:ltr"> H-Aib-HGTFTSDLSI-αL-LEKKAAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:34); <h2 style=";text-align:left;direction:ltr"> H-Aib-HGTFTSDLSILLEKKAAQEFVEWLLAeGPSSGAPPPS-NH2(SEQ ID NO:35); <h2 style=";text-align:left;direction:ltr"> H-Aib-HGTFTSDLSILLEKQAA-Ac4c-EFVEWLLAeGPSSGAPPPS-NH2(SEQ ID NO:36); <h2 style=";text-align:left;direction:ltr"> H-Aib-HGTFTSDLSILLEKKAA-Ac3c-EFVEWLLAeGPSSGAPPPS-NH2(SEQ ID NO:37); H-Aib-HGTFTSDLSILLEKKAA-Ac4c-EFVEWLLAeGPSSGAPPPS-NH2 (SEQ ID NO: 38); H-Aib-HGTFTSDLSILLEKQAA-Ac3c-EFVEWLLAeGPSSGAPPPS-NH2 (SEQ ID NO: 39); H-Aib-HGTFTSDYSILLEKQAA-Ac3c-EFVEWLLAeGPSSGAPPPS-NH2 (SEQ ID NO: 40); H-Aib-HGTFTSDYSILLEKQAA-Ac4c-EFVEWLLAeGPSSGAPPPS-NH2 (SEQ ID NO: 41); H-Aib-HGTFTSDYSILLEKKAAQEFVEWLLAeGPSSGAPPPS-NH2 (SEQ ID NO: 42); H-Aib-HGTFTSDYSILLEKQAAQEFVEWLLAGGPSSGAPPPS-NH2 (SEQ ID NO: 43); H-Aib-HGTFTSDYSILLEKQAAQEFVEWLLAeGPSSGAPPPS-NH2 (SEQ ID NO: 44); H-Aib-QGTFTSDYSILLEKKAAQEFVEWLLAGGPSSGAPPPS-NH2 (SEQ ID NO: 45); H-Aib-QGTFTSDYSI-αL-LEKKAAQEFVEWLLAGGPSSGAPPPS-NH2 (SEQ ID NO: 46); H-Aib-QGTFTSDYSILLEKKAA-Aib-EFVEWLLAGGPSGAPPPS-NH2 (SEQ ID NO: 47); H-Aib-QGTFTSDYSI-αL-LEKKAA-Aib-EFVEWLLAGPGPSSGAPPPS-NH2; (SEQ ID NO: 48); αK is alpha-methyl-Lys, αY is alpha-methyl-Tyr, αL is alpha-methyl-Leu, Iva is isovaline, e is D-Glu, Ac3c is 1-aminocyclopropane-1-carboxylic acid, and Ac4c is 1-aminocyclobutane-1-carboxylic acid.

10. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, comprising or being a structure shown in any one of the following: H-Aib-HGTFTSDYS-αK-YLEEY1AAQEFVEWLLAGGPSSGAPPPS-NH2 (SEQ ID NO: 49); H-Aib-HGTFTSDYS-αK-YLEY1KAAQEFVEWLLAGGPSSGAPPPS-NH2 (SEQ ID NO: 50); H-Aib-HGTFTSDYSK-αY-LEY1KAAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:51); H-Aib-HGTFTSDYSK-Aib-LEY1KAAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:52); H-Aib-HGTFTSDYSKY-αL-EY1KAAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:53); H-Aib-HGTFTSDYSKYLEY1-αK-AAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:54); H-Aib-HGTFTSDYSKYLEY1K-Aib-AQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:55); H-Aib-HGTFTSDYS-αK-YLEY1KAAQEFVEWLIAGGPSSGAPPPS-NH2(SEQ ID NO:56); H-Aib-HGTFTSDYS-αK-LLEY1KAAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:57); H-Aib-HGTFTSDYS-αK-YLEY1KAQQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:58); Y-Aib-QGTFTSDYS-αK-LLEY1KAAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:59); H-Aib-HGTFTSDYS-αK-YLEY1KAAQEFVEWLIEGGPSSGAPPPS-NH2(SEQ ID NO:60); H-Aib-HGTFTSDYS-αK-LLEY1QAAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:61); H-Aib-HGTFTSDYS-αK-LLEY1IAAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:62); H-Aib-HGTFTSDYS-αK-ILEY1KAAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:63); H-Aib-HGTFTSDYSILLEY1KAAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:64); H-Aib-HGTFTSDYSI-αL-LEY1KAAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:65); H-Aib-HGTFTSDYS-αK-LLEY1KAA-αS-EFVEWLIEGGPSSGAPPPS-NH2(SEQ ID NO:66); Y-Aib-QGTFTSDYS-αK-LLEY1KAA-Iva-EFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:67); H-Aib-HGTFTSDYS-αK-LLEY1QAA-Iva-EFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:68); Y-Aib-QGTFTSDYS-αK-ILEY1KAA-Iva-EFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:69); H-Aib-HGTFTSDYS-αK-ILEY1QAA-Iva-EFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:70); H-Aib-HGTFTSDYS-αK-LLEY1KAA-Iva-EFVEWLIEGGPSSGAPPPS-NH2(SEQ ID NO:71); H-Aib-HGTFTSDYS-αK-ILEY1KAA-Iva-EFVEWLIEGGPSSGAPPPS-NH2(SEQ ID NO:72); H-Aib-HGTFTSDLS-αK-LLEY1KAA-Iva-EFVEWLIEGGPSSGAPPPS-NH2(SEQ ID NO:73); H-Aib-HGTFTSDLS-αK-ILEY1KAA-Iva-EFVEWLIEGGPSSGAPPPS-NH2(SEQ ID NO:74); H-Aib-HGTFTSDYSILLEY1KAA-Iva-EFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:75); H-Aib-HGTFTSDLSILLEY1KAA-Iva-EFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:76); H-Aib-HGTFTSDYSI-αL-LEY1KAA-Iva-EFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:77); H-Aib-HGTFTSDLSI-αL-LEY1KAA-Iva-EFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:78); H-Aib-HGTFTSDYSI-αL-LEY1KAAQEFVEWLLAeGPSSGAPPPS-NH2(SEQ ID NO:79); H-Aib-HGTFTSDLSI-αL-LEY1KAA-Ac4c-EFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:80); H-Aib-HGTFTSDLSI-αL-LEY1KAAQEFVEWLLAeGPSSGAPPPS-NH2(SEQ ID NO:81); H-Aib-HGTFTSDLSI-αL-LEY1KAAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:82); H-Aib-HGTFTSDLSILLEY1KAAQEFVEWLLAeGPSSGAPPPS-NH2(SEQ ID NO:83); H-Aib-HGTFTSDLSILLEY1QAA-Ac4c-EFVEWLLAeGPSSGAPPPS-NH2(SEQ ID NO:84); H-Aib-HGTFTSDLSILLEY1KAA-Ac3c-EFVEWLLAeGPSSGAPPPS-NH2(SEQ ID NO:85); H-Aib-HGTFTSDLSILLEY1KAA-Ac4c-EFVEWLLAeGPSSGAPPPS-NH2(SEQ ID NO:86); H-Aib-HGTFTSDLSILLEY1QAA-Ac3c-EFVEWLLAeGPSSGAPPPS-NH2(SEQ ID NO:87); H-Aib-HGTFTSDYSILLEY1QAA-Ac3c-EFVEWLLAeGPSSGAPPPS-NH2(SEQ ID NO:88); H-Aib-HGTFTSDYSILLEY1QAA-Ac4c-EFVEWLLAeGPSSGAPPPS-NH2(SEQ ID NO:89); H-Aib-HGTFTSDYSILLEY1KAAQEFVEWLLAeGPSSGAPPPS-NH2(SEQ ID NO:90); H-Aib-HGTFTSDYSILLEY1QAAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:91); H-Aib-HGTFTSDYSILLEY1QAAQEFVEWLLAeGPSSGAPPPS-NH2(SEQ ID NO:92); H-Aib-QGTFTSDYSILLEY1KAAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:93); H-Aib-QGTFTSDYSI-αL-LEY1KAAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:94); and H-Aib-QGTFTSDYSI-αL-LEY1KAA-Aib-EFVEWLLAGPSSGAPPPS-NH2 (SEQ ID NO: 96); in, Y1 is a Lys, Orn, Dap, Dab or Cys residue whose side chain is linked to a substituent, preferably a Lys residue whose side chain is linked to a substituent; αK is alpha-methyl-Lys, αY is alpha-methyl-Tyr, αL is alpha-methyl-Leu, Iva is isovaline, e is D-Glu, Aib is α-aminoisobutyric acid, Ac3c is 1-aminocyclopropane-1-carboxylic acid, and Ac4c is 1-aminocyclobutane-1-carboxylic acid.

11. The compound according to any one of claims 2 to 10 or a pharmaceutically acceptable salt thereof, wherein: Y1 is a Lys, Orn, Dap, Dab or Cys residue with a side chain connected to a substituent, the structure of which is shown below: -Z1-Z2, wherein Z1 comprises 0-10 amino acid residues independently selected from Gly, Glu, γGlu, OEG, and Z2 is selected from C 12-32 A fatty acid; wherein OEG is [2-(2-amino-ethoxy)-ethoxy]-acetyl; Preferably, Z1 comprises the structure shown below: -(OEG) a -(γGlu) b -; wherein a is any integer between 0 and 4, and b is any integer between 1 and 2; Z2 contains the following structure: -C(O)-(CH2) c -COOH, c is any integer between 10 and 30; Preferably, the substituent comprises the structure shown below: {[2-(2-Amino-ethoxy)-ethoxy]-acetyl} a -(γGlu) b -C(O)-(CH2) c -COOH; Wherein, a is any integer between 0 and 4, b is any integer between 1 and 2, and c is any integer between 10 and 30; Preferably, a is 1, 2 or 3, b is 1 or 2, and c is 16-20; More preferably, a is 2, b is 1 or 2, and c is 16, 18 or 20; More preferably, a is 2, b is 1 or 2, and c is 16 or 18.

12. The compound according to claim 2-11 or a pharmaceutically acceptable salt thereof, wherein: X 16 Selected from Y1; Y1 is a Lys residue with a side chain connected to a substituent, and the substituent is covalently connected to the ε-amino group of the Lys residue through an amide bond; the structure of the substituent is shown below: -Z1-Z2, wherein Z1 comprises 0-10 amino acid residues independently selected from Gly, Glu, γGlu, OEG, and Z2 is selected from C 12-32 A fatty acid; wherein OEG is [2-(2-amino-ethoxy)-ethoxy]-acetyl; Preferably, Z1 comprises the structure shown below: -(OEG) a -(γGlu) b ; Wherein, a is any integer between 0 and 4, and b is any integer between 1 and 2; Z2 contains the following structure: -CO-(CH2) c -COOH, c is any integer between 10 and 30; Preferably, the substituent comprises the structure shown below: {[2-(2-Amino-ethoxy)-ethoxy]-acetyl} a -(γGlu) b -CO-(CH2) c -COOH; Wherein, a is any integer between 0 and 4, b is any integer between 1 and 2, and c is any integer between 10 and 30; Preferably, a is 1, 2 or 3, b is 1 or 2, and c is any integer from 16 to 20; More preferably, a is 2, b is 1 or 2, and c is 16, 18 or 20; More preferably, a is 2, b is 1 or 2, and c is 16 or 18.

13. The compound according to any one of claims 2 to 12 or a pharmaceutically acceptable salt thereof, wherein: Y1 is K(-OEG-OEG-γGlu-C(O)-(CH2) 16 -COOH), K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH), or K(-OEG-OEG-γGlu-C(O)-(CH2) 20 -COOH); Preferably, Y1 is K(-OEG-OEG-γGlu-C(O)-(CH2) 16 -COOH), whose structural formula is: ,or Y1 is K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH), whose structural formula is: More preferably, Y1 has the following structure:

14. The compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, which is selected from any of the following structures: H-Aib-HGTFTSDYS-αK-YLEE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-AAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:97); H-Aib-HGTFTSDYS-αK-YLE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-KAAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:98); H-Aib-HGTFTSDYSK-αY-LE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-KAAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:99)! H-Aib-HGTFTSDYSK-Aib-LE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-KAAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:100); H-Aib-HGTFTSDYSKY-αL-E-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-KAAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:101); H-Aib-HGTFTSDYSKYLE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-αK-AAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:102); H-Aib-HGTFTSDYSKYLE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-K-Aib-AQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:103); H-Aib-HGTFTSDYS-αK-YLE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-KAAQEFVEWLIAGGPSSGAPPPS-NH2(SEQ ID NO:104); H-Aib-HGTFTSDYS-αK-LLE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-KAAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:105); H-Aib-HGTFTSDYS-αK-YLE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-KAQQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:106); Y-Aib-QGTFTSDYS-αK-LLE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-KAAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:107); H-Aib-HGTFTSDYS-αK-YLE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-KAAQEFVEWLIEGGPSSGAPPPS-NH2(SEQ ID NO:108); H-Aib-HGTFTSDYS-αK-LLE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-QAAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:109); H-Aib-HGTFTSDYS-αK-LLE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-IAAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:110); H-Aib-HGTFTSDYS-αK-ILE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-KAAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:111); H-Aib-HGTFTSDYSILLE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-KAAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:112); H-Aib-HGTFTSDYSI-αL-LE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-KAAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:113); H-Aib-HGTFTSDYS-αK-LLE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-KAA-αS-EFVEWLIEGGPSSGAPPPS-NH2(SEQ ID NO:114); Y-Aib-QGTFTSDYS-αK-LLE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-KAA-Iva-EFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:115); H-Aib-HGTFTSDYS-αK-LLE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-QAA-Iva-EFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:116); Y-Aib-QGTFTSDYS-αK-ILE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-KAA-Iva-EFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:117)! H-Aib-HGTFTSDYS-αK-ILE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-QAA-Iva-EFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:118); H-Aib-HGTFTSDYS-αK-LLE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-KAA-Iva-EFVEWLIEGGPSSGAPPPS-NH2(SEQ ID NO:119); H-Aib-HGTFTSDYS-αK-ILE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-KAA-Iva-EFVEWLIEGGPSSGAPPPS-NH2(SEQ ID NO:120); H-Aib-HGTFTSDLS-αK-LLE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-KAA-Iva-EFVEWLIEGGPSSGAPPPS-NH2(SEQ ID NO:121); H-Aib-HGTFTSDLS-αK-ILE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-KAA-Iva-EFVEWLIEGGPSSGAPPPS-NH2(SEQ ID NO:122); H-Aib-HGTFTSDYSILLE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-KAA-Iva-EFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:123)! H-Aib-HGTFTSDLSILLE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-KAA-Iva-EFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:124); H-Aib-HGTFTSDYSI-αL-LE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-KAA-Iva-EFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:125); H-Aib-HGTFTSDDLSI-αL-LE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-KAA-Iva-EFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:126); H-Aib-HGTFTSDYSI-αL-LE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-KAAQEFVEWLLA-e-GPSSGAPPPS-NH2(SEQ ID NO:127); H-Aib-HGTFTSDDLSI-αL-LE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-KAA-Ac4c-EFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:128); H-Aib-HGTFTSDLSI-αL-LE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-KAAQEFVEWLLA-e-GPSSGAPPPS-NH2(SEQ ID NO:129); H-Aib-HGTFTSDLSI-αL-LE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-KAAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:130); H-Aib-HGTFTSDLSILLE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-KAAQEFVEWLLA-e-GPSSGAPPPS-NH2(SEQ ID NO:131); H-Aib-HGTFTSDLSILLE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-QAA-Ac4c-EFVEWLLA-e-GPSSGAPPPS-NH2(SEQ ID NO:132); H-Aib-HGTFTSDLSILLE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-KAA-Ac3c-EFVEWLLA-e-GPSSGAPPPS-NH2(SEQ ID NO:133); H-Aib-HGTFTSDLSILLE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-KAA-Ac4c-EFVEWLLA-e-GPSSGAPPPS-NH2(SEQ ID NO:134); H-Aib-HGTFTSDLSILLE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-QAA-Ac3c-EFVEWLLA-e-GPSSGAPPPS-NH2(SEQ ID NO:135); H-Aib-HGTFTSDYSILLE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-QAA-Ac3c-EFVEWLLA-e-GPSSGAPPPS-NH2(SEQ ID NO:136)? H-Aib-HGTFTSDYSILLE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-QAA-Ac4c-EFVEWLLA-e-GPSSGAPPPS-NH2(SEQ ID NO:137)? H-Aib-HGTFTSDYSILLE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-KAAQEFVEWLLA-e-GPSSGAPPPS-NH2(SEQ ID NO:138); H-Aib-HGTFTSDYSILLE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-QAAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:139); H-Aib-HGTFTSDYSILLE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-QAAQEFVEWLLA-e-GPSSGAPPPS-NH2(SEQ ID NO:140); H-Aib-QGTFTSDYSILLE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-KAAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:141); H-Aib-QGTFTSDYSI-αL-LE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-CAAQEFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:142); H-Aib-QGTFTSDYSILLE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-KAA-Aib-EFVEWLLAGGPSSGAPPPS-NH2 (SEQ ID NO: 143); and H-Aib-QGTFTSDYSI-αL-LE-K(-OEG-OEG-γGlu-C(O)-(CH2) 18 -COOH)-KAA-Aib-EFVEWLLAGGPSSGAPPPS-NH2(SEQ ID NO:144); wherein αK is alpha-methyl-Lys, αY is alpha-methyl-Tyr, αL is alpha-methyl-Leu, Iva is isovaline, e is D-Glu, Aib is α-aminoisobutyric acid, Ac3c is 1-aminocyclopropane-1-carboxylic acid, Ac4c is 1-aminocyclobutane-1-carboxylic acid, and OEG is [2-(2-amino-ethoxy)-ethoxy]-acetyl.

15. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, which has agonist activity against at least one of the following receptors: GLP-1 receptor, GIP receptor and GCG receptor; preferably, the compound or a pharmaceutically acceptable salt thereof has triple agonist activity against GLP-1 receptor, GIP receptor and GCG receptor.

16. A GLP-1 / GIP / GCG receptor triagonist comprising the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt or solvate thereof, or a GLP-1 / GIP / GCG receptor triagonist according to claim 16; and pharmaceutically acceptable excipients or drug carriers.

18. Use of the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, the GLP-1 / GIP / GCG receptor triagonist according to claim 16, or the pharmaceutical composition according to claim 17 in the preparation of a medicament for preventing or treating a disease or condition related to metabolic disorders; Preferably, the metabolic disorder-related disease or condition is selected from diabetes or diabetes-related conditions, obesity or obesity-related conditions, and fatty liver disease associated with metabolic dysfunction.

19. A method for preventing or treating a disease or condition associated with a metabolic disorder, comprising administering to a subject in need thereof a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, a GLP-1 / GIP / GCG receptor triagonist according to claim 16, or a pharmaceutical composition according to claim 17; Preferably, the metabolic disorder-related disease or condition is selected from diabetes or diabetes-related conditions, obesity or obesity-related conditions, and fatty liver disease associated with metabolic dysfunction.

20. A method for preparing the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, which comprises the step of chemically synthesizing the compound.

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