Amylin analogue and pharmaceutical use thereof

Abstract

Provided are an amylin analogue and a pharmaceutical use thereof. Provided are a compound or a pharmaceutically acceptable salt thereof, an amylin analogue comprising the compound, a pharmaceutical composition and a pharmaceutical use thereof. The amylin analogue is a polypeptide analogue derived from pramlintide, has an agonist effect on a human amylin receptor and a human calcitonin receptor, and can be used for treatment of metabolic diseases such as obesity and diabetes.

Description

Amylin analogs and their medical uses Technical Field

[0001] The present disclosure belongs to the field of biomedicine, and specifically relates to a compound having dual agonist effects on human amylin receptor and human calcitonin receptor and its medical use. Background Art

[0002] Amylin is a 37-amino acid peptide secreted by pancreatic beta cells and works with insulin to regulate blood sugar levels. Amylin slows gastric emptying, delaying the entry of sugar from food into the bloodstream, thereby helping to reduce post-meal blood sugar spikes. Amylin also inhibits glucagon secretion, slowing the liver's release of glucose into the bloodstream and thus slowing the rise in blood sugar. Amylin also acts on the brain to promote satiety, thereby reducing food intake. In summary, the synergistic effect of amylin and insulin can help reduce the body's total insulin requirement and control food intake. However, diabetic patients often lack this hormone, resulting in suboptimal blood sugar control. Increasing amylin levels through drug administration may help control blood sugar levels and reduce weight in diabetic patients. However, amylin itself has a short half-life and an unstable physical structure. Under physiological conditions, it easily forms amyloid fibrils, leading to inactivation, making it unsuitable for direct pharmaceutical use. The FDA has approved the amylin analog drug Pramlintide, which greatly changes the property of amylin that easily generates amyloid fibrils by replacing the amino acids at positions 25, 28, and 29 of human amylin with proline.

[0003] However, the half-life of pramlintide is still very low, and the frequency of dosing twice to three times a day makes its compliance very poor. Novo Nordisk developed an amylin receptor and calcitonin receptor agonist, Cagrilintide, which greatly increased the half-life of amylin to about 170 hours by introducing fatty acid chains that can bind to albumin, and increased the dosing frequency to once a week. However, whether it is pramlintide or canagliflozin, they still cannot avoid the problem of molecular instability, hydrolysis and formation of amyloid fibers at physiological pH, which means that they can only be stored in acidic preparations, and are prone to adverse reactions near the injection site during clinical administration. Therefore, it is necessary to improve its stability at physiological pH to produce higher clinical value.

[0004] Amylin receptors (AMYRs) include the insulin-like peptide 1 receptor (AMY1R), the insulin-like peptide 2 receptor (AMY2R), and the insulin-like peptide 3 receptor (AMY3R), which are heterodimers of the calcitonin receptor (CTR) and three receptor activity-modifying proteins, RAMP1, RAMP2, and RAMP3, respectively. The structural characteristics of AMYRs result in insulin-like peptides activating both AMYRs and CTRs. Studies have found that compared to single AMYR agonists, dual AMYR / CTR agonists have a better effect on weight loss.

[0005] The present disclosure aims to provide a compound that exhibits dual agonist effects on the amylin receptor and the calcitonin receptor. Furthermore, compared to existing dual agonists of the amylin receptor and the calcitonin receptor, the compound of the present disclosure exhibits superior in vivo pharmacokinetic properties, improved physical and chemical stability at physiological pH, and enhanced efficacy in lowering blood sugar and reducing weight in vivo. Summary of the Invention

[0006] The object of the present invention is to provide a compound or a pharmaceutically acceptable salt thereof, an amylin analog, a pharmaceutical composition, a medical use, and a method for preventing or treating a disease.

[0007] Compound or pharmaceutically acceptable salt thereof

[0008] In some embodiments, it comprises a compound having a structure represented by the following formula (I) or a pharmaceutically acceptable salt thereof: X1-X2-X3-Thr-Ala-Thr-X7-Ala-Thr-X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -Leu-X 17 -X 18 -Ser-Ser- X 21 -X 22 -X 23 -X 24 -Pro-X 26 -Leu-Pro-Pro-Thr-X 31 -Val-X 33 -Ser-X 35 -Thr-X 37 (I); SEQ ID NO: 86;

[0009] Among them, X1, X2, X3, X7, X 10 、X 11 、X 12、X 13 、X 14 、X 15 、X 17 、X 18 、X 21 、X 22 、X 23 、X 24 、X 26 、X 31 、X 33 、X 35 and X 37 The peptide segment is independently selected from any natural amino acid, unnatural amino acid, or a peptide segment composed of natural amino acids and / or unnatural amino acids.

[0010] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0011] X1 is an amino acid residue selected from Lys or is absent;

[0012] X2 is an amino acid residue selected from Cys, homoCys, Pen or Abu;

[0013] X3 is an amino acid residue selected from Asn, Gln, Asp, Glu or Y1;

[0014] X7 is an amino acid residue selected from Cys, homoCys, Pen or Abu;

[0015] X 10 an amino acid residue selected from Gln, Asn, Glu, Asp, or Y1;

[0016] X 11 an amino acid residue selected from Arg, homoArg, Orn, D-Arg, or Y1;

[0017] X 12 an amino acid residue selected from Leu, homoLeu, N-Me-Leu, α-Me-Leu or D-Leu;

[0018] X 13 is an amino acid residue of Ala or Aib;

[0019] X 14 is the amino acid residue of Aib or Ala;

[0020] X 15 is the amino acid residue of Phe;

[0021] X 17 an amino acid residue selected from Val or Aib;

[0022] X 18an amino acid residue selected from His, Aib, or Y1;

[0023] X 21 is an amino acid residue of Asn, Gln, Glu, Ala or Aib;

[0024] X 22 an amino acid residue selected from Asn, Ala, or Y1;

[0025] X 23 an amino acid residue selected from Phe, 2-Pal, 4-Pal, hPhe or 3-Pal;

[0026] X 24 is the amino acid residue of Gly;

[0027] X 26 an amino acid residue selected from Ile or N-Me-Ile;

[0028] X 31 an amino acid residue selected from Asn, Asp, Glu, Gln, or Y1;

[0029] X 33 is the amino acid residue of Gly;

[0030] X 35 an amino acid residue selected from Glu, Asn, Asp or Gln;

[0031] X 37 An amino acid residue selected from Tyr or Pro.

[0032] In some embodiments, Y1 is selected from Lys, Orn, Dap, Dab or Cys residues with or without a side chain attached to a substituent. In some embodiments, Y1 is selected from Lys, Orn, Dap, Dab or Cys residues with a side chain attached to a substituent.

[0033] In some embodiments, Y1 is selected from a Lys residue whose side chain is linked to a substituent.

[0034] In some embodiments, X 13 X 14 is Ala-Aib, Ala-Ala, Aib-Ala, or Aib-Aib. In some embodiments, X 13 X 14 is Ala-Aib, Aib-Aib, or Aib-Ala. In some embodiments, X 13 X 14 It is Ala-Aib.

[0035] In some embodiments, X2 is an amino acid residue selected from Cys, Pen, or Abu.

[0036] In some embodiments, X3 is selected from the amino acid residue of Gln or Y1.

[0037] In some embodiments, X7 is selected from the amino acid residues of Cys, homoCys, Pen or Abu; in some embodiments, X7 is selected from the amino acid residues of Cys, Pen; in some embodiments, X7 is selected from the amino acid residue of Cys.

[0038] In some embodiments, X 10 An amino acid residue selected from Gln, Asn, Glu, Asp, or Y1; in some embodiments, X 10 An amino acid residue selected from Gln or Y1; in some embodiments, X 10 An amino acid residue selected from Gln.

[0039] In some embodiments, X 12 An amino acid residue selected from Leu, homoLeu, N-Me-Leu, α-Me-Leu, or D-Leu; in some embodiments, X 12 An amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu, or D-Leu; in some embodiments, X 12 Selected from Leu or α-Me-Leu.

[0040] In some embodiments, X 17 An amino acid residue selected from Val or Aib. In some embodiments, X 17 In some embodiments, X 17 An amino acid residue selected from Aib.

[0041] In some embodiments, X 18 An amino acid residue selected from His, Aib or Y1. In some embodiments, X 18 In some embodiments, X 18 In some embodiments, X 18 Selected from Y1.

[0042] In some embodiments, X 21 X is an amino acid residue of Aib or Ala. 21 is an amino acid residue of Aib. In some embodiments, X 21 It is an amino acid residue of Ala.

[0043] In some embodiments, X 22 An amino acid residue selected from Ala or Y1.

[0044] In some embodiments, X 23 It is the amino acid residue of 3-Pal.

[0045] In some embodiments, X 26 X is an amino acid residue of Ile or N-Me-Ile. 26 In some embodiments, X 26 It is the amino acid residue of N-Me-Ile.

[0046] In some embodiments, X 31 In some embodiments, X 31 In some embodiments, X 31 Selected from Y1.

[0047] In some embodiments, X 35 It is the amino acid residue of Glu.

[0048] In some embodiments, X 37 It is the amino acid residue of Pro.

[0049] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0050] X1 does not exist;

[0051] X2 is an amino acid residue selected from Cys, Pen or Abu;

[0052] X3 is selected from the amino acid residue of Gln or Y1;

[0053] X7 is an amino acid residue selected from Cys or Pen;

[0054] X 10 an amino acid residue selected from Gln or Y1;

[0055] X 11 an amino acid residue selected from Arg, homoArg, Orn, or Y1;

[0056] X 12 an amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu;

[0057] X 13 is an amino acid residue of Ala or Aib;

[0058] X14 is an amino acid residue of Ala or Aib;

[0059] X 15 is the amino acid residue of Phe;

[0060] X 17 is the amino acid residue of Val or Aib;

[0061] X 18 an amino acid residue selected from His or Aib or Y1;

[0062] X 21 is the amino acid residue of Aib or Ala;

[0063] X 22 an amino acid residue selected from Ala or Y1;

[0064] X 23 is the amino acid residue of 3-Pal;

[0065] X 24 is the amino acid residue of Gly;

[0066] X 26 is an amino acid residue of Ile or N-Me-Ile;

[0067] X 31 is the amino acid residue of Asp or Y1;

[0068] X 33 is the amino acid residue of Gly;

[0069] X 35 is the amino acid residue of Glu;

[0070] X 37 is the amino acid residue of Pro;

[0071] Y1 is selected from the group consisting of Lys, Orn, Dap, Dab, and Cys residues whose side chains are linked to substituents. In some embodiments, Y1 is a Lys residue whose side chains are linked to substituents.

[0072] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0073] X1 does not exist;

[0074] X2 is an amino acid residue selected from Cys, Pen or Abu;

[0075] X3 is selected from the amino acid residue of Gln or Y1;

[0076] X7 is an amino acid residue selected from Cys or Pen;

[0077] X 10 an amino acid residue selected from Gln or Y1;

[0078] X 11 an amino acid residue selected from Arg, homoArg, Orn, or Y1;

[0079] X 12 an amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu;

[0080] X 13 X 14 Selected from Ala-Aib, Aib-Ala or Aib-Aib;

[0081] X 15 is the amino acid residue of Phe;

[0082] X 17 is the amino acid residue of Val or Aib;

[0083] X 18 an amino acid residue selected from His or Aib or Y1;

[0084] X 21 is the amino acid residue of Aib or Ala;

[0085] X 22 an amino acid residue selected from Ala or Y1;

[0086] X 23 is the amino acid residue of 3-Pal;

[0087] X 24 is the amino acid residue of Gly;

[0088] X 26 is an amino acid residue of Ile or N-Me-Ile;

[0089] X 31 is the amino acid residue of Asp or Y1;

[0090] X 33 is the amino acid residue of Gly;

[0091] X 35 is the amino acid residue of Glu;

[0092] X 37 is the amino acid residue of Pro;

[0093] Y1 is a Lys residue whose side chain is linked to a substituent.

[0094] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0095] X1 does not exist;

[0096] X2 is an amino acid residue selected from Cys, Pen or Abu;

[0097] X3 is selected from the amino acid residue of Gln or Y1;

[0098] X7 is an amino acid residue selected from Cys or Pen;

[0099] X 10 an amino acid residue selected from Gln or Y1;

[0100] X 11 an amino acid residue selected from Arg, homoArg, Orn, or Y1;

[0101] X 12 an amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu;

[0102] X 13 is the amino acid residue of Ala;

[0103] X 14 is the amino acid residue of Aib;

[0104] X 15 is the amino acid residue of Phe;

[0105] X 17 is the amino acid residue of Val or Aib;

[0106] X 18 an amino acid residue selected from His or Aib or Y1;

[0107] X 21 is the amino acid residue of Aib or Ala;

[0108] X 22 an amino acid residue selected from Ala or Y1;

[0109] X 23 is the amino acid residue of 3-Pal;

[0110] X 24 is the amino acid residue of Gly;

[0111] X 26 is an amino acid residue of Ile or N-Me-Ile;

[0112] X 31 is the amino acid residue of Asp or Y1;

[0113] X 33 is the amino acid residue of Gly;

[0114] X 35 is the amino acid residue of Glu;

[0115] X 37 is the amino acid residue of Pro;

[0116] Y1 is a Lys residue whose side chain is linked to a substituent.

[0117] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0118] X1 does not exist;

[0119] X2 is an amino acid residue selected from Cys, Pen or Abu;

[0120] X3 is selected from the amino acid residue of Gln or Y1;

[0121] X7 is the amino acid residue of Cys;

[0122] X 10 is the amino acid residue of Gln;

[0123] X 11 an amino acid residue selected from Arg, homoArg, Orn, or Y1;

[0124] X 12 an amino acid residue selected from Leu or α-Me-Leu;

[0125] X 13 is the amino acid residue of Ala,

[0126] X 14 is the amino acid residue of Aib;

[0127] X 15 is the amino acid residue of Phe;

[0128] X 17 is the amino acid residue of Val or Aib;

[0129] X 18 an amino acid residue selected from His or Aib or Y1;

[0130] X 21 is the amino acid residue of Aib or Ala;

[0131] X 22 an amino acid residue selected from Ala or Y1;

[0132] X23 is the amino acid residue of 3-Pal;

[0133] X 24 is the amino acid residue of Gly;

[0134] X 26 is an amino acid residue of Ile or N-Me-Ile;

[0135] X 31 is the amino acid residue of Asp or Y1;

[0136] X 33 is the amino acid residue of Gly;

[0137] X 35 is the amino acid residue of Glu;

[0138] X 37 is the amino acid residue of Pro;

[0139] Y1 is a Lys residue whose side chain is connected to a substituent.

[0140] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0141] X1 does not exist;

[0142] X2 is an amino acid residue selected from Cys;

[0143] X3 is selected from the amino acid residue of Gln or Y1;

[0144] X7 is the amino acid residue of Cys;

[0145] X 10 is the amino acid residue of Gln;

[0146] X 11 an amino acid residue selected from Arg;

[0147] X 12 an amino acid residue selected from Leu;

[0148] X 13 is the amino acid residue of Ala,

[0149] X 14 is the amino acid residue of Aib;

[0150] X 15 is the amino acid residue of Phe;

[0151] X 17 is the amino acid residue of Val or Aib;

[0152] X 18an amino acid residue selected from His, Aib, or Y1;

[0153] X 21 is the amino acid residue of Aib or Ala;

[0154] X 22 an amino acid residue selected from Ala or Y1;

[0155] X 23 is the amino acid residue of 3-Pal;

[0156] X 24 is the amino acid residue of Gly;

[0157] X 26 is an amino acid residue of Ile or N-Me-Ile;

[0158] X 31 is the amino acid residue of Asp or Y1;

[0159] X 33 is the amino acid residue of Gly;

[0160] X 35 is the amino acid residue of Glu;

[0161] X 37 is the amino acid residue of Pro;

[0162] Y1 is a Lys residue whose side chain is connected to a substituent.

[0163] In some embodiments, it comprises a compound having a structure represented by the following formula (Ia) or a pharmaceutically acceptable salt thereof: X1-X2-X3-Thr-Ala-Thr-X7-Ala-Thr-X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -Leu-Val-X 18 -Ser-Ser- X 21 -X 22 -X 23 -X 24 -Pro-Ile-Leu-Pro-Pro-Thr-X 31 -Val-X 33 -Ser-X 35 -Thr-X 37 (Ia); SEQ ID NO: 87;

[0164] Among them, X1, X2, X3, X7, X 10 、X 11、X 12 、X 13 、X 14 、X 15 、X 18 、X 21 、X 22 、X 23 、X 24 、X 31 、X 33 、X 35 and X 37 The peptide segment is independently selected from any natural amino acid, unnatural amino acid, or a peptide segment composed of natural amino acids and / or unnatural amino acids.

[0165] In some embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt thereof, wherein:

[0166] X1 is an amino acid residue selected from Lys or is absent;

[0167] X2 is an amino acid residue selected from Cys, homoCys, Pen or Abu;

[0168] X3 is an amino acid residue selected from Asn, Gln, Asp, Glu or Y1;

[0169] X7 is an amino acid residue selected from Cys, homoCys, Pen or Abu;

[0170] X 10 an amino acid residue selected from Gln, Asn, Glu, Asp, or Y1;

[0171] X 11 an amino acid residue selected from Arg, homoArg, Orn, D-Arg, or Y1;

[0172] X 12 an amino acid residue selected from Leu, homoLeu, N-Me-Leu, α-Me-Leu or D-Leu;

[0173] X 13 is an amino acid residue of Ala or Aib;

[0174] X 14 is the amino acid residue of Aib or Ala;

[0175] X 15 is the amino acid residue of Phe;

[0176] X 18 an amino acid residue selected from His or Y1;

[0177] X 21is an amino acid residue of Asn, Gln, Glu, Ala or Aib;

[0178] X 22 an amino acid residue selected from Asn, Ala, or Y1;

[0179] X 23 an amino acid residue selected from Phe, 2-Pal, 4-Pal, hPhe or 3-Pal;

[0180] X 24 is the amino acid residue of Gly;

[0181] X 31 an amino acid residue selected from Asn, Asp, Glu, Gln, or Y1;

[0182] X 33 is the amino acid residue of Gly;

[0183] X 35 an amino acid residue selected from Glu, Asn, Asp or Gln;

[0184] X 37 An amino acid residue selected from Tyr or Pro.

[0185] In some embodiments, Y1 is selected from Lys, Orn, Dap, Dab or Cys residues with or without a side chain attached to a substituent. In some embodiments, Y1 is selected from Lys, Orn, Dap, Dab or Cys residues with a side chain attached to a substituent.

[0186] In some embodiments, Y1 is selected from a Lys residue whose side chain is linked to a substituent.

[0187] In some embodiments, X 13 X 14 is Ala-Aib, Ala-Ala, Aib-Ala, or Aib-Aib. In some embodiments, X 13 X 14 is Ala-Aib, Aib-Aib, or Aib-Ala. In some embodiments, X 13 X 14 It is Ala-Aib.

[0188] In some embodiments, X2 is an amino acid residue selected from Cys, Pen, or Abu.

[0189] In some embodiments, X3 is selected from the amino acid residue of Gln or Y1.

[0190] In some embodiments, X7 is selected from the amino acid residues of Cys, homoCys, Pen or Abu; in some embodiments, X7 is selected from the amino acid residues of Cys, Pen; in some embodiments, X7 is selected from the amino acid residue of Cys.

[0191] In some embodiments, X 10 An amino acid residue selected from Gln, Asn, Glu, Asp, or Y1; in some embodiments, X 10 An amino acid residue selected from Gln or Y1; in some embodiments, X 10 An amino acid residue selected from Gln.

[0192] In some embodiments, X 12 An amino acid residue selected from Leu, homoLeu, N-Me-Leu, α-Me-Leu, or D-Leu; in some embodiments, X 12 An amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu, or D-Leu; in some embodiments, X 12 Selected from Leu or α-Me-Leu.

[0193] In some embodiments, X 21 is the amino acid residue of Aib.

[0194] In some embodiments, X 22 An amino acid residue selected from Ala or Y1.

[0195] In some embodiments, X 23 It is the amino acid residue of 3-Pal.

[0196] In some embodiments, X 31 An amino acid residue selected from Asp or Y1.

[0197] In some embodiments, X 35 It is the amino acid residue of Glu.

[0198] In some embodiments, X 37 It is the amino acid residue of Pro.

[0199] In some embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt thereof, wherein:

[0200] X1 does not exist;

[0201] X2 is an amino acid residue selected from Cys, Pen or Abu;

[0202] X3 is selected from the amino acid residue of Gln or Y1;

[0203] X7 is an amino acid residue selected from Cys or Pen;

[0204] X 10 an amino acid residue selected from Gln or Y1;

[0205] X 11 an amino acid residue selected from Arg, homoArg, Orn, or Y1;

[0206] X 12 an amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu;

[0207] X 13 is an amino acid residue of Ala or Aib;

[0208] X 14 is an amino acid residue of Ala or Aib;

[0209] X 15 is the amino acid residue of Phe;

[0210] X 18 an amino acid residue selected from His or Y1;

[0211] X 21 is the amino acid residue of Aib;

[0212] X 22 an amino acid residue selected from Ala or Y1;

[0213] X 23 is the amino acid residue of 3-Pal;

[0214] X 24 is the amino acid residue of Gly;

[0215] X 31 is the amino acid residue of Asp or Y1;

[0216] X 33 is the amino acid residue of Gly;

[0217] X 35 is the amino acid residue of Glu;

[0218] X 37 is the amino acid residue of Pro;

[0219] Y1 is selected from the group consisting of Lys, Orn, Dap, Dab, and Cys residues whose side chains are linked to substituents. In some embodiments, Y1 is a Lys residue whose side chains are linked to substituents.

[0220] In some embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt thereof, wherein:

[0221] X1 does not exist;

[0222] X2 is an amino acid residue selected from Cys, Pen or Abu;

[0223] X3 is selected from the amino acid residue of Gln or Y1;

[0224] X7 is an amino acid residue selected from Cys or Pen;

[0225] X 10 an amino acid residue selected from Gln or Y1;

[0226] X 11 an amino acid residue selected from Arg, homoArg, Orn, or Y1;

[0227] X 12 an amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu;

[0228] X 13 X 14 Selected from Ala-Aib, Aib-Ala or Aib-Aib;

[0229] X 15 is the amino acid residue of Phe;

[0230] X 18 an amino acid residue selected from His or Y1;

[0231] X 21 is the amino acid residue of Aib;

[0232] X 22 an amino acid residue selected from Ala or Y1;

[0233] X 23 is the amino acid residue of 3-Pal;

[0234] X 24 is the amino acid residue of Gly;

[0235] X 31 is the amino acid residue of Asp or Y1;

[0236] X 33 is the amino acid residue of Gly;

[0237] X 35 is the amino acid residue of Glu;

[0238] X 37is the amino acid residue of Pro;

[0239] Y1 is a Lys residue whose side chain is linked to a substituent.

[0240] In some embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt thereof, wherein:

[0241] X1 does not exist;

[0242] X2 is an amino acid residue selected from Cys, Pen or Abu;

[0243] X3 is selected from the amino acid residue of Gln or Y1;

[0244] X7 is an amino acid residue selected from Cys or Pen;

[0245] X 10 an amino acid residue selected from Gln or Y1;

[0246] X 11 an amino acid residue selected from Arg, homoArg, Orn, or Y1;

[0247] X 12 an amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu;

[0248] X 13 is the amino acid residue of Ala;

[0249] X 14 is the amino acid residue of Aib;

[0250] X 15 is the amino acid residue of Phe;

[0251] X 18 an amino acid residue selected from His or Y1;

[0252] X 21 is the amino acid residue of Aib;

[0253] X 22 an amino acid residue selected from Ala or Y1;

[0254] X 23 is the amino acid residue of 3-Pal;

[0255] X 24 is the amino acid residue of Gly;

[0256] X 31 is the amino acid residue of Asp or Y1;

[0257] X 33is the amino acid residue of Gly;

[0258] X 35 is the amino acid residue of Glu;

[0259] X 37 is the amino acid residue of Pro;

[0260] Y1 is a Lys residue whose side chain is linked to a substituent.

[0261] In some embodiments, the compound of the structure represented by formula (Ia) or a pharmaceutically acceptable salt thereof, wherein: X1 is absent;

[0262] X2 is an amino acid residue selected from Cys, Pen or Abu;

[0263] X3 is selected from the amino acid residue of Gln or Y1;

[0264] X7 is the amino acid residue of Cys;

[0265] X 10 is the amino acid residue of Gln;

[0266] X 11 an amino acid residue selected from Arg, homoArg, Orn, or Y1;

[0267] X 12 an amino acid residue selected from Leu or α-Me-Leu;

[0268] X 13 is the amino acid residue of Ala,

[0269] X 14 is the amino acid residue of Aib;

[0270] X 15 is the amino acid residue of Phe;

[0271] X 18 an amino acid residue selected from His or Y1;

[0272] X 21 is the amino acid residue of Aib;

[0273] X 22 an amino acid residue selected from Ala or Y1;

[0274] X 23 is the amino acid residue of 3-Pal;

[0275] X 24 is the amino acid residue of Gly;

[0276] X 31is the amino acid residue of Asp or Y1;

[0277] X 33 is the amino acid residue of Gly;

[0278] X 35 is the amino acid residue of Glu;

[0279] X 37 is the amino acid residue of Pro;

[0280] Y1 is a Lys residue whose side chain is connected to a substituent.

[0281] In some embodiments, the present disclosure provides a compound having a structure represented by the following formula (II) or a pharmaceutically acceptable salt thereof: R1-X1-X2-X3-Thr-Ala-Thr-X7-Ala-Thr-X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -Leu-X 17 -X 18 -Ser- Ser-X 21 -X 22 -X 23 -X 24 -Pro-X 26 -Leu-Pro-Pro-Thr-X 31 -Val-X 33 -Ser-X 35 -Thr-X 37 -R2(II); SEQ ID NO:88;

[0282] Among them, X1, X2, X3, X7, X 10 、X 11 、X 12 、X 13 、X 14 、X 15 、X 18 、X 17 、X 21 、X 22 、X 23 、X 24 、X 26 、X 31 、X 33 、X 35 and X 37 Independently selected from any natural amino acid, unnatural amino acid, or a peptide segment consisting of natural amino acids and / or unnatural amino acids.

[0283] In some embodiments, R1 is H, alkyl, acyl, benzoyl, trifluoroacetyl, or pyroglutamyl.

[0284] In some specific embodiments, R1 is H, C 1-4 Alkyl (e.g., methyl, ethyl, 1-propyl or 2-propyl), C 1-4 acyl (e.g., acetyl, formyl, propionyl, 1-butyryl, and 2-methylpropionyl), benzoyl, trifluoroacetyl, or pyroglutamyl.

[0285] In some specific embodiments, R1 is H or acetyl. In some specific embodiments, R1 is acetyl.

[0286] In some embodiments, R2 is -NH2 or -OH; in some specific embodiments, R2 is -NH2.

[0287] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein:

[0288] R1 is H, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pyroglutamyl;

[0289] R2 is -NH2 or -OH;

[0290] X1 is an amino acid residue selected from Lys or is absent;

[0291] X2 is an amino acid residue selected from Cys, homoCys, Pen or Abu;

[0292] X3 is an amino acid residue selected from Asn, Gln, Asp, Glu or Y1;

[0293] X7 is an amino acid residue selected from Cys, homoCys, Pen or Abu;

[0294] X 10 an amino acid residue selected from Gln, Asn, Glu, Asp, or Y1;

[0295] X 11 an amino acid residue selected from Arg, homoArg, Orn, D-Arg, or Y1;

[0296] X 12 an amino acid residue selected from Leu, hLeu, N-Me-Leu, α-Me-Leu or D-Leu;

[0297] X 13 is the amino acid residue of Aib or Ala;

[0298] X 14is the amino acid residue of Aib or Ala;

[0299] X 15 is the amino acid residue of Phe;

[0300] X 17 an amino acid residue selected from Val or Aib;

[0301] X 18 an amino acid residue selected from His, Aib, or Y1;

[0302] X 21 is an amino acid residue of Asn, Gln, Glu, Ala or Aib;

[0303] X 22 an amino acid residue selected from Asn, Ala, or Y1;

[0304] X 23 an amino acid residue selected from Phe, 2-Pal, 4-Pal, hPhe or 3-Pal;

[0305] X 24 is the amino acid residue of Gly;

[0306] X 26 an amino acid residue selected from Ile or N-Me-Ile;

[0307] X 31 an amino acid residue selected from Asn, Asp, Glu or Gln, or Y1;

[0308] X 33 is the amino acid residue of Gly;

[0309] X 35 an amino acid residue selected from Glu, Asn, Asp or Gln;

[0310] X 37 an amino acid residue selected from Tyr or Pro;

[0311] Y1 is selected from Lys, Orn, Dap, Dab or Cys residues with or without a side chain substituent. In some embodiments, Y1 is selected from Lys, Orn, Dap, Dab or Cys residues with a side chain substituent. In some embodiments, Y1 is selected from Lys, Orn, Dap, Dab or Cys residues with a side chain substituent.

[0312] In some embodiments, X 13 X 14 is Ala-Aib, Ala-Ala, Aib-Ala, or Aib-Aib. In some embodiments, X 13 X 14is Ala-Aib, Aib-Aib, or Aib-Ala. In some embodiments, X 13 X 14 It is Ala-Aib.

[0313] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein:

[0314] X1 does not exist;

[0315] X2 is an amino acid residue selected from Cys, Pen or Abu;

[0316] X3 is selected from the amino acid residue of Gln or Y1;

[0317] X7 is an amino acid residue selected from Cys or Pen;

[0318] X 10 an amino acid residue selected from Gln or Y1;

[0319] X 11 an amino acid residue selected from Arg, homoArg, Orn, or Y1;

[0320] X 12 an amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu;

[0321] X 13 is the amino acid residue of Aib or Ala;

[0322] X 14 is the amino acid residue of Aib or Ala;

[0323] X 15 is the amino acid residue of Phe;

[0324] X 17 is the amino acid residue of Val or Aib;

[0325] X 18 an amino acid residue selected from His or Aib or Y1;

[0326] X 21 is the amino acid residue of Aib or Ala;

[0327] X 22 an amino acid residue selected from Ala or Y1;

[0328] X 23 is the amino acid residue of 3-Pal;

[0329] X 24 is the amino acid residue of Gly;

[0330] X 26 is an amino acid residue of Ile or N-Me-Ile;

[0331] X 31 is the amino acid residue of Asp or Y1;

[0332] X 33 is the amino acid residue of Gly;

[0333] X 35 is the amino acid residue of Glu;

[0334] X 37 is the amino acid residue of Pro;

[0335] Y1 is selected from the group consisting of Lys, Orn, Dap, Dab, and Cys residues whose side chains are linked to substituents. In some embodiments, Y1 is a Lys residue whose side chains are linked to substituents;

[0336] R1 is H, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl, or pyroglutamyl; in some embodiments, R1 is H, alkyl, or acetyl. In some embodiments, R1 is acetyl.

[0337] R2 is -NH2 or -OH; in some embodiments, R2 is -NH2.

[0338] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein:

[0339] X1 does not exist;

[0340] X2 is an amino acid residue selected from Cys, Pen or Abu;

[0341] X3 is selected from the amino acid residue of Gln or Y1;

[0342] X7 is an amino acid residue selected from Cys or Pen;

[0343] X 10 an amino acid residue selected from Gln or Y1;

[0344] X 11 an amino acid residue selected from Arg, homoArg, Orn, or Y1;

[0345] X 12 an amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu;

[0346] X 13 X 14 Selected from Ala-Aib, Aib-Aib or Aib-Ala;

[0347] X 15 is the amino acid residue of Phe;

[0348] X 17 is the amino acid residue of Val or Aib;

[0349] X 18 an amino acid residue selected from His or Aib or Y1;

[0350] X 21 is the amino acid residue of Aib or Ala;

[0351] X 22 an amino acid residue selected from Ala or Y1;

[0352] X 23 is the amino acid residue of 3-Pal;

[0353] X 24 is the amino acid residue of Gly;

[0354] X 26 is an amino acid residue of Ile or N-Me-Ile;

[0355] X 31 is the amino acid residue of Asp or Y1;

[0356] X 33 is the amino acid residue of Gly;

[0357] X 35 is the amino acid residue of Glu;

[0358] X 37 is the amino acid residue of Pro;

[0359] Y1 is selected from the group consisting of Lys, Orn, Dap, Dab, and Cys residues whose side chains are linked to substituents. In some embodiments, Y1 is a Lys residue whose side chains are linked to substituents;

[0360] R1 is H, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl, or pyroglutamyl; in some embodiments, R1 is H, alkyl, or acetyl. In some embodiments, R1 is acetyl.

[0361] R2 is -NH2 or -OH; in some embodiments, R2 is -NH2.

[0362] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein:

[0363] R1 is acetyl, R2 is -NH2;

[0364] X1 does not exist;

[0365] X2 is an amino acid residue selected from Cys, Pen or Abu;

[0366] X3 is selected from the amino acid residue of Gln or Y1;

[0367] X7 is an amino acid residue selected from Cys or Pen;

[0368] X 10 an amino acid residue selected from Gln or Y1;

[0369] X 11 an amino acid residue selected from Arg, homoArg, Orn, or Y1;

[0370] X 12 an amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu;

[0371] X 13 is the amino acid residue of Ala

[0372] X 14 is the amino acid residue of Aib;

[0373] X 15 is the amino acid residue of Phe;

[0374] X 17 is the amino acid residue of Val or Aib;

[0375] X 18 an amino acid residue selected from His or Aib or Y1;

[0376] X 21 is the amino acid residue of Aib or Ala;

[0377] X 22 an amino acid residue selected from Ala or Y1;

[0378] X 23 is the amino acid residue of 3-Pal;

[0379] X 24 is the amino acid residue of Gly;

[0380] X 26 is an amino acid residue of Ile or N-Me-Ile;

[0381] X 31 is the amino acid residue of Asp or Y1;

[0382] X 33 is the amino acid residue of Gly;

[0383] X 35 is the amino acid residue of Glu;

[0384] X 37 is the amino acid residue of Pro;

[0385] Y1 is a Lys residue whose side chain is linked to a substituent.

[0386] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein:

[0387] R1 is acetyl, R2 is -NH2;

[0388] X1 does not exist;

[0389] X2 is an amino acid residue selected from Cys, Pen or Abu;

[0390] X3 is selected from the amino acid residue of Gln or Y1;

[0391] X7 is an amino acid residue selected from Cys;

[0392] X 10 is the amino acid residue of Gln;

[0393] X 11 an amino acid residue selected from Arg, homoArg, Orn, or Y1;

[0394] X 12 an amino acid residue selected from Leu or α-Me-Leu;

[0395] X 13 is the amino acid residue of Ala

[0396] X 14 is the amino acid residue of Aib;

[0397] X 15 is the amino acid residue of Phe;

[0398] X 17 is the amino acid residue of Val or Aib;

[0399] X 18 an amino acid residue selected from His or Aib or Y1;

[0400] X 21 is the amino acid residue of Aib or Ala;

[0401] X 22 an amino acid residue selected from Ala or Y1;

[0402] X 23is the amino acid residue of 3-Pal;

[0403] X 24 is the amino acid residue of Gly;

[0404] X 26 is an amino acid residue of Ile or N-Me-Ile;

[0405] X 31 is the amino acid residue of Asp or Y1;

[0406] X 33 is the amino acid residue of Gly;

[0407] X 35 is the amino acid residue of Glu;

[0408] X 37 is the amino acid residue of Pro;

[0409] Y1 is a Lys residue whose side chain is linked to a substituent.

[0410] In some embodiments, the present disclosure provides a compound having a structure represented by the following formula (IIa) or a pharmaceutically acceptable salt thereof: R1-X1-X2-X3-Thr-Ala-Thr-X7-Ala-Thr-X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -Leu-Val-X 18 -Ser-Ser- X 21 -X 22 -X 23 -X 24 -Pro-Ile-Leu-Pro-Pro-Thr-X 31 -Val-X 33 -Ser-X 35 -Thr-X 37 -R2(IIa); SEQ ID NO: 89;

[0411] Among them, X1, X2, X3, X7, X 10 、X 11 、X 12 、X 13 、X 14 、X 15 、X 18 、X 21 、X 22 、X 23 、X 24 、X 31 、X33 、X 35 and X 37 Independently selected from any natural amino acid, unnatural amino acid, or a peptide segment consisting of natural amino acids and / or unnatural amino acids.

[0412] In some embodiments, R1 is H, alkyl, acyl, benzoyl, trifluoroacetyl, or pyroglutamyl.

[0413] In some specific embodiments, R1 is H, C 1-4 Alkyl (e.g., methyl, ethyl, 1-propyl or 2-propyl), C 1-4 acyl (e.g., acetyl, formyl, propionyl, 1-butyryl, and 2-methylpropionyl), benzoyl, trifluoroacetyl, or pyroglutamyl.

[0414] In some specific embodiments, R1 is H or acetyl. In some specific embodiments, R1 is acetyl.

[0415] In some embodiments, R2 is -NH2 or -OH; in some specific embodiments, R2 is -NH2.

[0416] In some embodiments, the compound of formula (IIa) or a pharmaceutically acceptable salt thereof, wherein:

[0417] R1 is H, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pyroglutamyl;

[0418] R2 is -NH2 or -OH;

[0419] X1 is an amino acid residue selected from Lys or is absent;

[0420] X2 is an amino acid residue selected from Cys, homoCys, Pen or Abu;

[0421] X3 is an amino acid residue selected from Asn, Gln, Asp, Glu or Y1;

[0422] X7 is an amino acid residue selected from Cys, homoCys, Pen or Abu;

[0423] X 10 an amino acid residue selected from Gln, Asn, Glu, Asp, or Y1;

[0424] X 11 an amino acid residue selected from Arg, homoArg, Orn, D-Arg, or Y1;

[0425] X 12an amino acid residue selected from Leu, hLeu, N-Me-Leu, α-Me-Leu or D-Leu;

[0426] X 13 is the amino acid residue of Aib or Ala;

[0427] X 14 is the amino acid residue of Aib or Ala;

[0428] X 15 is the amino acid residue of Phe;

[0429] X 18 an amino acid residue selected from His or Y1;

[0430] X 21 is an amino acid residue of Asn, Gln, Glu, Ala or Aib;

[0431] X 22 an amino acid residue selected from Asn, Ala, or Y1;

[0432] X 23 an amino acid residue selected from Phe, 2-Pal, 4-Pal, hPhe or 3-Pal;

[0433] X 24 is the amino acid residue of Gly;

[0434] X 31 an amino acid residue selected from Asn, Asp, Glu or Gln, or Y1;

[0435] X 33 is the amino acid residue of Gly;

[0436] X 35 an amino acid residue selected from Glu, Asn, Asp or Gln;

[0437] X 37 an amino acid residue selected from Tyr or Pro;

[0438] Y1 is selected from Lys, Orn, Dap, Dab or Cys residues with or without a side chain substituent. In some embodiments, Y1 is selected from Lys, Orn, Dap, Dab or Cys residues with a side chain substituent. In some embodiments, Y1 is selected from Lys, Orn, Dap, Dab or Cys residues with a side chain substituent.

[0439] In some embodiments, X 13 X 14 is Ala-Aib, Ala-Ala, Aib-Ala, or Aib-Aib. In some embodiments, X 13X 14 is Ala-Aib, Aib-Aib, or Aib-Ala. In some embodiments, X 13 X 14 It is Ala-Aib.

[0440] In some embodiments, the compound of formula (IIa) or a pharmaceutically acceptable salt thereof, wherein:

[0441] X1 does not exist;

[0442] X2 is an amino acid residue selected from Cys, Pen or Abu;

[0443] X3 is selected from the amino acid residue of Gln or Y1;

[0444] X7 is an amino acid residue selected from Cys or Pen;

[0445] X 10 an amino acid residue selected from Gln or Y1;

[0446] X 11 an amino acid residue selected from Arg, homoArg, Orn, or Y1;

[0447] X 12 an amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu;

[0448] X 13 is the amino acid residue of Aib or Ala;

[0449] X 14 is the amino acid residue of Aib or Ala;

[0450] X 15 is the amino acid residue of Phe;

[0451] X 18 an amino acid residue selected from His or Y1;

[0452] X 21 is the amino acid residue of Aib;

[0453] X 22 an amino acid residue selected from Ala or Y1;

[0454] X 23 is the amino acid residue of 3-Pal;

[0455] X 24 is the amino acid residue of Gly;

[0456] X 31 is the amino acid residue of Asp or Y1;

[0457] X 33 is the amino acid residue of Gly;

[0458] X 35 is the amino acid residue of Glu;

[0459] X 37 is the amino acid residue of Pro;

[0460] Y1 is selected from the group consisting of Lys, Orn, Dap, Dab, and Cys residues whose side chains are linked to substituents. In some embodiments, Y1 is a Lys residue whose side chains are linked to substituents;

[0461] R1 is H, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl, or pyroglutamyl; in some embodiments, R1 is H, alkyl, or acetyl. In some embodiments, R1 is acetyl.

[0462] R2 is -NH2 or -OH; in some embodiments, R2 is -NH2.

[0463] In some embodiments, the compound of formula (IIa) or a pharmaceutically acceptable salt thereof, wherein:

[0464] X1 does not exist;

[0465] X2 is an amino acid residue selected from Cys, Pen or Abu;

[0466] X3 is selected from the amino acid residue of Gln or Y1;

[0467] X7 is an amino acid residue selected from Cys or Pen;

[0468] X 10 an amino acid residue selected from Gln or Y1;

[0469] X 11 an amino acid residue selected from Arg, homoArg, Orn, or Y1;

[0470] X 12 an amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu;

[0471] X 13 X 14 Selected from Ala-Aib, Aib-Aib or Aib-Ala;

[0472] X 15 is the amino acid residue of Phe;

[0473] X 18 an amino acid residue selected from His or Y1;

[0474] X 21 is the amino acid residue of Aib;

[0475] X 22 an amino acid residue selected from Ala or Y1;

[0476] X 23 is the amino acid residue of 3-Pal;

[0477] X 24 is the amino acid residue of Gly;

[0478] X 31 is the amino acid residue of Asp or Y1;

[0479] X 33 is the amino acid residue of Gly;

[0480] X 35 is the amino acid residue of Glu;

[0481] X 37 is the amino acid residue of Pro;

[0482] Y1 is selected from the group consisting of Lys, Orn, Dap, Dab, and Cys residues whose side chains are linked to substituents. In some embodiments, Y1 is a Lys residue whose side chains are linked to substituents;

[0483] R1 is H, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl, or pyroglutamyl; in some embodiments, R1 is H, alkyl, or acetyl. In some embodiments, R1 is acetyl.

[0484] R2 is -NH2 or -OH; in some embodiments, R2 is -NH2.

[0485] In some embodiments, the compound of formula (IIa) or a pharmaceutically acceptable salt thereof, wherein:

[0486] R1 is acetyl, R2 is -NH2;

[0487] X1 does not exist;

[0488] X2 is an amino acid residue selected from Cys, Pen or Abu;

[0489] X3 is selected from the amino acid residue of Gln or Y1;

[0490] X7 is an amino acid residue selected from Cys or Pen;

[0491] X 10 an amino acid residue selected from Gln or Y1;

[0492] X 11 an amino acid residue selected from Arg, homoArg, Orn, or Y1;

[0493] X 12 an amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu;

[0494] X 13 is the amino acid residue of Ala

[0495] X 14 is the amino acid residue of Aib;

[0496] X 15 is the amino acid residue of Phe;

[0497] X 18 an amino acid residue selected from His or Y1;

[0498] X 21 is the amino acid residue of Aib;

[0499] X 22 an amino acid residue selected from Ala or Y1;

[0500] X 23 is the amino acid residue of 3-Pal;

[0501] X 24 is the amino acid residue of Gly;

[0502] X 31 is the amino acid residue of Asp or Y1;

[0503] X 33 is the amino acid residue of Gly;

[0504] X 35 is the amino acid residue of Glu;

[0505] X 37 is the amino acid residue of Pro;

[0506] Y1 is a Lys residue whose side chain is linked to a substituent.

[0507] In some embodiments, the compound of formula (IIa) or a pharmaceutically acceptable salt thereof, wherein:

[0508] R1 is acetyl, R2 is -NH2;

[0509] X1 does not exist;

[0510] X2 is an amino acid residue selected from Cys, Pen or Abu;

[0511] X3 is selected from the amino acid residue of Gln or Y1;

[0512] X7 is an amino acid residue selected from Cys;

[0513] X 10 is the amino acid residue of Gln;

[0514] X 11 an amino acid residue selected from Arg, homoArg, Orn, or Y1;

[0515] X 12 an amino acid residue selected from Leu or α-Me-Leu;

[0516] X 13 is the amino acid residue of Ala

[0517] X 14 is the amino acid residue of Aib;

[0518] X 15 is the amino acid residue of Phe;

[0519] X 18 an amino acid residue selected from His or Y1;

[0520] X 21 is the amino acid residue of Aib;

[0521] X 22 an amino acid residue selected from Ala or Y1;

[0522] X 23 is the amino acid residue of 3-Pal;

[0523] X 24 is the amino acid residue of Gly;

[0524] X 31 is the amino acid residue of Asp or Y1;

[0525] X 33 is the amino acid residue of Gly;

[0526] X 35 is the amino acid residue of Glu;

[0527] X 37 is the amino acid residue of Pro;

[0528] Y1 is a Lys residue whose side chain is linked to a substituent.

[0529] In some embodiments, the compound represented by the structure of formula (Ia) or formula (IIa) or a pharmaceutically acceptable salt thereof is selected from any one of the following (i) to (vi):

[0530] (i) X1 is absent, X2 is an amino acid residue selected from Cys, Pen or Abu, X3 is Y1, X7 is an amino acid residue selected from Cys or Pen, X 10 is the amino acid residue of Gln, X 11 An amino acid residue selected from Arg, hArg or Orn, X 12 An amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 18 is the amino acid residue of His, X 21 is the amino acid residue of Aib, X 22 is the amino acid residue of Ala, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 31 is the amino acid residue of Asp, X 33 is the amino acid residue of Gly, X 35 An amino acid residue selected from Glu, X 37 is the amino acid residue of Pro;

[0531] (ii) X1 is absent, X2 is an amino acid residue selected from Cys, Pen or Abu, X3 is an amino acid residue of Gln, X7 is an amino acid residue selected from Cys or Pen, X 10 An amino acid residue selected from Gln or Y1, X 11 An amino acid residue selected from Arg, homoArg or Orn, X 12 An amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 18 is the amino acid residue of His, X 21 is the amino acid residue of Aib, X 22 is the amino acid residue of Ala, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 31 is the amino acid residue of Asp, X 33 is the amino acid residue of Gly, X 35 is the amino acid residue of Glu, X 37 is the amino acid residue of Pro;

[0532] (iii) X1 is absent, X2 is an amino acid residue selected from Cys, Pen or Abu, X3 is an amino acid residue of Gln, X7 is an amino acid residue selected from Cys or Pen, X 10 is the amino acid residue of Gln, X 11 An amino acid residue selected from Arg, homoArg, Orn or Y1, X 12 An amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 18 is the amino acid residue of His, X 21 is the amino acid residue of Aib, X 22 is the amino acid residue of Ala, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 31 is the amino acid residue of Asp, X 33 is the amino acid residue of Gly, X 35 is the amino acid residue of Glu, X 37 is the amino acid residue of Pro;

[0533] (iv) X1 is absent, X2 is an amino acid residue selected from Cys, Pen or Abu, X3 is an amino acid residue of Gln, X7 is an amino acid residue selected from Cys or Pen, X 10 is the amino acid residue of Gln, X 11 An amino acid residue selected from Arg, homoArg or Orn, X 12 An amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 18 An amino acid residue selected from His or Y1, X 21 is the amino acid residue of Aib, X 22 is the amino acid residue of Ala, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 31 is the amino acid residue of Asp, X 33 is the amino acid residue of Gly, X 35 is the amino acid residue of Glu, X 37is the amino acid residue of Pro;

[0534] (v) X1 is absent, X2 is an amino acid residue selected from Cys, Pen or Abu, X3 is an amino acid residue of Gln, X7 is an amino acid residue selected from Cys or Pen, X 10 is the amino acid residue of Gln, X 11 An amino acid residue selected from Arg, homoArg or Orn, X 12 An amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 18 is the amino acid residue of His, X 21 is the amino acid residue of Aib, X 22 An amino acid residue selected from Ala or Y1, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 31 is the amino acid residue of Asp, X 33 is the amino acid residue of Gly, X 35 is the amino acid residue of Glu, X 37 is an amino acid residue of Pro; or,

[0535] (vi) X1 is absent, X2 is an amino acid residue selected from Cys, Pen or Abu, X3 is an amino acid residue of Gln, X7 is an amino acid residue selected from Cys or Pen, X 10 is the amino acid residue of Gln, X 11 An amino acid residue selected from Arg, homoArg or Orn, X 12 An amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 18 is the amino acid residue of His, X 21 is the amino acid residue of Aib, X 22 is the amino acid residue of Ala, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 31 An amino acid residue selected from Asp or Y1, X 33 is the amino acid residue of Gly, X 35is the amino acid residue of Glu, X 37 It is the amino acid residue of Pro.

[0536] In some embodiments, the compound represented by the structure of Formula (I), Formula (Ia), Formula (II) or Formula (IIa), or a pharmaceutically acceptable salt thereof, is selected from any one of the following:

[0537] (a) X1 is absent, X2 is an amino acid residue selected from Cys, Pen or Abu, X3 is Y1, X7 is an amino acid residue selected from Cys or Pen, X 10 is the amino acid residue of Gln, X 11 An amino acid residue selected from Arg, hArg or Orn, X 12 An amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 17 is the amino acid residue of Val, X 18 is the amino acid residue of His, X 21 is the amino acid residue of Aib, X 22 is the amino acid residue of Ala, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 26 is the amino acid residue of Ile, X 31 is the amino acid residue of Asp, X 33 is the amino acid residue of Gly, X 35 An amino acid residue selected from Glu, X 37 is the amino acid residue of Pro;

[0538] or,

[0539] (a') X1 is absent, X2 is preferably Cys, X3 is Y1, X7 is an amino acid residue selected from Cys, X 10 is the amino acid residue of Gln, X 11 An amino acid residue selected from Arg, X 12 An amino acid residue selected from Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 17 is the amino acid residue of Val, X 18 is the amino acid residue of His, X 21 is the amino acid residue of Aib, X 22is the amino acid residue of Ala, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 26 is the amino acid residue of Ile, X 31 is the amino acid residue of Asp, X 33 is the amino acid residue of Gly, X 35 An amino acid residue selected from Glu, X 37 is the amino acid residue of Pro;

[0540] or,

[0541] (b) X1 is absent, X2 is an amino acid residue selected from Cys, Pen or Abu, X3 is an amino acid residue of Gln, X7 is an amino acid residue selected from Cys or Pen, X 10 It is Y1, X 11 An amino acid residue selected from Arg, homoArg or Orn, X 12 An amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 17 is the amino acid residue of Val, X 18 is the amino acid residue of His, X 21 is the amino acid residue of Aib, X 22 is the amino acid residue of Ala, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 26 is the amino acid residue of Ile, X 31 is the amino acid residue of Asp, X 33 is the amino acid residue of Gly, X 35 is the amino acid residue of Glu, X 37 is the amino acid residue of Pro;

[0542] or,

[0543] (b') X1 is absent, X2 is an amino acid residue selected from Cys, X3 is an amino acid residue of Gln, X7 is an amino acid residue selected from Cys, X 10 It is Y1, X 11 An amino acid residue selected from Arg, X 12 An amino acid residue selected from Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X15 is the amino acid residue of Phe, X 17 is the amino acid residue of Val, X 18 is the amino acid residue of His, X 21 is the amino acid residue of Aib, X 22 is the amino acid residue of Ala, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 26 is the amino acid residue of Ile, X 31 is the amino acid residue of Asp, X 33 is the amino acid residue of Gly, X 35 is the amino acid residue of Glu, X 37 is the amino acid residue of Pro;

[0544] or,

[0545] (c) X1 is absent, X2 is an amino acid residue selected from Cys, Pen or Abu, X3 is an amino acid residue of Gln, X7 is an amino acid residue selected from Cys or Pen, X 10 is the amino acid residue of Gln, X 11 It is Y1, X 12 An amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 17 is the amino acid residue of Val, X 18 is the amino acid residue of His, X 21 is the amino acid residue of Aib, X 22 is the amino acid residue of Ala, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 26 is the amino acid residue of Ile, X 31 is the amino acid residue of Asp, X 33 is the amino acid residue of Gly, X 35 is the amino acid residue of Glu, X 37 is the amino acid residue of Pro;

[0546] or,

[0547] (c') X1 is absent, X2 is an amino acid residue selected from Cys, X3 is an amino acid residue of Gln, X7 is an amino acid residue selected from Cys, X 10 is the amino acid residue of Gln, X11 It is Y1, X 12 An amino acid residue selected from Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 17 is the amino acid residue of Val, X 18 is the amino acid residue of His, X 21 is the amino acid residue of Aib, X 22 is the amino acid residue of Ala, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 26 is the amino acid residue of Ile, X 31 is the amino acid residue of Asp, X 33 is the amino acid residue of Gly, X 35 is the amino acid residue of Glu, X 37 is the amino acid residue of Pro;

[0548] or,

[0549] (d) X1 is absent, X2 is an amino acid residue selected from Cys, Pen or Abu, X3 is an amino acid residue of Gln, X7 is an amino acid residue selected from Cys or Pen, X 10 is the amino acid residue of Gln, X 11 An amino acid residue selected from Arg, homoArg or Orn, X 12 An amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 17 is the amino acid residue of Val or Aib, X 18 It is Y1, X 21 is the amino acid residue of Aib, X 22 is the amino acid residue of Ala, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 26 is an amino acid residue of Ile or N-Me-Ile, X 31 is the amino acid residue of Asp, X 33 is the amino acid residue of Gly, X 35 is the amino acid residue of Glu, X 37 is the amino acid residue of Pro;

[0550] or,

[0551] (d') X1 is absent, X2 is an amino acid residue selected from Cys, X3 is an amino acid residue of Gln, X7 is an amino acid residue selected from Cys, X 10 is the amino acid residue of Gln, X 11 An amino acid residue selected from Arg, homoArg or Orn, X 12 An amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 17 is the amino acid residue of Val or Aib, X 18 It is Y1, X 21 is the amino acid residue of Aib, X 22 is the amino acid residue of Ala, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 26 is an amino acid residue of Ile or N-Me-Ile, X 31 is the amino acid residue of Asp, X 33 is the amino acid residue of Gly, X 35 is the amino acid residue of Glu, X 37 is the amino acid residue of Pro;

[0552] or,

[0553] (e) X1 is absent, X2 is an amino acid residue selected from Cys, Pen or Abu, X3 is an amino acid residue of Gln, X7 is an amino acid residue selected from Cys or Pen, X 10 is the amino acid residue of Gln, X 11 An amino acid residue selected from Arg, homoArg or Orn, X 12 An amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 17 is the amino acid residue of Val, X 18 is the amino acid residue of His or Aib, X 21 is the amino acid residue of Aib or Ala, X 22 It is Y1, X 23 is the amino acid residue of 3-Pal, X24 is the amino acid residue of Gly, X 26 is the amino acid residue of Ile, X 31 is the amino acid residue of Asp, X 33 is the amino acid residue of Gly, X 35 is the amino acid residue of Glu, X 37 is the amino acid residue of Pro;

[0554] or,

[0555] (e') X1 is absent, X2 is an amino acid residue selected from Cys, Pen or Abu, X3 is an amino acid residue of Gln, X7 is an amino acid residue selected from Cys or Pen, X 10 is the amino acid residue of Gln, X 11 An amino acid residue selected from Arg, X 12 An amino acid residue selected from Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 17 is the amino acid residue of Val, X 18 is the amino acid residue of His or Aib, X 21 is the amino acid residue of Aib or Ala, X 22 It is Y1, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 26 is the amino acid residue of Ile, X 31 is the amino acid residue of Asp, X 33 is the amino acid residue of Gly, X 35 is the amino acid residue of Glu, X 37 is the amino acid residue of Pro;

[0556] or,

[0557] (f) X1 is absent, X2 is an amino acid residue selected from Cys, Pen or Abu, X3 is an amino acid residue of Gln, X7 is an amino acid residue selected from Cys or Pen, X 10 is the amino acid residue of Gln, X 11 An amino acid residue selected from Arg, homoArg or Orn, X 12 An amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X17 is the amino acid residue of Val, X 18 is the amino acid residue of His, X 21 is the amino acid residue of Aib, X 22 is the amino acid residue of Ala, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 26 is the amino acid residue of Ile, X 31 It is Y1, X 33 is the amino acid residue of Gly, X 35 is the amino acid residue of Glu, X 37 is the amino acid residue of Pro;

[0558] or,

[0559] (f) X1 is absent, X2 is an amino acid residue selected from Cys, X3 is an amino acid residue of Gln, X7 is an amino acid residue selected from Cys, X 10 is the amino acid residue of Gln, X 11 An amino acid residue selected from Arg, X 12 An amino acid residue selected from Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 17 is the amino acid residue of Val, X 18 is the amino acid residue of His, X 21 is the amino acid residue of Aib, X 22 is the amino acid residue of Ala, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 26 is the amino acid residue of Ile, X 31 It is Y1, X 33 is the amino acid residue of Gly, X 35 is the amino acid residue of Glu, X 37 It is the amino acid residue of Pro.

[0560] In some embodiments, as shown in any of the above (i) to (vi), (a) to (f), (a') to (f'), wherein Y1 is selected from a Lys, Orn, Dap, Dab, or Cys residue whose side chain is connected to a substituent. In some specific embodiments, Y1 is selected from a Lys residue whose side chain is connected to a substituent.

[0561] In some embodiments, as shown in any of the above (i) to (vi), (a) to (f), (a') to (f'), wherein R1 is hydrogen, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl, or pyroglutamyl. In some specific embodiments, wherein R1 is hydrogen or acetyl. In some specific embodiments, wherein R1 is acetyl.

[0562] In some embodiments, as shown in any of the above (i) to (vi), (a) to (f), (a') to (f'), wherein R2 is -NH2 or -OH. In some specific embodiments, wherein R2 is -NH2.

[0563] In some embodiments, the compound shown in any of the foregoing comprises a polypeptide sequence as described in any of the following:

[0564] Wherein, Y1 is selected from Lys, Orn, Dap, Dab or Cys residues, and the amino acid side chain of said Y1 may or may not be connected to a substituent. In some specific embodiments, Y1 is selected from Lys, Orn, Dap, Dab or Cys residues whose side chain is connected to a substituent. In some specific embodiments, Y1 is selected from Lys residues whose side chain is connected to a substituent.

[0565] In some specific embodiments, the compound shown in any of the foregoing comprises a polypeptide sequence as described in any of the following:

[0566] In some embodiments, the compound shown in any of the above items, wherein X2 and X7 form a disulfide bond, a methylenethioacetal bridge, a thioether bond, an o-phenylenedisulfide bridge, an m-phenylenedisulfide bridge, or a p-phenylenedisulfide bridge.

[0567] Illustratively, the disulfide bond, the methylenethioacetal bridge, the o-phenylenedisulfide bridge, the m-phenylenedisulfide bridge, and the p-phenylenedisulfide bridge are the following groups, respectively:

[0568] Illustratively, the thioether bond is selected from the group shown below:

[0569] In some specific embodiments, a disulfide bond or a methylenethioacetal bridge is formed between X2 and X7.

[0570] In some embodiments, one amino acid residue between X2 and X7 is selected from Cys, homoCys or Pen, and the other amino acid residue is selected from Cys, homoCys or Pen, and a disulfide bond, a methylenethioacetal bridge, an o-phenylenedisulfide bridge, an m-phenylenedisulfide bridge or a p-phenylenedisulfide bridge is formed between X2 and X7.

[0571] Illustratively, X2 is selected from Cys, homoCys or Pen, and X7 is selected from Cys, homoCys or Pen; a disulfide bond, a methylenethioacetal bridge, an o-phenylenedisulfide bridge, an m-phenylenedisulfide bridge or a p-phenylenedisulfide bridge is formed between X2 and X7.

[0572] In some specific embodiments, one of the amino acid residues between X2 and X7 is selected from Cys, hCys or Pen, and the other amino acid residue is Abu, and a thioether bond is formed between X2 and X7.

[0573] Illustratively, X2 is selected from Cys, homoCys or Pen, X7 is selected from Abu, and a thioether bond I is formed between X2 and X7. Alternatively, X2 is selected from Abu, X7 is selected from Cys, homoCys or Pen, and a thioether bond II is formed between X2 and X7.

[0574] In some embodiments, the compound shown in any of the foregoing comprises a polypeptide sequence as described in any of the following:

[0575] Among them, in the sequences shown in SEQ ID NOs: 38 to 45, a disulfide bond is formed between the side chain of the Cys residue at position X2 and the Cys residue at position X7; in the sequence shown in SEQ ID NO: 46, a thioether bond is formed between the side chain of the Abu residue at position X2 and the Cys residue at position X7; and in the sequences shown in SEQ ID NOs: 47 to 54 and 61-63, a methylenethioacetal bridge is formed between the side chain of the Cys residue at position X2 and the Cys residue at position X7.

[0576] homoR is homoarginine (i.e., homoArg, homoarginine), NMeL is N-Me-Leu (i.e., N-methyl-leucine), NMeI is N-Me-Ile (i.e., N-methyl-isoleucine), aMeL is a-Me-Leu (i.e., a-methyl-leucine), DL is D-Leu (i.e., D-leucine), Orn is ornithine, Aib is 2-aminoisobutyric acid, Abu is 2-aminobutyric acid, 3-Pal is 3-pyridylalanine, and Pen is penicillamine.

[0577] In some embodiments, the compound of any of the aforementioned structures comprises one or more (eg, 2, 3, 4, 5, 6, etc.) substituents.

[0578] In some embodiments, the substituent comprises a linker and a chemical moiety connected to the polypeptide backbone via the linker. Exemplarily, the substituent comprises the structure shown below: -Z1-Z2.

[0579] In some embodiments, the linker (Z1) comprises an amino acid, an aminopolyethylene glycol carboxylate, or a mixture thereof.

[0580] In some embodiments, Z1 comprises 0-10 amino acid residues independently selected from Glu, Gly, γGlu, AEEA, Ala, Ser, Thr. Exemplarily, Z1 includes, but is not limited to: γGlu, γGlu-γGlu, γGlu-γGlu-γGlu, γGlu-γGlu-γGlu-γGlu, Glu, Glu-Glu, Glu-γGlu, Glu-Al a, Glu-Glu-Ala, Ala, Ser, Ser-Ser, Thr, Thr-Thr, Thr-γGlu, Ala-γGlu, Ala-Ala-γGlu, Thr-Thr-γGlu, Gly, G ly-γGlu,Ser,Ser-γGlu,Ser-Ser,-Gly-Ser-Ser,Ser-Ser,-Gly-Ser-Ser-γGlu,Ser-Ser-Gly-Ser-Ser-Gly , Ser-Ser-Gly-Ser-Ser-Gly-γGlu, γGlu-AEEA, γGlu-AEEA-AEEA, γGlu-γGlu-AEEA, γGlu-γGlu-AEEA-AEEA, etc.

[0581] As described in this application, the "-AEEA-" structure is as follows:

[0582] In some embodiments, Z1 comprises the structure shown below: -(AEEA) 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 4 (e.g., 1, 2, 3, or 4); 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.

[0583] In some embodiments, the chemical moiety (Z2) connected to the linker is a fatty acid group. For example, 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 18 diacid), 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.

[0584] 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 12 and 22 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22). In some specific embodiments, c is any integer between 14 and 20 (e.g., 14, 15, 16, 17, 18, 19, or 20). In some specific embodiments, c is 14, 16, 18, or 20. In some specific embodiments, c is 16 or 18.

[0585] In some embodiments, the substituent has the structure shown below {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γGlu) b -CO-(CH2) c -COOH;

[0586] wherein a is any integer between 0 and 4 (e.g., 0, 1, 2, 3, or 4), b is any integer between 1 and 4 (e.g., 1, 2, 3, or 4), 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).

[0587] In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is any integer from 12 to 22 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22).

[0588] In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is any integer from 14 to 20 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22).

[0589] In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is 14, 16, 18 or 20.

[0590] In some specific embodiments, a is 1, 2 or 3, b is 1 or 2, and c is 14, 16, 18 or 20.

[0591] In some specific embodiments, a is 2 or 3, b is 1 or 2, and c is 14, 16, 18 or 20.

[0592] In some specific embodiments, a is 1 or 2, b is 3, and c is 14, 16, 18 or 20.

[0593] In some specific embodiments, a is 2, b is 1 or 2, and c is 16, 18, or 20. Alternatively, a is 1 or 2, b is 3, and c is 16, 18, or 20.

[0594] In some specific embodiments, a is 2, b is 1 or 2, and c is 16 or 18. Alternatively, a is 1 or 2, b is 3, and c is 16 or 18.

[0595] In some specific embodiments, a is 2, b is 1, and c is 16 or 18. Or, a is 1, b is 3, and c is 16 or 18. Or, a is 2, b is 3, and c is 16 or 18.

[0596] In some specific embodiments, the substituent comprises the following structure:

[0597] In some specific embodiments, the substituent comprises the following structure:

[0598] In some embodiments, the substituent is attached to a functional group in the polypeptide backbone that is suitable for attachment. Examples of amino acids that include such functional groups include, but are not limited to, Lys, Orn, Dap, Dab, or Cys residues.

[0599] In some embodiments, Y1 is a Lys, Orn, Dap, Dab or Cys residue of a side chain-linked substituent. In some embodiments, the structure of the substituent is: -Z1-Z2, wherein, in some embodiments, Z1 comprises (or is) 0-10 amino acid residues independently selected from Glu, Gly, γGlu, AEEA, Ala, Ser, Thr. Z2 comprises (or is) C 12-32 In some embodiments, the substituent is covalently linked to the amino acid side chain of Y1.

[0600] In some embodiments, Z1 comprises (or is) the structure shown below: -(AEEA) 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 4 (e.g., 1, 2, 3, or 4); in some specific embodiments, a is 1, 2, or 3, and b is 1, 2, or 3. 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. In some specific embodiments, a is 1 or 2, and b is 3. In some specific embodiments, a is 1, and b is 3. In some specific embodiments, a is 2, and b is 3.

[0601] 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). In some specific embodiments, c is any integer between 12 and 22 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22). In some specific embodiments, c is any integer between 14 and 20 (e.g., 14, 15, 16, 17, 18, 19, or 20). In some specific embodiments, c is 14, 16, 18, or 20. In some specific embodiments, c is 16 or 18.

[0602] In some embodiments, the substituent has the structure shown below {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γGlu)b -CO-(CH2) c -COOH;

[0603] wherein a is any integer between 0 and 4 (e.g., 0, 1, 2, 3, or 4), b is any integer between 1 and 4 (e.g., 1, 2, 3, or 4), 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).

[0604] In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is any integer from 12 to 22 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22). In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is any integer from 14 to 20 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22). In some specific embodiments, a is 1, 2 or 3, b is 1 or 2, and c is 14, 16, 18 or 20. In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is 14, 16, 18 or 20. In some specific embodiments, a is 2 or 3, b is 1 or 2, and c is 14, 16, 18 or 20. In some specific embodiments, a is 1 or 2, b is 3, and c is 14, 16, 18, or 20. In some specific embodiments, a is 2, b is 1 or 2, and c is 16, 18, or 20. Or, a is 1 or 2, b is 3, 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. Or, a is 1 or 2, b is 3, and c is 16 or 18.

[0605] In some specific embodiments, a is 2, b is 1, and c is 16 or 18. Or, a is 1, b is 3, and c is 16 or 18. Or, a is 2, b is 3, and c is 16 or 18.

[0606] In some embodiments, Y1 is a Lys residue with a side chain linked substituent, wherein the substituent is covalently linked to the ε-amino group of the Lys residue via an amide bond. In some embodiments, the Y1 is selected from: K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH), K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH),

[0607] K(-AEEA-AEEA-(γGlu)3-C(O)-C 18-COOH), or K(-AEEA-γGlu-C(O)-C 18 -COOH);

[0608] The K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH) has the structure:

[0609] , the K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[0610] The K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH) has the structure:

[0611] The K(-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[0612] In some embodiments, the Y1 comprises (or is) the structure shown below:

[0613] In some embodiments, the substituents may also be other chemical groups that can be used to extend the half-life in vivo, including but not limited to the substituents disclosed in WO2012168432, WO2012168431, WO2012168430, WO2016146739, and WO2022187305. The aforementioned patents are incorporated into the present disclosure by reference.

[0614] In some embodiments, the present disclosure provides a compound having a structure represented by the following formula (I) or a pharmaceutically acceptable salt thereof: X1-X2-X3-Thr-Ala-Thr-X7-Ala-Thr-X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -Leu-X 17 -X 18 -Ser-Ser- X 21 -X 22 -X 23 -X 24 -Pro-X 26 -Leu-Pro-Pro-Thr-X 31 -Val-X 33 -Ser-X35 -Thr-X 37 (I);

[0615] in:

[0616] X1 is an amino acid residue selected from Lys or is absent;

[0617] X2 is an amino acid residue selected from Cys, homoCys, Pen or Abu;

[0618] X3 is an amino acid residue selected from Asn, Gln, Asp, Glu or Y1;

[0619] X7 is an amino acid residue selected from Cys, homoCys, Pen or Abu;

[0620] X 10 an amino acid residue selected from Gln, Asn, Glu, Asp, or Y1;

[0621] X 11 an amino acid residue selected from Arg, homoArg, Orn, D-Arg, or Y1;

[0622] X 12 an amino acid residue selected from Leu, hLeu, N-MeLeu, α-Me-Leu or D-Leu;

[0623] X 13 is an amino acid residue of Ala or Aib;

[0624] X 14 is the amino acid residue of Aib or Ala;

[0625] X 15 is the amino acid residue of Phe;

[0626] X 17 an amino acid residue selected from Val or Aib;

[0627] X 18 an amino acid residue selected from His, Aib, or Y1;

[0628] X 21 is an amino acid residue of Asn, Gln, Glu, Ala or Aib;

[0629] X 22 an amino acid residue selected from Asn, Ala, or Y1;

[0630] X 23 an amino acid residue selected from Phe or 3-Pal;

[0631] X 24is the amino acid residue of Gly;

[0632] X 26 an amino acid residue selected from Ile or N-Me-Ile;

[0633] X 31 an amino acid residue selected from Asn, Asp, Glu, Gln, or Y1;

[0634] X 33 is the amino acid residue of Gly;

[0635] X 35 an amino acid residue selected from Glu, Asn, Asp or Gln;

[0636] X 37 an amino acid residue selected from Tyr or Pro;

[0637] Y1 is selected from the group consisting of Lys, Orn, Dap, Dab or Cys residues with a side chain substituent having the structure: -Z1-Z2.

[0638] Z1 contains (or is) the following structure: -(AEEA) a -(γGlu) b -, a is any integer between 0 and 4 (e.g., 0, 1, 2, 3 or 4), b is any integer between 1 and 4 (e.g., 1, 2, 3 or 4); and / or, 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).

[0639] In some embodiments, the substituent has the structure shown below {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γGlu) b -CO-(CH2) c -COOH;

[0640] wherein a is any integer between 0 and 4 (e.g., 0, 1, 2, 3, or 4), b is any integer between 1 and 4 (e.g., 1, 2, 3, or 4), 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).

[0641] In some specific embodiments, a is 1, 2 or 3, b is 1 or 2, and c is any integer from 12 to 22 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22). In some specific embodiments, a is 1, 2 or 3, b is 1 or 2, and c is any integer from 14 to 20 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22). In some specific embodiments, a is 1, 2 or 3, b is 1 or 2, and c is 14, 16, 18 or 20. In some specific embodiments, a is 2, b is 1 or 2, and c is 14, 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.

[0642] In some specific embodiments, Y1 is a Lys residue with a side chain connected to a substituent, and the substituent is covalently linked to the ε-amino group of the Lys residue through an amide bond. In some specific embodiments, the Y1 is selected from K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH) or K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH),

[0643] The K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH) has the structure:

[0644] , the K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[0645] In some embodiments, X 13 X 14 is Ala-Aib, Ala-Ala, Aib-Ala, or Aib-Aib. In some embodiments, X 13 X 14 It's Ala-Aib, Aib-Aib, or Aib-Ala.

[0646] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0647] X1 does not exist;

[0648] X2 is an amino acid residue selected from Cys, Pen or Abu;

[0649] X3 is selected from the amino acid residue of Gln or Y1;

[0650] X7 is an amino acid residue selected from Cys or Pen;

[0651] X 10 an amino acid residue selected from Gln or Y1;

[0652] X 11 an amino acid residue selected from Arg, homoArg, Orn, or Y1;

[0653] X 12 an amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu;

[0654] X 13 is an amino acid residue of Ala or Aib;

[0655] X 14 is an amino acid residue of Ala or Aib;

[0656] X 15 is the amino acid residue of Phe;

[0657] X 17 an amino acid residue selected from Val or Aib;

[0658] X 18 an amino acid residue selected from His, Aib, or Y1;

[0659] X 21 is the amino acid residue of Aib or Ala;

[0660] X 22 an amino acid residue selected from Ala or Y1;

[0661] X 23 is the amino acid residue of 3-Pal;

[0662] X 24 is the amino acid residue of Gly;

[0663] X 26 an amino acid residue selected from Ile or N-Me-Ile;

[0664] X 31 is the amino acid residue of Asp or Y1;

[0665] X 33 is the amino acid residue of Gly;

[0666] X 35 is the amino acid residue of Glu;

[0667] X 37 is the amino acid residue of Pro;

[0668] Y1 is selected from a Lys residue of a side chain-linked substituent, wherein the substituent has the structure: -Z1-Z2.

[0669] Z1 contains (or is) the following structure: -(AEEA) a -(γGlu) b -, a is any integer between 0 and 4 (e.g., 0, 1, 2, 3 or 4), b is any integer between 1 and 4 (e.g., 1, 2, 3 or 4); and / or, 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).

[0670] In some embodiments, the substituent has the structure shown below {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γGlu) b -CO-(CH2) c -COOH;

[0671] wherein a is any integer between 0 and 4 (e.g., 0, 1, 2, 3, or 4), b is any integer between 1 and 4 (e.g., 1, 2, 3, or 4), 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).

[0672] In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is any integer from 12 to 22 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22). In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is any integer from 14 to 20 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22). In some specific embodiments, a is 1, 2 or 3, b is 1 or 2, and c is 14, 16, 18 or 20. In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is 14, 16, 18 or 20. In some specific embodiments, a is 2 or 3, b is 1 or 2, and c is 14, 16, 18 or 20. In some specific embodiments, a is 1 or 2, b is 3, and c is 14, 16, 18, or 20. In some specific embodiments, a is 2, b is 1 or 2, and c is 16, 18, or 20. Or, a is 1 or 2, b is 3, 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. Or, a is 1 or 2, b is 3, and c is 16 or 18.

[0673] In some specific embodiments, a is 2, b is 1, and c is 16 or 18. Or, a is 1, b is 3, and c is 16 or 18. Or, a is 2, b is 3, and c is 16 or 18.

[0674] In some specific 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.

[0675] In some embodiments, Y1 is selected from the group consisting of: K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH), K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH),

[0676] K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH), or K(-AEEA-γGlu-C(O)-C 18 -COOH);

[0677] The K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH) has the structure:

[0678] , the K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[0679] The K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH) has the structure:

[0680] The K(-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[0681] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0682] X1 does not exist;

[0683] X2 is an amino acid residue selected from Cys, Pen or Abu;

[0684] X3 is selected from the amino acid residue of Gln or Y1;

[0685] X7 is an amino acid residue selected from Cys or Pen;

[0686] X 10 an amino acid residue selected from Gln or Y1;

[0687] X 11 an amino acid residue selected from Arg, homoArg, Orn, or Y1;

[0688] X 12 an amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu;

[0689] X 13 X 14 Selected from Ala-Aib, Aib-Ala or Aib-Aib;

[0690] X 15 is the amino acid residue of Phe;

[0691] X 17 an amino acid residue selected from Val or Aib;

[0692] X 18 an amino acid residue selected from His, Aib, or Y1;

[0693] X 21 is an amino acid residue of Ala or Aib;

[0694] X 22 an amino acid residue selected from Ala or Y1;

[0695] X23 is the amino acid residue of 3-Pal;

[0696] X 24 is the amino acid residue of Gly;

[0697] X 26 an amino acid residue selected from Ile or N-Me-Ile;

[0698] X 31 is the amino acid residue of Asp or Y1;

[0699] X 33 is the amino acid residue of Gly;

[0700] X 35 is the amino acid residue of Glu;

[0701] X 37 is the amino acid residue of Pro;

[0702] Y1 is a Lys residue having a side chain connected to a substituent having the structure shown below {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γGlu) b -CO-(CH2) c -COOH;

[0703] wherein a is any integer between 0 and 4 (e.g., 0, 1, 2, 3, or 4), b is any integer between 1 and 4 (e.g., 1, 2, 3, or 4), 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).

[0704] In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is any integer from 12 to 22 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22). In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is any integer from 14 to 20 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22). In some specific embodiments, a is 1, 2 or 3, b is 1 or 2, and c is 14, 16, 18 or 20. In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is 14, 16, 18 or 20. In some specific embodiments, a is 2 or 3, b is 1 or 2, and c is 14, 16, 18 or 20. In some specific embodiments, a is 1 or 2, b is 3, and c is 14, 16, 18, or 20. In some specific embodiments, a is 2, b is 1 or 2, and c is 16, 18, or 20. Or, a is 1 or 2, b is 3, 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. Or, a is 1 or 2, b is 3, and c is 16 or 18.

[0705] In some specific embodiments, a is 2, b is 1, and c is 16 or 18. Or, a is 1, b is 3, and c is 16 or 18. Or, a is 2, b is 3, and c is 16 or 18.

[0706] In some specific 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.

[0707] In some embodiments, Y1 is selected from the group consisting of: K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH), K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH),

[0708] K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH), or K(-AEEA-γGlu-C(O)-C 18 -COOH);

[0709] The K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH) has the structure:

[0710] , the K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[0711] The K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH) has the structure:

[0712] The K(-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[0713] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0714] X1 does not exist;

[0715] X2 is an amino acid residue selected from Cys, Pen or Abu;

[0716] X3 is selected from the amino acid residue of Gln or Y1;

[0717] X7 is an amino acid residue selected from Cys or Pen;

[0718] X 10 an amino acid residue selected from Gln or Y1;

[0719] X 11 an amino acid residue selected from Arg, homoArg, Orn, or Y1;

[0720] X 12 an amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu;

[0721] X 13 X 14 Selected from Ala-Aib;

[0722] X 15 is the amino acid residue of Phe;

[0723] X 17 an amino acid residue selected from Val or Aib;

[0724] X 18 an amino acid residue selected from His, Aib, or Y1;

[0725] X 21 is an amino acid residue of Ala or Aib;

[0726] X 22 an amino acid residue selected from Ala or Y1;

[0727] X 23is the amino acid residue of 3-Pal;

[0728] X 24 is the amino acid residue of Gly;

[0729] X 26 an amino acid residue selected from Ile or N-Me-Ile;

[0730] X 31 is the amino acid residue of Asp or Y1;

[0731] X 33 is the amino acid residue of Gly;

[0732] X 35 is the amino acid residue of Glu;

[0733] X 37 is the amino acid residue of Pro;

[0734] Y1 is a Lys residue having a side chain connected to a substituent having the structure shown below {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γGlu) b -CO-(CH2) c -COOH;

[0735] wherein a is any integer between 0 and 4 (e.g., 0, 1, 2, 3, or 4), b is any integer between 1 and 4 (e.g., 1, 2, 3, or 4), 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).

[0736] In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is any integer from 12 to 22 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22). In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is any integer from 14 to 20 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22). In some specific embodiments, a is 1, 2 or 3, b is 1 or 2, and c is 14, 16, 18 or 20. In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is 14, 16, 18 or 20. In some specific embodiments, a is 2 or 3, b is 1 or 2, and c is 14, 16, 18 or 20. In some specific embodiments, a is 1 or 2, b is 3, and c is 14, 16, 18, or 20. In some specific embodiments, a is 2, b is 1 or 2, and c is 16, 18, or 20. Or, a is 1 or 2, b is 3, 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. Or, a is 1 or 2, b is 3, and c is 16 or 18.

[0737] In some specific embodiments, a is 2, b is 1, and c is 16 or 18. Or, a is 1, b is 3, and c is 16 or 18. Or, a is 2, b is 3, and c is 16 or 18.

[0738] In some specific 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.

[0739] In some embodiments, Y1 is selected from the group consisting of: K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH), K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH),

[0740] K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH), or K(-AEEA-γGlu-C(O)-C 18 -COOH);

[0741] The K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH) has the structure:

[0742] , the K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[0743] The K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH) has the structure:

[0744] The K(-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[0745] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0746] X1 does not exist;

[0747] X2 is an amino acid residue selected from Cys, Pen or Abu;

[0748] X3 is selected from the amino acid residue of Gln or Y1;

[0749] X7 is the amino acid residue of Cys;

[0750] X 10 is the amino acid residue of Gln;

[0751] X 11 an amino acid residue selected from Arg, homoArg, Orn, or Y1;

[0752] X 12 an amino acid residue selected from Leu or α-Me-Leu;

[0753] X 13 is the amino acid residue of Ala,

[0754] X 14 is the amino acid residue of Aib;

[0755] X 15 is the amino acid residue of Phe;

[0756] X 17 an amino acid residue selected from Val or Aib;

[0757] X 18 an amino acid residue selected from His, Aib, or Y1;

[0758] X 21 is an amino acid residue of Ala or Aib;

[0759] X 22 an amino acid residue selected from Ala or Y1;

[0760] X23 is the amino acid residue of 3-Pal;

[0761] X 24 is the amino acid residue of Gly;

[0762] X 26 an amino acid residue selected from Ile or N-Me-Ile;

[0763] X 31 is the amino acid residue of Asp or Y1;

[0764] X 33 is the amino acid residue of Gly;

[0765] X 35 is the amino acid residue of Glu;

[0766] X 37 is the amino acid residue of Pro;

[0767] Said Y1 is selected from: K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH), K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH),

[0768] K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH), or K(-AEEA-γGlu-C(O)-C 18 -COOH);

[0769] The K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH) has the structure:

[0770] , the K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[0771] The K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH) has the structure:

[0772] The K(-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[0773] In some embodiments, in any of the aforementioned compounds, a disulfide bond, a methylenethioacetal bridge, a thioether bond, an o-phenylenedisulfide bridge, an m-phenylenedisulfide bridge, or a p-phenylenedisulfide bridge is formed between the amino acid residues at positions 2 and 7. In some specific embodiments, in any of the aforementioned compounds, a disulfide bond, a methylenethioacetal bridge, or a thioether bond is formed between the amino acid residues at positions 2 and 7.

[0774] In some embodiments, the present disclosure provides a compound having a structure represented by the following formula (II) or a pharmaceutically acceptable salt thereof: R1-X1-X2-X3-Thr-Ala-Thr-X7-Ala-Thr-X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -Leu-X 17 -X 18 -Ser- Ser-X 21 -X 22 -X 23 -X 24 -Pro-X 26 -Leu-Pro-Pro-Thr-X 31 -Val-X 33 -Ser-X 35 -Thr-X 37 -R2(II);

[0775] in:

[0776] R1 is H, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pyroglutamyl;

[0777] R2 is -NH2 or -OH;

[0778] X1 is an amino acid residue selected from Lys or is absent;

[0779] X2 is an amino acid residue selected from Cys, homoCys, Pen or Abu;

[0780] X3 is an amino acid residue selected from Asn, Gln, Asp, Glu or Y1;

[0781] X7 is an amino acid residue selected from Cys, homoCys, Pen or Abu;

[0782] X 10 an amino acid residue selected from Gln, Asn, Glu, Asp, or Y1;

[0783] X 11an amino acid residue selected from Arg, homoArg, Orn, D-Arg, or Y1;

[0784] X 12 an amino acid residue selected from Leu, hLeu, N-MeLeu, α-Me-Leu or D-Leu;

[0785] X 13 is an amino acid residue of Ala or Aib;

[0786] X 14 is the amino acid residue of Aib or Ala;

[0787] X 15 is the amino acid residue of Phe;

[0788] X 17 an amino acid residue selected from Val or Aib;

[0789] X 18 an amino acid residue selected from His, Aib, or Y1;

[0790] X 21 is an amino acid residue of Asn, Gln, Glu, Ala or Aib;

[0791] X 22 an amino acid residue selected from Asn, Ala, or Y1;

[0792] X 23 an amino acid residue selected from Phe, 2-Pal, 4-Pal, hPhe or 3-Pal;

[0793] X 24 is the amino acid residue of Gly;

[0794] X 26 an amino acid residue selected from Ile or N-Me-Ile;

[0795] X 31 an amino acid residue selected from Asn, Asp, Glu, Gln, or Y1;

[0796] X 33 is the amino acid residue of Gly;

[0797] X 35 an amino acid residue selected from Glu, Asn, Asp or Gln;

[0798] X 37 an amino acid residue selected from Tyr or Pro;

[0799] Y1 is selected from the group consisting of Lys, Orn, Dap, Dab or Cys residues with a side chain substituent having the structure: -Z1-Z2.

[0800] Z1 contains (or is) the following structure: -(AEEA) a -(γGlu) b -, a is any integer between 0 and 4 (e.g., 0, 1, 2, 3 or 4), b is any integer between 1 and 4 (e.g., 1, 2, 3 or 4); and / or, 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).

[0801] In some embodiments, the substituent has the structure shown below {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γGlu) b -CO-(CH2) c -COOH;

[0802] wherein a is any integer between 0 and 4 (e.g., 0, 1, 2, 3, or 4), b is any integer between 1 and 4 (e.g., 1, 2, 3, or 4), 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).

[0803] In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is any integer from 12 to 22 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22). In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is any integer from 14 to 20 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22). In some specific embodiments, a is 1, 2 or 3, b is 1 or 2, and c is 14, 16, 18 or 20. In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is 14, 16, 18 or 20. In some specific embodiments, a is 2 or 3, b is 1 or 2, and c is 14, 16, 18 or 20. In some specific embodiments, a is 1 or 2, b is 3, and c is 14, 16, 18, or 20. In some specific embodiments, a is 2, b is 1 or 2, and c is 16, 18, or 20. Or, a is 1 or 2, b is 3, 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. Or, a is 1 or 2, b is 3, and c is 16 or 18.

[0804] In some specific embodiments, a is 2, b is 1, and c is 16 or 18. Or, a is 1, b is 3, and c is 16 or 18. Or, a is 2, b is 3, and c is 16 or 18.

[0805] In some specific 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.

[0806] In some embodiments, Y1 is selected from the group consisting of: K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH), K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH),

[0807] K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH), or K(-AEEA-γGlu-C(O)-C 18 -COOH);

[0808] The K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH) has the structure:

[0809] , the K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[0810] The K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH) has the structure:

[0811] The K(-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[0812] In some embodiments, X 13 X 14 is Ala-Aib, Ala-Ala, Aib-Ala, or Aib-Aib. In some embodiments, X 13 X 14 is Ala-Aib, Aib-Aib, or Aib-Ala. In some embodiments, X 13 X 14 It is Ala-Aib.

[0813] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein:

[0814] R1 is acetyl, R2 is -NH2;

[0815] X1 does not exist;

[0816] X2 is an amino acid residue selected from Cys, Pen or Abu;

[0817] X3 is selected from the amino acid residue of Gln or Y1;

[0818] X7 is an amino acid residue selected from Cys or Pen;

[0819] X 10 an amino acid residue selected from Gln or Y1;

[0820] X 11 an amino acid residue selected from Arg, homoArg, Orn, or Y1;

[0821] X 12 an amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu;

[0822] X 13 is an amino acid residue of Ala or Aib;

[0823] X 14 is the amino acid residue of Aib or Ala;

[0824] X 15 is the amino acid residue of Phe;

[0825] X 17 an amino acid residue selected from Val or Aib;

[0826] X 18 an amino acid residue selected from His, Aib, or Y1;

[0827] X 21 is the amino acid residue of Aib or Ala;

[0828] X 22 an amino acid residue selected from Ala or Y1;

[0829] X 23 is the amino acid residue of 3-Pal;

[0830] X 24 is the amino acid residue of Gly;

[0831] X 26 an amino acid residue selected from Ile or N-Me-Ile;

[0832] X 31 is the amino acid residue of Asp or Y1;

[0833] X 33 is the amino acid residue of Gly;

[0834] X 35 is the amino acid residue of Glu;

[0835] X 37 It is the amino acid residue of Pro.

[0836] Y1 is selected from the group consisting of Lys, Orn, Dap, Dab or Cys residues with a side chain substituent having the structure: -Z1-Z2.

[0837] Z1 contains (or is) the following structure: -(AEEA) a -(γGlu) b -, a is any integer between 0 and 4 (e.g., 0, 1, 2, 3 or 4), b is any integer between 1 and 4 (e.g., 1, 2, 3 or 4); and / or, 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).

[0838] In some embodiments, the substituent has the structure shown below {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γGlu) b -CO-(CH2) c -COOH;

[0839] wherein a is any integer between 0 and 4 (e.g., 0, 1, 2, 3, or 4), b is any integer between 1 and 4 (e.g., 1, 2, 3, or 4), 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).

[0840] In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is any integer from 12 to 22 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22). In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is any integer from 14 to 20 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22). In some specific embodiments, a is 1, 2 or 3, b is 1 or 2, and c is 14, 16, 18 or 20. In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is 14, 16, 18 or 20. In some specific embodiments, a is 2 or 3, b is 1 or 2, and c is 14, 16, 18 or 20. In some specific embodiments, a is 1 or 2, b is 3, and c is 14, 16, 18, or 20. In some specific embodiments, a is 2, b is 1 or 2, and c is 16, 18, or 20. Or, a is 1 or 2, b is 3, 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. Or, a is 1 or 2, b is 3, and c is 16 or 18.

[0841] In some specific embodiments, a is 2, b is 1, and c is 16 or 18. Or, a is 1, b is 3, and c is 16 or 18. Or, a is 2, b is 3, and c is 16 or 18.

[0842] In some specific embodiments, Y1 is a Lys residue with a side chain connected to a substituent, and the substituent is covalently linked to the ε-amino group of the Lys residue through an amide bond. In some embodiments, the Y1 is selected from: K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH), K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH),

[0843] K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH), or K(-AEEA-γGlu-C(O)-C 18 -COOH);

[0844] The K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH) has the structure:

[0845] , the K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[0846] The K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH) has the structure:

[0847] The K(-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[0848] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein:

[0849] R1 is acetyl, R2 is -NH2;

[0850] X1 does not exist;

[0851] X2 is an amino acid residue selected from Cys, Pen or Abu;

[0852] X3 is selected from the amino acid residue of Gln or Y1;

[0853] X7 is an amino acid residue selected from Cys or Pen;

[0854] X 10 an amino acid residue selected from Gln or Y1;

[0855] X 11 an amino acid residue selected from Arg, homoArg, Orn, or Y1;

[0856] X 12 an amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu;

[0857] X 13 X 14Selected from Ala-Aib, Aib-Ala or Aib-Aib;

[0858] X 15 is the amino acid residue of Phe;

[0859] X 17 an amino acid residue selected from Val or Aib;

[0860] X 18 an amino acid residue selected from His, Aib, or Y1;

[0861] X 21 is the amino acid residue of Aib or Ala;

[0862] X 22 an amino acid residue selected from Ala or Y1;

[0863] X 23 is the amino acid residue of 3-Pal;

[0864] X 24 is the amino acid residue of Gly;

[0865] X 26 an amino acid residue selected from Ile or N-Me-Ile;

[0866] X 31 is the amino acid residue of Asp or Y1;

[0867] X 33 is the amino acid residue of Gly;

[0868] X 35 is the amino acid residue of Glu;

[0869] X 37 is the amino acid residue of Pro;

[0870] Y1 is a Lys residue having a side chain connected to a substituent having the structure shown below {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γGlu) b -CO-(CH2) c -COOH;

[0871] wherein a is any integer between 0 and 4 (e.g., 0, 1, 2, 3, or 4), b is any integer between 1 and 4 (e.g., 1, 2, 3, or 4), 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).

[0872] In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is any integer from 12 to 22 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22). In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is any integer from 14 to 20 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22). In some specific embodiments, a is 1, 2 or 3, b is 1 or 2, and c is 14, 16, 18 or 20. In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is 14, 16, 18 or 20. In some specific embodiments, a is 2 or 3, b is 1 or 2, and c is 14, 16, 18 or 20. In some specific embodiments, a is 1 or 2, b is 3, and c is 14, 16, 18, or 20. In some specific embodiments, a is 2, b is 1 or 2, and c is 16, 18, or 20. Or, a is 1 or 2, b is 3, 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. Or, a is 1 or 2, b is 3, and c is 16 or 18.

[0873] In some specific embodiments, a is 2, b is 1, and c is 16 or 18. Or, a is 1, b is 3, and c is 16 or 18. Or, a is 2, b is 3, and c is 16 or 18.

[0874] In some embodiments, Y1 is a Lys residue with a side chain linked substituent, wherein the substituent is covalently linked to the ε-amino group of the Lys residue via an amide bond. In some embodiments, the Y1 is selected from: K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH), K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH),

[0875] K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH), or K(-AEEA-γGlu-C(O)-C 18 -COOH);

[0876] The K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH) has the structure:

[0877] , the K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[0878] The K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH) has the structure:

[0879] The K(-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[0880] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein:

[0881] R1 is acetyl, R2 is -NH2;

[0882] X1 does not exist;

[0883] X2 is an amino acid residue selected from Cys, Pen or Abu;

[0884] X3 is selected from the amino acid residue of Gln or Y1;

[0885] X7 is an amino acid residue selected from Cys or Pen;

[0886] X 10 an amino acid residue selected from Gln or Y1;

[0887] X 11 an amino acid residue selected from Arg, homoArg, Orn, or Y1;

[0888] X 12 an amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu;

[0889] X 13 X 14 Selected from Ala-Aib;

[0890] X 15 is the amino acid residue of Phe;

[0891] X 17 an amino acid residue selected from Val or Aib;

[0892] X 18 an amino acid residue selected from His or Aib or Y1;

[0893] X 21 is an amino acid residue of Ala or Aib;

[0894] X 22 an amino acid residue selected from Ala or Y1;

[0895] X23 is the amino acid residue of 3-Pal;

[0896] X 24 is the amino acid residue of Gly;

[0897] X 26 an amino acid residue selected from Ile or N-Me-Ile;

[0898] X 31 is the amino acid residue of Asp or Y1;

[0899] X 33 is the amino acid residue of Gly;

[0900] X 35 is the amino acid residue of Glu;

[0901] X 37 is the amino acid residue of Pro;

[0902] Y1 is a Lys residue having a side chain connected to a substituent having the structure shown below {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γGlu) b -CO-(CH2) c -COOH;

[0903] wherein a is any integer between 0 and 4 (e.g., 0, 1, 2, 3, or 4), b is any integer between 1 and 4 (e.g., 1, 2, 3, or 4), 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).

[0904] In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is any integer from 12 to 22 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22). In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is any integer from 14 to 20 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22). In some specific embodiments, a is 1, 2 or 3, b is 1 or 2, and c is 14, 16, 18 or 20. In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is 14, 16, 18 or 20. In some specific embodiments, a is 2 or 3, b is 1 or 2, and c is 14, 16, 18 or 20. In some specific embodiments, a is 1 or 2, b is 3, and c is 14, 16, 18, or 20. In some specific embodiments, a is 2, b is 1 or 2, and c is 16, 18, or 20. Or, a is 1 or 2, b is 3, 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. Or, a is 1 or 2, b is 3, and c is 16 or 18.

[0905] In some specific embodiments, a is 2, b is 1, and c is 16 or 18. Or, a is 1, b is 3, and c is 16 or 18. Or, a is 2, b is 3, and c is 16 or 18.

[0906] In some embodiments, Y1 is a Lys residue with a side chain linked substituent, wherein the substituent is covalently linked to the ε-amino group of the Lys residue via an amide bond. In some embodiments, the Y1 is selected from: K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH), K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH),

[0907] K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH), or K(-AEEA-γGlu-C(O)-C 18 -COOH);

[0908] The K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH) has the structure:

[0909] , the K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[0910] The K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH) has the structure:

[0911] The K(-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[0912] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein:

[0913] R1 is acetyl, R2 is -NH2;

[0914] X1 does not exist;

[0915] X2 is an amino acid residue selected from Cys, Pen or Abu;

[0916] X3 is selected from the amino acid residue of Gln or Y1;

[0917] X7 is the amino acid residue of Cys;

[0918] X 10 is the amino acid residue of Gln;

[0919] X 11 an amino acid residue selected from Arg, homoArg, Orn, or Y1;

[0920] X 12 an amino acid residue selected from Leu or α-Me-Leu;

[0921] X 13 is the amino acid residue of Ala,

[0922] X 14 is the amino acid residue of Aib;

[0923] X 15 is the amino acid residue of Phe;

[0924] X 17 an amino acid residue selected from Val or Aib;

[0925] X 18 an amino acid residue selected from His, Aib, or Y1;

[0926] X 21 is the amino acid residue of Aib or Ala;

[0927] X 22 an amino acid residue selected from Ala or Y1;

[0928] X 23 is the amino acid residue of 3-Pal;

[0929] X 24 is the amino acid residue of Gly;

[0930] X 26 an amino acid residue selected from Ile or N-Me-Ile;

[0931] X 31 is the amino acid residue of Asp or Y1;

[0932] X 33 is the amino acid residue of Gly;

[0933] X 35 is the amino acid residue of Glu;

[0934] X 37 is the amino acid residue of Pro;

[0935] Said Y1 is selected from: K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH), K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH),

[0936] K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH), or K(-AEEA-γGlu-C(O)-C 18 -COOH);

[0937] The K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH) has the structure:

[0938] , the K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[0939] The K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH) has the structure:

[0940] The K(-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[0941] In some embodiments, the compound having a structure as shown in Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof is selected from any one of the following:

[0942] (a) X1 is absent, X2 is an amino acid residue selected from Cys, Pen or Abu, X3 is Y1, X7 is an amino acid residue selected from Cys or Pen, X 10 is the amino acid residue of Gln, X 11 An amino acid residue selected from Arg, hArg or Orn, X 12 An amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 17 is the amino acid residue of Val, X 18 is the amino acid residue of His, X 21 is the amino acid residue of Aib, X 22 is the amino acid residue of Ala, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 26 is the amino acid residue of Ile, X 31 is the amino acid residue of Asp, X 33 is the amino acid residue of Gly, X 35 An amino acid residue selected from Glu, X 37 is the amino acid residue of Pro;

[0943] or,

[0944] (a') X1 is absent, X2 is preferably Cys, X3 is Y1, X7 is an amino acid residue selected from Cys, X 10 is the amino acid residue of Gln, X 11 An amino acid residue selected from Arg, X 12 An amino acid residue selected from Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 17 is the amino acid residue of Val, X 18 is the amino acid residue of His, X 21 is the amino acid residue of Aib, X 22 is the amino acid residue of Ala, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X26 is the amino acid residue of Ile, X 31 is the amino acid residue of Asp, X 33 is the amino acid residue of Gly, X 35 An amino acid residue selected from Glu, X 37 is the amino acid residue of Pro;

[0945] or,

[0946] (b) X1 is absent, X2 is an amino acid residue selected from Cys, Pen or Abu, X3 is an amino acid residue of Gln, X7 is an amino acid residue selected from Cys or Pen, X 10 It is Y1, X 11 An amino acid residue selected from Arg, homoArg or Orn, X 12 An amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 17 is the amino acid residue of Val, X 18 is the amino acid residue of His, X 21 is the amino acid residue of Aib, X 22 is the amino acid residue of Ala, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 26 is the amino acid residue of Ile, X 31 is the amino acid residue of Asp, X 33 is the amino acid residue of Gly, X 35 is the amino acid residue of Glu, X 37 is the amino acid residue of Pro;

[0947] or,

[0948] (b') X1 is absent, X2 is an amino acid residue selected from Cys, X3 is an amino acid residue of Gln, X7 is an amino acid residue selected from Cys, X 10 It is Y1, X 11 An amino acid residue selected from Arg, X 12 An amino acid residue selected from Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 17 is the amino acid residue of Val, X 18 is the amino acid residue of His, X21 is the amino acid residue of Aib, X 22 is the amino acid residue of Ala, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 26 is the amino acid residue of Ile, X 31 is the amino acid residue of Asp, X 33 is the amino acid residue of Gly, X 35 is the amino acid residue of Glu, X 37 is the amino acid residue of Pro;

[0949] or,

[0950] (c) X1 is absent, X2 is an amino acid residue selected from Cys, Pen or Abu, X3 is an amino acid residue of Gln, X7 is an amino acid residue selected from Cys or Pen, X 10 is the amino acid residue of Gln, X 11 It is Y1, X 12 An amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 17 is the amino acid residue of Val, X 18 is the amino acid residue of His, X 21 is the amino acid residue of Aib, X 22 is the amino acid residue of Ala, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 26 is the amino acid residue of Ile, X 31 is the amino acid residue of Asp, X 33 is the amino acid residue of Gly, X 35 is the amino acid residue of Glu, X 37 is the amino acid residue of Pro;

[0951] or,

[0952] (c') X1 is absent, X2 is an amino acid residue selected from Cys, X3 is an amino acid residue of Gln, X7 is an amino acid residue selected from Cys, X 10 is the amino acid residue of Gln, X 11 It is Y1, X 12 An amino acid residue selected from Leu, X 13 is the amino acid residue of Ala, X 14is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 17 is the amino acid residue of Val, X 18 is the amino acid residue of His, X 21 is the amino acid residue of Aib, X 22 is the amino acid residue of Ala, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 26 is the amino acid residue of Ile, X 31 is the amino acid residue of Asp, X 33 is the amino acid residue of Gly, X 35 is the amino acid residue of Glu, X 37 is the amino acid residue of Pro;

[0953] or,

[0954] (d) X1 is absent, X2 is an amino acid residue selected from Cys, Pen or Abu, X3 is an amino acid residue of Gln, X7 is an amino acid residue selected from Cys or Pen, X 10 is the amino acid residue of Gln, X 11 An amino acid residue selected from Arg, homoArg or Orn, X 12 An amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 17 is the amino acid residue of Val or Aib, X 18 It is Y1, X 21 is the amino acid residue of Aib, X 22 is the amino acid residue of Ala, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 26 is an amino acid residue of Ile or N-Me-Ile, X 31 is the amino acid residue of Asp, X 33 is the amino acid residue of Gly, X 35 is the amino acid residue of Glu, X 37 is the amino acid residue of Pro;

[0955] or,

[0956] (d') X1 is absent, X2 is an amino acid residue selected from Cys, X3 is an amino acid residue of Gln, X7 is an amino acid residue selected from Cys, X 10 is the amino acid residue of Gln, X 11 An amino acid residue selected from Arg, homoArg or Orn, X 12 An amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 17 is the amino acid residue of Val or Aib, X 18 It is Y1, X 21 is the amino acid residue of Aib, X 22 is the amino acid residue of Ala, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 26 is an amino acid residue of Ile or N-Me-Ile, X 31 is the amino acid residue of Asp, X 33 is the amino acid residue of Gly, X 35 is the amino acid residue of Glu, X 37 is the amino acid residue of Pro;

[0957] or,

[0958] (e) X1 is absent, X2 is an amino acid residue selected from Cys, Pen or Abu, X3 is an amino acid residue of Gln, X7 is an amino acid residue selected from Cys or Pen, X 10 is the amino acid residue of Gln, X 11 An amino acid residue selected from Arg, homoArg or Orn, X 12 An amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 17 is the amino acid residue of Val, X 18 is the amino acid residue of His or Aib, X 21 is the amino acid residue of Aib or Ala, X 22 It is Y1, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 26is the amino acid residue of Ile, X 31 is the amino acid residue of Asp, X 33 is the amino acid residue of Gly, X 35 is the amino acid residue of Glu, X 37 is the amino acid residue of Pro;

[0959] or,

[0960] (e') X1 is absent, X2 is an amino acid residue selected from Cys, Pen or Abu, X3 is an amino acid residue of Gln, X7 is an amino acid residue selected from Cys or Pen, X 10 is the amino acid residue of Gln, X 11 An amino acid residue selected from Arg, X 12 An amino acid residue selected from Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 17 is the amino acid residue of Val, X 18 is the amino acid residue of His or Aib, X 21 is the amino acid residue of Aib or Ala, X 22 It is Y1, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 26 is the amino acid residue of Ile, X 31 is the amino acid residue of Asp, X 33 is the amino acid residue of Gly, X 35 is the amino acid residue of Glu, X 37 is the amino acid residue of Pro;

[0961] or,

[0962] (f) X1 is absent, X2 is an amino acid residue selected from Cys, Pen or Abu, X3 is an amino acid residue of Gln, X7 is an amino acid residue selected from Cys or Pen, X 10 is the amino acid residue of Gln, X 11 An amino acid residue selected from Arg, homoArg or Orn, X 12 An amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 17 is the amino acid residue of Val, X 18is the amino acid residue of His, X 21 is the amino acid residue of Aib, X 22 is the amino acid residue of Ala, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 26 is the amino acid residue of Ile, X 31 It is Y1, X 33 is the amino acid residue of Gly, X 35 is the amino acid residue of Glu, X 37 is the amino acid residue of Pro;

[0963] or,

[0964] (f) X1 is absent, X2 is an amino acid residue selected from Cys, X3 is an amino acid residue of Gln, X7 is an amino acid residue selected from Cys, X 10 is the amino acid residue of Gln, X 11 An amino acid residue selected from Arg, X 12 An amino acid residue selected from Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 17 is the amino acid residue of Val, X 18 is the amino acid residue of His, X 21 is the amino acid residue of Aib, X 22 is the amino acid residue of Ala, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 26 is the amino acid residue of Ile, X 31 It is Y1, X 33 is the amino acid residue of Gly, X 35 is the amino acid residue of Glu, X 37 It is the amino acid residue of Pro.

[0965] Y1 is selected from the group consisting of Lys, Orn, Dap, Dab or Cys residues with a side chain substituent having the structure: -Z1-Z2.

[0966] Z1 contains (or is) the following structure: -(AEEA) a -(γGlu) b -, a is any integer between 0 and 4 (e.g., 0, 1, 2, 3 or 4), b is any integer between 1 and 4 (e.g., 1, 2, 3 or 4); and / or, 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).

[0967] In some embodiments, the substituent has the structure shown below {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γGlu) b -CO-(CH2) c -COOH;

[0968] wherein a is any integer between 0 and 4 (e.g., 0, 1, 2, 3, or 4), b is any integer between 1 and 4 (e.g., 1, 2, 3, or 4), 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).

[0969] In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is any integer from 12 to 22 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22). In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is any integer from 14 to 20 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22). In some specific embodiments, a is 1, 2 or 3, b is 1 or 2, and c is 14, 16, 18 or 20. In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is 14, 16, 18 or 20. In some specific embodiments, a is 2 or 3, b is 1 or 2, and c is 14, 16, 18 or 20. In some specific embodiments, a is 1 or 2, b is 3, and c is 14, 16, 18, or 20. In some specific embodiments, a is 2, b is 1 or 2, and c is 16, 18, or 20. Or, a is 1 or 2, b is 3, 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. Or, a is 1 or 2, b is 3, and c is 16 or 18.

[0970] In some specific embodiments, a is 2, b is 1, and c is 16 or 18. Or, a is 1, b is 3, and c is 16 or 18. Or, a is 2, b is 3, and c is 16 or 18.

[0971] In some embodiments, Y1 is a Lys residue with a side chain linked substituent, wherein the substituent is covalently linked to the ε-amino group of the Lys residue via an amide bond. In some embodiments, the Y1 is selected from: K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH), K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH),

[0972] K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH), or K(-AEEA-γGlu-C(O)-C 18 -COOH);

[0973] The K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH) has the structure:

[0974] , the K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[0975] The K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH) has the structure:

[0976] The K(-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[0977] In some embodiments, in any of the aforementioned compounds, a disulfide bond, a methylenethioacetal bridge, a thioether bond, an o-phenylenedisulfide bridge, an m-phenylenedisulfide bridge, or a p-phenylenedisulfide bridge is formed between the amino acid residues at positions 2 and 7. In some specific embodiments, in any of the aforementioned compounds, a disulfide bond, a methylenethioacetal bridge, or a thioether bond is formed between the amino acid residues at positions 2 and 7.

[0978] In some embodiments, the present disclosure provides a compound having a structure represented by the following formula (Ia) or a pharmaceutically acceptable salt thereof: X1-X2-X3-Thr-Ala-Thr-X7-Ala-Thr-X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -Leu-Val-X 18-Ser-Ser- X 21 -X 22 -X 23 -X 24 -Pro-Ile-Leu-Pro-Pro-Thr-X 31 -Val-X 33 -Ser-X 35 -Thr-X 37 (Ia);

[0979] in:

[0980] X1 is an amino acid residue selected from Lys or is absent;

[0981] X2 is an amino acid residue selected from Cys, homoCys, Pen or Abu;

[0982] X3 is an amino acid residue selected from Asn, Gln, Asp, Glu or Y1;

[0983] X7 is an amino acid residue selected from Cys, homoCys, Pen or Abu;

[0984] X 10 an amino acid residue selected from Gln, Asn, Glu, Asp, or Y1;

[0985] X 11 an amino acid residue selected from Arg, homoArg, Orn, D-Arg, or Y1;

[0986] X 12 an amino acid residue selected from Leu, hLeu, N-MeLeu, α-Me-Leu or D-Leu;

[0987] X 13 is an amino acid residue of Ala or Aib;

[0988] X 14 is the amino acid residue of Aib or Ala;

[0989] X 15 is the amino acid residue of Phe;

[0990] X 18 an amino acid residue selected from His or Y1;

[0991] X 21 is an amino acid residue of Asn, Gln, Glu, Ala or Aib;

[0992] X 22 an amino acid residue selected from Asn, Ala, or Y1;

[0993] X23 an amino acid residue selected from Phe or 3-Pal;

[0994] X 24 is the amino acid residue of Gly;

[0995] X 31 an amino acid residue selected from Asn, Asp, Glu, Gln, or Y1;

[0996] X 33 is the amino acid residue of Gly;

[0997] X 35 an amino acid residue selected from Glu, Asn, Asp or Gln;

[0998] X 37 an amino acid residue selected from Tyr or Pro;

[0999] Y1 is selected from the group consisting of Lys, Orn, Dap, Dab or Cys residues with a side chain substituent having the structure: -Z1-Z2.

[1000] Z1 contains (or is) the following structure: -(AEEA) a -(γGlu) b -, a is any integer between 0 and 4 (e.g., 0, 1, 2, 3 or 4), b is any integer between 1 and 4 (e.g., 1, 2, 3 or 4); and / or, 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).

[1001] In some embodiments, the substituent has the structure shown below {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γGlu) b -CO-(CH2) c -COOH;

[1002] wherein a is any integer between 0 and 4 (e.g., 0, 1, 2, 3, or 4), b is any integer between 1 and 4 (e.g., 1, 2, 3, or 4), 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).

[1003] In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is any integer from 12 to 22 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22). In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is any integer from 14 to 20 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22). In some specific embodiments, a is 1, 2 or 3, b is 1 or 2, and c is 14, 16, 18 or 20. In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is 14, 16, 18 or 20. In some specific embodiments, a is 2 or 3, b is 1 or 2, and c is 14, 16, 18 or 20. In some specific embodiments, a is 1 or 2, b is 3, and c is 14, 16, 18, or 20. In some specific embodiments, a is 2, b is 1 or 2, and c is 16, 18, or 20. Or, a is 1 or 2, b is 3, 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. Or, a is 1 or 2, b is 3, and c is 16 or 18.

[1004] In some specific embodiments, a is 2, b is 1, and c is 16 or 18. Or, a is 1, b is 3, and c is 16 or 18. Or, a is 2, b is 3, and c is 16 or 18.

[1005] In some embodiments, Y1 is a Lys residue with a side chain linked substituent, wherein the substituent is covalently linked to the ε-amino group of the Lys residue via an amide bond. In some embodiments, the Y1 is selected from: K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH), K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH),

[1006] K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH), or K(-AEEA-γGlu-C(O)-C 18 -COOH);

[1007] The K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH) has the structure:

[1008] , the K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[1009] The K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH) has the structure:

[1010] The K(-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[1011] In some embodiments, X 13 X 14 is Ala-Aib, Ala-Ala, Aib-Ala, or Aib-Aib. In some embodiments, X 13 X 14 It's Ala-Aib, Aib-Aib, or Aib-Ala.

[1012] In some embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt thereof, wherein:

[1013] X1 does not exist;

[1014] X2 is an amino acid residue selected from Cys, Pen or Abu;

[1015] X3 is selected from the amino acid residue of Gln or Y1;

[1016] X7 is an amino acid residue selected from Cys or Pen;

[1017] X 10 an amino acid residue selected from Gln or Y1;

[1018] X 11 an amino acid residue selected from Arg, homoArg, Orn, or Y1;

[1019] X 12 an amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu;

[1020] X 13 is an amino acid residue of Ala or Aib;

[1021] X 14 is an amino acid residue of Ala or Aib;

[1022] X 15 is the amino acid residue of Phe;

[1023] X 18 an amino acid residue selected from His or Y1;

[1024] X21 is the amino acid residue of Aib;

[1025] X 22 an amino acid residue selected from Ala or Y1;

[1026] X 23 is the amino acid residue of 3-Pal;

[1027] X 24 is the amino acid residue of Gly;

[1028] X 31 is the amino acid residue of Asp or Y1;

[1029] X 33 is the amino acid residue of Gly;

[1030] X 35 is the amino acid residue of Glu;

[1031] X 37 is the amino acid residue of Pro;

[1032] Y1 is selected from a Lys residue of a side chain-linked substituent, wherein the substituent has the structure: -Z1-Z2.

[1033] Z1 contains (or is) the following structure: -(AEEA) a -(γGlu) b -, a is any integer between 0 and 4 (e.g., 0, 1, 2, 3 or 4), b is any integer between 1 and 4 (e.g., 1, 2, 3 or 4); and / or, 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).

[1034] In some embodiments, the substituent has the structure shown below {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γGlu) b -CO-(CH2) c -COOH;

[1035] wherein a is any integer between 0 and 4 (e.g., 0, 1, 2, 3, or 4), b is any integer between 1 and 4 (e.g., 1, 2, 3, or 4), 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).

[1036] In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is any integer from 12 to 22 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22). In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is any integer from 14 to 20 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22). In some specific embodiments, a is 1, 2 or 3, b is 1 or 2, and c is 14, 16, 18 or 20. In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is 14, 16, 18 or 20. In some specific embodiments, a is 2 or 3, b is 1 or 2, and c is 14, 16, 18 or 20. In some specific embodiments, a is 1 or 2, b is 3, and c is 14, 16, 18, or 20. In some specific embodiments, a is 2, b is 1 or 2, and c is 16, 18, or 20. Or, a is 1 or 2, b is 3, 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. Or, a is 1 or 2, b is 3, and c is 16 or 18.

[1037] In some specific embodiments, a is 2, b is 1, and c is 16 or 18. Or, a is 1, b is 3, and c is 16 or 18. Or, a is 2, b is 3, and c is 16 or 18.

[1038] In some embodiments, Y1 is a Lys residue with a side chain linked substituent, wherein the substituent is covalently linked to the ε-amino group of the Lys residue via an amide bond. In some embodiments, the Y1 is selected from: K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH), K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH),

[1039] K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH), or K(-AEEA-γGlu-C(O)-C 18 -COOH);

[1040] The K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH) has the structure:

[1041] , the K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[1042] The K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH) has the structure:

[1043] The K(-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[1044] In some embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt thereof, wherein:

[1045] X1 does not exist;

[1046] X2 is an amino acid residue selected from Cys, Pen or Abu;

[1047] X3 is selected from the amino acid residue of Gln or Y1;

[1048] X7 is an amino acid residue selected from Cys or Pen;

[1049] X 10 an amino acid residue selected from Gln or Y1;

[1050] X 11 an amino acid residue selected from Arg, homoArg, Orn, or Y1;

[1051] X 12 an amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu;

[1052] X 13 X 14 Selected from Ala-Aib, Aib-Ala or Aib-Aib;

[1053] X 15 is the amino acid residue of Phe;

[1054] X 18 an amino acid residue selected from His or Y1;

[1055] X 21 is the amino acid residue of Aib;

[1056] X 22 an amino acid residue selected from Ala or Y1;

[1057] X 23 is the amino acid residue of 3-Pal;

[1058] X 24 is the amino acid residue of Gly;

[1059] X 31 is the amino acid residue of Asp or Y1;

[1060] X 33 is the amino acid residue of Gly;

[1061] X 35 is the amino acid residue of Glu;

[1062] X 37 is the amino acid residue of Pro;

[1063] Y1 is a Lys residue having a side chain connected to a substituent having the structure shown below {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γGlu) b -CO-(CH2) c -COOH;

[1064] wherein a is any integer between 0 and 4 (e.g., 0, 1, 2, 3, or 4), b is any integer between 1 and 4 (e.g., 1, 2, 3, or 4), 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).

[1065] In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is any integer from 12 to 22 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22). In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is any integer from 14 to 20 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22). In some specific embodiments, a is 1, 2 or 3, b is 1 or 2, and c is 14, 16, 18 or 20. In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is 14, 16, 18 or 20. In some specific embodiments, a is 2 or 3, b is 1 or 2, and c is 14, 16, 18 or 20. In some specific embodiments, a is 1 or 2, b is 3, and c is 14, 16, 18, or 20. In some specific embodiments, a is 2, b is 1 or 2, and c is 16, 18, or 20. Or, a is 1 or 2, b is 3, 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. Or, a is 1 or 2, b is 3, and c is 16 or 18.

[1066] In some specific embodiments, a is 2, b is 1, and c is 16 or 18. Or, a is 1, b is 3, and c is 16 or 18. Or, a is 2, b is 3, and c is 16 or 18.

[1067] In some embodiments, Y1 is a Lys residue with a side chain linked substituent, wherein the substituent is covalently linked to the ε-amino group of the Lys residue via an amide bond. In some embodiments, the Y1 is selected from: K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH), K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH),

[1068] K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH), or K(-AEEA-γGlu-C(O)-C 18 -COOH);

[1069] The K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH) has the structure:

[1070] , the K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[1071] The K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH) has the structure:

[1072] The K(-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[1073] In some embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt thereof, wherein:

[1074] X1 does not exist;

[1075] X2 is an amino acid residue selected from Cys, Pen or Abu;

[1076] X3 is selected from the amino acid residue of Gln or Y1;

[1077] X7 is an amino acid residue selected from Cys or Pen;

[1078] X 10 an amino acid residue selected from Gln or Y1;

[1079] X 11 an amino acid residue selected from Arg, homoArg, Orn, or Y1;

[1080] X 12 an amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu;

[1081] X 13 X 14 Selected from Ala-Aib;

[1082] X 15 is the amino acid residue of Phe;

[1083] X 18 an amino acid residue selected from His or Y1;

[1084] X 21 is the amino acid residue of Aib;

[1085] X 22 an amino acid residue selected from Ala or Y1;

[1086] X 23 is the amino acid residue of 3-Pal;

[1087] X 24 is the amino acid residue of Gly;

[1088] X31 is the amino acid residue of Asp or Y1;

[1089] X 33 is the amino acid residue of Gly;

[1090] X 35 is the amino acid residue of Glu;

[1091] X 37 is the amino acid residue of Pro;

[1092] Y1 is a Lys residue having a side chain connected to a substituent having the structure shown below {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γGlu) b -CO-(CH2) c -COOH;

[1093] wherein a is any integer between 0 and 4 (e.g., 0, 1, 2, 3, or 4), b is any integer between 1 and 4 (e.g., 1, 2, 3, or 4), 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).

[1094] In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is any integer from 12 to 22 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22). In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is any integer from 14 to 20 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22). In some specific embodiments, a is 1, 2 or 3, b is 1 or 2, and c is 14, 16, 18 or 20. In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is 14, 16, 18 or 20. In some specific embodiments, a is 2 or 3, b is 1 or 2, and c is 14, 16, 18 or 20. In some specific embodiments, a is 1 or 2, b is 3, and c is 14, 16, 18, or 20. In some specific embodiments, a is 2, b is 1 or 2, and c is 16, 18, or 20. Or, a is 1 or 2, b is 3, 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. Or, a is 1 or 2, b is 3, and c is 16 or 18.

[1095] In some specific embodiments, a is 2, b is 1, and c is 16 or 18. Or, a is 1, b is 3, and c is 16 or 18. Or, a is 2, b is 3, and c is 16 or 18.

[1096] In some embodiments, Y1 is a Lys residue with a side chain linked substituent, wherein the substituent is covalently linked to the ε-amino group of the Lys residue via an amide bond. In some embodiments, the Y1 is selected from: K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH), K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH),

[1097] K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH), or K(-AEEA-γGlu-C(O)-C 18 -COOH);

[1098] The K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH) has the structure:

[1099] , the K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[1100] The K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH) has the structure:

[1101] The K(-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[1102] In some embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt thereof, wherein:

[1103] X1 does not exist;

[1104] X2 is an amino acid residue selected from Cys, Pen or Abu;

[1105] X3 is selected from the amino acid residue of Gln or Y1;

[1106] X7 is the amino acid residue of Cys;

[1107] X 10 is the amino acid residue of Gln;

[1108] X 11 an amino acid residue selected from Arg, homoArg, Orn, or Y1;

[1109] X 12 an amino acid residue selected from Leu or α-Me-Leu;

[1110] X 13 is the amino acid residue of Ala,

[1111] X 14 is the amino acid residue of Aib;

[1112] X 15 is the amino acid residue of Phe;

[1113] X 18 an amino acid residue selected from His or Y1;

[1114] X 21 is the amino acid residue of Aib;

[1115] X 22 an amino acid residue selected from Ala or Y1;

[1116] X 23 is the amino acid residue of 3-Pal;

[1117] X 24 is the amino acid residue of Gly;

[1118] X 31 is the amino acid residue of Asp or Y1;

[1119] X 33 is the amino acid residue of Gly;

[1120] X 35 is the amino acid residue of Glu;

[1121] X 37 is the amino acid residue of Pro;

[1122] The Y1 is selected from K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH), K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH),

[1123] K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH), or K(-AEEA-γGlu-C(O)-C 18 -COOH);

[1124] The K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH) has the structure:

[1125] , the K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[1126] The K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH) has the structure:

[1127] The K(-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[1128] In some embodiments, in any of the aforementioned compounds, a disulfide bond, a methylenethioacetal bridge, a thioether bond, an o-phenylenedisulfide bridge, an m-phenylenedisulfide bridge, or a p-phenylenedisulfide bridge is formed between the amino acid residues at positions 2 and 7. In some specific embodiments, in any of the aforementioned compounds, a disulfide bond, a methylenethioacetal bridge, or a thioether bond is formed between the amino acid residues at positions 2 and 7.

[1129] In some embodiments, the present disclosure provides a compound having a structure represented by the following formula (IIa) or a pharmaceutically acceptable salt thereof: R1-X1-X2-X3-Thr-Ala-Thr-X7-Ala-Thr-X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -Leu-Val-X 18 -Ser-Ser- X 21 -X 22 -X 23 -X 24 -Pro-Ile-Leu-Pro-Pro-Thr-X 31 -Val-X 33 -Ser-X 35 -Thr-X 37 -R2(IIa);

[1130] in:

[1131] R1 is H, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pyroglutamyl;

[1132] R2 is -NH2 or -OH;

[1133] X1 is an amino acid residue selected from Lys or is absent;

[1134] X2 is an amino acid residue selected from Cys, homoCys, Pen or Abu;

[1135] X3 is an amino acid residue selected from Asn, Gln, Asp, Glu or Y1;

[1136] X7 is an amino acid residue selected from Cys, homoCys, Pen or Abu;

[1137] X 10 an amino acid residue selected from Gln, Asn, Glu, Asp, or Y1;

[1138] X 11 an amino acid residue selected from Arg, homoArg, Orn, D-Arg, or Y1;

[1139] X 12 an amino acid residue selected from Leu, hLeu, N-MeLeu, α-Me-Leu or D-Leu;

[1140] X 13 is an amino acid residue of Ala or Aib;

[1141] X 14 is the amino acid residue of Aib or Ala;

[1142] X 15 is the amino acid residue of Phe;

[1143] X 18 an amino acid residue selected from His or Y1;

[1144] X 21 is an amino acid residue of Asn, Gln, Glu, Ala or Aib;

[1145] X 22 an amino acid residue selected from Asn, Ala, or Y1;

[1146] X 23 an amino acid residue selected from Phe, 2-Pal, 4-Pal, hPhe or 3-Pal;

[1147] X 24 is the amino acid residue of Gly;

[1148] X 31 an amino acid residue selected from Asn, Asp, Glu, Gln, or Y1;

[1149] X 33 is the amino acid residue of Gly;

[1150] X 35 an amino acid residue selected from Glu, Asn, Asp or Gln;

[1151] X 37 an amino acid residue selected from Tyr or Pro;

[1152] Y1 is selected from the group consisting of Lys, Orn, Dap, Dab or Cys residues with a side chain substituent having the structure: -Z1-Z2.

[1153] Z1 contains (or is) the following structure: -(AEEA) a -(γGlu) b -, a is any integer between 0 and 4 (e.g., 0, 1, 2, 3 or 4), b is any integer between 1 and 4 (e.g., 1, 2, 3 or 4); and / or, 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).

[1154] In some embodiments, the substituent has the structure shown below {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γGlu) b -CO-(CH2) c -COOH;

[1155] wherein a is any integer between 0 and 4 (e.g., 0, 1, 2, 3, or 4), b is any integer between 1 and 4 (e.g., 1, 2, 3, or 4), 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).

[1156] In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is any integer from 12 to 22 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22). In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is any integer from 14 to 20 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22). In some specific embodiments, a is 1, 2 or 3, b is 1 or 2, and c is 14, 16, 18 or 20. In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is 14, 16, 18 or 20. In some specific embodiments, a is 2 or 3, b is 1 or 2, and c is 14, 16, 18 or 20. In some specific embodiments, a is 1 or 2, b is 3, and c is 14, 16, 18, or 20. In some specific embodiments, a is 2, b is 1 or 2, and c is 16, 18, or 20. Or, a is 1 or 2, b is 3, 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. Or, a is 1 or 2, b is 3, and c is 16 or 18.

[1157] In some specific embodiments, a is 2, b is 1, and c is 16 or 18. Or, a is 1, b is 3, and c is 16 or 18. Or, a is 2, b is 3, and c is 16 or 18.

[1158] In some embodiments, Y1 is a Lys residue with a side chain linked substituent, wherein the substituent is covalently linked to the ε-amino group of the Lys residue via an amide bond. In some embodiments, the Y1 is selected from: K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH), K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH),

[1159] K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH), or K(-AEEA-γGlu-C(O)-C 18 -COOH);

[1160] The K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH) has the structure:

[1161] , the K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[1162] The K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH) has the structure:

[1163] The K(-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[1164] In some embodiments, X 13 X 14 is Ala-Aib, Ala-Ala, Aib-Ala, or Aib-Aib. In some embodiments, X 13 X 14 is Ala-Aib, Aib-Aib, or Aib-Ala. In some embodiments, X 13 X 14 It is Ala-Aib.

[1165] In some embodiments, the compound of formula (IIa) or a pharmaceutically acceptable salt thereof, wherein:

[1166] R1 is acetyl, R2 is -NH2;

[1167] X1 does not exist;

[1168] X2 is an amino acid residue selected from Cys, Pen or Abu;

[1169] X3 is selected from the amino acid residue of Gln or Y1;

[1170] X7 is an amino acid residue selected from Cys or Pen;

[1171] X 10 an amino acid residue selected from Gln or Y1;

[1172] X 11 an amino acid residue selected from Arg, homoArg, Orn, or Y1;

[1173] X 12 an amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu;

[1174] X 13 is an amino acid residue of Ala or Aib;

[1175] X 14 is the amino acid residue of Aib or Ala;

[1176] X 15 is the amino acid residue of Phe;

[1177] X 18 an amino acid residue selected from His or Y1;

[1178] X 21 is the amino acid residue of Aib;

[1179] X 22 an amino acid residue selected from Ala or Y1;

[1180] X 23 is the amino acid residue of 3-Pal;

[1181] X 24 is the amino acid residue of Gly;

[1182] X 31 is the amino acid residue of Asp or Y1;

[1183] X 33 is the amino acid residue of Gly;

[1184] X 35 is the amino acid residue of Glu;

[1185] X 37 It is the amino acid residue of Pro.

[1186] Y1 is selected from the group consisting of Lys, Orn, Dap, Dab or Cys residues with a side chain substituent having the structure: -Z1-Z2.

[1187] Z1 contains (or is) the following structure: -(AEEA) a -(γGlu) b -, a is any integer between 0 and 4 (e.g., 0, 1, 2, 3 or 4), b is any integer between 1 and 4 (e.g., 1, 2, 3 or 4); and / or, 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).

[1188] In some embodiments, the substituent has the structure shown below {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γGlu) b -CO-(CH2) c -COOH;

[1189] wherein a is any integer between 0 and 4 (e.g., 0, 1, 2, 3, or 4), b is any integer between 1 and 4 (e.g., 1, 2, 3, or 4), 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).

[1190] In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is any integer from 12 to 22 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22). In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is any integer from 14 to 20 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22). In some specific embodiments, a is 1, 2 or 3, b is 1 or 2, and c is 14, 16, 18 or 20. In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is 14, 16, 18 or 20. In some specific embodiments, a is 2 or 3, b is 1 or 2, and c is 14, 16, 18 or 20. In some specific embodiments, a is 1 or 2, b is 3, and c is 14, 16, 18, or 20. In some specific embodiments, a is 2, b is 1 or 2, and c is 16, 18, or 20. Or, a is 1 or 2, b is 3, 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. Or, a is 1 or 2, b is 3, and c is 16 or 18.

[1191] In some specific embodiments, a is 2, b is 1, and c is 16 or 18. Or, a is 1, b is 3, and c is 16 or 18. Or, a is 2, b is 3, and c is 16 or 18.

[1192] In some embodiments, Y1 is a Lys residue with a side chain linked substituent, wherein the substituent is covalently linked to the ε-amino group of the Lys residue via an amide bond. In some embodiments, the Y1 is selected from: K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH), K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH),

[1193] K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH), or K(-AEEA-γGlu-C(O)-C 18 -COOH);

[1194] The K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH) has the structure:

[1195] , the K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[1196] The K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH) has the structure:

[1197] The K(-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[1198] In some embodiments, the compound of formula (IIa) or a pharmaceutically acceptable salt thereof, wherein:

[1199] R1 is acetyl, R2 is -NH2;

[1200] X1 does not exist;

[1201] X2 is an amino acid residue selected from Cys, Pen or Abu;

[1202] X3 is selected from the amino acid residue of Gln or Y1;

[1203] X7 is an amino acid residue selected from Cys or Pen;

[1204] X 10 an amino acid residue selected from Gln or Y1;

[1205] X 11 an amino acid residue selected from Arg, homoArg, Orn, or Y1;

[1206] X 12 an amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu;

[1207] X 13 X 14 Selected from Ala-Aib, Aib-Ala or Aib-Aib;

[1208] X 15 is the amino acid residue of Phe;

[1209] X 18 an amino acid residue selected from His or Y1;

[1210] X 21 is the amino acid residue of Aib;

[1211] X 22 an amino acid residue selected from Ala or Y1;

[1212] X 23 is the amino acid residue of 3-Pal;

[1213] X 24 is the amino acid residue of Gly;

[1214] X 31 is the amino acid residue of Asp or Y1;

[1215] X 33 is the amino acid residue of Gly;

[1216] X 35 is the amino acid residue of Glu;

[1217] X 37 is the amino acid residue of Pro;

[1218] Y1 is a Lys residue having a side chain connected to a substituent having the structure shown below {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γGlu) b -CO-(CH2) c -COOH;

[1219] wherein a is any integer between 0 and 4 (e.g., 0, 1, 2, 3, or 4), b is any integer between 1 and 4 (e.g., 1, 2, 3, or 4), 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).

[1220] In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is any integer from 12 to 22 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22). In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is any integer from 14 to 20 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22). In some specific embodiments, a is 1, 2 or 3, b is 1 or 2, and c is 14, 16, 18 or 20. In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is 14, 16, 18 or 20. In some specific embodiments, a is 2 or 3, b is 1 or 2, and c is 14, 16, 18 or 20. In some specific embodiments, a is 1 or 2, b is 3, and c is 14, 16, 18, or 20. In some specific embodiments, a is 2, b is 1 or 2, and c is 16, 18, or 20. Or, a is 1 or 2, b is 3, 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. Or, a is 1 or 2, b is 3, and c is 16 or 18.

[1221] In some specific embodiments, a is 2, b is 1, and c is 16 or 18. Or, a is 1, b is 3, and c is 16 or 18. Or, a is 2, b is 3, and c is 16 or 18.

[1222] In some embodiments, Y1 is a Lys residue with a side chain linked substituent, wherein the substituent is covalently linked to the ε-amino group of the Lys residue via an amide bond. In some embodiments, the Y1 is selected from: K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH), K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH),

[1223] K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH), or K(-AEEA-γGlu-C(O)-C 18 -COOH);

[1224] The K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH) has the structure:

[1225] , the K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[1226] The K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH) has the structure:

[1227] The K(-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[1228] In some embodiments, the compound of formula (IIa) or a pharmaceutically acceptable salt thereof, wherein:

[1229] R1 is acetyl, R2 is -NH2;

[1230] X1 does not exist;

[1231] X2 is an amino acid residue selected from Cys, Pen or Abu;

[1232] X3 is selected from the amino acid residue of Gln or Y1;

[1233] X7 is an amino acid residue selected from Cys or Pen;

[1234] X 10 an amino acid residue selected from Gln or Y1;

[1235] X 11 an amino acid residue selected from Arg, homoArg, Orn, or Y1;

[1236] X 12 an amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu;

[1237] X 13 X 14 Selected from Ala-Aib;

[1238] X 15 is the amino acid residue of Phe;

[1239] X 18 an amino acid residue selected from His or Y1;

[1240] X 21 is the amino acid residue of Aib;

[1241] X 22 an amino acid residue selected from Ala or Y1;

[1242] X 23 is the amino acid residue of 3-Pal;

[1243] X 24is the amino acid residue of Gly;

[1244] X 31 is the amino acid residue of Asp or Y1;

[1245] X 33 is the amino acid residue of Gly;

[1246] X 35 is the amino acid residue of Glu;

[1247] X 37 is the amino acid residue of Pro;

[1248] Y1 is a Lys residue having a side chain connected to a substituent having the structure shown below {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γGlu) b -CO-(CH2) c -COOH;

[1249] wherein a is any integer between 0 and 4 (e.g., 0, 1, 2, 3, or 4), b is any integer between 1 and 4 (e.g., 1, 2, 3, or 4), 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).

[1250] In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is any integer from 12 to 22 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22). In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is any integer from 14 to 20 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22). In some specific embodiments, a is 1, 2 or 3, b is 1 or 2, and c is 14, 16, 18 or 20. In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is 14, 16, 18 or 20. In some specific embodiments, a is 2 or 3, b is 1 or 2, and c is 14, 16, 18 or 20. In some specific embodiments, a is 1 or 2, b is 3, and c is 14, 16, 18, or 20. In some specific embodiments, a is 2, b is 1 or 2, and c is 16, 18, or 20. Or, a is 1 or 2, b is 3, 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. Or, a is 1 or 2, b is 3, and c is 16 or 18.

[1251] In some specific embodiments, a is 2, b is 1, and c is 16 or 18. Or, a is 1, b is 3, and c is 16 or 18. Or, a is 2, b is 3, and c is 16 or 18.

[1252] In some embodiments, Y1 is a Lys residue with a side chain linked substituent, wherein the substituent is covalently linked to the ε-amino group of the Lys residue via an amide bond. In some embodiments, the Y1 is selected from: K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH), K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH),

[1253] K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH), or K(-AEEA-γGlu-C(O)-C 18 -COOH);

[1254] The K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH) has the structure:

[1255] , the K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[1256] The K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH) has the structure:

[1257] The K(-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[1258] In some embodiments, the compound of formula (IIa) or a pharmaceutically acceptable salt thereof, wherein:

[1259] R1 is acetyl, R2 is -NH2;

[1260] X1 does not exist;

[1261] X2 is an amino acid residue selected from Cys, Pen or Abu;

[1262] X3 is selected from the amino acid residue of Gln or Y1;

[1263] X7 is the amino acid residue of Cys;

[1264] X 10 is the amino acid residue of Gln;

[1265] X 11 an amino acid residue selected from Arg, homoArg, Orn, or Y1;

[1266] X 12 an amino acid residue selected from Leu or α-Me-Leu;

[1267] X 13 is the amino acid residue of Ala,

[1268] X 14 is the amino acid residue of Aib;

[1269] X 15 is the amino acid residue of Phe;

[1270] X 18 an amino acid residue selected from His or Y1;

[1271] X 21 is the amino acid residue of Aib;

[1272] X 22 an amino acid residue selected from Ala or Y1;

[1273] X 23 is the amino acid residue of 3-Pal;

[1274] X 24 is the amino acid residue of Gly;

[1275] X 31 is the amino acid residue of Asp or Y1;

[1276] X 33 is the amino acid residue of Gly;

[1277] X 35 is the amino acid residue of Glu;

[1278] X 37 is the amino acid residue of Pro;

[1279] The Y1 is selected from K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH), K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH),

[1280] K(-AEEA-AEEA-(γGlu)3-C(O)-C 18-COOH), or K(-AEEA-γGlu-C(O)-C 18 -COOH);

[1281] The K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH) has the structure:

[1282] , the K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[1283] The K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH) has the structure:

[1284] The K(-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[1285] In some embodiments, the compound represented by the structure of formula (Ia) or formula (IIa) or a pharmaceutically acceptable salt thereof is selected from any one of the following (i) to (vi):

[1286] (i) X1 is absent, X2 is an amino acid residue selected from Cys, Pen or Abu, X3 is Y1, X7 is an amino acid residue selected from Cys or Pen, X 10 is the amino acid residue of Gln, X 11 An amino acid residue selected from Arg, hArg or Orn, X 12 An amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 18 is the amino acid residue of His, X 21 is the amino acid residue of Aib, X 22 is the amino acid residue of Ala, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 31 is the amino acid residue of Asp, X 33 is the amino acid residue of Gly, X 35 An amino acid residue selected from Glu, X 37 is the amino acid residue of Pro;

[1287] (ii) X1 is absent, X2 is an amino acid residue selected from Cys, Pen or Abu, X3 is an amino acid residue of Gln, X7 is an amino acid residue selected from Cys or Pen, X 10 An amino acid residue selected from Gln or Y1, X 11 An amino acid residue selected from Arg, homoArg or Orn, X 12 An amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 18 is the amino acid residue of His, X 21 is the amino acid residue of Aib, X 22 is the amino acid residue of Ala, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 31 is the amino acid residue of Asp, X 33 is the amino acid residue of Gly, X 35 is the amino acid residue of Glu, X 37 is the amino acid residue of Pro;

[1288] (iii) X1 is absent, X2 is an amino acid residue selected from Cys, Pen or Abu, X3 is an amino acid residue of Gln, X7 is an amino acid residue selected from Cys or Pen, X 10 is the amino acid residue of Gln, X 11 An amino acid residue selected from Arg, homoArg, Orn or Y1, X 12 An amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 18 is the amino acid residue of His, X 21 is the amino acid residue of Aib, X 22 is the amino acid residue of Ala, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 31 is the amino acid residue of Asp, X 33 is the amino acid residue of Gly, X 35 is the amino acid residue of Glu, X 37is the amino acid residue of Pro;

[1289] (iv) X1 is absent, X2 is an amino acid residue selected from Cys, Pen or Abu, X3 is an amino acid residue of Gln, X7 is an amino acid residue selected from Cys or Pen, X 10 is the amino acid residue of Gln, X 11 An amino acid residue selected from Arg, homoArg or Orn, X 12 An amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 18 An amino acid residue selected from His or Y1, X 21 is the amino acid residue of Aib, X 22 is the amino acid residue of Ala, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 31 is the amino acid residue of Asp, X 33 is the amino acid residue of Gly, X 35 is the amino acid residue of Glu, X 37 is the amino acid residue of Pro;

[1290] (v) X1 is absent, X2 is an amino acid residue selected from Cys, Pen or Abu, X3 is an amino acid residue of Gln, X7 is an amino acid residue selected from Cys or Pen, X 10 is the amino acid residue of Gln, X 11 An amino acid residue selected from Arg, homoArg or Orn, X 12 An amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 18 is the amino acid residue of His, X 21 is the amino acid residue of Aib, X 22 An amino acid residue selected from Ala or Y1, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 31 is the amino acid residue of Asp, X 33 is the amino acid residue of Gly, X 35is the amino acid residue of Glu, X 37 is an amino acid residue of Pro; or,

[1291] (vi) X1 is absent, X2 is an amino acid residue selected from Cys, Pen or Abu, X3 is an amino acid residue of Gln, X7 is an amino acid residue selected from Cys or Pen, X 10 is the amino acid residue of Gln, X 11 An amino acid residue selected from Arg, homoArg or Orn, X 12 An amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 18 is the amino acid residue of His, X 21 is the amino acid residue of Aib, X 22 is the amino acid residue of Ala, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 31 An amino acid residue selected from Asp or Y1, X 33 is the amino acid residue of Gly, X 35 is the amino acid residue of Glu, X 37 It is the amino acid residue of Pro.

[1292] Y1 is selected from the group consisting of Lys, Orn, Dap, Dab or Cys residues with a side chain substituent having the structure: -Z1-Z2.

[1293] Z1 contains (or is) the following structure: -(AEEA) a -(γGlu) b -, a is any integer between 0 and 4 (e.g., 0, 1, 2, 3 or 4), b is any integer between 1 and 4 (e.g., 1, 2, 3 or 4); and / or, 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).

[1294] In some embodiments, the substituent has the structure shown below {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(γGlu) b-CO-(CH2) c -COOH;

[1295] wherein a is any integer between 0 and 4 (e.g., 0, 1, 2, 3, or 4), b is any integer between 1 and 4 (e.g., 1, 2, 3, or 4), 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). K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH), K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH),

[1296] K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH), or K(-AEEA-γGlu-C(O)-C 18 -COOH);

[1297] The K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH) has the structure:

[1298] , the K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[1299] The K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH) has the structure:

[1300] The K(-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[1301] In some embodiments, in any of the aforementioned compounds, a disulfide bond, a methylenethioacetal bridge, a thioether bond, an o-phenylenedisulfide bridge, an m-phenylenedisulfide bridge, or a p-phenylenedisulfide bridge is formed between the amino acid residues at positions 2 and 7. In some specific embodiments, in any of the aforementioned compounds, a disulfide bond, a methylenethioacetal bridge, or a thioether bond is formed between the amino acid residues at positions 2 and 7.

[1302] In some embodiments, the compound shown in any of the foregoing or a pharmaceutically acceptable salt thereof comprises (or is) a structure shown in any of the following:

[1303] Compound1,Ac-CK(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH)TATC-ATQ-RLAAibFLVHSS-Aib-A-[3-Pal]-GPILPPT-DVGSETP-NH2,SEQ ID NO:64

[1304] Compound 2,Ac-C-QTATC-ATK(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH)-RLAAibFLVHSS-Aib-A-[3-Pal]-GPILPPT-DVGSETP-NH2,SEQ ID NO:65

[1305] Compound 3,Ac-C-QTATC-ATQ-K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH)LAAibFLVHSS-Aib-A-[3-Pal]-GPILPPT-DVGSETP-NH2,SEQ ID NO:66

[1306] Compound 4,Ac-C-QTATC-ATQ-RLAAibFLVK(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH)SS-Aib-A-[3-Pal]-GPILPPT-DVGSETP-NH2,SEQ ID NO:67

[1307] Compound 5,Ac-C-QTATC-ATQ-RLA-Aib-FLVHSS-Aib-K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH)-[3-Pal]-GPILPPTDVGSETP-NH2,SEQ ID NO:68

[1308] Compound 6,Ac-C-QTATC-ATQ-RLA-Aib-FLVHSS-Aib-A-[3-Pal]-GPILPPT-K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH)VGSETP-NH2,SEQ ID NO:69

[1309] Compound 7,Ac-Pen-QTATC-ATQ-RLA-AibFLVHSS-AibK(-AEEA-AEEA-γGlu-C(O)-C 18-COOH)-[3-Pal]-GPILPPT-DVGSETP-NH2, SEQ ID NO:70

[1310] Compound 8, Ac-Pen-QTAT-Pen-ATQ-RLA-Aib-FLVHSS-Aib-K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH)-[3-Pal]-GPILPPTDVGSETP-NH2, SEQ ID NO:71

[1311] Compound 9, Ac-Abu-QTATCATQ-RLA-Aib-FLVHSS-Aib-K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH)-[3-Pal]-GPILPPTDVGSETP-NH2, SEQ ID NO:72

[1312] Compound 10, Ac-CQTATCATQ-RLA-Aib-FLVHSS-Aib-K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH)-[3-Pal]-GPILPPT-DVGSETP-NH2, SEQ ID NO:73

[1313] Compound 11, Ac-CQTATCATQ-RLA-Aib-FLVK(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH)SS-Aib-A-[3-Pal]-GPILPPTDVGSETP-NH2, SEQ ID NO:74

[1314] Compound 12, Ac-CK(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH)TATCATQ-RLA-Aib-FLVHSS-Aib-A-[3-Pal]-GPILPPTDVGSETP-NH2, SEQ ID NO:75

[1315] Compound 13, Ac-CQTATCATQ-[homoR]-LA-Aib-FLVK(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH)SS-Aib-A-[3-Pal]-GPILPPTDVGSETP-NH2, SEQ ID NO:76

[1316] Compound 14, Ac-CQTATCATQ-Orn-LA-Aib-FLVK(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH)SS-Aib-A-[3-Pal]-GPILPPTDVGSETP-NH2, SEQ ID NO:77

[1317] Compound 15, Ac-CQTATCATQ-R-NMeL-A-Aib-FLV-K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH)SS-Aib-A-[3-Pal]-GPILPPTDVGSETP-NH2, SEQ ID NO:78

[1318] Compound 16, Ac-CQTATCATQ-R-aMeL-A-Aib-FLV-K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH)SS-Aib-A-[3-Pal]-GPILPPTDVGSETP-NH2, SEQ ID NO:79

[1319] Compound 17, Ac-CQTATC-ATQ-R-[D-L]-A-Aib-FLV-K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH)SS-Aib-A-[3-Pal]-GPILPPTDVGSETP-NH2, SEQ ID NO:80

[1320] Compound 21, Ac-CQTATC-ATQRLA-Aib-FLVK(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH)SS-Aib-A-[3-Pal]-GP-[NMeI]-LPPTDVGSETP-NH2, SEQ ID NO:81

[1321] Compound 22, Ac-CQTATC-ATQRLA-Aib-FL-Aib-K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH)SS-Aib-A-[3-Pal]-GPILPPTDVGSETP-NH2, SEQ ID NO:82

[1322] Compound 23, Ac-CQTATC-ATQRLA-Aib-FLV-Aib-SSAK(-AEEA-AEEA-γGlu-C(O)-C 18-COOH)-[3-Pal]-GPILPPTDVGSETP-NH2, SEQ ID NO:83

[1323] Compound 24, Ac-CQTATC-ATQRLA-Aib-FLV-Aib-SSAK(-AEEA-AEEA-γGlu-γGlu-γGlu-C(O)-C 18 -COOH)-[3-Pal]-GPILPPTDVGSETP-NH2, SEQ ID NO:84

[1324] Compound 25, Ac-CQTATC-ATQRLA-Aib-FLV-Aib-SSAK(-AEEA-γGlu-γGlu-γGlu-C(O)-C 18 -COOH)-[3-Pal]-GPILPPTDVGSETP-NH2, SEQ ID NO:85

[1325] Among them, in compounds 1 to 8, a disulfide bond is formed between the Cys residue at position X2 and the side chain of the Cys residue at position X7; in compound 9, a thioether bond is formed between the Abu residue at position X2 and the side chain of the Cys residue at position X7; in the sequences shown in compounds 10 to 17 and compounds 21-25, a methylenethioacetal bridge is formed between the side chain of the Cys residue at position X2 and the Cys residue at position X7.

[1326] An exemplary structure is as follows:

[1327] Compound 1,

[1328] Compound 2,

[1329] Compound 3,

[1330] Compound 4,

[1331] Compound 5,

[1332] Compound 6,

[1333] Compound 7,

[1334] Compound 8,

[1335] Compound 9,

[1336] Compound 10,

[1337] Compound 11,

[1338] Compound 12,

[1339] Compound 13,

[1340] Compound 14,

[1341] Compound 15,

[1342] Compound 16,

[1343] Compound 17,

[1344] Compound 18,

[1345] Compound 19,

[1346] Compound 20,

[1347] Compound 21,

[1348] Compound 22,

[1349] Compound 23,

[1350] Compound 24,

[1351] Compound 25,

[1352] In some embodiments, the compound provided herein, or a pharmaceutically acceptable salt thereof, is a polypeptide analog of pramlintide as shown in SEQ ID NO:2.

[1353] In some embodiments, the amino acid residue at at least one of positions 13 and 14 of the polypeptide analog is Aib, and the amino acid numbering of the amylin analog adopts the amino acid sequence numbering shown in SEQ ID NO: 2.

[1354] In some embodiments, the amino acid residues at positions 13 and 14 of the pancreatic polypeptide analog are selected from the group consisting of: Ala-Aib, Aib-Ala, or Aib-Aib.

[1355] In some embodiments, the side chain of at least one amino acid residue in the polypeptide analog is linked to a substituent.

[1356] In some embodiments, the polypeptide analog comprises one or more amino acids as shown below:

[1357] The amino acid residue at position 1 is Lys or absent.

[1358] The amino acid residue at position 17 is Val or Aib,

[1359] The amino acid residue at position 18 is His, Aib or Y1,

[1360] The amino acid residue at position 21 is Asn, Gln, Glu, Ala or Aib,

[1361] The amino acid residue at position 22 is Asn, Ala or Y1,

[1362] The amino acid residue at position 23 is Phe, 2-Pal, 4-Pal, hPhe or 3-Pal,

[1363] The amino acid residue at position 26 is Ile or N-Me-Ile,

[1364] The amino acid residue at position 31 is Asn, Asp, Glu, Gln or Y1,

[1365] The amino acid residue at position 35 is Glu, Asn, Asp or Gln.

[1366] In some embodiments, the amylin analog comprises one or more amino acids as shown below:

[1367] The amino acid residue at position 2 is Cys, homoCys, Pen or Abu,

[1368] The amino acid residue at position 3 is Asn, Gln, Asp, Glu or Y1,

[1369] The amino acid residue at position 7 is Cys, homoCys, Pen or Abu,

[1370] The amino acid residue at position 10 is Gln, Asn, Glu, Asp or Y1,

[1371] The amino acid residue at position 11 is Arg, homoArg, Orn, D-Arg or Y1,

[1372] The amino acid residue at position 12 is Leu, homoLeu, N-Me-Leu, α-Me-Leu or D-Leu,

[1373] The amino acid residue at position 13 is Ala,

[1374] The amino acid residue at position 15 is Phe,

[1375] The amino acid residue at position 24 is Gly,

[1376] The amino acid residue at position 33 is Gly,

[1377] The amino acid residue at position 37 is Tyr or Pro.

[1378] In some specific embodiments, the amino acid residue at position 1 is absent.

[1379] In some specific embodiments, the amino acid residue at position 2 is Cys, Pen, or Abu.

[1380] In some specific embodiments, the amino acid residue at position 3 is Gln or Y1.

[1381] In some specific embodiments, the amino acid residue at position 7 is Cys or Pen. In some specific embodiments, the amino acid residue at position 7 is Cys.

[1382] In some specific embodiments, the amino acid residue at position 10 is Gln or Yl. In some specific embodiments, the amino acid residue at position 10 is Gln.

[1383] In some specific embodiments, the amino acid residue at position 11 is Arg, homoArg, Orn, or Y1.

[1384] In some specific embodiments, the amino acid residue at position 12 is Leu, N-Me-Leu, α-Me-Leu, or D-Leu. In some specific embodiments, the amino acid residue at position 12 is Leu or α-Me-Leu.

[1385] In some specific embodiments, the amino acid residue at position 13 is Ala.

[1386] In some specific embodiments, the amino acid residue at position 15 is Phe.

[1387] In some specific embodiments, the amino acid residue at position 17 is Val or Aib.

[1388] In some specific embodiments, the amino acid residue at position 18 is His, Aib, or Y1.

[1389] In some specific embodiments, the amino acid residue at position 21 is Aib or Ala.

[1390] In some specific embodiments, the amino acid residue at position 22 is Ala or Y1.

[1391] In some specific embodiments, the amino acid residue at position 23 is 3-Pal.

[1392] In some specific embodiments, the amino acid residue at position 24 is Gly.

[1393] In some specific embodiments, the amino acid residue at position 26 is Ile or N-Me-Ile.

[1394] In some specific embodiments, the amino acid residue at position 31 is Asp or Y1.

[1395] In some specific embodiments, the amino acid residue at position 33 is Gly.

[1396] In some specific embodiments, the amino acid residue at position 35 is Glu.

[1397] In some specific embodiments, the amino acid residue at position 37 is Pro.

[1398] In some embodiments, Y1 is selected from a Lys, Orn, Dap, Dab or Cys residue whose side chain is connected to a substituent. In some specific embodiments, Y1 is selected from a Lys residue whose side chain is connected to a substituent.

[1399] In some embodiments, the substituent comprises the structure shown below: -Z1-Z2; wherein:

[1400] Z1 contains the following structure:-(AEEA) 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 4 (e.g., 1, 2, 3, or 4); 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.

[1401] Z2 contains the following structure: -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 12 and 22 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22). In some specific embodiments, c is any integer between 14 and 20 (e.g., 14, 15, 16, 17, 18, 19, or 20). In some specific embodiments, c is 14, 16, 18, or 20. In some specific embodiments, c is 16 or 18.

[1402] In some embodiments, the substituent has 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 (e.g., 0, 1, 2, 3, or 4), b is any integer between 1 and 4 (e.g., 1, 2, 3, or 4), 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).

[1403] In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is any integer from 12 to 22 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22). In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is any integer from 14 to 20 (e.g., 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22). In some specific embodiments, a is 1, 2 or 3, b is 1 or 2, and c is 14, 16, 18 or 20. In some specific embodiments, a is 1, 2 or 3, b is 1, 2 or 3, and c is 14, 16, 18 or 20. In some specific embodiments, a is 2 or 3, b is 1 or 2, and c is 14, 16, 18 or 20. In some specific embodiments, a is 1 or 2, b is 3, and c is 14, 16, 18, or 20. In some specific embodiments, a is 2, b is 1 or 2, and c is 16, 18, or 20. Or, a is 1 or 2, b is 3, 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. Or, a is 1 or 2, b is 3, and c is 16 or 18.

[1404] In some specific embodiments, a is 2, b is 1, and c is 16 or 18. Or, a is 1, b is 3, and c is 16 or 18. Or, a is 2, b is 3, and c is 16 or 18.

[1405] In some specific embodiments, the substituent comprises the following structure:

[1406] In some specific embodiments, the substituent comprises the following structure:

[1407] In some embodiments, Y1 is a Lys residue with a side chain linked substituent, wherein the substituent is covalently linked to the ε-amino group of the Lys residue via an amide bond. In some embodiments, the Y1 is selected from: K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH), K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH),

[1408] K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH), or K(-AEEA-γGlu-C(O)-C 18 -COOH);

[1409] The K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH) has the structure:

[1410] , the K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[1411] The K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH) has the structure:

[1412] The K(-AEEA-γGlu-C(O)-C 18 -COOH) has the structure:

[1413] In some embodiments, the amylin analog forms a disulfide bond, a methylenethioacetal bridge, a thioether bond, an o-phenylenedisulfide bridge, an m-phenylenedisulfide bridge, or a p-phenylenedisulfide bridge between the amino acid residues at positions 2 and 7. In some specific embodiments, a disulfide bond or a methylenethioacetal bridge is formed between the amino acid residues at positions 2 and 7.

[1414] Illustratively, the disulfide bond, the methylenethioacetal bridge, the o-phenylenedisulfide bridge, the m-phenylenedisulfide bridge, and the p-phenylenedisulfide bridge are the following groups, respectively:

[1415] Illustratively, the thioether bond is selected from the group shown below:

[1416] In some embodiments, the N-terminus of the polypeptide analog may be optionally acetylated.

[1417] In some embodiments, the C-terminus of the polypeptide analog may be optionally amidated.

[1418] In some embodiments, the compounds of any structure disclosed herein are amphoteric 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.

[1419] In some embodiments, the present disclosure provides a prodrug that metabolizes to any one of the aforementioned compounds or a pharmaceutically acceptable salt thereof.

[1420] In some embodiments, any one of the aforementioned compounds or a pharmaceutically acceptable salt thereof is a conjugate formed by conjugation with a protein (eg, antibody), a polypeptide, a nucleic acid, or a compound.

[1421] In some embodiments, the present disclosure provides a compound or a pharmaceutically acceptable salt thereof, which has at least one of the following activities: calcitonin receptor agonist activity, amylin receptor agonist activity.

[1422] Exemplarily, the amylin receptor agonist activity refers to the agonist activity on the amyloid type 1 receptor (AMY1R), the amyloid type 2 receptor (AMY2R), and / or the amyloid type 3 receptor (AMY3R). It is generally known to those skilled in the art that the agonist activity of amylin and its analogs on the amyloid type 1 receptor (AMY1R) and the amyloid type 3 receptor (AMY3R) show a consistent trend of change. In some embodiments of the present disclosure, the AMY1R agonist activity is used to characterize the AMYR receptor agonist activity of the compound; in some embodiments of the present disclosure, the AMY3R agonist activity is used to characterize the AMYR receptor agonist activity of the compound.

[1423] In some embodiments, any compound provided herein, or a pharmaceutically acceptable salt thereof, is a dual agonist of the calcitonin receptor and the amylin receptor.

[1424] As used herein, and with reference to one or more receptors, "activity," "activation," "activation," and the like refer to the ability of a compound (such as a peptide herein) to bind to a receptor and induce a response at the receptor as measured using assays known in the art (such as the in vitro assays described in the Examples of this disclosure).

[1425] 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 value is a measure of the concentration of compound required to achieve half of the compound's maximal activity in a particular assay.

[1426] In some embodiments of the present disclosure, for example, when the compound is evaluated for its agonist activity against human amylin receptor using the assay described in the Test Examples, the compound of the present disclosure has an EC of ≤1.0 μM, ≤0.8 μM, ≤0.5 μM, ≤0.1 μM, ≤0.08 μM, ≤0.05 μM, ≤0.02 μM, ≤0.01 μM, ≤0.008 μM, ≤0.005 μM, ≤0.002 μM, or ≤0.001 μM. 50 .

[1427] In some embodiments of the present disclosure, for example, when evaluating the agonist activity of the compound on the human calcitonin receptor using the assay described in the Test Examples, the compound of the present disclosure has an EC of ≤1.0 μM, ≤0.8 μM, ≤0.5 μM, ≤0.1 μM, ≤0.08 μM, ≤0.05 μM, ≤0.02 μM, ≤0.01 μM, ≤0.008 μM, ≤0.005 μM, ≤0.002 μM, or ≤0.001 μM. 50 .

[1428] In some embodiments, the compounds of the present disclosure or their pharmaceutically acceptable salts have stronger efficacy in lowering blood sugar and reducing weight in vivo. For example, the compounds of the present disclosure or their pharmaceutically acceptable salts have stronger efficacy in lowering blood sugar and reducing weight in vivo than pramlintide.

[1429] In some embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, have increased solubility. For example, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, have increased solubility relative to Pramlintide or Cagrilintide.

[1430] In some specific embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, have increased solubility at physiological pH. For example, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, have increased solubility at physiological pH relative to pramlintide or canagliflozin. In some embodiments, the solubility of the compounds of the present disclosure is ≥ 10 mg / mL, 15 mg / mL, 20 mg / mL, or 25 mg / mL.

[1431] In some specific embodiments, the physiological pH range includes a pH of pH 7.0 or thereabouts. In some specific embodiments, the physiological pH range relates to any pH value within the range of pH 6.0-8.0. For example, the pH is 6.8-7.8, 6.5-7.5, 6.9-7.7, 7.0-7.5, 7.3-7.4, 7.3-7.5, etc.

[1432] In some embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, have increased physical stability. For example, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, have increased physical stability relative to Pramlintide or Cagrilintide.

[1433] In some specific embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, have improved physical stability at physiological pH.

[1434] As used in this disclosure, the term "physical stability" of a polypeptide of the present invention or its formulation refers to the tendency of the polypeptide to form biologically inactive and / or insoluble aggregates due to exposure to thermal-mechanical stress and / or interaction with destabilizing interfaces and surfaces (e.g., hydrophobic surfaces and interfaces). The physical stability of an aqueous polypeptide formulation can be evaluated by visual inspection, the ThT fibrillation assay (sometimes also referred to as the ThT fibrillogenesis assay) and / or turbidity assay described elsewhere herein. Alternatively, it can be assessed by measurement methods well known in the art.

[1435] In some specific embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, have a reduced tendency to aggregate to form amyloid fibrils. For example, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, have a reduced tendency to aggregate to form amyloid fibrils relative to pramlintide or cagrilintide.

[1436] In some specific embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, have a reduced tendency to aggregate to form amyloid fibrils at physiological pH conditions. For example, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, have a reduced tendency to aggregate to form amyloid fibrils at physiological pH conditions relative to pramlintide or canaglitinide.

[1437] In some specific embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, maintain physical stability for 25 hours or more in a fibrillogenesis assay. For example, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, maintain physical stability for 30 hours, 40 hours, 50 hours, 55 hours, 60 hours, 65 hours, 70 hours, 75 hours, 80 hours, 85 hours, 90 hours, 91 hours, 92 hours, 93 hours, 94 hours, 95 hours, 96 hours or more in a fibrillogenesis assay (including any range between any of the above values).

[1438] In some embodiments, the compounds of the present disclosure or their pharmaceutically acceptable salts have improved pharmacokinetic properties. For example, the compounds of the present disclosure or their pharmaceutically acceptable salts have an extended half-life (t 1 / 2 For example, the compounds of the present disclosure or pharmaceutically acceptable salts thereof have a prolonged half-life (t 1 / 2 ).

[1439] In some embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, have increased chemical stability. For example, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, have increased chemical stability relative to Pramlintide or Cagrilintide.

[1440] As used in this disclosure, the term "chemical stability" refers to the absence of chemical covalent changes in the polypeptide structure compared to the parent (native) polypeptide structure, thereby avoiding the formation of chemical degradation products with potentially lower potency and / or potentially increased immunogenicity. Depending on the type and properties of the parent polypeptide and the environment to which the polypeptide is exposed, a variety of chemical degradation products may be formed. The elimination of chemical degradation is most likely not completely avoided, and increased amounts of chemical degradation products are often seen during the storage and use of polypeptide formulations, as is well known to those skilled in the art. The chemical stability of a polypeptide can be assessed by measuring the amount of chemical degradation products at various time points after exposure to different environmental conditions (the formation of degradation products can often be accelerated, for example, by increasing the temperature). The amount of each individual degradation product is often determined by separating the degradation products according to molecular size and / or charge using various chromatographic techniques (e.g., SEC-HPLC and / or RP-HPLC).

[1441] The present invention modifies the islet amylin, for example, by replacing the amino acid residue at position 14 with Aib, which can effectively improve the physical stability of the polypeptide, reduce the tendency to aggregate to form amyloid fibers; and effectively improve the solubility of the polypeptide under physiological pH conditions. On the other hand, by modifying the amino acid site, the agonist activity of the polypeptide is also significantly improved. For example, replacing the amino acid residue at position 14 with Aib can significantly enhance the agonist activity of AMYR and CTR. Alternatively, replacing the amino acid residue at position 14 with Ala or the amino acid residue at position 13 with Aib can significantly enhance the agonist activity of CTR.

[1442] In some embodiments, the present disclosure can significantly increase the physical and / or chemical stability of the polypeptide, increase the solubility of the polypeptide at physiological pH conditions, and reduce the tendency of the polypeptide to aggregate to form amyloid fibers by performing at least one amino acid substitution in amylin, for example, replacing position 21 with Aib, position 22 with Ala, position 23 with 3-Pal, position 31 with Asp, and / or position 35 with Glu. In some embodiments, amino acid site modification further enhances the agonist activity of the polypeptide on the receptor.

[1443] The present invention can significantly improve the pharmacokinetic properties and prolong the half-life of the polypeptide by selecting specific sites for connecting fatty acid chains in pancreatic amylin, for example, connecting to the amino acid side chain at position 18, 22, 31, 10, 11, or 3.

[1444] In some embodiments, the present disclosure obtains polypeptide analogs with significantly prolonged half-life by selecting specific sites for linking fatty acid chains in amylin, for example, linking to the amino acid side chains at positions 18, 22, and 31.

[1445] For example, the compounds of the present disclosure or pharmaceutically acceptable salts thereof have a half-life in animals of ≥30 min, 1 h, 1.5 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 , 6.5h, 6.8h, 7.0h, 7.2h, 7.5h, 7.8h, 8.0h, 8.2h, 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, 21.0h, 22.5h, 23.0h, 24.0h, 25h, 26.0h, 27.0h, 28.0h, 29.0h, 30h, 40h, 50h, 60h, 70h, 80h, 90h, 100h, 120h, 150h, 200h, etc. (including any range between the above any point values).

[1446] Amylin analogs

[1447] In some embodiments, the present disclosure provides an amylin analog comprising any of the aforementioned compounds or a pharmaceutically acceptable salt thereof.

[1448] In some embodiments of the present disclosure, the amylin analog has human amylin receptor agonist activity and human calcitonin receptor agonist activity.

[1449] In some embodiments of the present disclosure, when the agonist activity on the human amylin receptor is determined using the method described in the test examples, the amylin analog has an EC of ≤1.0 μM, ≤0.8 μM, ≤0.5 μM, ≤0.1 μM, ≤0.08 μM, ≤0.05 μM, ≤0.02 μM, ≤0.01 μM, ≤0.008 μM, ≤0.005 μM, ≤0.002 μM, or ≤0.001 μM. 50 .

[1450] In some embodiments of the present disclosure, for example, when determining agonist activity on the human calcitonin receptor using the assay described in the Test Examples, the amylin analog has an EC of ≤1.0 μM, ≤0.8 μM, ≤0.5 μM, ≤0.1 μM, ≤0.08 μM, ≤0.05 μM, ≤0.02 μM, ≤0.01 μM, ≤0.008 μM, ≤0.005 μM, ≤0.002 μM, or ≤0.001 μM. 50 .

[1451] In some embodiments, the amylin analogs disclosed herein have a stronger efficacy in lowering blood sugar and reducing weight in vivo. For example, the amylin analogs disclosed herein have a stronger efficacy in lowering blood sugar and reducing weight in vivo than pramlintide.

[1452] In some embodiments, the amylin analogs disclosed herein have increased solubility. For example, the amylin analogs disclosed herein have increased solubility relative to pramlintide or canaglitintide.

[1453] In some specific embodiments, the amylin analogs disclosed herein have increased solubility under physiological pH conditions. For example, the amylin analogs disclosed herein have increased solubility under physiological pH conditions relative to pramlintide or canagliflozin. In some embodiments, the solubility of the amylin analogs disclosed herein is ≥10 mg / mL, 15 mg / mL, 20 mg / mL, or 25 mg / mL.

[1454] In some embodiments, the amylin analogs disclosed herein have increased physical stability. For example, the amylin analogs disclosed herein have increased physical stability relative to pramlintide or canagliflozin. In some specific embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, have improved physical stability at physiological pH.

[1455] In some specific embodiments, the amylin analogs disclosed herein have a reduced tendency to aggregate to form amyloid fibrils. For example, the amylin analogs disclosed herein have a reduced tendency to aggregate to form amyloid fibrils relative to pramlintide or cagrilintide.

[1456] In some specific embodiments, the amylin analogs disclosed herein have a reduced tendency to aggregate to form amyloid fibrils under physiological pH conditions. For example, the amylin analogs disclosed herein have a reduced tendency to aggregate to form amyloid fibrils under physiological pH conditions relative to pramlintide or cagrilintide.

[1457] In some specific embodiments, the amylin analogs of the present disclosure maintain physical stability for 25 hours or more in a fibrillogenesis assay. For example, the amylin analogs of the present disclosure maintain physical stability for 30 hours, 40 hours, 50 hours, 55 hours, 60 hours, 65 hours, 70 hours, 75 hours, 80 hours, 85 hours, 90 hours, 91 hours, 92 hours, 93 hours, 94 hours, 95 hours, 96 hours or more in a fibrillogenesis assay (including any range between any of the above values).

[1458] In some embodiments, the amylin analogs of the present disclosure have improved pharmacokinetic properties. For example, the amylin analogs of the present disclosure have an extended half-life (t 1 / 2 For example, the amylin analogs of the present disclosure have an extended half-life (t 1 / 2 ).

[1459] For example, the amylin analogs of the present disclosure have a half-life in animals of ≥30 min, 1 h, 1.5 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, 7.5 h, 8.5 h, 9.5 h, 10.5 h, 11.5 h, 12.5 h, 13.5 h, 14.5 h, 15.5 h, 16.5 h, 17.5 h, 18.5 h, 19.5 h, 20.5 h, 21.5 h, 22.5 h, 23.5 h, 24.5 h, 25.5 h, 26.5 h, 27.5 h, 28.5 h, 29.5 h, 30.5 h, 31.5 h, 32.5 h, 33.5 h, 34.5 h, 35.5 h, 36.5 h, 37.5 h, 38.5 h, 39.5 h, 40.5 h, 41.5 h, 42.5 h, 43.5 h, 44.5 h, 45.5 h, 46.5 h, 47.5 h, 48.5 h, 49.5 h, 50.5 h, 51.5 h, 52.5 h, 53.5 h, 54.5 h, 55.5 h, 56.5 h, 57.5 h, 58.5 h, 59.5 h, h, 6.5h, 6.8h, 7.0h, 7.2h, 7.5h, 7.8h, 8.0h, 8.2h, 8.5h, 8.8h, 9.0h, 9.2h, 9.5 h, 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, 15.0 h, 15.2h, 15.5h, 15.8h, 16.0h, 16.5h, 16.0h, 17.0h, 17.5h, 18.0h, 18.5h, 19.0 h, 19.5h, 20.0h, 21.0h, 22.5h, 23.0h, 24.0h, 25h, 26.0h, 27.0h, 28.0h, 29.0h, 30h, 40h, 50h, 60h, 70h, 80h, 90h, 100h, 120h, 150h, 200h, etc. (including any range between the above any point values).

[1460] AMYR / CTR dual agonists

[1461] In some embodiments, the present disclosure provides dual agonists of AMYR / CTR comprising any of the aforementioned compounds or pharmaceutically acceptable salts thereof.

[1462] In some embodiments of the present disclosure, when the agonist activity on human amylin receptor is determined using the method described in the test examples, the dual agonist of AMYR / CTR has an EC of ≤1.0 μM, ≤0.8 μM, ≤0.5 μM, ≤0.1 μM, ≤0.08 μM, ≤0.05 μM, ≤0.02 μM, ≤0.01 μM, ≤0.008 μM, ≤0.005 μM, ≤0.002 μM, or ≤0.001 μM. 50 .

[1463] In some embodiments of the present disclosure, for example, when determining agonist activity on the human calcitonin receptor using the assay described in the Test Examples, the dual agonists of AMYR / CTR have an EC of ≤1.0 μM, ≤0.8 μM, ≤0.5 μM, ≤0.1 μM, ≤0.08 μM, ≤0.05 μM, ≤0.02 μM, ≤0.01 μM, ≤0.008 μM, ≤0.005 μM, ≤0.002 μM, or ≤0.001 μM. 50 .

[1464] In some embodiments, the AMYR / CTR dual agonists disclosed herein have stronger efficacy in lowering blood sugar and reducing weight in vivo. For example, the AMYR / CTR dual agonists disclosed herein have stronger efficacy in lowering blood sugar and reducing weight in vivo than pramlintide.

[1465] In some embodiments, the dual AMYR / CTR agonists disclosed herein have increased solubility. For example, the dual AMYR / CTR agonists disclosed herein have increased solubility relative to Pramlintide or Cagrilintide.

[1466] In some specific embodiments, the dual AMYR / CTR agonists disclosed herein have increased solubility at physiological pH. For example, the dual AMYR / CTR agonists disclosed herein have increased solubility at physiological pH relative to pramlintide or canagliflozin. In some embodiments, the solubility of the dual AMYR / CTR agonists disclosed herein is ≥ 10 mg / mL, 15 mg / mL, 20 mg / mL, or 25 mg / mL.

[1467] In some embodiments, the AMYR / CTR dual agonists disclosed herein have increased physical stability. For example, the AMYR / CTR dual agonists disclosed herein have increased physical stability relative to pramlintide or canagliflozin. In some specific embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, have improved physical stability at physiological pH.

[1468] In some specific embodiments, the dual AMYR / CTR agonists disclosed herein have a reduced tendency to aggregate to form amyloid fibrils. For example, the dual AMYR / CTR agonists disclosed herein have a reduced tendency to aggregate to form amyloid fibrils relative to pramlintide or cagrilintide.

[1469] In some specific embodiments, the dual agonists of AMYR / CTR disclosed herein have a reduced tendency to aggregate to form amyloid fibrils at physiological pH conditions. For example, the dual agonists of AMYR / CTR disclosed herein have a reduced tendency to aggregate to form amyloid fibrils at physiological pH conditions relative to pramlintide or canaglitintide.

[1470] In some specific embodiments, the dual agonists of AMYR / CTR disclosed herein maintain physical stability for 25 hours or more in a fibrillogenesis assay. For example, the dual agonists of AMYR / CTR disclosed herein maintain physical stability for 30 hours, 40 hours, 50 hours, 55 hours, 60 hours, 65 hours, 70 hours, 75 hours, 80 hours, 85 hours, 90 hours, 91 hours, 92 hours, 93 hours, 94 hours, 95 hours, 96 hours or more in a fibrillogenesis assay (including any ranges between any of the above values).

[1471] In some embodiments, the dual agonists of AMYR / CTR disclosed herein have improved pharmacokinetic properties. For example, the dual agonists of AMYR / CTR disclosed herein have an extended half-life (t 1 / 2 For example, the dual agonists of AMYR / CTR in the present disclosure have a prolonged half-life (t 1 / 2 ).

[1472] For example, the dual agonists of AMYR / CTR in the present disclosure have a half-life in animals of ≥30 min, 1 h, 1.5 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, 6.2h, 6.5h, 6.8h, 7.0h, 7.2h, 7.5h, 7.8h, 8.0h, 8.2h, 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, 21.0h, 22.5h, 23.0h, 24.0h, 25h, 26.0h, 27.0h, 28.0h, 29.0h, 30h, 40h, 50h, 60h, 70h, 80h, 90h, 100h, 120h, 150h, 200h, etc. (including any range between the above any point values).

[1473] Pharmaceutical composition

[1474] In one aspect, the present application provides a pharmaceutical composition comprising the aforementioned compound or a pharmaceutically acceptable salt thereof, an amylin analog, or an AMYR / CTR dual agonist.

[1475] In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient or pharmaceutical carrier.

[1476] In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, an amylin analog, or an AMYR / CTR dual agonist. In some embodiments, the pharmaceutical composition may contain 0.01 to 99% by weight of the aforementioned compound or a pharmaceutically acceptable salt thereof, an amylin analog, or an AMYR / CTR dual agonist per unit dose, or the amount of the aforementioned compound or a pharmaceutically acceptable salt thereof, an amylin analog, or an AMYR / CTR dual agonist per unit dose of the pharmaceutical composition is 0.1-2000 mg, in some embodiments, 1-1000 mg.

[1477] Medical uses and treatments

[1478] In one aspect, the present invention discloses any of the following uses of the aforementioned compound or a pharmaceutically acceptable salt thereof, an amylin analog, an AMYR / CTR dual agonist, or a pharmaceutical composition:

[1479] (1) Use as a medicine or for the preparation of a medicine;

[1480] (2) Use as a dual agonist of the insulin amyloid peptide receptor and the calcitonin receptor, or for preparing a dual agonist for activating the insulin amyloid peptide receptor and the calcitonin receptor;

[1481] (3) Use for lowering blood sugar or preparing a drug for lowering blood sugar;

[1482] (4) Use for weight control or the preparation of a medicament for weight control;

[1483] (5) Use of a drug for reducing food intake, reducing β-cell apoptosis, increasing β-cell function and β-cell mass and / or restoring β-cell glucose sensitivity, or for preparing a drug for reducing food intake, reducing β-cell apoptosis, increasing β-cell function and β-cell mass and / or restoring β-cell glucose sensitivity.

[1484] In some embodiments, the medicament is for preventing and / or treating a disease or condition associated with a metabolic disorder.

[1485] In some embodiments, the metabolic disorder-related disease or condition comprises diabetes, diabetes-related conditions, obesity, obesity-related conditions, weight management, non-alcoholic steatohepatitis.

[1486] In one aspect, the present disclosure provides a method for preventing or treating a disease, comprising administering a preventively or therapeutically effective amount of an amylin analog or a pharmaceutical composition to a subject in need thereof.

[1487] In some embodiments, the subject suffers from a disease or condition associated with a metabolic disorder.

[1488] In some embodiments, the metabolic disorder-related disease or condition comprises diabetes, diabetes-related conditions, obesity, obesity-related conditions, weight management, non-alcoholic steatohepatitis.

[1489] Devices and kits

[1490] In some embodiments, the present disclosure relates to devices comprising a compound or a pharmaceutically acceptable salt thereof, an amylin analog, an AMYR / CTR dual agonist, or a pharmaceutical composition for delivering the compound to a subject. Such devices can be used to administer the amylin analog to a patient by a variety of delivery methods, including intravenous administration or other methods recognized by those skilled in the art.

[1491] In some embodiments, the present disclosure relates to a kit comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof, an amylin analog, an AMYR / CTR dual agonist, or a pharmaceutical composition. In certain embodiments, the kit further comprises packaging and / or instructions for use.

[1492] In some embodiments, the device or kit can be used for the prevention or treatment of diseases or conditions as described above.

[1493] Preparation method

[1494] In some embodiments, the present disclosure provides a method for preparing a compound or a pharmaceutically acceptable salt thereof, an amylin analog, or an AMYR / CTR dual agonist, the method comprising preparing a compound of any of the aforementioned structures or a pharmaceutically acceptable salt thereof by a chemical synthesis method or a biological semi-synthetic method.

[1495] In some embodiments, the chemical synthesis method is solid phase synthesis.

[1496] Illustratively, the polypeptide compound provided by the present disclosure is synthesized by a solid-phase method, and the synthesis carrier is Rink-amide MBHA (Xi'an Lanxiao Technology) resin. The α-amino group of the amino acid derivative used in the synthesis process is protected by an Fmoc group (fluorenylcarbonyl), and the side chains of the amino acids are selected from the following protecting groups according to the different functional groups: the cysteine ​​side chain thiol group, the glutamine side chain amino group, and the 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 is protected by Boc (tert-butyloxycarbonyl), the lysine side chain amino group is protected by Boc or Mtt (4-methyltrityl), the threonine side chain hydroxyl group, the tyrosine side chain phenol group, and the serine side chain hydroxyl group are protected by t-Bu (tert-butyl), and the aspartic acid and glutamic acid side chain carboxyl groups are protected by O-tBu (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 condensed 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. Unless otherwise specified, the peptide is cleaved from the solid support by reacting with a mixture of trifluoroacetic acid: water: triisopropylsilane: mercaptoethanol (91:3:3:3, v:v:v) with the resin. The crude solid peptide compound is then precipitated with methyl tert-butyl ether.

[1497] In some embodiments, the polypeptide compounds provided herein utilize disulfide bonds to form a ring. When X2 and X7 are selected from any of the amino acid residues Cys, hCys, and Pen, the crude polypeptide is dissolved in a mixture of 50% acetic acid and water, and excess iodine is added to oxidize the sulfhydryl groups to form disulfide bonds. The excess iodine is then neutralized with ascorbic acid. After the reaction, the mixed solution is diluted with water and purified using a C-18 reverse-phase preparative chromatography column to obtain a pure polypeptide compound.

[1498] In some embodiments, the polypeptide compounds provided herein utilize a methylene sulfide bridge, a p-xylylenedisulfide bridge, an m-xylylenedisulfide bridge, or an o-xylylenedisulfide bridge to form a ring. When X2 and X7 are selected from any amino acid residues selected from Cys, hCys, and Pen, the crude polypeptide is dissolved in an ammonium bicarbonate buffer containing 50% acetonitrile at a pH of 8.5, and a cyclization reaction is carried out with the aid of tris(2-carboxyethyl)phosphine and diiodomethane, 1,4-bis(bromomethyl)benzene, 1,3-bis(bromomethyl)benzene, 1,2-bis(bromomethyl)benzene, or the like to obtain cyclized products connected by a methylene sulfide bridge, a p-xylylenedisulfide bridge, an m-xylylenedisulfide bridge, or an o-xylylenedisulfide bridge, respectively. Finally, the purified polypeptide compound is separated and purified by a C-18 reverse-phase preparative chromatography column to obtain a pure product.

[1499] In some embodiments, the polypeptide compounds provided by the present disclosure utilize thioether bonds to form a ring. When any one of X2 and X7 is selected from the amino acid residues of Cys, hCys, and Pen and the other position is selected from the amino acid residue of Abu, X2 and X7 are connected by a thioether bridge, and the amino acid residue of Abu is generated by the reaction of hSer (TBDMS) (homoserine (tert-butyldimethylsilane). The resin peptide with hSer (TBDMS) at a specific position is treated with triphenylphosphine and trichloroacetonitrile. After treatment with the dichloromethane solution, the peptide was cleaved from the solid support by reacting with a mixture of trifluoroacetic acid: water: triisopropylsilane: anisole (91:3:3:3, volume ratio) with the resin. The crude peptide was then precipitated with methyl tert-butyl ether to yield a solid crude peptide compound. The crude peptide was dissolved in 30% acetonitrile in ammonium bicarbonate and the pH was adjusted to 8.5. The reaction was allowed to proceed for 12 hours to yield the thioether-bridged cyclized product. The pure peptide compound was then purified using a C-18 reverse-phase preparative chromatography column.

[1500] In some embodiments, the present disclosure uses a biosemisynthetic method to prepare polypeptide compounds. For example, a method similar to that disclosed in patents CN201510459093 and US9732137 for preparing semaglutide (SEQ ID NO: 4) is used. BRIEF DESCRIPTION OF THE DRAWINGS

[1501] FIG1 shows the changes in rat body weight over time after administration of the compounds of the present disclosure.

[1502] FIG2 shows the changes in blood glucose in STZ rats after administration of the compounds of the present disclosure. DETAILED DESCRIPTION

[1503] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[1504] In the context of this application, 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.

[1505] The terms "amylin," "human amylin," or "Amylin" refer to the polypeptide human amylin having the sequence set forth in SEQ ID NO: 1. The term includes, but is not limited to, the naturally occurring human amylin sequence comprising 37 amino acids. Human amylin has the following primary amino acid sequence: Lys-Cys-Asn-Thr-Ala-Thr-Cys-Ala-Thr-Gln-Arg-Leu-Ala-Asn-Phe-Leu-Val-His-Ser-Ser-Asn-Asn-Phe-Gly-Ala-Ile-Leu-Ser-Ser-Thr-Asn-Val-Gly-Ser-Asn-Thr-Tyr (SEQ ID NO: 1).

[1506] Human amylin has a disulfide bond between two Cys residues and a C-terminal amide. The structure is shown below:

[1507] As used herein, the term "analog of amylin" or "amylin analog" refers to a variant of SEQ ID NO: 1. For example, the variant includes, but is not limited to, one or more substitutions and / or one or more deletions and / or one or more additions of any amino acid residue to any natural or non-natural amino acid, synthetic amino acid or peptidomimetics, and / or the substituent is linked to any of the natural or non-natural amino acid, synthetic amino acid or peptidomimetics at any available position. In the amylin analog or peptide defined above, when the substituent is linked to any of the natural or non-natural amino acid, synthetic amino acid or peptidomimetics at any available position, the resulting amylin may also be referred to herein as an "amylin derivative", "derivative of the present disclosure", "derivative of amylin", "polypeptide compound" or "derivative of peptide".

[1508] The term "pramlintide" refers to a synthetic polypeptide having the sequence set forth in SEQ ID NO: 2. Pramlintide has the following primary amino acid sequence: Lys-Cys-Asn-Thr-Ala-Thr-Cys-Ala-Thr-Gln-Arg-Leu-Ala-Asn-Phe-Leu-Val-His-Ser-Ser-Asn-Asn-Phe-Gly-Pro-Ile-Leu-Pro-Pro-Thr-Asn-Val-Gly-Ser-Asn-Thr-Tyr (SEQ ID NO: 2)

[1509] Pramlintide has a disulfide bond between two Cys residues and a C-terminal amide group. The structure is shown below:

[1510] The term "analog of pramlintide" or "pramlintide analog" refers to a variant of the polypeptide shown in SEQ ID NO: 2.

[1511] The terms "hAmylin", "hCT" or "sCT", unless further explained, refer to native human amylin, native human calcitonin polypeptide or native salmon calcitonin polypeptide, respectively.

[1512] The terms "AMYR" or "CTR", "hAMYR" or "hCTR", unless further explained, refer to native human amylin receptor or native human calcitonin receptor, respectively.

[1513] The term "canagliflozin" is a dual agonist of the islet amyloid receptor and the calcitonin receptor, and its structure is shown below:

[1514] SEQ ID NO:3

[1515] 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.

[1516] The term "polypeptide" refers to a sequence of two or more amino acids. In the context of this application, "polypeptide", "compound", "polypeptide compound" are used interchangeably.

[1517] Amino acids are molecules containing an amino group and a carboxylic acid group and optionally containing one or more additional groups that are often referred to as side chains. The term "amino acid" includes proteinogenic (or natural) amino acids (wherein 20 kinds of 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). Typically, amino acid residues can be represented by their full names, their single-letter codes, and / or their three-letter codes. These three methods are fully equivalent.

[1518] The amino acid sequences of the present invention contain the standard single-letter or three-letter codes for the twenty amino acids. Unless otherwise specified, all amino acid residues in the present invention are preferably in the L-form. In addition, Aib is α-aminoisobutyric acid, D-Ala is D-alanine, hCys or homoCys is homocysteine, Pen is penicillamine, Abu is 2-aminobutyric acid, Orn is ornithine, hArg or homoArg is homoarginine, D-Arg is D-arginine, Lys (Ac) is Nε-acetyl lysine, hLeu or homoLeu is homoleucine, N-Me-Leu is N-methyl leucine, and N-Me-Ile is N-methyl Isoleucine, α-Me-Leu is α-methylleucine, D-Leu is D-leucine, 2-Pal is 2-pyridylalanine, 3-Pal is 3-pyridylalanine, 4-Pal is 4-pyridylalanine, hPhe is homophenylalanine, D-Ser is D-serine, Oxa is s-oxazolidine-4-carboxylic acid, Hyp is hydroxyproline, Pip is 4-aminopiperidine-4-carboxylic acid, Dap is 2,3-diaminopropionic acid, and Dab is 2,4-diaminopropionic acid.

[1519] “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).

[1520] "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.

[1521] The term agonist is defined as a substance that activates the receptor type in question, and the term AMYR / CTR dual agonist as used in the context of this disclosure refers to a substance or ligand that can activate both the amylin receptor and the calcitonin receptor.

[1522] 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.

[1523] The term "linker" as used herein includes suitable substituents that can connect a portion, such as a chemical portion, to a polypeptide, such as a polypeptide backbone. Thus, the linker and chemical portion together constitute a substituent. The portion connected to the linker can be any suitable portion.

[1524] The term "treatment" and grammatical variations thereof (e.g., "treated," "treating," "treat") refer to an approach for obtaining a favorable or desired clinical outcome. For the purposes of this disclosure, favorable or desired clinical outcomes include, but are not limited to, alleviation of symptoms, reduction in extent of disease, stabilization of the disease state (i.e., not worsening), delay or slowing of disease progression, improvement or alleviation of the disease state, and remission (whether partial or complete), whether detectable or undetectable. "Treatment" may also mean prolonging survival relative to the expected survival time if not receiving treatment. Thus, a subject (e.g., a human) in need of treatment may be a subject suffering from the disease or disorder in question. The term "treating" includes inhibiting or reducing the increase in severity of a pathological state or symptom (e.g., weight gain or hyperglycemia) relative to no treatment, and does not necessarily mean complete cessation of the associated disease, disorder, or condition.

[1525] The term "prevention" and its grammatical variants (e.g., "prevented," "preventing," "prevent") refer to an action intended to hinder or prevent the occurrence of a condition, disease, or disorder, or to alter its pathological condition. Thus, "prevention" may refer to a preventive or prophylactic measure. For the purposes of this disclosure, beneficial or desired clinical outcomes include, but are not limited to, preventing or slowing the symptoms, progression, or occurrence of a disease, whether detectable or undetectable. Thus, a subject (e.g., a human) in need of "prevention" may be a subject that does not suffer from the disease or disorder in question. Thus, the term "prevention" includes inhibiting or slowing the onset of a disease relative to no treatment, and is not necessarily intended to imply permanent prevention of the disease, disorder, or condition in question.

[1526] The "subject" or "patient" of the present application can be a mammal, including a human or a non-human mammal, such as a non-human primate (e.g., an ape, an Old World monkey, or a New World monkey), a livestock animal (e.g., a cow or a pig), a companion animal (e.g., a dog or a cat), or an experimental animal such as a rodent (e.g., a mouse or a rat).

[1527] Different expressions such as “X is selected from A, B, or C”, “X is selected from A, B and C”, “X is A, B or C”, and “X is A, B and C” all express the same meaning, that is, X can be any one or more of A, B, and C.

[1528] The term "fatty acid" refers to a carboxylic acid with a long fatty acid tail (chain), which may be saturated or unsaturated; in some embodiments, the fatty acid in the present disclosure is a C4-C 30 A straight-chain or branched aliphatic group of carboxylic acid.

[1529] "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.

[1530] "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.

[1531] The term "pharmaceutically acceptable salt" as used herein is intended to mean a salt that is not harmful to a patient or subject when administered to the patient or subject. It may be suitably a salt selected from, for example, acid addition salts and basic salts.

[1532] 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.

[1533] Example

[1534] 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.

[1535] Example 1. Preparation of target compound

[1536] Table 1. Experimental reagents

[1537] Table 2. Experimental instruments

[1538] 1.1 Chemical synthesis of compound 1

[1539] Compound 1

[1540] 1.1.1 Synthesis of polypeptide backbone

[1541] Rink-amide MBHA resin (0.54 mmole / g, 0.1 mmol) was weighed on a balance and placed in a disposable polypropylene solid-phase reaction tube for peptide synthesis. Nitrogen was added and the resin swelled with nitrogen-dimethylformamide (DMF, 10 mL) under nitrogen bubbling for 5 minutes. The DMF was then removed under vacuum and washed with DMF (10 mL). This washing was repeated twice before peptide solid-phase synthesis was performed on a Prelude-X automated peptide synthesizer using the Fmoc / tBu strategy. The condensation reaction was performed in DMF at room temperature for 12 minutes using 10 equivalents of HATU (equivalent to the resin support), 20 equivalents of 4-methylmorpholine, and 10 equivalents of the amino acid residue. The N-terminal Fmoc protecting group was deprotected using a DMF solution containing 25% 4-methylpiperidine at room temperature for two 10-minute reactions. In peptide backbone synthesis, the condensation of the next amino acid after the deprotection of the Aib amino acid residue was repeated three times, each for 25 minutes, to improve the quality of the crude peptide.

[1542] 1.1.2 Selective deprotection of the resin peptide protecting group Mtt ​​and side chain fatty acid modification

[1543] After the above peptide-resin extension is completed, a mixed solution of dichloromethane containing 30% hexafluoroisopropanol (10 mL) is added, and the mixture is shaken at room temperature for 45 minutes and then removed. A mixed solution of dichloromethane containing 30% hexafluoroisopropanol (10 mL) is added again, and the mixture is shaken at room temperature for 45 minutes and then removed. After the reaction, the resin is washed three times with DMF. The lysine side chain is extended using the Prelude-X fully automatic peptide synthesizer, and additional coupling / deprotection cycles involve amino acid building blocks Fmoc-AEEA-COOH and Fmoc-L-Glu-OtBu. In all couplings, 10 equivalents of HATU, 20 equivalents of 4-methylmorpholine and 10 equivalents of amino acid residues are used in DMF for reaction at room temperature for 12 minutes. The N-terminal Fmoc protecting group is deprotected using a DMF solution containing 25% 4-methylpiperidine at room temperature twice for 10 minutes each time. The final resin is washed three times with DCM and DMF respectively, and then 10 equivalents of HOOC-(CH2) are added. 18 A mixture of -COOtBu, 10 equivalents of HATU and 15 equivalents of diisopropylethylamine (DIEA) in DMF (8 mL) was reacted at room temperature for 3 hours to complete the fatty acid modification of the side chain.

[1544] 1.1.3 Product cleavage

[1545] The resin obtained in the previous step was washed three times with DMF and DCM, followed by vacuum drying. Freshly prepared cleavage buffer (trifluoroacetic acid: triisopropylsilane: water: mercaptoethanol = 91:3:3:3, volume ratio) (10 mL) was added and the mixture was shaken at room temperature for 1.5 hours. After the reaction, the mixture was filtered and a large amount of methyl tert-butyl ether was added to the filtrate to precipitate a solid. After centrifugation, the supernatant was removed, and the precipitate was washed twice with methyl tert-butyl ether and centrifuged to obtain a crude linear peptide.

[1546] 1.1.4 Product cyclization

[1547] The crude linear peptide was dissolved in a mixture of 50% acetic acid and water. Twenty equivalents of elemental iodine were added and reacted at room temperature to oxidize the free sulfhydryl groups to disulfide bonds. After ten minutes of reaction at room temperature, the excess iodine was neutralized with 1M aqueous ascorbic acid until the solution became colorless, yielding the crude peptide of Compound 1.

[1548] 1.1.5 Reverse-phase liquid chromatography purification of compound 1

[1549] The crude peptide of Compound 1 was diluted into a mixture of 0.1% trifluoroacetic acid, 20% acetonitrile, and 25% acetic acid / water. After filtration through a 0.45 μm membrane, the product was separated using a WATERS Prep150 LC reverse-phase HPLC system using buffers A (0.1% trifluoroacetic acid, 10% acetonitrile, aqueous solution) and B (0.1% trifluoroacetic acid, 90% acetonitrile, aqueous solution). The chromatographic column was an X-SELECT OBD C-18 reverse-phase column. During purification, the detection wavelength was set at 220 nm and the flow rate was 15 mL / min. The relevant fractions were collected and lyophilized to obtain the pure peptide of Compound 1 in a yield of 24.5%. The purity and molecular weight of the pure peptide were determined by analytical HPLC and liquid chromatography / mass spectrometry, resulting in a purity of 99.11%. The exact molecular weight of the compound was 4468.35.

[1550] 1.2. Chemical synthesis of compound 2-8

[1551] The polypeptide compounds of Examples 2-8 of the present invention were synthesized using the experimental protocol of Compound 1, and the purity and molecular weight of the compounds were determined by analytical high performance liquid chromatography and liquid chromatography / mass spectrometry, as shown in Table 3 below:

[1552] Table 3. Purity and measured molecular weight of the compounds

[1553] Compound 2,

[1554] Compound 3,

[1555] Compound 4,

[1556] Compound 5,

[1557] Compound 6,

[1558] Compound 7,

[1559] Compound 8,

[1560] 1.3. Chemical synthesis of compound 9

[1561] The synthesis of the polypeptide backbone of compound 9, the selective deprotection of the resin peptide protecting group Mtt, and the modification of the side chain fatty acid are the same as those of compound 1.

[1562] Compound 9,

[1563] 1.3.1 Preparation of Thioether-bridged Cyclic Peptides

[1564] After side chain modification, the resulting resin was washed three times with DMF and then DCM. The peptide resin containing the hSer (TBDMS) amino acid residue was then treated with a DCM solution (10 mL) containing 10 equivalents of triphenylphosphine and 10 equivalents of trichloroacetonitrile for two hours to yield the chlorinated product. The resin was washed three times with DCM and dried under vacuum. Freshly prepared cleavage buffer (trifluoroacetic acid: triisopropylsilane: water: anisole = 91:3:3:3, volume ratio) (10 mL) was added and the mixture was shaken at room temperature for 1.5 hours. After completion of the reaction, the mixture was filtered, and the filtrate was added to a large amount of methyl tert-butyl ether to precipitate the solid. After centrifugation, the supernatant was removed, and the precipitate was washed twice with methyl tert-butyl ether to yield the crude linear peptide. The crude peptide was dissolved in 100 mM ammonium bicarbonate buffer (pH 8.5) containing 30% acetonitrile. The reaction was allowed to proceed for 12 hours. After confirming the endpoint by UPLC monitoring, the reaction was terminated by acidification with TFA to yield the crude peptide numbered 9.

[1565] 1.3.2 Reverse-phase liquid chromatography purification of compound 9

[1566] The crude peptide solution of compound 9 obtained in the previous step was filtered through a 0.45 μm membrane and separated using a WATERS Prep150 LC reverse-phase high-performance liquid chromatography system. The buffers were A (0.1% trifluoroacetic acid, 10% acetonitrile, aqueous solution) and B (0.1% trifluoroacetic acid, 90% acetonitrile, aqueous solution). The chromatographic column was an X-SELECT OBD C-18 reverse-phase column. During the purification process, the chromatograph detection wavelength was set at 220 nm and the flow rate was 15 mL / min. The product-related fractions were collected and lyophilized to obtain the pure polypeptide of compound No. 9 with a yield of 2%. The purity and molecular weight of the pure polypeptide were determined by analytical high-performance liquid chromatography and liquid chromatography / mass spectrometry. The purity was 91.90%, and the measured precise molecular weight of the compound was 4507.42.

[1567] 1.4 Chemical synthesis of compound 10

[1568] The synthesis of the polypeptide backbone of compound 10, the selective deprotection of the resin peptide protecting group Mtt, and the modification of the side chain fatty acid are the same as those of compound 1.

[1569] 1.4.1 Product cleavage

[1570] The resin obtained after modification of the side chain fatty acids was washed three times with DMF and then DCM, followed by vacuum drying. Freshly prepared lysis buffer (trifluoroacetic acid: triisopropylsilane: water: mercaptoethanol = 91:3:3:3, volume ratio) was then added and the reaction was shaken at room temperature for 1.5 hours. After the reaction, a large amount of methyl tert-butyl ether was added to precipitate the solid. After centrifugation, the supernatant was removed, and the precipitate was washed twice with methyl tert-butyl ether to obtain the crude linear peptide.

[1571] 1.4.2 Product cyclization

[1572] The crude linear polypeptide was dissolved in a 100 mM ammonium bicarbonate (pH 8.5) buffer solution containing 50% acetonitrile, and 5 equivalents of tris(2-carboxyethyl)phosphine hydrochloride and 15 equivalents of diiodomethane were added. The mixture was reacted at room temperature for 12 hours. The reaction was monitored by UPLC. After confirming that the reaction reached the endpoint, the reaction system was acidified with TFA to terminate the reaction, thereby obtaining the crude polypeptide of Example No. 10.

[1573] 1.4.3 Reverse-phase liquid chromatography purification of compound 10

[1574] The crude peptide solution of compound 10 obtained in the previous step was diluted with water to an acetonitrile content of approximately 30%. After filtration through a 0.45 μm membrane, it was separated using a WATERS Prep150 LC reverse-phase high-performance liquid chromatography system with buffers A (0.1% trifluoroacetic acid, 10% acetonitrile, aqueous solution) and B (0.1% trifluoroacetic acid, 90% acetonitrile, aqueous solution). The chromatographic column was an X-SELECT OBD C-18 reverse-phase column. During the purification process, the chromatograph detection wavelength was set at 220 nm and the flow rate was 15 mL / min. The relevant fractions were collected and lyophilized to obtain the pure peptide of compound number 10 in a yield of 21%. The purity and molecular weight of the pure peptide were determined by analytical high-performance liquid chromatography and liquid chromatography / mass spectrometry, with a purity of 99.91% and an accurate molecular weight of 4539.40.

[1575] 1.5 Chemical Synthesis of Compounds 11-17 and 21-25

[1576] The polypeptide compounds Nos. 11-17 and 21-25 of this disclosure were synthesized using the experimental protocol of Compound 10, and the purity and molecular weight of the compounds were determined by analytical HPLC and LC / MS, as shown in Table 4 below.

[1577] Table 4. Purity and measured molecular weight of the compounds

[1578] Compound 11,

[1579] Compound 12,

[1580] Compound 13,

[1581] Compound 14,

[1582] Compound 15,

[1583] Compound 16,

[1584] Compound 17,

[1585] Compound 21,

[1586] Compound 22,

[1587] Compound 23,

[1588] Compound 24,

[1589] Compound 25,

[1590] Example 2. Biological test evaluation

[1591] The present invention is further described and explained below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

[1592] Table 5. Experimental reagents

[1593] Table 6. Test instruments

[1594] 2.1. Evaluation of the agonist activity of the example compounds at human amyloid type 3 receptor (hAMY3R) and human calcitonin receptor (hCTR)

[1595] 2.1.1 Experimental Purpose:

[1596] Compounds 18-20 were tested for their agonist activity at human islet amyloid type 3 receptor and human calcitonin receptor. The control polypeptide was pramlintide, the preparation method of which can be found in WO2012168432, which is incorporated herein by reference.

[1597] Compound 18 differs from pramlintide in that the 14th amino acid residue is Ala, Compound 19 differs from pramlintide in that the 14th amino acid residue is Aib, and Compound 20 differs from pramlintide in that the 13th amino acid residue is Aib. The preparation methods of Compounds 18-20 can refer to the preparation methods of pramlintide. The structures are shown below:

[1598] Compound 18, SEQ ID NO: 90

[1599] Compound 19, SEQ ID NO: 91

[1600] Compound 20, SEQ ID NO: 92

[1601] 2.1.2 Experimental methods:

[1602] Cell recovery and culture: Remove the 293T cell cryovial from the liquid nitrogen tank and rapidly thaw in a 37°C water bath. Immediately aspirate the cell suspension and add it to a centrifuge tube containing 5 mL of the corresponding culture medium. Centrifuge at 1000 rpm for 5 minutes. Discard the supernatant, pipette the cells evenly with 10 mL of culture medium, transfer them to a T75 flask, tighten the cap, and place in a 37°C, 5% CO2 incubator for culture until ready to use.

[1603] Transient cell transfection: On the first day, in a clean bench, discard the old culture medium; add 5 mL of PBS to the flask for washing, and discard the PBS; add 2 mL of 0.25% Trypsin-EDTA to the flask to digest the cells. Under a microscope, observe that the cells have detached from the bottom of the flask and most of them have become round. Add approximately 5 mL of culture medium to the flask to terminate the digestion, pipette evenly, and transfer to a 15 mL centrifuge tube. Centrifuge at 1000 rpm for 5 minutes, discard the supernatant, add an appropriate amount of culture medium, pipette evenly, and take a small amount of cells for counting. In a 6-well plate, 6 × 10 cells per well were added. 5 Plate the cells and culture them overnight in a 37°C, 5% CO2 incubator. The next day, prepare two EP tubes for each well in a clean bench.

[1604] EP tube 1: Dissolve the plasmid in 175ul OPTI-MEM at a concentration of 1μg CTR or 1μg CTR plus 1.5μg RAMP3 per well, along with P3000, and mix thoroughly.

[1605] EP tube 2: Dissolve Lipofectamine 3000 in 175 μl OPTI-MEM and incubate at room temperature for 5 minutes. Mix the two tubes and incubate at room temperature for 15 minutes. Then, add the mixture dropwise to a 6-well plate and perform validation 48 hours later.

[1606] Homogeneous time-resolved fluorescence (HTRF) method for detecting cAMP levels:

[1607] 1) Stimulation buffer 1x:

[1608] 2) Dilution of the molecule was performed in a 96-well U-shaped plate, with 50 μM as the highest concentration, and dilution was performed using 1X stimulation buffer, followed by 7 consecutive dilutions to a minimum concentration of 0.00001 μM.

[1609] 3) Add 5 μl of the diluted test molecule to each well of the SV 96-well plate. Add 5 μl of 20k cells (1E6 cells / mL) to each well. Resuspend the cells in serum-free, antibiotic-free DMEM supplemented with 0.2% casein (final concentration 0.1%), as per the experimental protocol. Cover with parafilm and incubate for 30 min at 37°C.

[1610] 4) After 30 minutes, add 5 μl of cAMP-d2 diluted in Lysis & Detection Buffer 1 (1:19 dilution). Then add 5 μl of anti-cAMP-cryptate diluted in Lysis & Detection Buffer 1 (1:19 dilution), cover with sealing film, and incubate at room temperature for 1 hour.

[1611] 5) Remove the sealing film and detect the signal in a Tecan microplate reader, 665em / 620em (320ex).

[1612] 2.1.3 Experimental data processing method:

[1613] Data were analyzed using Microsoft Excel and GraphPad Prism 9. EC50 values ​​were calculated using the Excel slide rule 620 / 665 reading ratio using GraphPad Prism 9. Specific values ​​are shown in Table 7-1 below.

[1614] Table 7-1. Agonist activity of compounds 18-20 at human islet amyloid type 3 receptor and calcitonin receptor

[1615] From the results in Table 7-1, we can see that X 14 The modification of the amino acid residues of Aib significantly enhances the dual agonist activity of the polypeptide molecular skeleton on hAMY3R / hCTR compared to pramlintide. 13 is the amino acid residue of Aib or X 14 The amino acid residues containing Ala will significantly enhance the agonist activity of the polypeptide molecular skeleton on hCTR compared to pramlintide.

[1616] 2.2. Evaluation of the agonist activity of the example compounds at human amyloid type 1 receptor (hAMY1R) and human calcitonin receptor (hCTR)

[1617] 2.2.1 Experimental Purpose:

[1618] Compounds Nos. 1-17 were tested for their agonist activity at human islet amyloid receptor and human calcitonin receptor.

[1619] 2.2.2 Experimental methods:

[1620] Cell recovery and culture: Remove the 293T cell cryovial from the liquid nitrogen tank and rapidly thaw in a 37°C water bath. Immediately aspirate the cell suspension and add it to a centrifuge tube containing 5 mL of the corresponding culture medium. Centrifuge at 1000 rpm for 5 minutes. Discard the supernatant, pipette the cells evenly with 10 mL of culture medium, transfer them to a T75 flask, tighten the cap, and place in a 37°C, 5% CO2 incubator for culture until ready to use.

[1621] Transient cell transfection: On the first day, in a clean bench, discard the old culture medium; add 5 mL of PBS to the flask for washing, and discard the PBS; add 2 mL of 0.25% Trypsin-EDTA to the flask to digest the cells. Under a microscope, observe that the cells have detached from the bottom of the flask and most of them have become round. Add approximately 5 mL of culture medium to the flask to terminate the digestion, pipette evenly, and transfer to a 15 mL centrifuge tube. Centrifuge at 1000 rpm for 5 minutes, discard the supernatant, add an appropriate amount of culture medium, pipette evenly, and take a small amount of cells for counting. In a 6-well plate, 6 × 10 cells per well were added. 5 Plate the cells and culture them overnight in a 37°C, 5% CO2 incubator. The next day, prepare two EP tubes for each well in a clean bench.

[1622] EP tube 1: Dissolve the plasmid in 175 μl OPTI-MEM at a concentration of 1 μg CTR (Sino Biological, HG16023-UT) or 1 μg CTR plus 1.5 μg RAMP1 (Fenghui Biotechnology, F103114) and P3000 per well and mix thoroughly.

[1623] EP tube 2: Dissolve Lipofectamine 3000 in 175 μl OPTI-MEM and incubate at room temperature for 5 minutes. Mix the two tubes and incubate at room temperature for 15 minutes. Then, add the mixture dropwise to a 6-well plate and perform validation 48 hours later.

[1624] Homogeneous time-resolved fluorescence (HTRF) method for detecting cAMP levels:

[1625] 1) Stimulation Buffer 1x:

[1626] 2) Dilution of the molecule was performed in a 96-well U-shaped plate, with 50 μM as the highest concentration, and dilution was performed using 1X stimulation buffer, followed by 7 consecutive dilutions to a minimum concentration of 0.00001 μM.

[1627] 3) Add 5 μl of the diluted test molecule to each well of the SV 96-well plate. Add 5 μl of 20k cells (1E6 cells / mL) to each well. Resuspend the cells in serum-free, antibiotic-free DMEM supplemented with 0.2% casein (final concentration 0.1%), as per the experimental protocol. Cover with parafilm and incubate for 30 min at 37°C.

[1628] 4) After 30 minutes, add 5 μl of cAMP-d2 diluted in Lysis & Detection Buffer 1 (1:19 dilution). Then add 5 μl of anti-cAMP-cryptate diluted in Lysis & Detection Buffer 1 (1:19 dilution), cover with sealing film, and incubate at room temperature for 1 hour.

[1629] 5) Remove the sealing film and detect the signal in a Tecan microplate reader, 665em / 620em (320ex).

[1630] 2.2.3 Experimental data processing method:

[1631] Data were analyzed using Microsoft Excel and GraphPad Prism 9. EC was calculated using GraphPad Prism 9 after using the Excel slide rule 620 / 665 reading ratio. 50 Specific values ​​are shown in Table 7 below.

[1632] Table 7-2. Agonist activity of compounds at human pancreatic amyloid type 1 receptor and calcitonin receptor

[1633] 2.2.4 Experimental Conclusions:

[1634] The compounds disclosed herein generally have strong hAMY1R / hCTR dual agonist activity and therefore have better potential for treating metabolic diseases.

[1635] 2.3 Evaluation of the agonist activity of the example compounds at human amyloid type 1 receptor (hAMY1R) and human calcitonin receptor (hCTR)

[1636] 2.3.1 Experimental Purpose:

[1637] Compounds Nos. 21-25 were tested for their agonist activity at human islet amyloid receptor and human calcitonin receptor.

[1638] 2.3.2 Experimental methods:

[1639] Cell recovery and culture: Remove the 293T cell cryovial from the liquid nitrogen tank and rapidly thaw in a 37°C water bath. Immediately aspirate the cell suspension and add it to a centrifuge tube containing 5 mL of the corresponding culture medium. Centrifuge at 1000 rpm for 5 minutes. Discard the supernatant, pipette the cells evenly with 10 mL of culture medium, transfer them to a T75 flask, tighten the cap, and place in a 37°C, 5% CO2 incubator for culture until ready to use.

[1640] Transient cell transfection: On the first day, in a clean bench, discard the old culture medium; add 5 mL of PBS to the flask for washing, and discard the PBS; add 2 mL of 0.25% Trypsin-EDTA to the flask to digest the cells. Under a microscope, observe that the cells have detached from the bottom of the flask and most of them have become round. Add approximately 5 mL of culture medium to the flask to terminate the digestion, pipette evenly, and transfer to a 15 mL centrifuge tube. Centrifuge at 1000 rpm for 5 minutes, discard the supernatant, add an appropriate amount of culture medium, pipette evenly, and take a small amount of cells for counting. In a 6-well plate, 6 × 10 cells per well were added. 5 Plate the cells and culture them overnight in a 37°C, 5% CO2 incubator. The next day, prepare two EP tubes for each well in a clean bench.

[1641] EP tube 1: Dissolve the plasmid CTR (NCBI reference sequence number: NP_001158210.1) 1 μg per well, or CTR 1 μg plus RAMP1 (Fenghui Bio, F103114) 1.5 μg and P3000 in 175 μl OPTI-MEM and mix well.

[1642] EP tube 2: Dissolve Lipofectamine 3000 in 175 μl OPTI-MEM and incubate at room temperature for 5 minutes. Mix the two tubes and incubate at room temperature for 15 minutes. Then, add the mixture dropwise to a 6-well plate and perform validation 48 hours later.

[1643] Homogeneous time-resolved fluorescence (HTRF) method for detecting cAMP levels:

[1644] 1) Stimulation Buffer 1x:

[1645] 2) Dilution of the molecule was performed in a 96-well U-shaped plate, with 50 μM as the highest concentration, and dilution was performed using 1X stimulation buffer, followed by 7 consecutive dilutions to a minimum concentration of 0.00001 μM.

[1646] 3) Add 5 μl of the diluted test molecule to each well of the SV 96-well plate. Add 5 μl of 20k cells (1E6 cells / mL) to each well. Resuspend the cells in serum-free, antibiotic-free DMEM supplemented with 0.2% casein (final concentration 0.1%), as per the experimental protocol. Cover with parafilm and incubate for 30 min at 37°C.

[1647] 4) After 30 minutes, add 5 μl of cAMP-d2 diluted in Lysis & Detection Buffer 1 (1:19 dilution). Then add 5 μl of anti-cAMP-cryptate diluted in Lysis & Detection Buffer 1 (1:19 dilution), cover with sealing film, and incubate at room temperature for 1 hour.

[1648] 5) Remove the sealing film and detect the signal in a Tecan microplate reader, 665em / 620em (320ex).

[1649] 2.3.3 Experimental data processing method:

[1650] Data were analyzed using Microsoft Excel and GraphPad Prism 9. EC was calculated using GraphPad Prism 9 after using the Excel slide rule 620 / 665 reading ratio. 50 Specific values ​​are shown in Table 7 below.

[1651] Table 7-3. Agonist activity of compounds at human islet amyloid type 1 receptor and calcitonin receptor

[1652] 2.3.4 Experimental Conclusions:

[1653] The compounds disclosed herein generally have strong hAMY1R / hCTR dual agonist activity and therefore have better potential for treating metabolic diseases.

[1654] 2.4 Evaluation of the agonist activity of the example compounds at human amyloid type 3 receptor (hAMY3R) and human calcitonin receptor (hCTR)

[1655] 2.4.1 Experimental Purpose:

[1656] Compounds were tested for their agonist activity at human islet amyloid receptor and human calcitonin receptor.

[1657] 2.4.2 Experimental methods:

[1658] Cell recovery and culture: Remove the BHK-21 cell cryovial from the liquid nitrogen tank and rapidly thaw in a 37°C water bath. Immediately aspirate the cell suspension and add it to a centrifuge tube containing 5 mL of the corresponding culture medium. Centrifuge at 1000 rpm for 5 minutes. Discard the supernatant, pipette the cells evenly with 10 mL of culture medium, transfer them to a T75 flask, tighten the cap, and place in a 37°C, 5% CO2 incubator for culture until ready to use.

[1659] Transient cell transfection: On the first day, in a clean bench, discard the old culture medium; add 5 mL of PBS to the flask for washing, and discard the PBS; add 2 mL of 0.25% Trypsin-EDTA to the flask to digest the cells. Under a microscope, observe that the cells have detached from the bottom of the flask and most of them have become round. Add approximately 5 mL of culture medium to the flask to terminate the digestion, pipette evenly, and transfer to a 15 mL centrifuge tube. Centrifuge at 1000 rpm for 5 minutes, discard the supernatant, add an appropriate amount of culture medium, pipette evenly, and take a small amount of cells for counting. In a 6-well plate, 4 × 10 cells per well were added.5 The cells were plated and placed in a 37°C, 5% CO2 incubator overnight. HD transfection reagent was used for transfection. 2 μg of CTR plasmid or 2 μg of CTR plus 6 μg of RAMP3 were added to each well of cells. The cells were tested 48 hours after transfection.

[1660] Homogeneous time-resolved fluorescence (HTRF) method for detecting cAMP levels:

[1661] 1) Stimulation Buffer 1x:

[1662] 2) Dilution of the molecule was performed in a 96-well U-shaped plate, with 50 μM as the highest concentration. 1X stimulation buffer was used for dilution, and the dilution was performed seven times to a minimum concentration of 0.00001 μM.

[1663] 3) Add 5 μl of the diluted test molecule to each SV 96-well plate. Add 5 μl of 20,000 cells (1E6 cells / mL) to each well. Resuspend the cells in serum-free, antibiotic-free MEM medium supplemented with 0.2% casein (final concentration 0.1%), as per the experimental protocol. Cover with parafilm and incubate for 30 min at 37°C.

[1664] 4) After 30 minutes, add 5 μl of cAMP-d2 diluted in Lysis & Detection Buffer 1 (1:19 dilution). Then add 5 μl of anti-cAMP-cryptate diluted in Lysis & Detection Buffer 1 (1:19 dilution), cover with sealing film, and incubate at room temperature for 1 hour.

[1665] 5) Remove the sealing film and detect the signal in a Tecan microplate reader, 665em / 620em (320ex).

[1666] 2.4.3 Experimental data processing method:

[1667] Data were analyzed using Microsoft Excel and GraphPad Prism 9. EC was calculated using GraphPad Prism 9 after using the Excel slide rule 620 / 665 reading ratio. 50 Specific values ​​are shown in Table 7 below.

[1668] Table 7-4. Agonist activity of compounds at human islet amyloid type 3 receptor and calcitonin receptor

[1669] 2.4.4 Experimental Conclusions:

[1670] The compounds disclosed herein generally possess potent dual agonist activity against hAMY3R / hCTR.

[1671] 2.5 Pharmacokinetic properties of the compound in rats

[1672] Plasma stability is one of the factors that affect the pharmacokinetics of peptide drugs. The pharmacokinetics of peptide drugs in the body are also affected by factors such as their absorption and clearance in the body.

[1673] 2.5.1 Experimental Purpose:

[1674] Male SD rats were used as test animals, and the candidate peptide molecules were injected intravenously once to understand the pharmacokinetic characteristics of the candidate molecules in SD rats (plasma).

[1675] 2.5.2 Experimental methods:

[1676] Male SD rats, weighing approximately 200-250g and aged 6-7 weeks, were used. Peptide compound solutions were prepared using 1× PBS and administered intravenously at a dose of 20 nmol / kg, with three animals receiving each molecule. Blood samples (60 μL each) were collected at 5 min, 15 min, 0.5 h, 1 h, 2 h, 4 h, 6 h, Day 1, Day 2, Day 4, Day 7, and Day 10 after the infusion and transferred to centrifuge tubes 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.

[1677] 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.

[1678] LC-MS analysis methods: (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; column Kinetex 2.6 μm PS C18 100A (3 mm × 100 mm); column temperature 40°C. (2) Mass spectrometry conditions: Mass spectrometry was performed using an electrospray ionization source (ESI) in positive ion analysis mode and multiple reaction monitoring (MRM) scanning.

[1679] Experimental data processing method: SCIEX OS (Version 2.1.6) software was used to quantify blood drug concentration data, and PKSolver (Version 2.0) software was used to calculate pharmacokinetic parameters.

[1680] 2.5.3 Experimental results:

[1681] Through the above experimental method, the specific data obtained are as follows Table 8:

[1682] Table 8. Pharmacokinetic test results

[1683] 2.5.4 Experimental Conclusions:

[1684] Through research, it was found that the compounds disclosed herein have good pharmacokinetic characteristics after intravenous injection in mice. The compounds disclosed herein have a long half-life in vivo and have advantages in disease treatment.

[1685] 2.6 Stability of compounds under neutral conditions (ThT)

[1686] Amylin has a tendency to aggregate to form insoluble amyloid fibrils. Examining its tendency to aggregate to form amyloid fibrils is a commonly used indicator for assessing its stability. This test uses the time it takes for fibril formation (lag time) to assess amyloid fibril formation under mechanical stress.

[1687] Thioflavin T (ThT) is a benzothiazole dye that exhibits enhanced fluorescence upon binding to amyloid fibrils. It is commonly used for the diagnosis of amyloid fibrils. In the presence of amyloid fibrils, thioflavin T emits bright fluorescence with excitation and emission maxima at 450 and 485 nm, respectively. The fluorescence changes linearly over the range of 0 to 2.0 μg / mL amyloid fibrils. Therefore, amyloid fibril formation can be assessed by measuring the fluorescence signal using a microplate reader.

[1688] 2.6.1 Experimental Purpose:

[1689] To assess the propensity of amylin analogs to aggregate to form amyloid fibrils.

[1690] 2.6.2 Experimental methods:

[1691] In a biological safety cabinet, the example compound was ×Adjust to 250 μM in PBS (pH = 7.4), and then add ThT (Sigma-Aldrich) with a final concentration of 1 μM. Then mix it and add it to a 96-well plate (OptiPlate-96, white Opaque 96 well Microplate, Perkin Elmer) at a volume of 200 μL / well, with three replicates for each sample. The fluorescence value change was read using a SpectraMax microplate reader for the first time (oscillation 20s; wavelength: Excitation at 450nm, auto Cutoff and Emission at 485nm) as 0h. Then seal the 96-well plate with a sealing film and place it on a microplate constant temperature oscillator at 37°C and incubate at 960rpm. Subsequently, read the fluorescence signal at different time points according to the initial SpectraMax microplate reader settings, and then continue to oscillate after sealing the plate with a sealing film. Until the end of the experiment. Microsoft Excel and GraphPad Prism 9 were used for analysis.

[1692] 2.6.3 Experimental results:

[1693] Through the above experimental method, the specific data obtained are as follows Table 9:

[1694] Table 9. ThT detection results

[1695] 2.6.4 Experimental Conclusions:

[1696] Through research, it was found that compounds 1, 4, 5, 7, 10-11, and 21-25 in the present disclosure have better stability than canagliflozin at neutral pH, indicating that they have more advantages than canagliflozin in terms of drugability.

[1697] 2.7 Acute food intake experiment in rats

[1698] 2.7.1 Experimental Purpose:

[1699] Evaluation of the inhibitory effect of compounds on rat food intake

[1700] 2.7.2 Experimental methods:

[1701] This experiment selected 300-350g body weight Sprague Dawley (SD) male rats. Before the experiment began, the rats entered the animal facility one week in advance to adapt to the new environment. During the adaptation period and the entire experimental period, the animals were free to eat and drink water. On the day of administration, the rats were randomly divided into groups according to their body weight, with 4 animals in each group and one animal per cage raised separately. The test drug was injected subcutaneously at 16:00 with a volume of 5ml / kg, and the control group was given the same volume of corresponding solvent. After administration, the cumulative food intake of each rat 0-24h, 24-48h and 2 days after administration was recorded, and the food intake inhibition rate compared to the control group was calculated. Data processing was analyzed using Microsoft Excel and GraphPad Prism 9.

[1702] 2.7.3 Experimental results:

[1703] Through the above experimental method, the specific data obtained are as follows Table 10:

[1704] Table 10. Food intake results

[1705] 2.7.4 Experimental Conclusions:

[1706] The study found that compound 11 can inhibit the food intake of rats in a dose-dependent manner, and at the same dose (10 nmol / kg), the food intake inhibition rate of compound 11 is stronger than that of canagliflozin.

[1707] 2.8 Drug efficacy evaluation experiment in diet-induced obese rats

[1708] 2.8.1 Experimental Purpose:

[1709] To evaluate the weight-reducing effects of the compounds in obese rats.

[1710] 2.8.2 Experimental methods:

[1711] This experiment selected 5-week-old Sprague Dawley (SD) male rats. Before the start of the experiment, the rats entered the animal facility one week in advance to adapt to the new environment; after the adaptation, the rats in the high-fat model group were fed a high-fat diet (Research diet, D12451). During the adaptation period and the entire experimental period, the animals were free to eat and drink water. Before administration, each animal was pre-administered at 16:00 (only acupuncture was performed without drug injection) for one week. On the day of administration, the rats were randomly divided into 9 groups according to their body weight, with 4-5 animals in each group and one animal per cage raised separately. The test drug was injected subcutaneously at 16:00 at a volume of 5ml / kg. Compound 11 was administered once every two days, and the control group was given the same volume of the corresponding solvent for a total of 24 days of administration. The weight of each rat was detected before daily administration, and a weight change curve was drawn over time. Data processing was analyzed using Microsoft Excel and GraphPad Prism 9.

[1712] 2.8.3 Experimental results:

[1713] Through the above experimental method, the specific data obtained are as follows Table 11 and Figure 1:

[1714] Table 11. Results of rat body weight changes

[1715] 2.8.4 Experimental Conclusions:

[1716] Through research, it was found that compound 11 has the effect of reducing weight.

[1717] 2.9 Streptozotocin (STZ) efficacy evaluation experiment in rats

[1718] 2.9.1 Experimental Purpose:

[1719] Evaluation of the hypoglycemic effect of compounds on STZ rats

[1720] 2.9.2 Experimental methods:

[1721] This experiment selected 200-250g Sprague Dawley (SD) male rats. Before the start of the experiment, the rats entered the animal facility one week in advance to acclimate to the new environment. After acclimatization, each group of rats fasted overnight and were intraperitoneally injected with STZ at a dose of 50mg / kg based on body weight. Three days after STZ injection, the blood glucose of each group of rats was tested. Blood glucose values ​​within the range of 20-30mM were considered to be successful modeling. On the day of administration, the successfully modeled rats were randomly divided into 7 groups of 4 animals per group based on blood glucose and body weight. The test drug was subcutaneously injected at a volume of 5ml / kg at 16:00, and compound 11 was administered once every two days. The blood glucose of each rat was tested before daily administration, and a blood glucose change curve over time was plotted, and the area under the curve of blood glucose change was calculated. Data processing was analyzed using Microsoft Excel and GraphPad Prism 9.

[1722] 2.9.3 Experimental results:

[1723] Through the above experimental method, the specific data obtained are as follows Table 12 and Figure 2:

[1724] Table 12. Changes in blood glucose in STZ rats

[1725] 2.9.4 Experimental Conclusions:

[1726] Through research, it was found that compound 11 has an excellent blood sugar lowering effect.

Claims

1. A compound having the structure represented by the following formula (I) or a pharmaceutically acceptable salt thereof: X1-X2-X3-Thr-Ala-Thr-X7-Ala-Thr-X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -Leu-X 17 -X 18 -Ser-Ser-X 21 -X 22 -X 23 -X 24 -Pro-X 26 -Leu-Pro-Pro-Thr-X 31 -Val-X 33 -Ser-X 35 -Thr-X 37 (I)； in: X1 is an amino acid residue selected from Lys or is absent; X2 is an amino acid residue selected from Cys, homoCys, Pen or Abu; X3 is an amino acid residue selected from Asn, Gln, Asp, Glu or Y1; X7 is an amino acid residue selected from Cys, homoCys, Pen or Abu; X 10 an amino acid residue selected from Gln, Asn, Glu, Asp, or Y1; X 11 an amino acid residue selected from Arg, homoArg, Orn, D-Arg, or Y1; X 12 an amino acid residue selected from Leu, homoLeu, N-Me-Leu, α-Me-Leu or D-Leu; X 13 is an amino acid residue of Ala or Aib; X 14 is the amino acid residue of Aib or Ala; X 15 is the amino acid residue of Phe; X 17 an amino acid residue selected from Val or Aib; X 18 an amino acid residue selected from His, Aib, or Y1; X 21 is an amino acid residue of Asn, Gln, Glu, Ala or Aib; X 22 an amino acid residue selected from Asn, Ala, or Y1; X 23 an amino acid residue selected from Phe, 2-Pal, 4-Pal, hPhe or 3-Pal; X 24 is the amino acid residue of Gly; X 26 an amino acid residue selected from Ile or N-Me-Ile; X 31 an amino acid residue selected from Asn, Asp, Glu, Gln, or Y1; X 33 is the amino acid residue of Gly; X 35 an amino acid residue selected from Glu, Asn, Asp or Gln; X 37 an amino acid residue selected from Tyr or Pro; Y1 is selected from Lys, Orn, Dap, Dab or Cys residues with or without a substituent attached to the side chain, preferably Lys, Orn, Dap, Dab or Cys residues with a substituent attached to the side chain.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: X1 is an amino acid residue selected from Lys or is absent; X2 is an amino acid residue selected from Cys, homoCys, Pen or Abu; X3 is an amino acid residue selected from Asn, Gln, Asp, Glu or Y1; X7 is an amino acid residue selected from Cys, homoCys, Pen or Abu; X 10 an amino acid residue selected from Gln, Asn, Glu, Asp, or Y1; X 11 an amino acid residue selected from Arg, homoArg, Orn, D-Arg, or Y1; X 12 an amino acid residue selected from Leu, homoLeu, N-Me-Leu, α-Me-Leu or D-Leu; X 13 is an amino acid residue of Ala or Aib; X 14 is the amino acid residue of Aib or Ala; X 15 is the amino acid residue of Phe; X 17 is the amino acid residue of Val; X 18 an amino acid residue selected from His or Y1; X 21 is an amino acid residue of Asn, Gln, Glu, Ala or Aib; X 22 an amino acid residue selected from Asn, Ala, or Y1; X 23 an amino acid residue selected from Phe, 2-Pal, 4-Pal, hPhe or 3-Pal; X 24 is the amino acid residue of Gly; X 26 is the amino acid residue of Ile; X 31 an amino acid residue selected from Asn, Asp, Glu, Gln, or Y1; X 33 is the amino acid residue of Gly; X 35 an amino acid residue selected from Glu, Asn, Asp or Gln; X 37 an amino acid residue selected from Tyr or Pro; Y1 is selected from Lys, Orn, Dap, Dab or Cys residues with or without a substituent attached to the side chain, preferably Lys, Orn, Dap, Dab or Cys residues with a substituent attached to the side chain.

3. A compound having the structure represented by the following formula (II) or a pharmaceutically acceptable salt thereof: R1-X1-X2-X3-Thr-Ala-Thr-X7-Ala-Thr-X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -Leu-X 17 -X 18 -Ser-Ser-X 21 -X 22 -X 23 -X 24 -Pro-X 26 -Leu-Pro-Pro-Thr-X 31 -Val-X 33 -Ser-X 35 -Thr-X 37 -R2 (II); in: R1 is H, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl, pyroglutamyl; R2 is -NH2 or -OH; X1 is an amino acid residue selected from Lys or is absent; X2 is an amino acid residue selected from Cys, homoCys, Pen or Abu; X3 is an amino acid residue selected from Asn, Gln, Asp, Glu or Y1; X7 is an amino acid residue selected from Cys, homoCys, Pen or Abu; X 10 an amino acid residue selected from Gln, Asn, Glu, Asp, or Y1; X 11 an amino acid residue selected from Arg, homoArg, Orn, D-Arg, or Y1; X 12 an amino acid residue selected from Leu, homoLeu, N-Me-Leu, α-Me-Leu or D-Leu; X 13 is an amino acid residue of Ala or Aib; X 14 is the amino acid residue of Aib or Ala; X 15 is the amino acid residue of Phe; X 17 an amino acid residue selected from Val or Aib; X 18 an amino acid residue selected from His, Aib, or Y1; X 21 is an amino acid residue of Asn, Gln, Glu, Ala, or Aib; X 22 an amino acid residue selected from Asn, Ala, or Y1; X 23 an amino acid residue selected from Phe, 2-Pal, 4-Pal, hPhe or 3-Pal; X 24 is the amino acid residue of Gly; X 26 an amino acid residue selected from Ile or N-Me-Ile; X 31 an amino acid residue selected from Asn, Asp, Glu, Gln, or Y1; X 33 is the amino acid residue of Gly; X 35 an amino acid residue selected from Glu, Asn, Asp or Gln; X 37 an amino acid residue selected from Tyr or Pro; Y1 is selected from Lys, Orn, Dap, Dab or Cys residues with or without a substituent attached to the side chain, preferably Lys, Orn, Dap, Dab or Cys residues with a substituent attached to the side chain.

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein: R1 is H, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl, pyroglutamyl; R2 is -NH2 or -OH; X1 is an amino acid residue selected from Lys or is absent; X2 is an amino acid residue selected from Cys, homoCys, Pen or Abu; X3 is an amino acid residue selected from Asn, Gln, Asp, Glu or Y1; X7 is an amino acid residue selected from Cys, homoCys, Pen or Abu; X 10 an amino acid residue selected from Gln, Asn, Glu, Asp, or Y1; X 11 an amino acid residue selected from Arg, homoArg, Orn, D-Arg, or Y1; X 12 an amino acid residue selected from Leu, homoLeu, N-Me-Leu, α-Me-Leu or D-Leu; X 13 is an amino acid residue of Ala or Aib; X 14 is the amino acid residue of Aib or Ala; X 15 is the amino acid residue of Phe; X 17 is the amino acid residue of Val; X 18 an amino acid residue selected from His or Y1; X 21 is an amino acid residue of Asn, Gln, Glu, Ala or Aib; X 22 an amino acid residue selected from Asn, Ala, or Y1; X 23 an amino acid residue selected from Phe, 2-Pal, 4-Pal, hPhe or 3-Pal; X 24 is the amino acid residue of Gly; X 26 is the amino acid residue of Ile; X 31 an amino acid residue selected from Asn, Asp, Glu or Gln, or Y1; X 33 is the amino acid residue of Gly; X 35 an amino acid residue selected from Glu, Asn, Asp or Gln; X 37 an amino acid residue selected from Tyr or Pro; Y1 is selected from the group consisting of Lys, Orn, Dap, Dab or Cys residues of side chain-linked substituents; Preferably, R1 is acetyl and R2 is -NH2.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein: X1 does not exist; X2 is an amino acid residue selected from Cys, Pen or Abu; X3 is selected from the amino acid residue of Gln or Y1; X7 is an amino acid residue selected from Cys or Pen; X 10 an amino acid residue selected from Gln or Y1; X 11 an amino acid residue selected from Arg, homoArg, Orn, or Y1; X 12 an amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu; X 13 is an amino acid residue of Ala or Aib; X 14 is the amino acid residue of Aib or Ala; X 15 is the amino acid residue of Phe; X 17 an amino acid residue selected from Val or Aib; X 18 an amino acid residue selected from His, Aib, or Y1; X 21 is the amino acid residue of Aib or Ala; X 22 an amino acid residue selected from Ala or Y1; X 23 is the amino acid residue of 3-Pal; X 24 is the amino acid residue of Gly; X 26 an amino acid residue selected from Ile or N-Me-Ile; X 31 is the amino acid residue of Asp or Y1; X 33 is the amino acid residue of Gly; X 35 is the amino acid residue of Glu; X 37 is the amino acid residue of Pro; Y1 is selected from Lys, Orn, Dap, Dab or Cys residues whose side chains are linked to substituents, preferably Lys residues whose side chains are linked to substituents.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein: X 13 X 14 Selected from Ala-Aib, Aib-Aib or Aib-Ala.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, which is selected from any one of the following (i) to (vi): (i) X1 does not exist; X2 is an amino acid residue selected from Cys, Pen or Abu; X3 is selected from the amino acid residue of Gln or Y1; X7 is an amino acid residue selected from Cys or Pen; X 10 an amino acid residue selected from Gln or Y1; X 11 an amino acid residue selected from Arg, homoArg, Orn, or Y1; X 12 an amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu; X 13 is an amino acid residue of Ala or Aib; X 14 is the amino acid residue of Aib or Ala; X 15 is the amino acid residue of Phe; X 17 is the amino acid residue of Val; X 18 an amino acid residue selected from His or Y1; X 21 is the amino acid residue of Aib; X 22 an amino acid residue selected from Ala or Y1; X 23 is the amino acid residue of 3-Pal; X 24 is the amino acid residue of Gly; X 26 is the amino acid residue of Ile; X 31 is the amino acid residue of Asp or Y1; X 33 is the amino acid residue of Gly; X 35 is the amino acid residue of Glu; X 37 is the amino acid residue of Pro; Y1 is selected from the group consisting of Lys, Orn, Dap, Dab or Cys residues whose side chains are linked to substituents, preferably Lys residues whose side chains are linked to substituents; (ii) X1 does not exist; X2 is an amino acid residue selected from Cys, Pen or Abu; X3 is selected from the amino acid residue of Gln or Y1; X7 is an amino acid residue selected from Cys or Pen; X 10 an amino acid residue selected from Gln or Y1; X 11 an amino acid residue selected from Arg, homoArg, Orn, or Y1; X 12 an amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu; X 13 X 14 Selected from Ala-Aib, Aib-Aib or Aib-Ala; X 15 is the amino acid residue of Phe; X 17 is the amino acid residue of Val; X 18 an amino acid residue selected from His or Y1; X 21 is the amino acid residue of Aib; X 22 an amino acid residue selected from Ala or Y1; X 23 is the amino acid residue of 3-Pal; X 24 is the amino acid residue of Gly; X 26 is the amino acid residue of Ile; X 31 is the amino acid residue of Asp or Y1; X 33 is the amino acid residue of Gly; X 35 is the amino acid residue of Glu; X 37 is the amino acid residue of Pro; Y1 is a Lys residue of a side chain-linked substituent; (iii) X1 does not exist; X2 is an amino acid residue selected from Cys, Pen or Abu; X3 is selected from the amino acid residue of Gln or Y1; X7 is an amino acid residue selected from Cys or Pen; X 10 an amino acid residue selected from Gln or Y1; X 11 an amino acid residue selected from Arg, homoArg, Orn, or Y1; X 12 an amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu; X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib; X 15 is the amino acid residue of Phe; X 17 is the amino acid residue of Val; X 18 an amino acid residue selected from His or Y1; X 21 is the amino acid residue of Aib; X 22 an amino acid residue selected from Ala or Y1; X 23 is the amino acid residue of 3-Pal; X 24 is the amino acid residue of Gly; X 26 is the amino acid residue of Ile; X 31 is the amino acid residue of Asp or Y1; X 33 is the amino acid residue of Gly; X 35 is the amino acid residue of Glu; X 37 is the amino acid residue of Pro; Y1 is a Lys residue of a side chain-linked substituent; (iv) X1 does not exist; X2 is an amino acid residue selected from Cys, Pen or Abu; X3 is selected from the amino acid residue of Gln or Y1; X7 is the amino acid residue of Cys; X 10 is the amino acid residue of Gln; X 11 an amino acid residue selected from Arg, homoArg, Orn, or Y1; X 12 an amino acid residue selected from Leu or α-Me-Leu; X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib; X 15 is the amino acid residue of Phe; X 17 is the amino acid residue of Val; X 18 an amino acid residue selected from His or Y1; X 21 is the amino acid residue of Aib; X 22 an amino acid residue selected from Ala or Y1; X 23 is the amino acid residue of 3-Pal; X 24 is the amino acid residue of Gly; X 26 is the amino acid residue of Ile; X 31 is the amino acid residue of Asp or Y1; X 33 is the amino acid residue of Gly; X 35 is the amino acid residue of Glu; X 37 is the amino acid residue of Pro; Y1 is a Lys residue of a side chain-linked substituent; (v) X1 does not exist; X2 is an amino acid residue selected from Cys, Pen or Abu; X3 is selected from the amino acid residue of Gln or Y1; X7 is an amino acid residue selected from Cys or Pen; X 10 an amino acid residue selected from Gln or Y1; X 11 an amino acid residue selected from Arg, homoArg, Orn, or Y1; X 12 an amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu; X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib; X 15 is the amino acid residue of Phe; X 17 an amino acid residue selected from Val or Aib; X 18 an amino acid residue selected from His or Aib or Y1; X 21 is the amino acid residue of Aib or Ala; X 22 an amino acid residue selected from Ala or Y1; X 23 is the amino acid residue of 3-Pal; X 24 is the amino acid residue of Gly; X 26 is an amino acid residue of Ile or N-Me-Ile; X 31 is the amino acid residue of Asp or Y1; X 33 is the amino acid residue of Gly; X 35 is the amino acid residue of Glu; X 37 is the amino acid residue of Pro; Y1 is a Lys residue of a side chain-linked substituent; (vi) X1 does not exist; X2 is the amino acid residue of Cys; X3 is the amino acid residue of Gln; X7 is the amino acid residue of Cys; X 10 is the amino acid residue of Gln; X 11 is the amino acid residue of Arg; X 12 is the amino acid residue of Leu; X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib; X 15 is the amino acid residue of Phe; X 17 an amino acid residue selected from Val or Aib; X 18 an amino acid residue selected from Aib or Y1; X 21 an amino acid residue selected from Aib or Ala; X 22 an amino acid residue selected from Ala or Y1; X 23 is the amino acid residue of 3-Pal; X 24 is the amino acid residue of Gly; X 26 An amino acid residue selected from Ile or N-Me-Ile X 31 is the amino acid residue of Asp or Y1; X 33 is the amino acid residue of Gly; X 35 is the amino acid residue of Glu; X 37 is the amino acid residue of Pro; Y1 is a Lys residue whose side chain is connected to a substituent.

8. The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, which is selected from any one of the following (a) to (f): (a) X1 does not exist, X2 is an amino acid residue selected from Cys, Pen or Abu, preferably Cys, X3 is Y1, X7 is an amino acid residue selected from Cys or Pen, preferably Cys, X 10 is the amino acid residue of Gln, X 11 An amino acid residue selected from Arg, hArg or Orn, preferably Arg, X 12 an amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu, preferably Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 17 is the amino acid residue of Val, X 18 is the amino acid residue of His, X 21 is the amino acid residue of Aib, X 22 is the amino acid residue of Ala, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 26 is the amino acid residue of Ile, X 31 is the amino acid residue of Asp, X 33 is the amino acid residue of Gly, X 35 an amino acid residue selected from Glu, X 37 is an amino acid residue of Pro; or, (b) X1 does not exist, X2 is an amino acid residue selected from Cys, Pen or Abu, preferably Cys, X3 is the amino acid residue of Gln, X7 is an amino acid residue selected from Cys or Pen, preferably Cys, X 10 It's Y1. X 11 an amino acid residue selected from Arg, homoArg or Orn, preferably Arg, X 12 an amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu, preferably Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 17 is the amino acid residue of Val, X 18 is the amino acid residue of His, X 21 is the amino acid residue of Aib, X 22 is the amino acid residue of Ala, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 26 is the amino acid residue of Ile, X 31 is the amino acid residue of Asp, X 33 is the amino acid residue of Gly, X 35 is the amino acid residue of Glu, X 37 is an amino acid residue of Pro; or, (c) X1 does not exist, X2 is an amino acid residue selected from Cys, Pen or Abu, preferably Cys, X3 is the amino acid residue of Gln, X7 is an amino acid residue selected from Cys or Pen, preferably Cys, X 10 is the amino acid residue of Gln, X 11 It's Y1. X 12 an amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu, preferably Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 17 is the amino acid residue of Val, X 18 is the amino acid residue of His, X 21 is the amino acid residue of Aib, X 22 is the amino acid residue of Ala, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 26 is the amino acid residue of Ile, X 31 is the amino acid residue of Asp, X 33 is the amino acid residue of Gly, X 35 is the amino acid residue of Glu, X 37 is an amino acid residue of Pro; or, (d) X1 does not exist, X2 is an amino acid residue selected from Cys, Pen or Abu, preferably Cys, X3 is the amino acid residue of Gln, X7 is an amino acid residue selected from Cys or Pen, preferably Cys, X 10 is the amino acid residue of Gln, X 11 an amino acid residue selected from Arg, homoArg or Orn, X 12 an amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 17 is the amino acid residue of Val or Aib, X 18 It's Y1. X 21 is the amino acid residue of Aib, X 22 is the amino acid residue of Ala, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 26 is an amino acid residue of Ile or N-Me-Ile, X 31 is the amino acid residue of Asp, X 33 is the amino acid residue of Gly, X 35 is the amino acid residue of Glu, X 37 is an amino acid residue of Pro; or, (e) X1 does not exist, X2 is an amino acid residue selected from Cys, Pen or Abu, X3 is the amino acid residue of Gln, X7 is an amino acid residue selected from Cys or Pen, X 10 is the amino acid residue of Gln, X 11 an amino acid residue selected from Arg, homoArg or Orn, preferably Arg, X 12 an amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu, preferably Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 17 is the amino acid residue of Val, X 18 is an amino acid residue of His or Aib, X 21 is an amino acid residue of Aib or Ala, X 22 It's Y1. X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 26 is the amino acid residue of Ile, X 31 is the amino acid residue of Asp, X 33 is the amino acid residue of Gly, X 35 is the amino acid residue of Glu, X 37 is an amino acid residue of Pro; or, (f) X1 does not exist, X2 is an amino acid residue selected from Cys, Pen or Abu, preferably Cys, X3 is the amino acid residue of Gln, X7 is an amino acid residue selected from Cys or Pen, preferably Cys, X 10 is the amino acid residue of Gln, X 11 an amino acid residue selected from Arg, homoArg or Orn, preferably Arg, X 12 an amino acid residue selected from Leu, N-Me-Leu, α-Me-Leu or D-Leu, preferably Leu, X 13 is the amino acid residue of Ala, X 14 is the amino acid residue of Aib, X 15 is the amino acid residue of Phe, X 17 is the amino acid residue of Val, X 18 is the amino acid residue of His, X 21 is the amino acid residue of Aib, X 22 is the amino acid residue of Ala, X 23 is the amino acid residue of 3-Pal, X 24 is the amino acid residue of Gly, X 26 is the amino acid residue of Ile, X 31 It's Y1. X 33 is the amino acid residue of Gly, X 35 is the amino acid residue of Glu, X 37 is the amino acid residue of Pro; in, Y1 is selected from Lys, Orn, Dap, Dab or Cys residues whose side chains are linked to substituents, preferably Lys residues whose side chains are linked to substituents.

9. The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein The X2 and X7 form a disulfide bond, a methylenethioacetal bridge, a thioether bond, an o-phenylenedisulfide bridge, an m-phenylenedisulfide bridge, or a p-phenylenedisulfide bridge, preferably a disulfide bond, a methylenethioacetal bridge, or a thioether bond; Preferably, X2 is selected from Cys, homoCys or Pen, X7 is selected from Cys, homoCys or Pen, and X2 and X7 form a disulfide bond, a methylenethioacetal bridge, an o-phenylenedisulfide bridge, an m-phenylenedisulfide bridge or a p-phenylenedisulfide bridge; Preferably, one of the amino acid residues between X2 and X7 is selected from Cys, homoCys or Pen, and the other amino acid residue is Abu, and a thioether bond is formed between X2 and X7.

10. A compound or a pharmaceutically acceptable salt thereof, wherein The compound is a polypeptide analog of pramlintide as shown in SEQ ID NO: 2, wherein the amino acid residue at at least one of positions 13 and 14 in the polypeptide analog is Aib, and the amino acid numbering of the polypeptide analog adopts the amino acid sequence numbering shown in SEQ ID NO: 2; and the side chain of at least one amino acid residue in the polypeptide analog is connected to a substituent.

11. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein the amino acid residues at positions 13 and 14 are selected from the group consisting of Ala-Aib, Aib-Ala, or Aib-Aib.

12. The compound according to claim 10 or 11, or a pharmaceutically acceptable salt thereof, comprising one or more amino acids as shown below: The amino acid residue at position 1 is Lys or absent, preferably absent; The amino acid residue at position 10 is selected from Gln or Y1, preferably Gln; The amino acid residue at position 11 is Arg, homoArg, Orn, D-Arg or Y1, preferably Arg, homoArg, Orn or Y1; The amino acid residue at position 12 is Leu, homoLeu, N-Me-Leu, α-Me-Leu or D-Leu, preferably Leu, N-Me-Leu, α-Me-Leu or D-Leu, more preferably Leu or α-Me-Leu; The amino acid residue at position 17 is Val or Aib; The amino acid residue at position 18 is His, Aib, or Y1; The amino acid residue at position 21 is Asn, Gln, Glu, Ala or Aib, preferably Aib or Ala; The amino acid residue at position 22 is Asn, Ala or Y1, preferably Ala or Y1; The amino acid residue at position 23 is Phe, 2-Pal, 4-Pal, hPhe or 3-Pal, preferably 3-Pal; The amino acid residue at position 26 is Ile or N-Me-Ile; The amino acid residue at position 31 is Asn, Asp, Glu, Gln or Y1, preferably Asp or Y1; The amino acid residue at position 35 is Glu, Asn, Asp or Gln, preferably Glu; in, Y1 is selected from Lys, Orn, Dap, Dab or Cys residues with or without a substituent attached to the side chain, preferably a Lys residue with a substituent attached to the side chain.

13. The compound according to any one of claims 10 to 12, or a pharmaceutically acceptable salt thereof, wherein the amino acid residue at position 2 relative to the amino acid sequence of SEQ ID NO: 2 is Cys, hCys, Pen, or Abu, and / or the amino acid residue at position 7 relative to the amino acid sequence of SEQ ID NO: 2 is Cys, hCys, Pen, or Abu; Preferably, the amino acid residues at positions 2 and 7 in the amylin analog form a disulfide bond, a methylenethioacetal bridge, a thioether bond, an o-phenylenedisulfide bridge, an m-phenylenedisulfide bridge, or a p-phenylenedisulfide bridge, preferably a disulfide bond, a methylenethioacetal bridge, or a thioether bond; Preferably, any amino acid residue selected from Cys, hCys, and Pen forms a disulfide bond, a methylenethioacetal bridge, an o-phenylenedisulfide bridge, an m-phenylenedisulfide bridge, or a p-phenylenedisulfide bridge with any amino acid residue selected from Cys, hCys, and Pen, preferably forming a methylenethioacetal bridge or a thioether bond; Preferably, the amino acid residue of Cys, hCys or Pen forms a thioether bond with the amino acid residue of Abu.

14. The compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, which has a structure as shown in any one of the following: C-Y1-TATCATQRLA-Aib-FLVHSS-Aib-A-[3-Pal]-GPILPPTDVGSETP (SEQ ID NO:4); CQTATCAT-Y1-RLA-Aib-FLVHSS-Aib-A-[3-Pal]-GPILPPTDVGSETP (SEQ ID NO: 5); CQTATCATQ-Y1-LA-Aib-FLVHSS-Aib-A-[3-Pal]-GPILPPTDVGSETP (SEQ ID NO: 6); CQTATCATQRLA-Aib-FLV-Y1-SS-Aib-A-[3-Pal]-GPILPPTDVGSETP(SEQ ID NO:7); CQTATCATQRLA-Aib-FLVHSS-Aib-Y1-[3-Pal]-GPILPPTDVGSETP(SEQ ID NO:8); CQTATCATQRLA-Aib-FLVHSS-Aib-A-[3-Pal]-GPILPPT-Y1-VGSETP(SEQ ID NO:9); Pen-QTATCATQ-RLA-Aib-FLVHSS-Aib-Y1-[3-Pal]-GPILPPTDVGSETP(SEQ ID NO:10); Pen-QTAT-Pen-ATQRLA-Aib-FLVHSS-Aib-Y1-[3-Pal]-GPILPPTDVGSETP(SEQ ID NO:11); Abu-QTATCATQRLA-Aib-FLVHSS-Aib-Y1-[3-Pal]-GPILPPTDVGSETP(SEQ ID NO:12); CQTATCATQRLA-Aib-FLVHSS-Aib-Y1-[3-Pal]-GPILPPTDVGSETP(SEQ ID NO:13); CQTATCATQRLA-Aib-FLV-Y1-SS-Aib-A-[3-Pal]-GPILPPTDVGSETP(SEQ ID NO:14); C-Y1-TATCATQ-RLA-Aib-FLVHSS-Aib-A-[3-Pal]-GPILPPTDVGSETP(SEQ ID NO:15); CQTATCATQ-[homoR]-LA-Aib-FLV-Y1-SS-Aib-A-[3-Pal]-GPILPPTDVGSETP, SEQ ID NO:16; CQTATCATQ-[Orn]-LA-Aib-FLV-Y1-SS-Aib-A-[3-Pal]-GPILPPTDVGSETP(SEQ ID NO:17); CQTATCATQR-[NMeL]-A-Aib-FLV-Y1-SS-Aib-A-[3-Pal]-GPILPPTDVGSETP(SEQ ID NO:18); CQTATCATQR-[aMeL]-A-Aib-FLV-Y1-SS-Aib-A-[3-Pal]-GPILPPTDVGSETP(SEQ ID NO:19); CQTATCATQR-[DL]-A-Aib-FLV-Y1-SS-Aib-A-[3-Pal]-GPILPPTDVGSETP(SEQ ID NO:20); CQTATC-ATQRLA-Aib-FLV-Y1-SS-Aib-A-[3-Pal]-GP-[NMeI]-LPPTDVGSETP(SEQ ID NO:55); CQTATC-ATQRLA-Aib-FL-Aib-Y1-SS-Aib-A-[3-Pal]-GPILPPTDVGSETP (SEQ ID NO: 56); CQTATC-ATQRLA-Aib-FLV-Aib-SSA-Y1-[3-Pal]-GPILPPTDVGSETP (SEQ ID NO: 57); Preferably, it has the following structure: Ac-C-Y1-TATCATQRLA-Aib-FLVHSS-Aib-A-[3-Pal]-GPILPPTDVGSETP-NH2 (SEQ ID NO: 38); Ac-CQTATCAT-Y1-RLA-Aib-FLVHSS-Aib-A-[3-Pal]-GPILPPTDVGSETP-NH2 (SEQ ID NO: 39); Ac-CQTATCATQ-Y1-LA-Aib-FLVHSS-Aib-A-[3-Pal]-GPILPPTDVGSETP-NH2 (SEQ ID NO: 40); Ac-CQTATCATQRLA-Aib-FLV-Y1-SS-Aib-A-[3-Pal]-GPILPPTDVGSETP-NH2 (SEQ ID NO: 41); Ac-CQTATCATQRLA-Aib-FLVHSS-Aib-Y1-[3-Pal]-GPILPPTDVGSETP-NH2 (SEQ ID NO: 42); Ac-CQTATCATQRLA-Aib-FLVHSS-Aib-A-[3-Pal]-GPILPPT-Y1-VGSETP-NH2 (SEQ ID NO: 43); Ac-Pen-QTATCATQ-RLA-Aib-FLVHSS-Aib-Y1-[3-Pal]-GPILPPTDVGSETP-NH2 (SEQ ID NO: 44); Ac-Pen-QTAT-Pen-ATQRLA-Aib-FLVHSS-Aib-Y1-[3-Pal]-GPILPPTDVGSETP-NH2 (SEQ ID NO: 45); Ac-Abu-QTATCATQRLA-Aib-FLVHSS-Aib-Y1-[3-Pal]-GPILPPTDVGSETP-NH2 (SEQ ID NO: 46); Ac-CQTATCATQRLA-Aib-FLVHSS-Aib-Y1-[3-Pal]-GPILPPTDVGSETP-NH2 (SEQ ID NO: 47); Ac-CQTATCATQRLA-Aib-FLV-Y1-SS-Aib-A-[3-Pal]-GPILPPTDVGSETP-NH2 (SEQ ID NO: 48); Ac-C-Y1-TATCATQ-RLA-Aib-FLVHSS-Aib-A-[3-Pal]-GPILPPTDVGSETP-NH2 (SEQ ID NO: 49); Ac-CQTATCATQ-[homoR]-LA-Aib-FLV-Y1-SS-Aib-A-[3-Pal]-GPILPPTDVGSETP-NH2 (SEQ ID NO: 50); Ac-CQTATCATQ-[Orn]-LA-Aib-FLV-Y1-SS-Aib-A-[3-Pal]-GPILPPTDVGSETP-NH2 (SEQ ID NO: 51); Ac-CQTATCATQR-[NMeL]-A-Aib-FLV-Y1-SS-Aib-A-[3-Pal]-GPILPPTDVGSETP-NH2 (SEQ ID NO: 52); Ac-CQTATCATQR-[aMeL]-A-Aib-FLV-Y1-SS-Aib-A-[3-Pal]-GPILPPTDVGSETP-NH2 (SEQ ID NO: 53); Ac-CQTATCATQR-[DL]-A-Aib-FLV-Y1-SS-Aib-A-[3-Pal]-GPILPPTDVGSETP-NH2 (SEQ ID NO: 54); Ac-CQTATCATQRLA-Aib-FLV-Y1-SS-Aib-A-[3-Pal]-GP-[NMeI]-LPPTDVGSETP-NH2 (SEQ ID NO: 61); Ac-CQTATCATQRLA-Aib-FL-Aib-Y1-SS-Aib-A-[3-Pal]-GPILPPTDVGSETP-NH2 (SEQ ID NO: 62); Ac-CQTATCATQRLA-Aib-FLV-Aib-SSA-Y1-[3-Pal]-GPILPPTDVGSETP-NH2 (SEQ ID NO: 63); in, Ac- indicates N-terminal acetylation; -NH2 indicates C-terminal amidation; homoR indicates homoarginine; NMeL indicates N-Me-Leu; NMeI stands for N-Me-Ile; aMeL indicates a-Me-Leu; DL indicates D-Leu; Y1 is selected from Lys, Orn, Dap, Dab or Cys residues with or without a side chain connected to a substituent, preferably a Lys, Orn, Dap, Dab or Cys residue with a side chain connected to a substituent, more preferably a Lys residue with a side chain connected to a substituent; In the sequences shown in SEQ ID NOs: 38 to 45, a disulfide bond is formed between the side chains of the Cys residue at position X2 and the Cys residue at position X7; In the sequence shown in SEQ ID NO:46, a thioether bond is formed between the side chain of the Abu residue at position X2 and the Cys residue at position X7; In the sequences shown in SEQ ID NOs: 47 to 54 and 61 to 63, a methylenethioacetal bridge is formed between the side chains of the Cys residue at position X2 and the Cys residue at position X7.

15. The compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein Y1 includes a substituent having the structure shown below: -Z1-Z2; Wherein: Z1 comprises 0-10 amino acid residues independently selected from Glu, Gly, γGlu, AEEA, Ala, Ser, Thr; preferably comprises the following structure: -(AEEA) a -(γGlu) b -; wherein a is any integer between 0 and 4, and b is any integer between 1 and 4; Z2 contains C 12 -C 32 Fatty acids; preferably comprising the structure shown below: -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 4, and c is any integer between 10 and 30; Preferably, a is 1, 2 or 3, b is 1, 2 or 3, and c is any integer from 12 to 22; More preferably, a is 1 or 2, b is 1, 2 or 3, and c is 14, 16, 18 or 20; More preferably, a is 2, b is 1 or 2, and c is 14, 16, 18 or 20; More preferably, a is 2, b is 1 or 2, and c is 16 or 18; or, a is 1 or 2, b is 3, and c is 16 or 18.

16. The compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, wherein Y1 is a Lys residue with a side chain-linked substituent, wherein the substituent is covalently linked to the ε-amino group of the Lys residue via an amide bond; preferably, Y1 is selected from: K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH), K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH), K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH), or K(-AEEA-γGlu-C(O)-C 18 -COOH); The K(-AEEA-AEEA-γGlu-C(O)-C 16 -COOH) has the structure: , the K(-AEEA-AEEA-γGlu-C(O)-C 18 -COOH) has the structure: The K(-AEEA-AEEA-(γGlu)3-C(O)-C 18 -COOH) has the structure: The K(-AEEA-(γGlu)3-C(O)-C 18 -COOH) has the structure:

17. The compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, wherein the compound has any of the following structures: Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, Compound 16, Compound 17, Compound 18, Compound 19, Compound 20, Compound 21, Compound 22, Compound 23, Compound 24, Compound 25, 18. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, which is an amylin analog, and the compound or a pharmaceutically acceptable salt thereof has at least one of the following properties: (1) agonist activity of the calcitonin receptor (CTR) and / or agonist activity of the amylin receptor (AMYR); preferably, the agonist activity of both the calcitonin receptor and the amylin receptor; (2) improved physical stability under physiological pH conditions, for example, physical stability of ≥50 hours (preferably ≥60, 70, 80, 90 or 96 hours) under physiological pH conditions; (3) Prolonged in vivo pharmacokinetic properties.

19. A pharmaceutical composition comprising the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient or pharmaceutical carrier.

20. Use of the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 19, in the preparation of an AMYR / CTR dual agonist, or a medicament for preventing or treating a disease or condition associated with a metabolic disorder; Preferably, the metabolic disorder-related disease or condition is selected from diabetes or diabetes-related conditions, obesity or obesity-related conditions, and non-alcoholic steatohepatitis.

21. 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 18 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 19; Preferably, the metabolic disorder-related disease or condition is selected from diabetes or diabetes-related conditions, obesity or obesity-related conditions, and non-alcoholic steatohepatitis.

22. A method for preparing a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, wherein: The method is a chemical synthesis method or a biological semi-synthetic method.

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