GLP-1 / GCG / GIP tri-receptor agonists and uses thereof

Abstract

The invention relates to a tri-receptor agonist. The agonist comprises a polypeptide as shown in a formula (I) which is shown in the description, namely X < 1 > X < 2 > X < 3 > GTX < 6 > TSDYSIX < 13 > X < 14 > DX < 16 > X < 17 > X < 18 > X < 19 > X < 20 > X < 21 > FX < 23 > X < 24 > X < 25 > LX < 27 > X < 28 > GGPSSGAPPPS (I), x2 is Aib; x3 is Q or H; x6 is a non-natural amino acid; x13 is L or Y; x14 is L or K; x16 is E, K or R; x17 is K, R or I; x18 is A, R or K; x19 is Q or A; x20 is R, K, Q, H or Aib; x21 is D, A or E; x23 is I or V; x24 is E or Q; x25 is W or Y; x27 is I or L; and X28 is E or A. The agonist has relatively strong agonistic activity on three receptors, namely GLP-1, GCG and GIP, and can be used for treating metabolic disorder related diseases.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of biological medicine, and in particular, the present application relates to a GLP-1 / GCG / GIP three-receptor agonist and use thereof, more particularly, the present application relates to a compound having formula (I) or a pharmaceutically acceptable salt or solvate thereof, a pharmaceutical composition and use thereof. BACKGROUND

[0002] Diabetes is a metabolic disease closely related to obesity and non-alcoholic steatohepatitis (NASH), and its prevalence and incidence continue to increase worldwide. At present, although glucagon-like peptide-1 (GLP-1) receptor agonists have been approved for the treatment of type 2 diabetes mellitus (T2DM), such as dulaglutide and semaglutide, due to the characteristics of metabolic diseases such as complexity and heterogeneity, especially type 2 diabetes mellitus accompanied by obesity and other multiple complications, the efficacy of single target treatment is limited. Acting on multiple targets can improve the effect of treating such diseases. However, the combination of multiple drugs such as compound preparations will complicate drug development and clinical research, but the development of single-molecule multi-target drugs can effectively avoid such problems.

[0003] Based on the effectiveness and safety of GLP-1 receptor agonists, the current research idea is to develop them into single-molecule multi-target drugs with other intestinal hormones such as glucagon (GCG) and glucose-dependent insulinotropic polypeptide (GIP). Acting on multiple targets at the same time can balance the side effects and deficiencies of different targets, and has stable pharmacokinetic characteristics, which can ultimately bring better therapeutic effect than single target. SUMMARY

[0004] The present application aims to at least partially solve one of the problems in the prior art. To this end, the present application provides a GLP-1 / GCG / GIP three-receptor agonist, which can exhibit strong agonistic activity on GLP-1, GCG and GIP three receptors.

[0005] The present application is based on the following findings of the inventors:

[0006] Glucagon-like peptide-1 (GLP-1) is a polypeptide hormone secreted by L-cells in the intestine after eating, which can stimulate the beta cells of the islets of Langerhans to secrete insulin, thereby stabilizing the postprandial fluctuation of blood glucose. Its effect of lowering blood glucose is glucose concentration dependent, and while regulating blood glucose, it greatly reduces the risk of hypoglycemia. In recent years, drugs based on GLP-1, such as liraglutide, dulaglutide and semaglutide, have gradually occupied a very important position in diabetes drugs. GLP-1 drugs have a weight loss effect when lowering blood glucose, and the mechanism is that GLP-1 acts on the gastrointestinal tract to delay gastric emptying and intestinal peristalsis, and acts on the central nervous system to suppress appetite, thereby achieving the purpose of reducing food intake. However, when GLP-1 receptor agonist drugs are used for weight loss, the dosage generally needs to be large, which is easy to produce gastrointestinal side effects and poor tolerance.

[0007] Glucagon (GCG) is a polypeptide hormone secreted by alpha cells in the islets of Langerhans, which can promote glycogenolysis and gluconeogenesis, significantly increase blood glucose; at the same time, it can also activate lipase, promote lipolysis, increase fatty acid oxidation, and increase energy consumption, and has the effects of reducing fat and weight. Due to its hyperglycemic effect, it can be used for the treatment of hypoglycemia, but its application in obesity and weight loss is limited, especially in obese patients with type II diabetes.

[0008] Glucose-dependent insulinotropic polypeptide (GIP) is a polypeptide hormone secreted by K cells in the intestine. GIP and GLP-1 are both incretins, and both can promote insulin secretion and lower blood glucose in a blood glucose concentration-dependent manner, and the blood glucose lowering effect mediated by GIP is stronger than that of GLP-1. However, due to receptor tolerance caused by high blood glucose, diabetic patients show insensitivity to GIP, so the use of GIP receptor agonists alone in diabetic patients does not achieve the purpose of improving blood glucose.

[0009] Research has found that the causes of metabolic disorder-related diseases (such as diabetes, obesity and NASH) are complex, and the curative effect of single target drugs is relatively limited.

[0010] Therefore, in one aspect of the present application, a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof is provided. According to an embodiment of the present application, the compound represented by formula (I) is X1X2X3GTX6TSDYSIX13X 14 DX 16 X 17 X 18 X 19 X 20 X 21 FX 23 X 24 X 25 LX 27 X 28GGPSSGAPPPS(I), wherein, X1 is Y or H; X2 is Aib; X3 is Q or H; X6 is a non-natural amino acid; X 13 is L or Y; X 14 is L or K; X 16 is E, K or R; X 17 is K, R or I; X 18 is A, R or K; X 19 is Q or A; X 20 is R, K, Q, H or Aib; X 21 is D, A or E; X 23 is I or V; X 24 is E or Q; X 25 is W or Y; X 27 is I or L; X 28 is E or A; wherein, when X 16 is K, X 14 is K. The above-mentioned compound of the present application or a pharmaceutically acceptable salt or solvate thereof exhibits strong agonistic activity on three receptor targets of GLP-1, GCG and GIP, can effectively control blood glucose and reduce body weight, and can be used for preventing or treating metabolic disorder related diseases, especially obesity, diabetes, dyslipidemia related diseases, fatty liver disease, metabolic syndrome and non-alcoholic fatty liver disease and the like.

[0011] In another aspect of the present application, the present application provides a pharmaceutical composition. According to an embodiment of the present application, the pharmaceutical composition comprises the aforementioned compound or a pharmaceutically acceptable salt or solvate thereof. The pharmaceutical composition of the present application can effectively prevent or treat metabolic disorder related diseases, especially obesity, diabetes, dyslipidemia related diseases, fatty liver disease, metabolic syndrome and non-alcoholic fatty liver disease and the like.

[0012] In still another aspect of the present application, the present application provides use of the aforementioned compound or a pharmaceutically acceptable salt or solvate thereof or the aforementioned pharmaceutical composition in the preparation of a medicament for treating or preventing metabolic disorder related diseases.

[0013] Additional aspects and advantages of the present application will be in part apparent and in part pointed out hereinafter. BRIEF DESCRIPTION OF DRAWINGS

[0014] The above and / or additional aspects and advantages of the present application will become apparent and be readily appreciated from the following description, including the appended drawings.

[0015] Figure 1 The detection results of blood glucose and AUC of each group in Example 4 of the present application 0～90min ;

[0016] Figure 2 The results of the measurement of blood glucose and AUC for each group in Example 5 of the present application 0～90min The results of the measurement of blood glucose for each group in Example 6 of the present application

[0017] Figure 3 The results of the measurement of blood glucose for each group in Example 6 of the present application

[0018] Figure 4 The results of the measurement of glycated hemoglobin for each group in Example 6 of the present application

[0019] Figure 5 The results of the measurement of body weight change rate for each group in Example 7 of the present application

[0020] Figure 6 The results of the measurement of cumulative food intake for each group in Example 7 of the present application. DETAILED DESCRIPTION

[0021] Embodiments of the present application are described in detail below. The embodiments described below are exemplary only and are not to be construed as limiting the present application.

[0022] It is to be noted that the terms "first", "second", and the like do not denote any quantity or order but are used only to distinguish one element from another. Thus, a feature specified as "first" can imply or be implicitly understood to include one or more of the features, and a feature specified as "second" can imply or be implicitly understood to include one or more of the features. Further, in the description of the present application, the meaning of "a plurality" is two or more unless otherwise specified.

[0023] In this document, the terms "comprise" or "comprising" are used in the sense of "including" and mean that items include the "comprised" items but not other non-mentioned items.

[0024] In this document, the terms "optionally", "optional" or "option" generally mean that the subsequently described event or circumstance can or can not occur, and the description includes instances where the event or circumstance occurs and instances where it does not.

[0025] In this document, the term "solvate" refers to a complex of defined stoichiometry between a solute (here, a compound according to the present application or a pharmaceutically acceptable salt thereof) and a solvent. The solvent can be water, ethanol or other pharmaceutically acceptable representative small-molecule organic, such as including but not limited to acetic acid or lactic acid. When the above solvent is water, such solvate is often referred to as a hydrate.

[0026] In this document, amino acids are referred to using the conventional single-letter and three-letter codes for natural amino acids, as well as the commonly accepted three-letter codes for other α-amino acids, for example, α-aminoisobutyric acid can be represented by both codes Aib and B. Unless otherwise specified, all amino acid residues in the present invention are preferably in the L-configuration.

[0027] Among them, the structural formula of Aib or B is

[0028] In this document, the terms "(L)-α-Me-(2-F)-Phe" and "αMeF(2F)" refer to α-methyl 2-fluorophenylalanine, the structural formula of which is

[0029]

[0030] In this article, the sequence structure "-NH2" refers to the amidation of -COOH on the C-terminus of the amino acid to -CONH2, for example, in Y-Aib-QGTX6TSDYSIL-K ({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-C 18 -CO2H)DKIAQKAFIEYLLAGGPSSGAPPPS-NH2 "-NH2" indicates that the free carboxyl group -COOH in the C-terminal serine S is amidated to -CONH2.

[0031] As used herein, the term "OEG" refers to {[2-(2-amino-ethoxy)-ethoxy]-acetyl, the structural formula of which is shown below:

[0032]

[0033] As used herein, the term "agonist" refers to a substance (ligand) that activates the receptor type in question.

[0034] As used herein, the term "treatment" refers to any process used to obtain a desired pharmacological and / or physiological effect. The effect may be preventive in terms of completely or partially preventing a disease or its symptoms, and / or therapeutic in terms of partially or completely curing a disease and / or the adverse effects caused by the disease. "Treatment" as used herein covers diseases in mammals, particularly humans, and includes: (a) preventing the occurrence of a disease or condition in individuals who are susceptible to the disease but have not yet been diagnosed with the disease; (b) inhibiting the disease, such as arresting the progression of the disease; or (c) alleviating the disease, such as alleviating the symptoms associated with the disease. "Treatment" as used herein covers any medication that administers a drug or compound to an individual to treat, cure, alleviate, improve, reduce or inhibit the individual's disease, including but not limited to administering a drug containing a compound described herein to an individual in need.

[0035] In the present text, the term "non-alcoholic fatty liver disease (NAFLD)" generally refers to a clinicopathological syndrome characterized by excessive accumulation of fat in hepatocytes, other than that caused by alcohol and other clear hepatotoxic factors, acquired metabolic stress-induced liver injury closely related to insulin resistance and genetic susceptibility, including but not limited to simple fatty liver (SFL), non-alcoholic steatohepatitis (NASH) and its related cirrhosis.

[0036] The present application provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, a pharmaceutical composition and uses thereof, which will be described in detail below.

[0037] The present application provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, a pharmaceutical composition and uses thereof, which will be described in detail below.

[0038] In one aspect of the present application, the present application provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. According to an embodiment of the present application, the compound of formula (I) is X1X2X3GTX6TSDYSIX 13 X 14 DX16X 17 X 18 X 19 X 20 X 21 FX 23 X 24 X 25 LX 27 X 28 GGPSSGAPPPS(I), wherein X1 is Y or H; X2 is Aib; X3 is Q or H; X6 is a non-natural amino acid; X 13 is L or Y; X 14 is L or K; X 16 is E, K or R; X 17 is K, R or I; X 18 is A, R or K; X 19 is Q or A; X 20 is R, K, Q, H or Aib; X 21 is D, A or E; X 23 is I or V; X 24 is E or Q; X 25 is W or Y; X 27 is I or L; X 28 is E or A; wherein X 16 is K, X 14K. The above-mentioned compound of the present application or its pharmaceutically acceptable salt or solvate (or referred to as an agonist) exhibits strong agonistic activity on three receptor targets of GLP-1, GCG and GIP, and by optimizing the activity of each receptor, side effects caused by over-activity of one or more receptors can be avoided, and the agonist has the advantages of good activity of each receptor and effective control of blood sugar and reduction of body weight; at the same time, the agonist has strong stability in vivo, and can prolong the action time of the drug to achieve the frequency of once-a-week administration. Therefore, the agonist can be used for preventing or treating metabolic disorder related diseases, especially obesity, diabetes, dyslipidemia related diseases, fatty liver disease, metabolic syndrome and non-alcoholic fatty liver disease.

[0039] According to an embodiment of the present application, X1 is Y; X2 is Aib; X3 is Q or H; X6 is aMeF (2F); X 13 is L; X 14 is L or K; X 16 is E or K; X 17 is K or I; X 18 is A or R; X 19 is Q; X 20 is R, Q or Aib; X 21 is A or E; X 23 is I; X 24 is E; X 25 is W or Y; X 27 is L; X 28 is E or A; wherein, X 16 is K, X 14 is K. In this way, the agonistic activity on three receptor targets of GLP-1, GCG and GIP can be further enhanced.

[0040] According to an embodiment of the present application, the compound represented by the formula (I) has at least one of the following structures:

[0041] Y-Aib-QGTX6TSDYSILLDEKAQRDFIEWLLEGGPSSGAPPPS;

[0042] Y-Aib-HGTX6TSDYSILLDEKAQRDFIEWLLAGGPSSGAPPPS;

[0043] Y-Aib-HGTX6TSDYSILLDEIAQKDFIEWLLEGGPSSGAPPPS;

[0044] H-Aib-QGTX6TSDYSILLDEIAQKDFIEWLLEGGPSSGAPPPS;

[0045] Y-Aib-QGTX6TSDYSILLDEKAQQAFIEYLLEGGPSSGAPPPS;

[0046] Y-Aib-QGTX6TSDYSILLDEKAQQDFIEWLIAGGPSSGAPPPS;

[0047] Y-Aib-QGTX6TSDYSILLDERAAKEFIEWLLEGGPSSGAPPPS;

[0048] Y-Aib-QGTX6TSDYSILLDERAAKEFIEWLIAGGPSSGAPPPS;

[0049] Y-Aib-HGTX6TSDYSILLDEKAQREFIEWLLAGGPSSGAPPPS;

[0050] Y-Aib-HGTX6TSDYSILLDEKAQRAFIEYLLAGGPSSGAPPPS;

[0051] Y-Aib-HGTX6TSDYSILLDEKAQREFIEWLLEGGPSSGAPPPS;

[0052] Y-Aib-HGTX6TSDYSILLDEKRQREFIEWLLAGGPSSGAPPPS;

[0053] Y-Aib-QGTX6TSDYSILLDEKAQQEFIEWLLEGGPSSGAPPPS;

[0054] Y-Aib-HGTX6TSDYSILLDEKAQQEFIEWLLAGGPSSGAPPPS;

[0055] Y-Aib-HGTX6TSDYSILLDEKAQQAFIEYLLAGGPSSGAPPPS;

[0056] Y-Aib-QGTX6TSDYSILLDEKRQQAFIEYLLEGGPSSGAPPPS;

[0057] Y-Aib-HGTX6TSDYSILLDEKAQRAFIEYLLEGGPSSGAPPPS;

[0058] Y-Aib-QGTX6TSDYSILLDEKAQRAFIEYLLEGGPSSGAPPPS;

[0059] Y-Aib-HGTX6TSDYSILLDEKRQREFIEWLLEGGPSSGAPPPS;

[0060] Y-Aib-QGTX6TSDYSILLDEKRARAFIEYLLAGGPSSGAPPPS;

[0061] Y-Aib-HGTX6TSDYSILLDEKRAREFIEWLLEGGPSSGAPPPS;

[0062] Y-Aib-QGTX6TSDYSILLDEKAQQEFIEWLLAGGPSSGAPPPS;

[0063] Y-Aib-QGTX6TSDYSILLDEKAQQEFIEWLIAGGPSSGAPPPS;

[0064] Y-Aib-QGTX6TSDYSILLDEKAQQAFVQWLIAGGPSSGAPPPS;

[0065] Y-Aib-QGTX6TSDYSILLDEKRAQAFIEYLLEGGPSSGAPPPS;

[0066] Y-Aib-QGTX6TSDYSILLDEKAQRAFIEYLLAGGPSSGAPPPS;

[0067] Y-Aib-QGTX6TSDYSILLDEIAQKAFIEYLLAGGPSSGAPPPS;

[0068] Y-Aib-QGTX6TSDYSILLDEIAQKAFIEYLIAGGPSSGAPPPS;

[0069] Y-Aib-QGTX6TSDYSILLDEIAQKAFVQWLIAGGPSSGAPPPS;

[0070] Y-Aib-HGTX6TSDYSILLDEKAQ-Aib-EFIEWLLAGGPSSGAPPPS;

[0071] Y-Aib-QGTX6TSDYSILLDEKAQ-Aib-AFIEYLLAGGPSSGAPPPS;

[0072] Y-Aib-HGTX6TSDYSILLDEKRQ-Aib-EFIEWLLAGGPSSGAPPPS;

[0073] Y-Aib-QGTX6TSDYSILLDEKRQ-Aib-EFIEWLLAGGPSSGAPPPS;

[0074] Y-Aib-QGTX6TSDYSILLDEKRQ-Aib-AFIEYLLAGGPSSGAPPPS;

[0075] Y-Aib-QGTX6TSDYSILKDKIAQQAFIEYLLEGGPSSGAPPPS;

[0076] Y-Aib-QGTX6TSDYSILKDKIAQ-Aib-AFIEYLLEGGPSSGAPPPS;

[0077] Y-Aib-HGTX6TSDYSILLDEKRQQAFIEYLLEGGPSSGAPPPS;

[0078] Y-Aib-HGTX6TSDYSILLDEKRQRAFIEYLLAGGPSSGAPPPS;

[0079] Y-Aib-HGTX6TSDYSILLDEKRQRAFIEYLLEGGPSSGAPPPS;

[0080] Y-Aib-HGTX6TSDYSILLDEKRQKAFIEYLLAGGPSSGAPPPS;

[0081] Y-Aib-QGTX6TSDYSILKDKIAQQAFIEYLLAGGPSSGAPPPS;

[0082] Y-Aib-QGTX6TSDYSILLDEKRQRAFIEYLLEGGPSSGAPPPS;

[0083] Y-Aib-QGTX6TSDYSILLDRIRQKEFIEWLLAGGPSSGAPPPS;

[0084] Y-Aib-QGTX6TSDYSILLDRIRQKAFIEYLLEGGPSSGAPPPS;

[0085] Y-Aib-QGTX6TSDYSILLDRKRQQEFIEWLLAGGPSSGAPPPS;

[0086] Y-Aib-QGTX6TSDYSILLDRKRQQAFIEYLLAGGPSSGAPPPS;

[0087] Y-Aib-QGTX6TSDYSILLDEKKQ-Aib-EFIEWLLAGGPSSGAPPPS;

[0088] Y-Aib-QGTX6TSDYSILLDEKKQKAFIEYLLAGGPSSGAPPPS;

[0089] H-Aib-QGTX6TSDYSILLDEKRQRAFIEYLLAGGPSSGAPPPS;

[0090] Y-Aib-QGTX6TSDYSILLDEKRQRAFIEYLLAGGPSSGAPPPS;

[0091] Y-Aib-QGTX6TSDYSILLDEKRQRAFVEYLLAGGPSSGAPPPS;

[0092] Y-Aib-QGTX6TSDYSIYLDEKAQRAFIEYLLAGGPSSGAPPPS;

[0093] Y-Aib-QGTX6TSDYSIYLDEKAQRAFIEYLLEGGPSSGAPPPS;

[0094] Y-Aib-QGTX6TSDYSILKDKIAQ-Aib-AFIEYLLAGGPSSGAPPPS;

[0095] Y-Aib-QGTX6TSDYSILKDKIAQKAFIEYLLAGGPSSGAPPPS;

[0096] Y-Aib-QGTX6TSDYSILKDKIAQKAFIEYLLEGGPSSGAPPPS;

[0097] Y-Aib-QGTX6TSDYSILKDRIAQRAFIEYLLEGGPSSGAPPPS;

[0098] Y-Aib-QGTX6TSDYSILKDKIRQQAFIEYLLEGGPSSGAPPPS;

[0099] Y-Aib-QGTX6TSDYSILKDKIRQ-Aib-AFIEYLLEGGPSSGAPPPS;

[0100] Y-Aib-Q G TX6TSDYSILKDKIRQ-Aib-AFIEYLLAGGPSSGAPPPS;

[0101] Y-Aib-Q G TX6TSDYSILKDKIRQ-Aib-AFIEYLLAGGPSSGAPPPS;

[0102] Y-Aib-Q G TX6TSDYSILKDKIRQ-Aib-AFIEYLLAGGPSSGAPPPS;

[0103] Y-Aib-Q G TX6TSDYSILKDKIRQ-Aib-AFIEYLLAGGPSSGAPPPS;

[0104] Y-Aib-Q G TX6TSDYSILKDKIRQ-Aib-AFIEYLLAGGPSSGAPPPS;

[0105] H-Aib-Q G TX6TSDYSILLDEKRQQAFIEYLLAGGPSSGAPPPS;

[0106] H-Aib-Q G TX6TSDYSILLDEKRQQAFIEYLLAGGPSSGAPPPS;

[0107] H-Aib-H G TX6TSDYSILLDRKAQHAFIEYLLAGGPSSGAPPPS;

[0108] H-Aib-H G TX6TSDYSILLDRKAQHAFIEYLLAGGPSSGAPPPS;

[0109] H-Aib-H G TX6TSDYSILLDRKAQHAFIEYLLAGGPSSGAPPPS;

[0110] H-Aib-Q G TX6TSDYSILLDRKAQHAFIEYLLAGGPSSGAPPPS;

[0111] H-Aib-Q G TX6TSDYSILLDRKAQHAFIEYLLAGGPSSGAPPPS;

[0112] wherein X6is aMeF(2F).

[0113] It is to be noted that the “-” between the amino acids and between the amino acids in the polypeptides of the above compounds represents an amide bond. Exemplarily, the “-” in “H-Aib-Q” represents an amide bond.

[0114] According to embodiments of the present application, the compound having Formula (I) or a pharmaceutically acceptable salt or solvate thereof further comprises a modification group attached to at least one of the amino acids in X 14 , X 17 , and X 20 .

[0115] According to embodiments of the present application, at least one of X 14 , X 17 , and X 20 is K, and the modification group is attached to the epsilon-amino group of the K side chain of at least one of X 14 , X 17 , and X 20 via an amide bond.

[0116] According to embodiments of the present application, X 14 and / or X 17 is K, and the modification group is attached to the epsilon-amino group of the K side chain of X 14 and / or X 17 via an amide bond.

[0117] According to embodiments of the present application, the modification group has the structure: {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(yGlu) b -CO-(CH2) c -CO2H, wherein a is any integer from 1 to 3, b is any integer from 1 to 3, and c is any integer from 14 to 20.

[0118] In some alternative embodiments of the present application, a is 1. In some alternative embodiments of the present application, a is 2. In some alternative embodiments of the present application, a is 3.

[0119] In some alternative embodiments of the present application, b is 1. In some alternative embodiments of the present application, b is 2. In some alternative embodiments of the present application, b is 3.

[0120] In some alternative embodiments of the present application, c is any integer from 14 to 20. Illustratively, c is 14, 15, 16, 17, 18, 19, and 20 or a range of values between any two of these values as end point values, such as 14-18, 16-18, or 16-20.

[0121] It is to be noted that the "-" in the above modification groups indicates a chemical bond between the chemical groups; illustratively, "[2-(2-amino-ethoxy)-ethoxy]-acetyl" is synonymous with "OEG"; the "-" in "CO-CH2" indicates a chemical bond between the chemical groups; a, b and c represent the number of different groups; "Glu" and "E" are synonymous and both refer to glutamic acid; "CO2H" refers to a COOH group.

[0122] According to embodiments of the present application, the modification group has at least one of the following structures:

[0123]

[0124] According to embodiments of the present application, the C-terminal amide of the amino acid S in position 39 of the compound of formula (I) is formed.

[0125] It is to be noted that the amide formation refers to the substitution of the -OH in the -COOH of the serine S of the compound of formula (I) by an amino group -NH2, i.e. the amide formation of the -COOH of the serine S of the compound of formula (I) to -CONH2.

[0126] According to embodiments of the present application, the compound of formula (I) has at least one of the following structures:

[0127] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 18 -CO2H)AQRDFIEWLLEGGPSSGAPPPS;

[0128] Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 18 -CO2H)AQRDFIEWLLAGGPSSGAPPPS;

[0129] Y-Aib-HGTX6TSDYSILLDEIAQ-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}2-yGlu-CO-(CH2) 18 -CO2H)DFIEWLLEGGPSSGAPPPS;

[0130] H-Aib-QGTX6TSDYSILLDEIAQ-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}2-yGlu-CO-(CH2) 18 -CO2H)DFIEWLLEGGPSSGAPPPS;

[0131] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 18 -CO2H)AQQAFIEYLLEGGPSSGAPPPS;

[0132] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 18 -CO2H)AQQDFIEWLIAGGPSSGAPPPS;

[0133] Y-Aib-QGTX6TSDYSILLDERAA-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}2-yGlu-CO-(CH2) 18 -CO2H)EFIEWLLEGGPSSGAPPPS;

[0134] Y-Aib-QGTX6TSDYSILLDERAA-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}2-yGlu-CO-(CH2) 18 -CO2H)EFIEWLIAGGPSSGAPPPS;

[0135] Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 16 -CO2H)AQREFIEWLLAGGPSSGAPPPS;

[0136] Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 16 -CO2H)AQRAFIEYLLAGGPSSGAPPPS;

[0137] Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 16 -CO2H)AQREFIEWLLEGGPSSGAPPPS;

[0138] Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2)16 -CO2H)RQREFIEWLLAGGPSSGAPPPS;

[0139] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-gammaGlu-CO-(CH2) 18 -CO2H)AQQEFIEWLLEGGPSSGAPPPS;

[0140] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-gammaGlu-CO-(CH2) 16 -CO2H)AQQEFIEWLLEGGPSSGAPPPS;

[0141] Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-gammaGlu-CO-(CH2) 16 -CO2H)AQQEFIEWLLAGGPSSGAPPPS;

[0142] Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-gammaGlu-CO-(CH2) 18 -CO2H)AQQAFIEYLLAGGPSSGAPPPS;

[0143] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-gammaGlu-CO-(CH2) 16 -CO2H)RQQAFIEYLLEGGPSSGAPPPS;

[0144] Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-gammaGlu-CO-(CH2) 18 -CO2H)AQRAFIEYLLAGGPSSGAPPPS;

[0145] Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-gammaGlu-CO-(CH2) 18 -CO2H)AQRAFIEYLLEGGPSSGAPPPS;

[0146] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)AQRAFIEYLLEGPGPSSGAPPPS;

[0147] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)RQRAFIEYLLAGPGPSSGAPPPS;

[0148] Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)RQREFIEWLLEGPSSGAPPPS;

[0149] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)RARAFIEYLLAGPGPSSGAPPPS;

[0150] Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)RAREFIEWLLEGPSSGAPPPS;

[0151] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)AQQEFIEWLLAGPGPSSGAPPPS;

[0152] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)AQQEFIEWLIAGGPSSGAPPPS;

[0153] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18-CO2H)AQQAFVQWLIAGGPSSGAPPPS;

[0154] Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 18 -CO2H)RQQAFIEYLLEGGPSSGAPPPS;

[0155] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 18 -CO2H)RAQAFIEYLLEGGPSSGAPPPS;

[0156] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 18 -CO2H)AQRAFIEYLLAGGPSSGAPPPS;

[0157] Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 18 -CO2H)RQREFIEWLLAGGPSSGAPPPS;

[0158] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 18 -CO2H)RQRAFIEYLLEGGPSSGAPPPS;

[0159] Y-Aib-QGTX6TSDYSILLDEIAQ-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}2-yGlu-CO-(CH2) 18 -CO2H)AFIEYLLAGGPSSGAPPPS;

[0160] Y-Aib-QGTX6TSDYSILLDEIAQ-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}2-yGlu-CO-(CH2) 18 -CO2H)AFIEYLIAGGPSSGAPPPS;

[0161] Y-Aib-QGTX6TSDYSILLDEIAQ-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl} 2- γGlu-CO-(CH2)4-CO2H) AQ-Aib-EFIEWLLAGGPSSGAPPPS-NH2; 18 Y-Aib-QGTX6TSDYSILLDEIAQ-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl} 2- γGlu-CO-(CH2)4-CO2H) AQ-Aib-EFIEWLLAGGPSSGAPPPS-NH2;

[0162] Y-Aib-QGTX6TSDYSILLDEIAQ-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl} 2- γGlu-CO-(CH2)4-CO2H) AQ-Aib-EFIEWLLAGGPSSGAPPPS-NH2; 16 Y-Aib-QGTX6TSDYSILLDEIAQ-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl} 2- γGlu-CO-(CH2)4-CO2H) AQ-Aib-EFIEWLLAGGPSSGAPPPS-NH2;

[0163] Y-Aib-QGTX6TSDYSILLDEIAQ-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl} 2- γGlu-CO-(CH2)4-CO2H) AQ-Aib-EFIEWLLAGGPSSGAPPPS-NH2; 16 Y-Aib-QGTX6TSDYSILLDEIAQ-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl} 2- γGlu-CO-(CH2)4-CO2H) AQ-Aib-EFIEWLLAGGPSSGAPPPS-NH2;

[0164] Y-Aib-QGTX6TSDYSILLDEIAQ-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl} 2- γGlu-CO-(CH2)4-CO2H) AQ-Aib-EFIEWLLAGGPSSGAPPPS-NH2; 16 Y-Aib-QGTX6TSDYSILLDEIAQ-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl} 2- γGlu-CO-(CH2)4-CO2H) AQ-Aib-EFIEWLLAGGPSSGAPPPS-NH2;

[0165] Y-Aib-QGTX6TSDYSILLDEIAQ-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl} 2- γGlu-CO-(CH2)4-CO2H) AQ-Aib-EFIEWLLAGGPSSGAPPPS-NH2; 16 Y-Aib-QGTX6TSDYSILLDEIAQ-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl} 2- γGlu-CO-(CH2)4-CO2H) AQ-Aib-EFIEWLLAGGPSSGAPPPS-NH2;

[0166] Y-Aib-QGTX6TSDYSILLDEIAQ-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl} 2- γGlu-CO-(CH2)4-CO2H) AQ-Aib-EFIEWLLAGGPSSGAPPPS-NH2; 16 Y-Aib-QGTX6TSDYSILLDEIAQ-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl} 2- γGlu-CO-(CH2)4-CO2H) AQ-Aib-EFIEWLLAGGPSSGAPPPS-NH2;

[0167] Y-Aib-QGTX6TSDYSILLDEIAQ-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl} 2- γGlu-CO-(CH2)4-CO2H) AQ-Aib-EFIEWLLAGGPSSGAPPPS-NH2; 16 Y-Aib-QGTX6TSDYSILLDEIAQ-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl} 2- γGlu-CO-(CH2)4-CO2H) AQ-Aib-EFIEWLLAGGPSSGAPPPS-NH2;

[0168] Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 16 -CO2H)DKIAQ-Aib-AFIEYLLEGGPSSGAPPPS-NH2;

[0169] Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 16 -CO2H)RQQAFIEYLLEGGPSSGAPPPS;

[0170] Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 16 -CO2H)RQRAFIEYLLAGGPSSGAPPPS;

[0171] Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 16 -CO2H)RQRAFIEYLLEGGPSSGAPPPS;

[0172] Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 16 -CO2H)RQKAFIEYLLAGGPSSGAPPPS-NH2;

[0173] Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 16 -CO2H)DKIAQQAFIEYLLAGGPSSGAPPPS-NH2;

[0174] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 16 -CO2H)RQRAFIEYLLEGGPSSGAPPPS;

[0175] Y-Aib-QGTX6TSDYSILLDRIRQ-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2)16 -CO2H) EFIEWLLAGGPSSGAPPPS;

[0176] Y-Aib-QGTX6TSDYSILLDR-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 16 -CO2H) AFIEYLLEGGPSSGAPPPS;

[0177] Y-Aib-QGTX6TSDYSILLDR-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 18 -CO2H) RQQEFIEWLLAGGPSSGAPPPS;

[0178] Y-Aib-QGTX6TSDYSILLDR-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 18 -CO2H) RQQAFIEYLLAGGPSSGAPPPS;

[0179] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 16 -CO2H) KQ-Aib-EFIEWLLAGGPSSGAPPPS-NH2;

[0180] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 16 -CO2H) KQKAFIEYLLAGGPSSGAPPPS-NH2;

[0181] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 18 -CO2H) KQKAFIEYLLAGGPSSGAPPPS-NH2;

[0182] Y-Aib-QGTX6TSDYSILLDEKKQ-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 16 -CO2H) AFIEYLLAGGPSSGAPPPS-NH2;

[0183] H-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 18 -CO2H)RQRAFIEYLLAGGPSSGAPPPS;

[0184] Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 16 -CO2H)RQRAFIEYLLAGGPSSGAPPPS;

[0185] Y-Aib-QGTX6TSDYSIYLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 16 -CO2H)AQRAFIEYLLAGGPSSGAPPPS;

[0186] Y-Aib-QGTX6TSDYSIYLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 16 -CO2H)AQRAFIEYLLAGGPSSGAPPPS;

[0187] Y-Aib-QGTX6TSDYSIYLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 16 -CO2H)AQRAFIEYLLAGGPSSGAPPPS;

[0188] Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 18 -CO2H)DKIAQ-Aib-AFIEYLLAGGPSSGAPPPS-NH2;

[0189] Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 16 -CO2H)DKIAQ-Aib-AFIEYLLAGGPSSGAPPPS-NH2;

[0190] Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 16-CO2H)DKIAQKAFIEYLLAGGPSSGAPPPS-NH2;

[0191] Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 16 -CO2H)DKIAQKAFIEYLLEGGPSSGAPPPS-NH2;

[0192] Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 16 -CO2H)DRIAQRAFIEYLLEGGPSSGAPPPS;

[0193] Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 16 -CO2H)DKIRQQAFIEYLLEGGPSSGAPPPS-NH2;

[0194] Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 16 -CO2H)DKIRQ-Aib-AFIEYLLEGGPSSGAPPPS-NH2;

[0195] Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 16 -CO2H)DKIRQ-Aib-AFIEYLLAGGPSSGAPPPS-NH2;

[0196] Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 16 -CO2H)DRIRQQAFIEYLLEGGPSSGAPPPS;

[0197] Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 16 -CO2H)DRIRQQAFIEYLLAGGPSSGAPPPS;

[0198] Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)DRRAQQAFVEYLLAGGPSSGAPPPS;

[0199] Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)DRRAQQAFVEYLLAGGPSSGAPPPS;

[0200] H-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)RQQAFIEYLLLEGGPSSGAPPPS;

[0201] H-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)RQQAFIEYLLAGGPSSGAPPPS;

[0202] H-Aib-HGTX6TSDYSILLDR-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)AQHAFIEYLLLEGGPSSGAPPPS;

[0203] H-Aib-HGTX6TSDYSILLDR-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)AQQAFIEYLLAGGPSSGAPPPS;

[0204] H-Aib-HGTX6TSDYSILLDR-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)AQHAFIEYLLAGGPSSGAPPPS;

[0205] H-Aib-QGTX6TSDYSILLDR-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16-CO2H) AQHAFIEYLLAGGPSSGAPPPS;

[0206] H-Aib-QGTX6TSDYSILLDR-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 16 -CO2H) AQHEFIEWLLEGGPSSGAPPPS;

[0207] wherein X6 is aMeF(2F).

[0208] It is to be noted that the “-” between the amino acids and between the amino acids in the polypeptide of the above compound represents an amide bond; illustratively, the “-” in “H-Aib-Q” represents an amide bond. The “-” in the above modification group represents a chemical bond connecting the chemical groups; illustratively, the “-” in “{[2-(2-amino-ethoxy)-ethoxy]-acetyl}-yGlu-CO-(CH2) 18 -CO2H” represents a chemical bond connecting the chemical groups.

[0209] Pharmaceutical composition

[0210] In another aspect of the present application, the present application provides a pharmaceutical composition. According to an embodiment of the present application, the pharmaceutical composition comprises the aforementioned compound or a pharmaceutically acceptable salt or solvate thereof. The pharmaceutical composition of the present application can be effective in preventing or treating metabolic disorder-related diseases, in particular, obesity, diabetes, dyslipidemia-related diseases, fatty liver disease, metabolic syndrome, and non-alcoholic fatty liver disease.

[0211] According to an embodiment of the present application, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0212] Use

[0213] In yet another aspect of the present application, the present application provides use of the aforementioned compound or a pharmaceutically acceptable salt or solvate thereof or the aforementioned pharmaceutical composition in the manufacture of a medicament for preventing or treating metabolic disorder-related diseases.

[0214] According to an embodiment of the present application, the metabolic disorder-related diseases include obesity, diabetes, dyslipidemia-related diseases, fatty liver disease, metabolic syndrome, and non-alcoholic fatty liver disease.

[0215] Method for preventing or treating metabolic disorder-related diseases

[0216] In yet another aspect of the present application, the present application provides a method for preventing or treating a metabolic disorder-related disease. According to an embodiment of the present application, the method comprises administering to a subject a pharmaceutically acceptable amount of the aforementioned compound or a pharmaceutically acceptable salt or solvate thereof or the aforementioned pharmaceutical composition.

[0217] According to an embodiment of the present application, the metabolic disorder-related disease includes obesity, diabetes, a dyslipidemia-related disease, fatty liver disease, metabolic syndrome, and non-alcoholic fatty liver disease.

[0218] It is to be noted that the "pharmaceutically acceptable amount" can vary depending on the mode of administration and the severity of the disease to be treated, and is preferably an effective amount. The selection of the pharmaceutically acceptable amount can be determined by one of ordinary skill in the art according to various factors (e.g., through clinical trials). The factors include, but are not limited to, pharmacokinetic parameters of the active ingredient such as bioavailability, metabolism, half-life, etc.; the severity of the disease to be treated in the patient, the weight of the patient, the immune status of the patient, the route of administration, etc. For example, several separate doses can be administered daily, or the dose can be proportionally reduced, as required by the exigencies of the therapeutic situation.

[0219] The aspects of the present application will be explained with reference to the embodiments below. Those skilled in the art will appreciate that the following embodiments are only for illustrative purposes and should not be construed as limiting the scope of the present application. In the embodiments, unless a specific technique or condition is specified, the technique or condition described in the literature in the art or according to the product manual is used. When the manufacturer of the reagent or instrument is not specified, it is a conventional product that can be obtained from the market.

[0220] Example 1: Preparation of polypeptide compounds

[0221] 1. Human GLP-1, human GCG, human GIP, and each polypeptide compound (a tri-receptor agonist) were synthesized according to Table 1 below, and the structure of each polypeptide compound is shown in Table 1.

[0222] Table 1: Structure of compounds of tri-receptor agonists

[0223]

[0224]

[0225]

[0226] Note: The amino acid code "X" in the sequence column of the above table is the aforementioned unnatural amino acid αMeF(2F).

[0227] The specific steps for preparing the fatty acid side chain-modified polypeptide compound are as follows:

[0228] 1) Put the resin into a 150ml reactor and soak for 2 hours with 50ml dichloromethane (DCM). Wash the resin with dimethylformamide (DMF) and then dry, repeat this four times and dry the resin. Weigh Fmoc-C-terminal first amino acid (with protection), DCM and N,N-diisopropyl ethylamine (DIEA) into the reactor, then put the reactor into a 30°C shaker for 2 hours. Block with methanol solution (methanol: DIEA: DCM = 1:1:2) for half an hour, then wash with DMF four times and dry. Add 20% piperidine solution to the reactor to remove the Fmoc protection group. After deprotection, wash with DMF four times and then dry.

[0229] 2) Weigh Fmoc-C-terminal second amino acid (with protection), 1-hydroxybenzotriazole (HOBT) and N,N-diisopropyl carbodiimide (DIC) into the reactor, then put the reactor into a 30°C shaker for 1 hour. Take a small amount of resin for testing, use the ninhydrin method to test, if the resin has color, it means the condensation is not complete, continue to react. After the reaction is complete, wash the resin with DMF four times and then dry. Add a certain amount of 20% piperidine (piperidine / DMF = 1:4) to the reactor and put it on the decolorizing shaker for 20 min to remove the Fmoc protection group on the resin. After deprotection, wash with DMF four times and then dry to test whether the protection is removed.

[0230] 3) Connect amino acids according to the steps in turn, one of which uses a special protected raw material (Lys with side chain). Add Boc anhydride to protect the N-terminal amino group. Remove the special protection group of the Lys side chain and connect the side chain structure according to step 2. Use a cleavage reagent to completely remove the polypeptide protection group and cut it off from the resin, and send it for purification.

[0231] 2, separate the target peptide from impurities by reverse phase liquid chromatography, freeze-dry the collected target peptide into powder, and identify the purity and mass spectrum. The purity detected by HPLC is greater than 95%. The mass spectrum identifies the molecular weight of the polypeptide, which is consistent with the theoretical molecular weight.

[0232] Example 2: In vitro cell activity assay

[0233] By applying polypeptide, human GLP-1, human GCG and human GIP to HEK293 cells expressing GLP-1R, GCGR and GIPR respectively, and using cAMP detection kit (Cisbio, 62AM6PEC) to detect the cAMP produced by the receptor cells, an EC 50 curve is established to calculate the EC

[0234] 1) Preparation of Assay buffer: Take complete culture medium (DMEM medium + 10% FBS), and then add 4 / 1000 of 500mM IBMX stock solution, cAMP-d2 working solution and anti-cAMP-crytate working solution according to the instructions of the cAMP detection kit;

[0235] 2) Dilute the sample to be tested into 500nM stock solution, human control polypeptides GLP-1, GCG and GIP into 200nM stock solution, and then add 20μL into 80μL Assay buffer (diluted 5 times) in a gradient step by step, including 8 compound gradients of stock solution;

[0236] 3) Preparation of cell suspension: immediately after taking out the cells HEK293-GLP-1R, HEK293-GCGR and HEK293-GIPR from liquid nitrogen, melt completely in a 37℃ water bath within 1.5min, and then add the cells drop by drop into a 15mL centrifuge tube containing 8mL warm medium on the clean bench, centrifuge at 900rpm for 5min, discard the supernatant, resuspend the cells with 1mL complete culture medium (blow 15 times), immediately mix 20μL of the suspension with an equal volume of trypan blue, take 20μL to calculate the number of viable cells, and then dilute the cells to 4×10 5 cells / mL with complete culture medium;

[0237] 4) Divide the 384-well plate into GLP-1R cell, GCGR cell and GIPR cell areas, and add 5μL of cell suspension to each well in the corresponding area of the plate using a 12-channel variable channel adjustable dispenser, and then add 5μL of test sample (polypeptide compound prepared in Example 1) and positive control (human GLP-1, human GCG or human GIP prepared in Example 1) gradient dilution to the corresponding cells of the 384-well plate using a 12-channel variable channel adjustable dispenser (the same concentration of sample in duplicate wells); negative control: 10μL assay buffer per well, set 3 wells per 384-well plate, cover with white sealing film, and place in a 37℃ constant temperature incubator, and take out after half an hour;

[0238] 5) Before use, dilute the cAMP-d2 working solution and anti-cAMP-crytate working solution 20 times with the lysis buffer in the kit, add 5μL of lysis buffer and 5μL of diluted anti-cAMP-crytate working solution to each well of the negative control, then mix the diluted cAMP-d2 working solution and anti-cAMP-crytate working solution 1:1, add 10μL per well to the sample group, cover with a white cover, and place at room temperature in the dark for 1h or at 4℃ overnight;

[0239] 6) The fluorescence values at 665 nm, 620 nm were detected in a multifunctional enzyme label instrument. The signal ratio was non-linearly fitted with sample concentration using a four-parameter equation in GraphPad Prism 6 to obtain EC 50 values, and the specific results are shown in Table 2.

[0240] Table 2: In vitro activity detection results of different receptor cells

[0241]

[0242]

[0243]

[0244] Experimental conclusion: The polypeptide compound of the present application maintains high agonistic activity on GLP-1R, GCGR and GIPR.

[0245] Example 3: Pharmacokinetic study in rats

[0246] Male Sprague Dawley rats were used to conduct pharmacokinetic studies on each polypeptide compound prepared in Example 1. Each group had 3 male rats, the animals were free to drink water and were not fasted, the dose was 50 nmol / kg, and a single subcutaneous injection was given (see Table 3 for specific polypeptide compounds). After administration, plasma was collected at the specified time points and the concentration of each polypeptide compound in the plasma was detected by LC-MS / MS method. The pharmacokinetic parameters were calculated based on the concentration data to describe the pharmacokinetic properties of the polypeptide after subcutaneous administration in rats. The experimental results are shown in Table 3:

[0247] Table 3: Summary of pharmacokinetic parameters of some three-target polypeptides in rats

[0248]

[0249] Note: T max : peak time; C max : peak concentration; AUC last : area under the curve at 0-t; AUC INF : area under the curve at 0-∞; T 1 / 2 : elimination half-life.

[0250] Experimental conclusion: Except that PT-61 has poor absorption in rats, the other polypeptides have good absorption in rats, high blood drug concentration and long half-life.

[0251] LY3298176 in the following Examples 4-6 is a new drug for type 2 diabetes commercially available tirzepatide. The Vehicle group refers to injection of the corresponding solvent, i.e. the Vehicle group does not contain polypeptide compounds compared with the polypeptide compound drug group.

[0252] It should be noted that the significance level in the following Examples 4-6 is marked as the significance analysis result of each group (LY3298176 group and other polypeptide compound group) compared with the Vehicle group.

[0253] Example 4: Glucose tolerance evaluation in normal C57BL / 6 mice

[0254] This example evaluates the effects of HEC-PT74, HEC-PT75, HEC-PT77, HEC-PT78, HEC-PT80, and HEC-PT82 on glucose tolerance in normal C57BL / 6 mice.

[0255] Experimental method: Normal C57BL / 6 mice were randomly divided into 8 groups (Vehicle group, LY3298176 group, HEC-PT74 group, HEC-PT75 group, HEC-PT77 group, HEC-PT78 group, HEC-PT80 group, and HEC-PT82 group) according to blood glucose and body weight, with 8 mice in each group. For the LY3298176 group, HEC-PT74 group, HEC-PT75 group, HEC-PT77 group, HEC-PT78 group, HEC-PT80 group, and HEC-PT82 group, each animal was subcutaneously injected with the corresponding drug, and the dose was 3 nmol / kg. For the Vehicle group, the corresponding solvent (i.e. PBS solution) was subcutaneously injected. 12 hours after single administration, the animals were fasted for 12 hours and allowed to drink water freely. The blood glucose baseline value of each group of animals was determined by tail vein blood sampling, and then 2 g / kg of glucose solution was intraperitoneally injected, and blood glucose was detected at 15, 30, 60, and 90 min after glucose administration. According to the blood glucose values determined at different time points, the blood glucose concentration-time curve was drawn, and the AUC 0～90min As shown in Tables 4 and Figure 1

[0256] Table 4: Effects of HEC-PT74, HEC-PT75, HEC-PT77, HEC-PT78, HEC-PT80, and HEC-PT82 on glucose tolerance in normal C57 mice 24 hours after single administration

[0257]

[0258] Note: The same column with lowercase letters indicates a significant difference (P < 0.05) compared with the Vehicle group.

[0259] ​Experimental conclusion: After single administration for 24h, each administration group can improve the glucose tolerance of normal C57 mice. Among them, HEC-PT75, HEC-PT80 and HEC-PT82 are better than the positive control LY3298176 in improving glucose tolerance.

[0260] Example 5: Glucose tolerance evaluation in normal C57BL / 6 mice

[0261] This example evaluates the effects of HEC-PT86, HEC-PT96, HEC-PT112, HEC-PT113, HEC-PT114 and HEC-PT119 on the glucose tolerance of normal C57BL / 6 mice.

[0262] Experimental method: Normal C57BL / 6 mice were randomly divided into 8 groups (Vehicle group, LY3298176 group, HEC-PT86 group, HEC-PT96 group, HEC-PT112 group, HEC-PT113 group, HEC-PT114 group, HEC-PT119 group) according to blood glucose and body weight, 8 in each group. For LY3298176 group, HEC-PT86 group, HEC-PT96 group, HEC-PT112 group, HEC-PT113 group, HEC-PT114 group, HEC-PT119 group, each animal was subcutaneously injected with the corresponding drug, and the dose was 3 nmol / kg. For the control group, the corresponding vehicle was subcutaneously injected. After single administration for 12h, the animals were fasted for 12h and free water. The blood glucose of each group of animals was determined by tail vein blood sampling, then 2g / kg of glucose solution was intraperitoneally injected, and the blood glucose was detected at 15, 30, 60 and 90min after administration. According to the blood glucose values measured at different time points, the blood glucose concentration-time curve was drawn, and the AUC 0～90min As shown in Table 5 and Figure 2 .

[0263] Table 5: Effects of HEC-PT86, HEC-PT96, HEC-PT112, HEC-PT113, HEC-PT114 and HEC-PT119 on glucose tolerance of normal C57 mice after single administration for 24h

[0264]

[0265] Note: The same column with lowercase letters indicates significant difference (P<0.05) compared with the Vehicle group.

[0266] Experimental conclusion: After single administration for 24h, each administration group can improve the glucose tolerance of normal C57 mice. Among them, HEC-PT112 and HEC-PT113 are better than the positive control LY3298176.

[0267] Example 6: In vivo efficacy evaluation in db / db mouse model

[0268] This example evaluates the effect of HEC-PT74, HEC-PT77, HEC-PT85, HEC-PT86 on blood glucose in db / db mice.

[0269] Experimental method: 7-8 week old db / db mice were randomly divided into 6 groups (Vehicle group, LY3298176 group, HEC-PT74 group, HEC-PT77 group, HEC-PT85 group, HEC-PT86 group) according to blood glucose and body weight values, 9 mice per group. For LY3298176 group, HEC-PT74 group, HEC-PT77 group, HEC-PT85 group and HEC-PT86 group, each animal was subcutaneously injected with the corresponding drug, and the dose of each administration was 10 nmol / kg, and the administration was performed every three days; for the Vehicle group, the corresponding solvent was subcutaneously injected. Animal blood glucose was detected before each administration.

[0270] Experimental results: HEC-PT74, HEC-PT77, HEC-PT85, HEC-PT86 groups can significantly reduce blood glucose after administration, and the blood glucose value reaches the lowest level at about 24h, and the effect is slightly better than that of the same dose of positive control LY3298176. Compared with Vehicle, the blood glucose value of HEC-PT86 group mice was significantly reduced after long-term repeated administration, and remained stable for a long time, and the hypoglycemic effect was better than that of LY3298176 group, and the specific data are shown in Table 6 and Figures 3-4 .

[0271] Table 6: Effect of long-term administration of HEC-PT74, HEC-PT77, HEC-PT85, HEC-PT86 on blood glucose of db / db mice

[0272]

[0273] Note: The same column with lowercase letters indicates significant difference (P<0.05) compared with the Vehicle group

[0274] Experimental conclusion: Long-term administration of HEC-PT74, HEC-PT77, HEC-PT85, HEC-PT86 can significantly improve the blood glucose level of type II diabetes model db / db mice, and the hypoglycemic level is not inferior to that of positive control LY3298176. Among them, HEC-PT86 has better hypoglycemic effect than LY3298176, and there is a statistical difference.

[0275] Example 7: Study in diet-induced obese C57BL / 6 mice (DIO)

[0276] This example evaluates the effects of long-term repeated administration of HEC-PT77, HEC-PT86 and HEC-PT112 on body weight and food intake of DIO obese mice.

[0277] Experimental method: C57 / BL6 mice were randomly divided into normal group NFD and model group HFD at the age of five weeks. The normal group was fed with ordinary maintenance feed, and the other groups were fed with high-fat feed D12492. The body weight and food intake of the mice were monitored every 3 weeks. After 16 weeks of feeding, the body weight of the model group and the normal group mice was (49.0 ± 2.3) g and (31.0 ± 2.0) g, respectively, and the difference between the two groups was statistically significant. The normal group was divided into Control group, and the model mice were divided into Vehicle group, Semaglutide group, LY3298176 group, HEC-PT77 group, HEC-PT86 group and HEC-PT112 group, 10 mice in each group. For Semaglutide group, LY3298176 group, HEC-PT77 group, HEC-PT86 group and HEC-PT112 group, each animal was subcutaneously injected with the corresponding drug; for Vehicle group, PBS was subcutaneously injected. After the first administration, 4 days of observation were carried out, and then each group was administered once every 3 days, and the dose of each group was 10 nmol / kg. Body weight and food intake were detected before each administration. After 3 weeks of administration, intraperitoneal glucose tolerance test was performed. The samples were collected 72 hours after the last administration, the liver weight was recorded, and the liver pathological condition and blood biochemical indicators of each group were detected. The test results are shown in Tables 7-10 and Figure 5 -6.

[0278] Among them, Semaglutide is a commercially available semaglutide.

[0279] Table 7: Effects of long-term administration of HEC-PT77, HEC-PT86 and HEC-PT112 on body weight of DIO mice

[0280]

[0281] Note: The same column with lowercase letters indicates a significant difference (P < 0.05) compared with the Vehicle group.

[0282] Table 8: Effects of long-term administration of HEC-PT77, HEC-PT86 and HEC-PT112 on food intake of DIO mice

[0283]

[0284]

[0285] Note: same column, different superscript lowercase letters indicate significant difference (P < 0.05) compared with the Vehicle group.

[0286] Table 9: Effects of HEC-PT77, HEC-PT86 and HEC-PT112 long-term administration on body weight and liver index of DIO mice

[0287] Group Body mass / g Liver / g Liver index / % Control 29.7 ± 1.8 a ]] 1.1 ± 0.1 a ]] 3.8 ± 0.0 a ]] Vehicle 48.1±2.6 2.2±0.4 4.6±0.0 Semaglutide 38.3 ± 2.9 a ]] 1.1 ± 0.1 a ]] 3.0 ± 0.0 a ]] LY3298176 32.6 ± 3.9 a ]] 1.0 ± 0.1 a ]] 3.0 ± 0.0 a ]] HEC-PT77 31.5 ± 3.2 a ]] 0.9 ± 0.1 a ]] 2.7 ± 0.0 a ]] HEC-PT86 32.3 ± 4.4 a ]] 0.9 ± 0.1 a ]] 2.7 ± 0.0 a ]] HEC-PT112 29.7 ± 2.5 a ]] 0.9 ± 0.1 a ]] 3.0 ± 0.0 a ]]

[0288] Note: same column, different superscript lowercase letters indicate significant difference (P < 0.05) compared with the Vehicle group.

[0289] Table 10: Effects of HEC-PT77, HEC-PT86 and HEC-PT112 long-term administration on liver function and blood lipids of DIO mice

[0290]

[0291] Note: same column, different superscript lowercase letters indicate significant difference (P < 0.05) compared with the Vehicle group.

[0292] Experimental results: after 4 weeks of administration, the weight loss and food intake inhibition effects of HEC-PT77 and HEC-PT86 were comparable to those of LY3298176, and superior to those of Semaglutide. The weight loss effect of HEC-PT112 was significantly better than that of LY3298176, and there was also a certain advantage in food intake inhibition. HEC-PT77, HEC-PT86 and HEC-PT112 also had obvious improvement on the liver function and blood lipids of DIO mice, and the effects were similar to those of LY3298176.

[0293] In the description of the present specification, the description of the terms "one embodiment", "some embodiments", "an example", "a specific example", or "some examples" and the like means that the specific features, structures, materials or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present application. In the present specification, the illustrative description of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any appropriate manner in any one or more embodiments or examples. In addition, different embodiments or examples described in the present specification and the features of different embodiments or examples can be combined and combined by those skilled in the art without contradiction.

[0294] Although the embodiments of the present application have been shown and described above, it is understood that the above-described embodiments are exemplary and are not to be construed as limiting the present application, and those skilled in the art can make changes, modifications, replacements and variations to the above-described embodiments within the scope of the present application.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof, characterized in that: X1X2X3GTX6TSDYSIX 13 X 14 DX 16 X 17 X 18 X 19 X 20 X 21 FX 23 X 24 X 25 LX 27 X 28 GGPSSGAPPPS (I)， Wherein, X1 is Y or H; X2 is Aib; X3 is Q or H; X6 is an unnatural amino acid; X 13 is L or Y; X 14 is L or K; X 16 is E, K or R; X 17 is K, R or I; X 18 A, R or K; X 19 Q or A; X 20 is R, K, Q, H or Aib; X 21 is D, A or E; X 23 I or V; X 24 is E or Q; X 25 is W or Y; X 27 I or L; X 28 is E or A; Among them, X 16 When K, X 14 For K.

2. The compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, characterized in that X1 is Y; X2 is Aib; X3 is Q or H; X6 is αMeF(2F); X 13 is L; X 14 is L or K; X 16 is E or K; X 17 is K or I; X 18 A or R; X 19 is Q; X 20 is R, Q or Aib; X 21 A or E; X 23 For I; X 24 is E; X 25 is W or Y; X 27 is L; X 28 is E or A; Among them, X 16 When K, X 14 For K.

3. The compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, characterized in that The compound represented by formula (I) has at least one of the following structures: Y-Aib-QGTX6TSDYSILLDEKAQRDFIEWLLEGPGPSSGAPPPS; Y-Aib-HGTX6TSDYSILLDEKAQRDFIEWLLAGPGPSSGAPPPS; Y-Aib-HGTX6TSDYSILLDEIAQKDFIEWLLEGPSSGAPPPS; H-Aib-QGTX6TSDYSILLDEIAQKDFIEWLLEGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDEKAQQAFIEYLLEGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDEKAQQDFIEWLIAGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDERAAKEFIEWLLEGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDERAAKEFIEWLIAGGPSSGAPPPS; Y-Aib-HGTX6TSDYSILLDEKAQREFIEWLLAGGPSSGAPPPS; Y-Aib-HGTX6TSDYSILLDEKAQRAFIEYLLAGGPSSGAPPPS; Y-Aib-HGTX6TSDYSILLDEKAQREFIEWLLEGPGPSSGAPPPS; Y-Aib-HGTX6TSDYSILLDEKRQREFIEWLLAGPGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDEKAQQEFIEWLLEGPGPSSGAPPPS; Y-Aib-HGTX6TSDYSILLDEKAQQEFIEWLLAGGPSSGAPPPS; Y-Aib-HGTX6TSDYSILLDEKAQQAFIEYLLAGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDEKRQQAFIEYLLEGPGPSSGAPPPS; Y-Aib-HGTX6TSDYSILLDEKAQRAFIEYLLEGPGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDEKAQRAFIEYLLEGPGPSSGAPPPS; Y-Aib-HGTX6TSDYSILLDEKRQREFIEWLLEGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDEKRARAFIEYLLAGGPSSGAPPPS; Y-Aib-HGTX6TSDYSILLDEKRAREFIEWLLEGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDEKAQQEFIEWLLAGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDEKAQQEFIEWLIAGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDEKAQQAFVQWLIAGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDEKRAQAFIEYLLEGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDEKAQRAFIEYLLAGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDEIAQKAFIEYLLAGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDEIAQKAFIEYLIAGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDEIAQKAFVQWLIAGGPSSGAPPPS; Y-Aib-HGTX6TSDYSILLDEKAQ-Aib-EFIEWLLAGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDEKAQ-Aib-AFIEYLLAGGPSSGAPPPS; Y-Aib-HGTX6TSDYSILLDEKRQ-Aib-EFIEWLLAGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDEKRQ-Aib-EFIEWLLAGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDEKRQ-Aib-AFIEYLLAGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILKDKIAQQAFIEYLLEGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILKDKIAQ-Aib-AFIEYLLEGGPSSGAPPPS; Y-Aib-HGTX6TSDYSILLDEKRQQAFIEYLLEGGPSSGAPPPS; Y-Aib-HGTX6TSDYSILLDEKRQRAFIEYLLAGGPSSGAPPPS; Y-Aib-HGTX6TSDYSILLDEKRQRAFIEYLLEGGPSSGAPPPS; Y-Aib-HGTX6TSDYSILLDEKRQKAFIEYLLAGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILKDKIAQQAFIEYLLAGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDEKRQRAFIEYLLEGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDRIRQKEFIEWLLAGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDRIRQKAFIEYLLEGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDRKRQQEFIEWLLAGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDRKRQQAFIEYLLAGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDEKKQ-Aib-EFIEWLLAGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDEKKQKAFIEYLLAGGPSSGAPPPS; H-Aib-QGTX6TSDYSILLDEKRQRAFIEYLLAGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDEKRQRAFIEYLLAGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDEKRQRAFVEYLLAGGPSSGAPPPS; Y-Aib-QGTX6TSDYSIYLDEKAQRAFIEYLLAGGPSSGAPPPS; Y-Aib-QGTX6TSDYSIYLDEKAQRAFIEYLLEGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILKDKIAQ-Aib-AFIEYLLAGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILKDKIAQKAFIEYLLAGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILKDKIAQKAFIEYLLEGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILKDRIAQRAFIEYLLEGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILKDKIRQQAFIEYLLEGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILKDKIRQ-Aib-AFIEYLLEGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILKDKIRQ-Aib-AFIEYLLAGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILKDRIRQQAFIEYLLEGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILKDRIRQQAFIEYLLAGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILKDRRAQQAFVEYLLAGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILKDRRAQQAFVEYLLEGGPSSGAPPPS; H-Aib-QGTX6TSDYSILLDEKRQQAFIEYLLEGGPSSGAPPPS; H-Aib-QGTX6TSDYSILLDEKRQQAFIEYLLAGGPSSGAPPPS; H-Aib-HGTX6TSDYSILLDRKAQHAFIEYLLEGPGPSSGAPPPS; H-Aib-HGTX6TSDYSILLDRKAQQAFIEYLLAGGPSSGAPPPS; H-Aib-HGTX6TSDYSILLDRKAQHAFIEYLLAGGPSSGAPPPS; H-Aib-QGTX6TSDYSILLDRKAQHAFIEYLLAGGPSSGAPPPS; H-Aib-QGTX6TSDYSILLDRKAQHEFIEWLLEGPGPSSGAPPPS; Wherein, X6 is αMeF(2F).

4. The compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, characterized in that Further comprising a modifying group, said modifying group and X 14 、X 17 and X 20 At least one of the amino acids is connected.

5. The compound according to claim 4, or a pharmaceutically acceptable salt or solvate thereof, characterized in that X 14 、X 17 and X 20 At least one of them is K, and the modifying group and X 14 、X 17 and X 20 The ε-amino group of at least one of the K side chains is connected via an amide bond; Preferably, X 14 and / or X 17 is K, the modifying group and X 14 and / or X 17 The ε-amino group of the K side chain is connected via an amide bond.

6. The compound according to claim 4, or a pharmaceutically acceptable salt or solvate thereof, characterized in that The modifying group has the following structure: {[2-(2-Amino-ethoxy)-ethoxy]-acetyl} a -(γGlu) b -CO-(CH2) c -CO2H, Wherein, a is any integer from 1 to 3, b is any integer from 1 to 3, and c is any integer from 14 to 20; Preferably, the modifying group has at least one of the following structures:

7. The compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, characterized in that The C-terminus of the amino acid S at position 39 of the compound represented by formula (I) is amidated.

8. The compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, characterized in that The compound represented by formula (I) has at least one of the following structures: Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)AQRDFIEWLLEGPSSGAPPPS; Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)AQRDFIEWLLAGPGPSSGAPPPS; Y-Aib-HGTX6TSDYSILLDEIAQ-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}2-γGlu-CO-(CH2) 18 -CO2H)DFIEWLLEGGPSSGAPPPS; H-Aib-QGTX6TSDYSILLDEIAQ-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}2-γGlu-CO-(CH2) 18 -CO2H)DFIEWLLEGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)AQQAFIEYLLEGPGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)AQQDFIEWLIAGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDERAA-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}2-γGlu-CO-(CH2) 18 -CO2H)EFIEWLLEGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDERAA-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}2-γGlu-CO-(CH2) 18 -CO2H)EFIEWLIAGGPSSGAPPPS; Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)AQREFIEWLLAGPGPSSGAPPPS; Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)AQRAFIEYLLAGPGPSSGAPPPS; Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)AQREFIEWLLEGPSSGAPPPS; Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)RQREFIEWLLAGPGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)AQQEFIEWLLEGPGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)AQQEFIEWLLEGPGPSSGAPPPS; Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)AQQEFIEWLLAGPGPSSGAPPPS; Y-Aib-HGTX6TSDYSILLDE-K(-{[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)AQQAFIEYLLAGPGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)RQQAFIEYLLEGPGPSSGAPPPS; Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)AQRAFIEYLLAGGPSSGAPPPS; Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)AQRAFIEYLLEGPGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)AQRAFIEYLLEGPGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)RQRAFIEYLLAGPGPSSGAPPPS; Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)RQREFIEWLLEGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)RARAFIEYLLAGPGPSSGAPPPS; Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)RAREFIEWLLEGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)AQQEFIEWLLAGPGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)AQQEFIEWLIAGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)AQQAFVQWLIAGGPSSGAPPPS; Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)RQQAFIEYLLEGPGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)RAQAFIEYLLEGPGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)AQRAFIEYLLAGGPSSGAPPPS; Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)RQREFIEWLLAGPGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)RQRAFIEYLLEGPGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDEIAQ-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}2-γGlu-CO-(CH2) 18 -CO2H)AFIEYLLAGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDEIAQ-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}2-γGlu-CO-(CH2) 18 -CO2H)AFIEYLIAGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDEIAQ-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}2-γGlu-CO-(CH2) 18 -CO2H)AFVQWLIAGGPSSGAPPPS; Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)AQ-Aib-EFIEWLLAGPGPSSGAPPPS-NH2; Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)AQ-Aib-AFIEYLLAGGPSSGAPPPS-NH2; Y-Aib-HGTX6TSDYSILLDEK({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)RQ-Aib-EFIEWLLAGPGPSSGAPPPS-NH2; Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)RQ-Aib-EFIEWLLAGPGPSSGAPPPS-NH2; Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)RQ-Aib-AFIEYLLAGGPSSGAPPPS-NH2; Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)DKIAQQAFIEYLLEGPGPSSGAPPPS-NH2; Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)DKIAQ-Aib-AFIEYLLEGPSSGAPPPS-NH2; Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)RQQAFIEYLLEGPGPSSGAPPPS; Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)RQRAFIEYLLAGPGPSSGAPPPS; Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)RQRAFIEYLLEGPGPSSGAPPPS; Y-Aib-HGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)RQKAFIEYLLAGPGPSSGAPPPS-NH2; Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)DKIAQQAFIEYLLAGGPSSGAPPPS-NH2; Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)RQRAFIEYLLEGPGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDRIRQ-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 CO2H)EFIEWLLAGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDRIRQ-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)AFIEYLLEGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDR-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)RQQEFIEWLLAGPGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDR-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)RQQAFIEYLLAGGGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)KQ-Aib-EFIEWLLAGPGPSSGAPPPS-NH2; Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)KQKAFIEYLLAGPGPSSGAPPPS-NH2; Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)KQKAFIEYLLAGPGPSSGAPPPS-NH2; Y-Aib-QGTX6TSDYSILLDEKKQ-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)AFIEYLLAGPGPSSGAPPPS-NH2; H-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)RQRAFIEYLLAGPGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)RQRAFIEYLLAGPGPSSGAPPPS; Y-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)RQRAFVEYLLAGGPSSGAPPPS; Y-Aib-QGTX6TSDYSIYLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)AQRAFIEYLLAGPGPSSGAPPPS; Y-Aib-QGTX6TSDYSIYLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)AQRAFIEYLLEGPGPSSGAPPPS; Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)DKIAQ-Aib-AFIEYLLAGGPSSGAPPPS-NH2; Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)DKIAQ-Aib-AFIEYLLAGGPSSGAPPPS-NH2; Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)DKIAQKAFIEYLLAGGPSSGAPPPS-NH2; Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)DKIAQKAFIEYLLEGPGPSSGAPPPS-NH2; Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)DRIAQRAFIEYLLEGPGPSSGAPPPS; Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)DKIRQQAFIEYLLEGPGPSSGAPPPS-NH2; Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)DKIRQ-Aib-AFIEYLLEGPSSGAPPPS-NH2; Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)DKIRQ-Aib-AFIEYLLAGGPSSGAPPPS-NH2; Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)DRIRQQAFIEYLLEGPGPSSGAPPPS; Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)DRIRQQAFIEYLLAGGPSSGAPPPS; Y-Aib-QGTX6TSDYSIL-K(-{[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)DRRAQQAFVEYLLAGGPSSGAPPPS; Y-Aib-QGTX6TSDYSIL-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)DRRAQQAFVEYLLEGPGPSSGAPPPS; H-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)RQQAFIEYLLEGPGPSSGAPPPS; H-Aib-QGTX6TSDYSILLDE-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)RQQAFIEYLLAGGGPSSGAPPPS; H-Aib-HGTX6TSDYSILLDR-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)AQHAFIEYLLEGPGPSSGAPPPS; H-Aib-HGTX6TSDYSILLDR-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)AQQAFIEYLLAGPGPSSGAPPPS; H-Aib-HGTX6TSDYSILLDR-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 18 -CO2H)AQHAFIEYLLAGPGPSSGAPPPS; H-Aib-QGTX6TSDYSILLDR-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)AQHAFIEYLLAGPGPSSGAPPPS; H-Aib-QGTX6TSDYSILLDR-K({[2-(2-amino-ethoxy)-ethoxy]-acetyl}-γGlu-CO-(CH2) 16 -CO2H)AQHEFIEWLLEGPSSGAPPPS; Wherein, X6 is αMeF(2F).

9. A pharmaceutical composition, characterized in that The invention comprises the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt or solvate thereof.

10. The pharmaceutical composition according to claim 9, characterized in that Further includes pharmaceutically acceptable excipients.

11. Use of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition according to any one of claims 9 to 10, in the preparation of a medicament for treating or preventing diseases related to metabolic disorders.

12. The use according to claim 11, characterized in that The metabolic disorder-related diseases include at least one of obesity, diabetes, dyslipidemia-related diseases, fatty liver disease, metabolic syndrome and non-alcoholic fatty liver disease.

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