Novel polypeptides and therapeutic uses thereof

Abstract

The present application relates to the field of polypeptide chemistry, and in particular to a polypeptide compound and its use in medicine.

Description

Technical Field

[0001] This invention relates to a polypeptide compound and its use in medicine. Background of the Invention Metabolic syndrome is a combination of medical conditions that increase the risk of developing type 2 diabetes, atherosclerotic vascular disease, heart disease, and stroke. Medical parameters defining metabolic syndrome include diabetes, impaired glucose tolerance, elevated fasting blood glucose, insulin resistance, central obesity, hypertension, elevated total cholesterol and triglycerides, elevated LDL cholesterol, and decreased HDL cholesterol. Diabetes includes type 1 diabetes, type 2 diabetes, and gestational diabetes. The greatest dangers of diabetes lie primarily in its severe complications and high mortality rate. Data shows that diabetes is the leading cause of lower limb amputation and new-onset blindness in adults.

[0003] Obesity is a medical condition; the accumulation of excess body fat can adversely affect health and life expectancy, and due to its increasing prevalence in adults and children, it has become one of the leading causes of preventable death in modern times. It increases the likelihood of various other diseases, including heart disease, type 2 diabetes, obstructive sleep apnea, certain types of cancer, and osteoarthritis. It is typically caused by a combination of factors, including excessive food intake, reduced energy expenditure, and genetic predisposition. At the same body mass index (BMI), Asians have higher visceral fat levels than Caucasians, resulting in greater insulin resistance. Asians with normal weight and type 2 diabetes have significantly lower insulin sensitivity than non-diabetic individuals. Excess fat leads to insulin resistance and damage to beta cells, impairing glucose regulation. Multiple obesity-related metabolic abnormalities significantly increase the risk of cardiovascular disease. Clinical statistics show that over 70% of type 2 diabetes cases are caused by being overweight. Therefore, reducing weight and body fat in diabetic patients is a crucial way to effectively control and even reverse the progression of diabetes. However, existing small-molecule weight-loss drugs have significant side effects. Glucagon-like peptide-1 (GLP-1) receptor agonists control blood sugar by promoting insulin secretion, improving insulin sensitivity, and reducing glucagon release. Therefore, GLP-1 drugs are suitable for treating metabolic diseases, especially diabetes. GLP-1 receptor agonists such as exenatide and liraglutide have shown weight-reducing effects in animal studies and clinical trials, with relatively few side effects. Liraglutide has been approved in the United States for the treatment of diabetes and obesity, making it the only drug approved for these two conditions.

[0004] However, existing GLP-1 inhibitors all have significant gastrointestinal side effects. These side effects affect patient adherence, reducing the dosage and user base. Based on the physiological mechanism of the GLP-1 receptor, GLP-1 drugs have a slow effect on weight loss, requiring higher doses than those used for diabetes treatment in clinical practice, leading to more pronounced gastrointestinal side effects. Most patients experience an average weight loss of less than 5%, and weight rebound is significant after discontinuation of the medication.

[0005] Therefore, there is a clinical need for drugs that can lower blood sugar, reduce blood lipids and body fat, and reduce weight.

[0006] Patients with diabetes have a higher risk of cardiovascular disease; therefore, they need to strictly control their blood lipid levels. Clinical studies have shown that long-term use of statins may increase the risk of diabetes. Statins and fibrates have significant side effects and both have individuals who are intolerant. Currently, there are no ideal treatments for non-alcoholic fatty liver disease. The polypeptide compounds of this invention can not only lower blood sugar but also significantly reduce triglycerides and total cholesterol, especially low-density cholesterol (LDL), potentially addressing both high blood sugar and high blood lipids in the "three highs" simultaneously, and are expected to have significant benefits for the cardiovascular health of users. The polypeptides of this invention are more suitable for diabetic patients or those with prediabetes than statins. The polypeptides of this invention can provide new treatment options for these diseases. The polypeptides of this invention are applicable to various diseases caused by abnormal lipid metabolism, including hyperlipidemia and non-alcoholic fatty liver disease. The polypeptides of this invention can also be used for hypertension, arteriosclerosis, coronary heart disease, peripheral artery disease, stroke, or any combination of these diseases.

[0007] Most diabetic patients are middle-aged or elderly and need to take multiple medications. This inevitably involves the compatibility and matching of drugs. Besides drug cross-reactions and the potential for increased toxic side effects from multiple medications, the different durations of action and frequencies of administration of different drugs also add to the inconvenience for patients. Therefore, the polypeptides of this invention not only enhance efficacy and reduce toxic side effects but also provide convenience for patients, thereby improving treatment outcomes.

[0008] The peptides of this invention can also be used to treat diabetes, similar to GLP-1 inhibitors. Because these peptides reduce weight and body fat and improve insulin resistance, they not only have excellent hypoglycemic effects but should also be particularly effective for a high proportion of diabetic patients who are overweight. Many overweight or obese individuals, although not medically diagnosed with diabetes, exhibit prediabetic symptoms such as impaired glucose tolerance and excessively high postprandial blood glucose; the peptides of this invention are also suitable for people with prediabetes. Summary of the Invention

[0009] In one aspect, the present invention relates to a peptide compound having formula (I) or a pharmaceutically acceptable salt or solvate thereof. Y-aib-EGTFTSD-X1-S-X11-X2-X12-E-X3-X4-A-X5-X6-X13-F-X7-X8-WL-X9-X14-G-X10 (I) Wherein, X1 represents an amino acid residue selected from L, K, C, or Y, or formula (II), or formula (III); X2 represents an amino acid residue selected from Q, A, aib, or Y; X3 represents an amino acid residue selected from E, C, or K, or formula (II), or formula (III); X4 represents an amino acid residue selected from E, C, or K, or formula (II), or formula (III); X5 represents an amino acid residue selected from V or A; X6 represents an amino acid residue selected from K, R, C, or Q, or formula (II), or formula (III); X7 represents an amino acid residue selected from I or V; X8 represents an amino acid residue selected from E, Q, N, K, X9 represents an amino acid residue selected from I, L, C, or K, or formula (II) or formula (III); X10 represents the absence of or GPSSGAPPP, GPPSGAPPP, GPSSGKPPP, GPSSGEPPP, GPSSaibAPPP, GPSSGAPP, GPSSGAP, GPSSGA, GPSSG, GPSS, GPS, GP, G; X11 represents an amino acid residue selected from I, C, S, or K, or formula (II) or formula (III); X12 represents an amino acid residue selected from L, C, or K, or formula (II) or formula (III); X13 represents an amino acid residue selected from L, E, or D; X14 represents an amino acid residue selected from A, C, K, or R, or formula (II) or formula (III); The structure of formula (II) or formula (III) is as follows: (II) or (III), The wavy line represents the connection point to the adjacent group, and n1 is an integer from 1 to 7. Optionally, in formula (II), the amino acid residue containing a side-chain amino group is modified with a long-acting group at its side-chain amino group, and in formula (III), the amino acid residue containing a side-chain thiol group is modified with a long-acting group at its side-chain thiol group; preferably, formula (II) is a lysine residue, and formula (III) is a cysteine ​​residue. Optionally, one or two amino acids selected from S or containing an amino or thiol group in the side chain are added to the C-terminus of X10, and the carboxyl group of the C-terminal amino acid is optionally amidated to a C-terminal amide, wherein the amino or thiol group containing the side chain has the structure shown in formula (II) or formula (III); when formula (II) or formula (III) is a C-terminal amino acid, its carboxyl group is COOH or CONH2, preferably, formula (II) is lysine and formula (III) is cysteine; Preferably, the long-lasting group has the structure of formula (IV): O1-O2-O3-O4-O5-O6-O7-O8- (IV), Where O1 represents the structure of formula (V) or (VI): (V) or (VI) Where n2 is an integer between 6 and 24, preferably between 10 and 24, and even more preferably between 16 and 22; Wherein the wavy line represents the linking point of an amino group connected to an adjacent group, O2-O3-O4-O5-O6-O7-O8- represents a linker, wherein each of O2 to O8 is independently represented by any one of the following amino acid residues or long chain structures: α-Glu, γ-Glu, α-Asp, β-Asp, α-hGlu, δ-hGlu, Gly, Ala, β-Ala, GABA or PEG2, or one or more of O2 to O8 are absent, provided that at least two of O2 to O8 are present, preferably, O2 to O8 contain at least one negatively charged portion.

[0010] According to any of the preceding aspects of the peptide compound, wherein O2-O3-O4-O5-O6-O7-O8- represents a linker selected from the group consisting of: γGlu-PEG2-γGlu-, γGlu-PEG2-2×γGlu-, γGlu-PEG2-, γGlu-2×PEG2-, γGlu-3×PEG2-, γGlu-PEG2-γGlu-PEG2-, γGlu-2×PEG2-γGlu-, γGlu-2×PEG2-2×γGlu-, 2×γGlu-, 2×γGlu-PEG2-, 2×γGlu-PEG2-γGlu-, 2×γGlu-PEG2-γGlu-, 2×γGlu-2×PEG2-, 2×γGlu-2×PEG2-γGlu-, 2×γGlu-2×PEG2-2×γGlu-.

[0011] According to the peptide compounds of the foregoing aspects, in some embodiments, O2-O3-O4-O5-O6-O7-O8- represents the linker γGlu-PEG2-, γGlu-2×PEG2-, γGlu-3×PEG2- selected from the group consisting of, and O1 represents the structure of formula (V) or (VI).

[0012] According to the peptide compounds of the foregoing aspects, in some embodiments, O2-O3-O4-O5-O6-O7-O8- represents the linker γGlu-PEG2-, γGlu-2×PEG2-, γGlu-3×PEG2- selected from the group consisting of, and O1 represents the structure of formula (V).

[0013] According to the peptide compounds of the foregoing aspects, in some embodiments, O2-O3-O4-O5-O6-O7-O8- represents the linker γGlu-2×PEG2-, γGlu-3×PEG2- selected from the group consisting of, and O1 represents the structure of formula (V).

[0014] According to the peptide compounds of the foregoing aspects, in some embodiments, O2-O3-O4-O5-O6-O7-O8- represents the linker γGlu-2×PEG2-, and O1 represents the structure of formula (V).

[0015] According to the peptide compounds of the foregoing aspects, in some embodiments, O2-O3-O4-O5-O6-O7-O8- represents the linker γGlu-2×PEG2-, O1 represents the structure of formula (V), and n2 is an integer from 16 to 22.

[0016] In some embodiments, the lysine side chain is conjugated with an amino group, and in this application, this molecular structure is simply referred to as K(x18), having the structure of formula (VII): (VII); In some embodiments, the lysine side chain is conjugated with a long-acting group. In this application, this molecular structure is simply referred to as K(x20) and has the structure of formula (VIII): (VIII); The wavy line represents the connection point to the adjacent amino acid residue.

[0017] Optionally, the C-terminal amino acid containing a side-chain thiol group added to X10 has its side-chain thiol group modified by a long-acting group of formula (IV). Optionally, a reactive group capable of reacting with the thiol group to form a covalent bond can be added between the side-chain thiol group and the long-acting group of the C-terminal amino acid as needed.

[0018] In some embodiments, the linking relationship between the side chain thiol of the amino acid containing the side chain thiol and the long-acting group is: side chain thiol of the amino acid containing the side chain thiol - thiol reactive group - optional linking group L - long-acting group.

[0019] In some embodiments, the side chain thiol of the amino acid containing the side chain thiol is attached to one end of the linking group L after reacting with a Michael reaction acceptor (e.g., maleimide or vinyl sulfone) or a thiol reactive group (e.g., iodoacetic acid or bromoacetic acid). Preferably, the other end of the linking group L is further covalently attached to a long-acting group of formula IV.

[0020] In some embodiments, the linking group L is -(CH2). n3 - and -(CH2CH2O) n4 -A long chain formed by arranging and combining elements according to structural needs, linked together by covalent bonds; or -(CH2) n3 -、-(CH2CH2O) n4 - Optionally, one or both ends of the chain contain amino or carboxyl groups, forming a long chain linked together by amide bonds. For example, the linking group L is selected from -NH-(CH2). n5 -(CH2CH2O) n6 -(CH2) n7 -,-NH-(CH2) n5 -(CH2CH2O) n6 -(CH2) n7 -NH-, -NH-(CH2) n5 -(CH2CH2O) n6 -(CH2) n7 -CO-, -NH-(CH2) n5 -(CH2CH2O) n6 -(CH2) n7 -NHCO-(CH2) n8 -,-NH-(CH2) n5 -(CH2CH2O) n6 -(CH2) n7 -NHCO-(CH2) n8 -NH- or any combination thereof, where n3, n4, n5, n6, n7, and n8 are each integers from 0 to 10, for example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0021] In some implementations, L is -NH-CH2-(CH2CH2O)3-(CH2)3-NH-.

[0022] In some embodiments, non-limiting illustrative examples of the Michael reaction acceptor or thiol reactive group being linked to the linking group L include The structures of the Michael reaction acceptor or thiol reactive group reacting with the side chain thiol group of an amino acid containing a side chain thiol group, as exemplified above, are as follows: The wavy line indicates the connection point with a long-acting group of formula (IV), for example, connected to O8. * indicates the connection point between the side chain thiol group of an amino acid containing a side chain thiol group and the other part of the amino acid.

[0023] Optionally, any amino acid in the polypeptide fragment represented by X10 may be replaced by an amino acid with an amino or thiol group on its side chain, said amino acid having the structure of formula (II) or formula (III). Optionally, the amino acid containing a side chain amino group is modified with a long-acting group on its side chain amino group, preferably having the structure of formula (IV); optionally, the amino acid containing a side chain thiol group is modified with a long-acting group on its side chain thiol group, preferably having the structure of formula (IV); optionally, a reactive group capable of reacting with the thiol group to form a covalent bond may be added between the side chain thiol group and the long-acting group as needed.

[0024] In some embodiments, the cysteine ​​side chain thiol group is conjugated with a long-acting group. In this application, this molecular structure is simply referred to as C(x18), having the structure of formula (IX): (IX); In some embodiments, the cysteine ​​side chain thiol group is conjugated with a long-acting group. In this application, this molecular structure is simply referred to as C(x20), having the structure of formula (X): (X); The wavy line represents the connection point to the adjacent group.

[0025] Optionally, the polypeptide fragments GPPSGAPPP, GPSSGKPPP, GPSSGEPPP, and GPSSaibAPPP represented by X10 can be reduced by 1, 2, 3, 4, 5, 6, 7, or 8 amino acids from the C-terminus to the N-terminus.

[0026] According to any of the foregoing peptide compounds, in some embodiments, X1 is L. According to any of the foregoing peptide compounds, in some embodiments, X1 is Y. According to any of the foregoing peptide compounds, in some embodiments, X1 is K. According to any of the foregoing peptide compounds, in some embodiments, X1 is C.

[0027] According to any of the foregoing peptide compounds, in some embodiments, X2 is Q. According to any of the foregoing peptide compounds, in some embodiments, X2 is Y. According to any of the foregoing peptide compounds, in some embodiments, X2 is A. According to any of the foregoing peptide compounds, in some embodiments, X2 is Aib.

[0028] According to any of the foregoing peptide compounds, in some embodiments, X3 is E. According to any of the foregoing peptide compounds, in some embodiments, X3 is K. According to any of the foregoing peptide compounds, in some embodiments, X3 is C.

[0029] According to any of the foregoing peptide compounds, in some embodiments, X4 is E. According to any of the foregoing peptide compounds, in some embodiments, X4 is K. According to any of the foregoing peptide compounds, in some embodiments, X4 is C.

[0030] According to any of the foregoing aspects of the peptide compound, in some embodiments, X5 is V. According to any of the foregoing aspects of the peptide compound, in some embodiments, X5 is A.

[0031] According to any of the foregoing peptide compounds, in some embodiments, X6 is K. According to any of the foregoing peptide compounds, in some embodiments, X6 is R. According to any of the foregoing peptide compounds, in some embodiments, X6 is Q. According to any of the foregoing peptide compounds, in some embodiments, X6 is C.

[0032] According to any of the foregoing peptide compounds, in some embodiments, X7 is I. According to any of the foregoing peptide compounds, in some embodiments, X7 is V.

[0033] According to any of the foregoing peptide compounds, in some embodiments, X8 is E. According to any of the foregoing peptide compounds, in some embodiments, X8 is N. According to any of the foregoing peptide compounds, in some embodiments, X8 is Q. According to any of the foregoing peptide compounds, in some embodiments, X8 is A. According to any of the foregoing peptide compounds, in some embodiments, X8 is K. According to any of the foregoing peptide compounds, in some embodiments, X8 is C.

[0034] According to any of the foregoing peptide compounds, in some embodiments, X9 is I. According to any of the foregoing peptide compounds, in some embodiments, X9 is L. According to any of the foregoing peptide compounds, in some embodiments, X9 is K. According to any of the foregoing peptide compounds, in some embodiments, X9 is Aib. According to any of the foregoing peptide compounds, in some embodiments, X9 is V.

[0035] In some embodiments of the peptide compound according to any of the foregoing aspects, X10 is absent. In some embodiments of the peptide compound according to any of the foregoing aspects, X10 is GPSSGAPPPSK. In some embodiments of the peptide compound according to any of the foregoing aspects, X10 is GPSSGAPPPSC. In some embodiments of the peptide compound according to any of the foregoing aspects, X10 is GPSSGAPPPS. In some embodiments of the peptide compound according to any of the foregoing aspects, X10 is GPSSGAPPPK. In some embodiments of the peptide compound according to any of the foregoing aspects, X10 is GPSSGAPPPC. In some embodiments of the peptide compound according to any of the foregoing aspects, X10 is GPSSGAPPP. In some embodiments of the peptide compound according to any of the foregoing aspects, X10 is GPSSGAPP. In some embodiments of the peptide compound according to any of the foregoing aspects, X10 is GPSSGAP. In some embodiments of the peptide compound according to any of the foregoing aspects, X10 is GPSS. In some embodiments of the peptide compound according to any of the foregoing aspects, X10 is GPS. According to any of the foregoing peptide compounds, in some embodiments, X10 is GP. According to any of the foregoing peptide compounds, in some embodiments, X10 is G.

[0036] According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L and X10 is GPSSGAPPPS. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L and X10 is GPSSGAPPPK. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L and X10 is GPSSGAPPPC. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L and X10 is GPSSGAPPP. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L and X10 is GPSSGAPP. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L and X10 is GPSSGAP. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L and X10 is GPSSGA. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L and X10 is GPSSG. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L and X10 is GPS. According to any of the foregoing peptide compounds, in some embodiments, X1 is L and X10 is GP. According to any of the foregoing peptide compounds, in some embodiments, X1 is L and X10 is G.

[0037] According to the peptide compound of any of the foregoing aspects, in some embodiments, X2 is Q and X10 is GPSSGAPPPS.

[0038] According to the peptide compound of any of the foregoing aspects, in some embodiments, X2 is Q and X10 is GPSSGAPPPK.

[0039] According to any of the foregoing peptide compounds, in some embodiments, X2 is Q and X10 is GPSSGAPPPC.

[0040] According to any of the foregoing peptide compounds, in some embodiments, X2 is A and X10 is GPSSGAPPPS.

[0041] According to any of the foregoing peptide compounds, in some embodiments, X2 is A and X10 is GPSSGAPPPK.

[0042] According to any of the foregoing peptide compounds, in some embodiments, X2 is A and X10 is GPSSGAPPPC.

[0043] According to any of the foregoing peptide compounds, in some embodiments, X2 is aib and X10 is GPSSGAPPPS.

[0044] According to any of the foregoing peptide compounds, in some embodiments, X2 is aib and X10 is GPSSGAPPPK.

[0045] According to the peptide compound of any of the foregoing aspects, in some embodiments, X2 is aib and X10 is GPSSGAPPPC.

[0046] According to the peptide compound of any of the foregoing aspects, in some embodiments, X2 is Q and X10 is GPSSGAPPP.

[0047] According to any of the foregoing peptide compounds, in some embodiments, X2 is Q and X10 is GPSSGAPP.

[0048] According to any of the foregoing peptide compounds, in some embodiments, X2 is Q and X10 is GPSSGAP.

[0049] According to the peptide compound of any of the foregoing aspects, in some embodiments, X2 is Q and X10 is GPSSGA.

[0050] According to any of the foregoing peptide compounds, in some embodiments, X2 is Q and X10 is GPSSG.

[0051] According to any of the foregoing peptide compounds, in some embodiments, X2 is Q and X10 is GPSS.

[0052] According to the peptide compound of any of the foregoing aspects, in some embodiments, X2 is Q and X10 is GPS.

[0053] According to any of the foregoing peptide compounds, in some embodiments, X2 is Q and X10 is GP.

[0054] According to the peptide compound of any of the foregoing aspects, in some embodiments, X2 is Q and X10 is G.

[0055] According to the peptide compound of any of the foregoing aspects, in some embodiments, X2 is A and X10 is GPSSGAPPP.

[0056] According to any of the foregoing peptide compounds, in some embodiments, X2 is A and X10 is GPSSGAPP.

[0057] According to any of the foregoing peptide compounds, in some embodiments, X2 is A and X10 is GPSSGAP.

[0058] According to any of the foregoing peptide compounds, in some embodiments, X2 is A and X10 is GPSSGA.

[0059] According to any of the foregoing peptide compounds, in some embodiments, X2 is A and X10 is GPSSG.

[0060] According to any of the foregoing peptide compounds, in some embodiments, X2 is A and X10 is GPSS.

[0061] According to any of the foregoing peptide compounds, in some embodiments, X2 is A and X10 is GPS.

[0062] According to the peptide compound of any of the foregoing aspects, in some embodiments, X2 is A and X10 is GP.

[0063] According to any of the foregoing peptide compounds, in some embodiments, X2 is A and X10 is G.

[0064] According to any of the foregoing peptide compounds, in some embodiments, X2 is A and X9 is K.

[0065] According to any of the foregoing peptide compounds, in some embodiments, X2 is aib and X10 is GPSSGAPPP.

[0066] According to any of the foregoing peptide compounds, in some embodiments, X2 is aib and X10 is GPSSGAPP.

[0067] According to any of the foregoing peptide compounds, in some embodiments, X2 is aib and X10 is GPSSGAP.

[0068] According to any of the foregoing peptide compounds, in some embodiments, X2 is aib and X10 is GPSSGA.

[0069] According to the peptide compound of any of the foregoing aspects, in some embodiments, X2 is aib and X10 is GPSSG.

[0070] According to any of the foregoing peptide compounds, in some embodiments, X2 is aib and X10 is GPSS.

[0071] According to any of the foregoing peptide compounds, in some embodiments, X2 is aib and X10 is GPS.

[0072] According to any of the foregoing peptide compounds, in some embodiments, X2 is aib and X10 is GP.

[0073] According to any of the foregoing peptide compounds, in some embodiments, X2 is aib and X10 is G.

[0074] According to any of the foregoing peptide compounds, in some embodiments, X2 is aib and X9 is K.

[0075] According to any of the foregoing peptide compounds, in some embodiments, X2 is Y and X10 is G.

[0076] According to any of the foregoing peptide compounds, in some embodiments, X1 is L and X2 is Q.

[0077] According to any of the foregoing peptide compounds, in some embodiments, X1 is L and X2 is A.

[0078] According to any of the foregoing peptide compounds, in some embodiments, X1 is L and X2 is aib.

[0079] According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is Q, and X10 is GPSSGAPPPS. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is Q, and X10 is GPSSGAPPPK. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is Q, and X10 is GPSSGAPPPC. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is Q, and X10 is GPSSGGAPPP. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is Q, and X10 is GPSSGAP. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is Q, and X10 is GPSSGA. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is Q, and X10 is GPSSG. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is Q, and X10 is GPSS. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is Q, and X10 is GPS. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is Q, and X10 is GP. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is Q, and X10 is G.

[0080] According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, and X10 is GPSSGAPPPS. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, and X10 is GPSSGAPPPK. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, and X10 is GPSSGAPPPC. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, and X10 is GPSSGGAPPP. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, and X10 is GPSSGAP. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, and X10 is GPSSGA. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, and X10 is GPSSG. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, and X10 is GPSS. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, and X10 is GPS. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, and X10 is GP. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, and X10 is G.

[0081] According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is aib, and X10 is GPSSGAPPPS. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is aib, and X10 is GPSSGAPPPK. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is aib, and X10 is GPSSGAPPPC. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is aib, and X10 is GPSSGGAPPP. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is aib, and X10 is GPSSGAP. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is aib, and X10 is GPSSGA. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is aib, and X10 is GPSSG. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is aib, and X10 is GPSS. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is aib, and X10 is GPS. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is aib, and X10 is GP. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is aib, and X10 is G.

[0082] According to any of the foregoing peptide compounds, in some embodiments, X1 is L, X2 is A, and X9 is K.

[0083] According to any of the foregoing peptide compounds, in some embodiments, X1 is L, X2 is aib, and X9 is K.

[0084] According to any of the foregoing peptide compounds, in some embodiments, X1 is L, X2 is Y, and X9 is K.

[0085] According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is Q, X5 is V, and X10 is GPSSGAPPPS. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is Q, X5 is V, and X10 is GPSSGAPPPK. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is Q, X5 is V, and X10 is GPSSGAPPPC.

[0086] According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, X5 is V, and X10 is GPSSGAPPPS. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, X5 is V, and X10 is GPSSGAPPPK. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, X5 is V, and X10 is GPSSGAPPPC.

[0087] According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is aib, X5 is V, and X10 is GPSSGAPPPS. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is aib, X5 is V, and X10 is GPSSGAPPPK. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is aib, X5 is V, and X10 is GPSSGAPPPC.

[0088] According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is Q, X3 is K, X5 is V, and X10 is GPSSGAPPPS. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is Q, X3 is K, X5 is V, and X10 is GPSSGAPPPK. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is Q, X3 is K, X5 is V, and X10 is GPSSGAPPPC.

[0089] According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, X3 is K, X5 is V, and X10 is GPSSGAPPPS. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, X3 is K, X5 is V, and X10 is GPSSGAPPPK. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, X3 is K, X5 is V, and X10 is GPSSGAPPPC.

[0090] According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is aib, X3 is K, X5 is V, and X10 is GPSSGAPPPS. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is aib, X3 is K, X5 is V, and X10 is GPSSGAPPPK. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is aib, X3 is K, X5 is V, and X10 is GPSSGAPPPC.

[0091] According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is Q, X3 is K, X5 is V, X7 is I, and X10 is GPSSGAPPPS. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is Q, X3 is K, X5 is V, X7 is I, and X10 is GPSSGAPPPK. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is Q, X3 is K, X5 is V, X7 is I, and X10 is GPSSGAPPPC.

[0092] According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, X3 is K, X5 is V, X7 is I, and X10 is GPSSGAPPPS. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, X3 is K, X5 is V, X7 is I, and X10 is GPSSGAPPPK. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, X3 is K, X5 is V, X7 is I, and X10 is GPSSGAPPPC.

[0093] According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is aib, X3 is K, X5 is V, X7 is I, and X10 is GPSSGAPPPS. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is aib, X3 is K, X5 is V, X7 is I, and X10 is GPSSGAPPPK. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is aib, X3 is K, X5 is V, X7 is I, and X10 is GPSSGAPPPC.

[0094] According to the peptide compound of any of the foregoing aspects, in some embodiments, X2 is A and X5 is V. According to the peptide compound of any of the foregoing aspects, in some embodiments, X2 is aib and X5 is V. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, and X5 is V. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is aib, and X5 is V. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is aib, X3 is K, and X5 is V. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is aib, X3 is K, and X5 is V.

[0095] According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, X3 is K, X5 is V, and X7 is I. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is aib, X3 is K, X5 is V, and X7 is I.

[0096] According to the peptide compound of any of the foregoing aspects, in some embodiments, X2 is Q and X9 is L. According to the peptide compound of any of the foregoing aspects, in some embodiments, X2 is Q, X9 is L, and X10 is GPSSGAPPPS. According to the peptide compound of any of the foregoing aspects, in some embodiments, X2 is Q, X9 is L, and X10 is GPSSGAPPPK. According to the peptide compound of any of the foregoing aspects, in some embodiments, X2 is Q, X9 is L, and X10 is GPSSGAPPPC.

[0097] According to the peptide compound of any of the foregoing aspects, in some embodiments, X2 is A and X9 is L. According to the peptide compound of any of the foregoing aspects, in some embodiments, X2 is A, X9 is L, and X10 is GPSSGAPPPS. According to the peptide compound of any of the foregoing aspects, in some embodiments, X2 is A, X9 is L, and X10 is GPSSGAPPPK. According to the peptide compound of any of the foregoing aspects, in some embodiments, X2 is A, X9 is L, and X10 is GPSSGAPPPC.

[0098] According to the peptide compound of any of the foregoing aspects, in some embodiments, X2 is aib and X9 is L. According to the peptide compound of any of the foregoing aspects, in some embodiments, X2 is aib, X9 is L, and X10 is GPSSGAPPPS. According to the peptide compound of any of the foregoing aspects, in some embodiments, X2 is aib, X9 is L, and X10 is GPSSGAPPPK. According to the peptide compound of any of the foregoing aspects, in some embodiments, X2 is aib, X9 is L, and X10 is GPSSGAPPPC.

[0099] According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is Q, X9 is L, and X10 is GPSSGAPPPS. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is Q, X9 is L, and X10 is GPSSGAPPPK. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is Q, X9 is L, and X10 is GPSSGAPPPC.

[0100] According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, X9 is L, and X10 is GPSSGAPPPS. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, X9 is L, and X10 is GPSSGAPPPK. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, X9 is L, and X10 is GPSSGAPPPC.

[0101] According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is aib, X9 is L, and X10 is GPSSGAPPPS. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is aib, X9 is L, and X10 is GPSSGAPPPK. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is aib, X9 is L, and X10 is GPSSGAPPPC.

[0102] According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is Q, X5 is V, X9 is L, and X10 is GPSSGAPPPS. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is Q, X5 is V, X9 is L, and X10 is GPSSGAPPPK. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is Q, X5 is V, X9 is L, and X10 is GPSSGAPPPC.

[0103] According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, X5 is V, X9 is L, and X10 is GPSSGAPPPS. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, X5 is V, X9 is L, and X10 is GPSSGAPPPK. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, X5 is V, X9 is L, and X10 is GPSSGAPPPC.

[0104] According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is aib, X5 is V, X9 is L, and X10 is GPSSGAPPPS. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is aib, X5 is V, X9 is L, and X10 is GPSSGAPPPK. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is aib, X5 is V, X9 is L, and X10 is GPSSGAPPPC.

[0105] According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is Q, X3 is K, X5 is V, X9 is L, and X10 is GPSSGAPPPS. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is Q, X3 is K, X5 is V, X9 is L, and X10 is GPSSGAPPPK. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is Q, X3 is K, X5 is V, X9 is L, and X10 is GPSSGAPPPC.

[0106] According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, X3 is K, X5 is V, X9 is L, and X10 is GPSSGAPPPS. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, X3 is K, X5 is V, X9 is L, and X10 is GPSSGAPPPK. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, X3 is K, X5 is V, X9 is L, and X10 is GPSSGAPPPC.

[0107] According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is aib, X3 is K, X5 is V, X9 is L, and X10 is GPSSGAPPPS. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is aib, X3 is K, X5 is V, X9 is L, and X10 is GPSSGAPPPK. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is aib, X3 is K, X5 is V, X9 is L, and X10 is GPSSGAPPPC.

[0108] According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is Q, X3 is K, X5 is V, X7 is I, X9 is L, and X10 is GPSSGAPPPS. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is Q, X3 is K, X5 is V, X7 is I, X9 is L, and X10 is GPSSGAPPPK. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is Q, X3 is K, X5 is V, X7 is I, X9 is L, and X10 is GPSSGAPPPC.

[0109] According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, X3 is K, X5 is V, X7 is I, X9 is L, and X10 is GPSSGAPPPS. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, X3 is K, X5 is V, X7 is I, X9 is L, and X10 is GPSSGAPPPK. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, X3 is K, X5 is V, X7 is I, X9 is L, and X10 is GPSSGAPPPC.

[0110] According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is aib, X3 is K, X5 is V, X7 is I, X9 is L, and X10 is GPSSGAPPPS. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is aib, X3 is K, X5 is V, X7 is I, X9 is L, and X10 is GPSSGAPPPK. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is aib, X3 is K, X5 is V, X7 is I, X9 is L, and X10 is GPSSGAPPPC.

[0111] According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is Q, X3 is K, X5 is V, X7 is V, X9 is L, and X10 is GPSSGAPPPS. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is Q, X3 is K, X5 is V, X7 is V, X9 is L, and X10 is GPSSGAPPPK. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is Q, X3 is K, X5 is V, X7 is V, X9 is L, and X10 is GPSSGAPPPC.

[0112] According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, X3 is K, X5 is V, X7 is V, X9 is L, and X10 is GPSSGAPPPS. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, X3 is K, X5 is V, X7 is V, X9 is L, and X10 is GPSSGAPPPK. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, X3 is K, X5 is V, X7 is V, X9 is L, and X10 is GPSSGAPPPC.

[0113] According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is aib, X3 is K, X5 is V, X7 is I, X9 is L, and X10 is GPSSGAPPPS. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is aib, X3 is K, X5 is V, X7 is V, X9 is L, and X10 is GPSSGAPPPK. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is aib, X3 is K, X5 is V, X7 is V, X9 is L, and X10 is GPSSGAPPPC.

[0114] According to any of the foregoing peptide compounds, in some embodiments, X1 is Y and X2 is Q. According to any of the foregoing peptide compounds, in some embodiments, X1 is Y and X2 is A. According to any of the foregoing peptide compounds, in some embodiments, X1 is Y and X2 is Aib. According to any of the foregoing peptide compounds, in some embodiments, X1 is Y and X2 is Y.

[0115] According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is Y, X3 is K, and X9 is L. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is Y, X2 is Y, X3 is K, and X9 is L. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is Y, X2 is Y, X3 is K, X5 is V, and X9 is L. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is Y, X2 is Y, X3 is K, X5 is V, X7 is V, and X9 is L. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is Y, X2 is Y, X3 is K, X5 is V, X7 is V, X8 is N, and X9 is L. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is Y, X2 is Y, X3 is K, X5 is V, X7 is V, X8 is N, and X9 is I. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is Y, X2 is Y, X3 is K, X5 is V, X7 is I, X8 is E, and X9 is L.

[0116] According to any of the foregoing peptide compounds, in some embodiments, X1 is L and X9 is I.

[0117] According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L and X9 is L. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is Q, and X9 is L. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is Q, X5 is V, and X9 is L. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is Q, X3 is K, X5 is V, X7 is I, X8 is E, and X9 is L.

[0118] According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L and X2 is A. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, and X9 is L. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, X3 is K, X5 is V, and X9 is L. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, X3 is K, X5 is V, X7 is I, X8 is E, and X9 is L.

[0119] According to any of the foregoing peptide compounds, in some embodiments, X1 is L and X2 is aib. According to any of the foregoing peptide compounds, in some embodiments, X1 is L, X2 is aib, and X9 is L. According to any of the foregoing peptide compounds, in some embodiments, X1 is L, X2 is aib, X5 is V, and X9 is L. According to any of the foregoing peptide compounds, in some embodiments, X1 is L, X2 is aib, X3 is K, X5 is V, and X9 is L. According to any of the foregoing peptide compounds, in some embodiments, X1 is L, X2 is aib, X3 is K, X5 is V, X7 is I, X8 is E, and X9 is L.

[0120] According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X4 is E, X9 is I or L, X11 is I, X12 is L, and X14 is A. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X4 is E, X5 is V, X9 is I or L, X11 is I, X12 is L, and X14 is A. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X3 is K, X4 is E, X5 is V, X9 is I or L, X11 is I, X12 is L, and X14 is A. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A or aib, X3 is K, X4 is E, X5 is V, X9 is I or L, X11 is I, X12 is L, and X14 is A. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A or aib, X3 is K, X4 is E, X5 is V, X7 is I, X9 is I or L, X11 is I, X12 is L, and X14 is A. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A or aib, X3 is K, X4 is E, X5 is V, X6 is R, X7 is I, X9 is I or L, X11 is I, X12 is L, X13 is L, and X14 is A. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A or aib, X3 is K, X4 is E, X5 is V, X6 is R, X7 is I, X8 is E, X9 is I or L, X11 is I, X12 is L, X13 is L, and X14 is A.

[0121] According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X3 is K, X4 is E, X5 is V, X6 is R, X7 is I, X8 is E, X9 is I or L, X11 is I, X12 is L, X13 is L, and X14 is A.

[0122] According to any of the foregoing peptide compounds, in some embodiments, X1 is L, X2 is A or aib, X3 is K, X4 is E, X5 is V, X6 is R, X7 is I, X8 is E, X9 is I or L, X11 is I, X12 is L, X13 is L, X14 is A, and X10 is selected from GPSSGAPPP, GPPSGAPPP, GPSSGKPPP, GPSSGEPPP, GPSSaibAPPP, GPSSGAPP, GPSSGAP, GPSSGA, GPSSG, GPSS, GPS, GP, or G. Alternatively, one or two amino acids selected from S or containing an amino or thiol group in the side chain are added to the C-terminus of X10, and the carboxyl group of the C-terminal amino acid is optionally amidated to a C-terminal amide, wherein the amino or thiol group containing the amino or thiol group has the structure shown in formula (II) or formula (III); when formula (II) or formula (III) is a C-terminal amino acid, its carboxyl group is COOH or CONH2, preferably, formula (II) is lysine and formula (III) is cysteine.

[0123] According to any of the foregoing peptide compounds, in some embodiments, X1 is L and X2 is Y. According to any of the foregoing peptide compounds, in some embodiments, X1 is L, X2 is Y, and X5 is V. According to any of the foregoing peptide compounds, in some embodiments, X1 is L, X2 is Y, X3 is K, and X5 is V.

[0124] According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, aib, or Y, X4 is E, and X11 is I or S. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, aib, or Y, X4 is E, and X11 is I. According to the peptide compound of any of the foregoing aspects, in some embodiments, X1 is L, X2 is A, aib, or Y, X3 is K, X4 is E, and X11 is I.

[0125] According to any of the foregoing peptide compounds, in some embodiments, X2 is Q, X9 is K, and the sequence consisting of X10 and the C-terminal amino acid is not GPSSGAPPPS or GPSSGAPPPSK.

[0126] According to any of the foregoing aspects of the peptide compound, in some embodiments, at least one of X1, X3, X4, X6, X8, X9, X11, X12, and X14 is formula (II) or formula (III). According to any of the foregoing aspects of the peptide compound, in some embodiments, at least one of X1, X3, X4, X6, X8, X9, X11, X12, and X14 is formula (II) or formula (III), and at least one side chain of formula (II) or formula (III) is conjugated with a long-acting group or a modifying group. According to any of the foregoing aspects of the peptide compound, in some embodiments, at least one of X1, X4, X8, X11, X12, and X14 is formula (II) or formula (III).

[0127] According to any of the foregoing peptide compounds, in some embodiments, at least one of X1, X3, X4, X6, X8, X9, X11, X12, and X14 is of formula (II) or formula (III), and the sequence consisting of X10, C-terminal X10, and C-terminal amino acids does not contain formula (II) or formula (III).

[0128] According to any of the foregoing peptide compounds, in some embodiments, at least one of X1, X3, X4, X6, X8, X9, X11, X12, and X14 is of formula (II) or formula (III), and the sequence of X10 and the C-terminal amino acids is not GPSSGAPPPK, GPSSGAPPPC, GPSSGAPPPSC, or GPSSGAPPPSK.

[0129] According to any of the foregoing peptide compounds, in some embodiments, X2 represents an amino acid residue selected from A, aib, or Y, and X12 is of formula (II) or formula (III).

[0130] According to any of the foregoing peptide compounds, in some embodiments, X1 is of formula (II) or formula (III).

[0131] According to any of the foregoing peptide compounds, in some embodiments, X1 is K(x18).

[0132] According to any of the foregoing peptide compounds, in some embodiments, X1 is K(x20).

[0133] According to any of the foregoing peptide compounds, in some embodiments, X3 is of formula (II) or formula (III).

[0134] According to any of the foregoing peptide compounds, in some embodiments, X3 is K(x18).

[0135] According to any of the foregoing peptide compounds, in some embodiments, X3 is K(x20).

[0136] According to any of the foregoing peptide compounds, in some embodiments, X4 is of formula (II) or formula (III).

[0137] According to any of the foregoing peptide compounds, in some embodiments, X4 is K(x18).

[0138] According to any of the foregoing peptide compounds, in some embodiments, X4 is K(x20).

[0139] According to any of the foregoing peptide compounds, in some embodiments, X6 is of formula (II) or formula (III).

[0140] According to any of the foregoing peptide compounds, in some embodiments, X6 is K(x18).

[0141] According to any of the foregoing peptide compounds, in some embodiments, X6 is K(x20).

[0142] According to any of the foregoing peptide compounds, in some embodiments, X8 is of formula (II) or formula (III).

[0143] According to any of the foregoing peptide compounds, in some embodiments, X8 is K(x18).

[0144] According to any of the foregoing peptide compounds, in some embodiments, X8 is K(x20).

[0145] According to any of the foregoing peptide compounds, in some embodiments, X9 is of formula (II) or formula (III).

[0146] According to any of the foregoing peptide compounds, in some embodiments, X9 is K(x18).

[0147] According to any of the foregoing peptide compounds, in some embodiments, X9 is K(x20).

[0148] According to any of the foregoing peptide compounds, in some embodiments, X11 is of formula (II) or formula (III).

[0149] According to any of the foregoing peptide compounds, in some embodiments, X11 is K(x18).

[0150] According to any of the foregoing peptide compounds, in some embodiments, X11 is K(x20).

[0151] According to any of the foregoing peptide compounds, in some embodiments, X12 is of formula (II) or formula (III).

[0152] According to any of the foregoing peptide compounds, in some embodiments, X12 is K(x18).

[0153] According to any of the foregoing peptide compounds, in some embodiments, X12 is K(x20).

[0154] According to any of the foregoing peptide compounds, in some embodiments, X14 is of formula (II) or formula (III).

[0155] According to any of the foregoing peptide compounds, in some embodiments, X14 is K(x18).

[0156] According to any of the foregoing peptide compounds, in some embodiments, X14 is K(x20).

[0157] The peptide compound according to any of the foregoing aspects, wherein the peptide compound is not the peptide compound described in PCT application number PCT / CN2020 / 070697.

[0158] According to any of the foregoing aspects, the peptide compound is selected from: 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. Compound 26. Compound 27. Compound 28. Compound 29. Compound 30. Compound 31. Compound 32. Compound 33. Compound 34. Compound 35. Compound 36. Compound 37. Compound 38. Compound 39. Compound 40. Compound 41. Compound 42. Compound 43. Compound 44. Compound 45. Compound 46. Compound 47. Compound 48. Compound 49. Compound 50. Compound 51. Compound 52. Compound 53. Compound 54. Compound 55. Compound 56. Compound 57. Compound 58. Compound 59. Compound 60. Compound 61. Compound 62. Compound 63. Compound 64. Compound 65. Compound 66. Compound 67. Compound 68. Compound 69. Compound 70. Compound 71. Compound 72. Compound 73. Compound 74. Compound 75. Compound 76. Compound 77. Compound 78. Compound 79. Compound 80. Compound 81. Compound 82. Compound 83. Compound 84. Compound 85. Compound 86. YaibEGTFTSDLSK(x20)ALEKEAVRLFIEWLIAGGPSSGA-NH2 Compound 87. YaibEGTFTSDLSIQLEEEAVRLFIEWLIK(x20)GGPSSGAPPPS-NH2 Compound 88. YaibEGTFTSDLSK(x18)ALEKEAVRLFIEWLKAGGPSS-NH2 Compound 89. YaibEGTFTSDLSIaibLEKEAVRLFIEWLIAGGPSSK(x18)-NH2 Compound 90. YaibEGTFTSDLSIQLEKEAVRLFIEWLIK(x18)GGPSSGA-NH2 Compound 91. YaibEGTFTSDLSK(x18)QLEKEAVRLFIEWLIAGGPSS-NH2 Compound 92. YaibEGTFTSDLSIaibLEKEAVRLFIEWLKAGGPSSGK(x18)-NH2 Compound 93.YaibEGTFTSDLSK(x20)QLEKEAVQDFVNWLLAGGPSSGAPPPS-NH2 Compound 94.YaibEGTFTSDLSIYLEKEAVRLFIEWLLK(x18)GGPSSGAPPPS-NH2 Compound 95.YaibEGTFTSDLSIALEKEAVRLFIEWLLAGGPSSGAPPPC(x20)-NH2 Compound 96.YaibEGTFTSDLSIQLEKEAVRLFIEWLIK(x18)GGPSSGAPPPS-NH2 Compound 97. YaibEGTFTSDLSK(x20)ALEKEAVKEFIAWLIAGGPSSGAPPPS-NH2 Compound 98. YaibEGTFTSDLSIALEKEAVRLFIEWLKAGGPSSK(x20)-NH2 Compound 99. YaibEGTFTSDLSIaibK(x20)EKEAVRLFIEWLIAGGPSSGAPPPS-NH2 Compound 100. YaibEGTFTSDLSIQLEKEAVRLFIEWLIK(x18)GGPSS-NH2 Compound 101. YaibEGTFTSDLSIaibK(x18)EKEAVRLFIEWLIAGGPSSGAPPPS-NH2 Compound 102.YaibEGTFTSDLSIaibLEKEAVRLFIEWLIAGGPSK(x20)-NH2 Compound 103.YaibEGTFTSDYSIYLEKEAVRLFIEWLLK(x20)GGPSSGAPPPS-NH2 Compound 104. YaibEGTFTSDLSIAC(x18)EKEAVRLFIEWLLAGGPSSGAPPPS-NH2 Compound 105.YaibEGTFTSDLSIALEKEAVRLFIEWLLAGGPSSGAPPPC(x18)-NH2 Compound 106.YaibEGTFTSDLSIQLEKEAVKLFVNWLIK(x20)GGPSSGAPPPS-NH2 Compound 107.YaibEGTFTSDLSIAC(x20)EKEAVRLFIEWLIAGGPSSGAPPPS-NH2 Compound 108.YaibEGTFTSDLSIaibLEKEAVRLFIEWLLK(x20)GGPSS-NH2 Compound 109.YaibEGTFTSDLSIaibLEKEAVRLFIEWLIAGGPSSGAPPPC ( x20)-NH2 Compound 110.YaibEGTFTSDLSIaibLEKEAVRLFIEWLIAGGPSSK(x20)-NH2 Compound 111.YaibEGTFTSDLSIALEKEAVRLFIEWLKAGGPSSGA-NH2 Compound 112.YaibEGTFTSDLSIALEKEAVRLFIEWLKAGGPSSGAPPPS-NH2 Compound 113.YaibEGTFTSDLSIQLEKEAVRLFIEWLLAGGPSSGAPPPC(x18)-NH2 Compound 114. YaibEGTFTSDK(x18)SIYLEKEAVRLFIEWLIAGGPSSGA-NH2 Compound 115.YaibEGTFTSDLSIALEKEAVRLFIEWLIAGGPSSGAK(x20)-NH2 Compound 116.YaibEGTFTSDLSIaibLEKEAVRLFIEWLIAGGPSSGAPPPC(x18)-NH2 Compound 117.YaibEGTFTSDK(x20)SIALEEEAVQDFVQWLIAGGPSSGAPPPS-NH2 Compound 118. YaibEGTFTSDLSC(x20)ALEKEAVKEFIAWLIAGGPSSGAPPPS-NH2 Compound 119.YaibEGTFTSDLSIYLEKEAVKLFIEWLIAGGPSSGK(x20)-NH2 Compound 120.YaibEGTFTSDLSIaibLEKEAVRLFIEWLLK(x20)GGPSSGA-NH2 Compound 121.YaibEGTFTSDLSIALEKEAVRLFIEWLKAGGPSS-NH2 Compound 122. YaibEGTFTSDK(x18)SIALEKEAVRLFIEWLLAGGPS-NH2 Compound 123.YaibEGTFTSDLSIaibLEKEAVRLFIEWLIAGGPK(x20)-NH2 Compound 124.YaibEGTFTSDLSIaibLEKK(x18)AVRLFIEWLKAGGPS-NH2 Compound 125. YaibEGTFTSDLSIALEKEAVRLFIEWLIK(x20)GGPSS-NH2 Compound 126.YaibEGTFTSDLSIaibLEKEAVRLFIEWLIAGGPK(x18)-NH2 Compound 127. YaibEGTFTSDLSIAK(x18)EKEAVRLFIEWLLAGGPSSGAPPPS-NH2 Compound 128.YaibEGTFTSDLSIaibLEKEAVRLFIEWLKAGGPSSG-NH2 Compound 129.YaibEGTFTSDLSIALEKEAVRLFIEWLKK(x20)GGPSSGAPPPS-NH2 Compound 130.YaibEGTFTSDLSIaibLEKEAVRLFIEWLKAGGPSSGAK(x18)-NH2 Compound 131.YaibEGTFTSDLSIaibLEKEAVRLFIEWLKAGGPSSGAPPPS-NH2 Compound 132. YaibEGTFTSDLSIQK(x18)EKEAVRLFIEWLKAGGPSS-NH2 Compound 133.YaibEGTFTSDLSIYLEKEAVRLFIEWLLK(x18)GGPS-NH2 Compound 134.YaibEGTFTSDLSIYLEKEAVKLFIEWLIAGGPSSGAPPPC(x18)-NH2 Compound 135.YaibEGTFTSDLSIaibLEKEAVRLFIEWLKAGGPSSGA-NH2 Compound 136.YaibEGTFTSDLSIaibLEKK(x20)AVRLFIEWLKAGGPSSGAPPPS-NH2 Compound 137. YaibEGTFTSDLSIALEC(x18)EAVRLFIEWLLAGGPSSGAPPPS-NH2 Compound 138.YaibEGTFTSDLSIYLEKEAVKLFIEWLIAGGPSSGAK(x20)-NH2 Compound 139. YaibEGTFTSDLSIYK(x20)EKEAVRLFIEWLKAGGPSSGA-NH2 Compound 140. YaibEGTFTSDK(x18)SIALEKEAVRLFIEWLKAGGPSSGAPPPS-NH2 Compound 141. YaibEGTFTSDLSIaibLEKK(x18)AVRLFIEWLKAGGPSSG-NH2 Compound 142.YaibEGTFTSDLSIYLEKEAVKLFIEWLIAGGPSSGAPPPK(x18)-NH2 Compound 143.YaibEGTFTSDLSIaibLEKEAVRLFIEWLC(x20)AGGPSSGAPPPS-NH2 Compound 144.YaibEGTFTSDLSIYLEKEAVRLFIEWLKAGGPSS-NH2 Compound 145. YaibEGTFTSDK(x20)SIaibLEKEAVRLFIEWLKAGGPSSGAPPPS-NH2 Compound 146.Y(aib)EGTFTSDLSIALEKEAVRLFIEWLIAGGPK(x20)-NH2 Compound 147.YaibEGTFTSDC(x18)SIaibLEKEAVRLFIEWLLAGGPSSGAPPPS-NH2 Compound 148.YaibEGTFTSDLSIaibLEKK(x18)AVRLFIEWLLAGGPSSGAPPPS-NH2 Compound 149.YaibEGTFTSDLSIALEKEAVRLFIEWLIAGGPSSGK(x18)-NH2 Compound 150.YaibEGTFTSDLSIYK(x18)EKEAVRLFIEWLLAGGPS-NH2 Compound 151. YaibEGTFTSDLSIALEKEAVRLFIEWLC(x20)AGGPSSGAPPPS-NH2 Compound 152. YaibEGTFTSDC(x20)SIALEKEAVRLFIEWLLAGGPSSGAPPPS-NH2 Compound 153. YaibEGTFTSDLSIQK(x18)EKEAVRLFIEWLKAGGPSSGA-NH2 Compound 154.YaibEGTFTSDLSIaibLEKEAVRLFIEWLC(x18)AGGPSSGAPPPS-NH2 Compound 155.YaibEGTFTSDLSIaibLEKEAVRLFIEWLIAGGPSK(x18)-NH2 Compound 156. YaibEGTFTSDLSIAK(x18)EKEAVRLFIEWLKAGGPSSGA-NH2 Compound 157. YaibEGTFTSDLSIALEKEAVRLFIEWLIAGGPSK(x18)-NH2 Compound 158. YaibEGTFTSDLSIYLEKEAVRLFIK(x18)WLIAGGPSS-NH2 Compound 159. YaibEGTFTSDLSIAK(x20)EKEAVRLFIEWLIAGGPSSGAPPPS-NH2 Compound 160.YaibEGTFTSDLSIQLEKEAVRLFIEWLIAGGPSSK(x18)-NH2 Compound 161. YaibEGTFTSDLSIaibK(x18)EKEAVRLFIEWLIAGGPSSGA-NH2 Compound 162. YaibEGTFTSDLSIALEKEAVRLFIEWLC(x20)AGGPSSGA-NH2 Compound 163. YaibEGTFTSDLSIALEKEAVRLFIEWLIAGGPSK(x20)-NH2 Compound 164.YaibEGTFTSDLSIALEKK(x18)AVRLFIEWLIAGGPSSGAPPPS-NH2 Compound 165.YaibEGTFTSDLSIALEKEAVRLFIEWLKAGGPSSG-NH2 Compound 166. YaibEGTFTSDLSIALEKK(x18)AVRLFIEWLLAGGPSSGA-NH2 Compound 167.YaibEGTFTSDLSIYLEKEAVRLFIK(x18)WLIAGGPSSGA-NH2 Compound 168. YaibEGTFTSDLSIaibLEKEAVRLFIEWLK(x20)AGGPSS-NH2 Compound 169.YaibEGTFTSDLSIQLEKEAVRLFIEWLKAGGPSSGAPP-NH2 Compound 170. YaibEGTFTSDLSIAK(x18)EKEAVRLFIEWLKAGGPSS-NH2 Compound 171.YaibEGTFTSDLSIaibLEKEAVRLFIEWLKAGGPS-NH2 Compound 172. YaibEGTFTSDLSIALEKK(x18)AVRLFIEWLLAGGPSS-NH2 Compound 173.YaibEGTFTSDLSC(x20)aibLEKEAVKEFIAWLIAGGPSSGAPPPS-NH2 Compound 174.YaibEGTFTSDLSIALEKEAVRLFIEWLKAGGPS-NH2 Compound 175. YaibEGTFTSDLSIALEKK(x20)AVRLFIEWLKAGGPSSGAPPPS-NH2 Compound 176.YaibEGTFTSDLSIALEKEAVRLFIEWLIAGGPSSGK(x20)-NH2 Compound 177. YaibEGTFTSDLSIALEKEAVRLFIEWLC(x18)AGGPSSGA-NH2 Compound 178.YaibEGTFTSDLSIQLEEEAVRLFIEWLK(x20)AGGPSSGAPPPS-NH2 Compound 179.YaibEGTFTSDLSIYLEKEAVRLFIEWLLC(x20)GGPSSGAPPPS-NH2 Compound 180.YaibEGTFTSDLSIALEKEAVRLFIEWLIAGGPK(x18)-NH2 Compound 181.YaibEGTFTSDLSIaibLEK(x18)EAVRLFIEWLIAGGPSSGAPPPS-NH2 Compound 182. YaibEGTFTSDLSIALEKEAVRLFIEWLLC(x20)GGPSS-NH2 Compound 183. YaibEGTFTSDLSIALEC(x20)EAVRLFIEWLIAGGPSSGAPPPS-NH2 Compound 184.YaibEGTFTSDLSIYLEKEAVRLFIEWLIAGGPSSK(x20)-NH2 Compound 185.YaibEGTFTSDYSIYLEKK(x20)AVRLFIEWLIAGGPSSGAPPPS-NH2 Compound 186.YaibEGTFTSDLSIQLEKEAVRLFIEWLIAGGPSK(x18)-NH2 Compound 187.YaibEGTFTSDLSIYLEKK(x20)AVRLFIEWLLAGGPSSGAPPPS-NH2 Compound 188.YaibEGTFTSDLSIaibLEKEAVRLFIC(x18)WLIAGGPSSGAPPPS-NH2 Compound 189.YaibEGTFTSDLSIQLEKEAVRLFIEWLIC(x18)GGPSSG-NH2 Compound 190. YaibEGTFTSDLSIALEKEAVK(x18)LFIEWLKAGGPSSGA-NH2 Compound 191.YaibEGTFTSDLSIALEKEAVRLFIEWLIAGGPSSK(x20)-NH2 Compound 192.YaibEGTFTSDLSIQLEKEAVRLFIEWLKK(x18)GGPSSGAPPPS-NH2 Compound 193. YaibEGTFTSDLSIALEKEAVK(x18)LFIEWLKAGGPSS-NH2 Compound 194.YaibEGTFTSDLSIYLEKK(x20)AVRLFIEWLKAGGPSSGAPPPS-NH2 Compound 195.YaibEGTFTSDLSIQLEKEAVRLFIK(x18)WLKAGGPSS-NH2 Compound 196.YaibEGTFTSDLSIYLEKK(x18)AVRLFIEWLKAGGPSSGA-NH2 Compound 197.YaibEGTFTSDLSIYLEKEAVRLFIK(x18)WLLAGGPSSGAPPPS-NH2 Compound 198.YaibEGTFTSDLSIQLEKEAVRLFIEWLKAGGPSSGAP-NH2 Compound 199. YaibEGTFTSDLSIALEKEAVK(x20)LFIEWLKAGGPSSGAPPPS-NH2 Compound 200.YaibEGTFTSDLSIYLEKEAVRLFIEWLIAGGPSSGAPPPC(x20)-NH2 Compound 201.YaibEGTFTSDLSIaibLEKEAVRLFIK(x18)WLLAGGPSSGAPPPS-NH2 Compound 202.YaibEGTFTSDLSIYLEKK(x18)AVRLFIEWLKAGGPSS-NH2 Compound 203.YaibEGTFTSDLSIALEKEAVK(x18)LFIEWLIAGGPSSGAPPPS-NH2 Compound 204.YaibEGTFTSDLSIQLEKEAVRLFIEWLKAGGPSSGA-NH2 Compound 205. YaibEGTFTSDLSIALEKEAVRLFIEWLLC(x18)GGPSS-NH2 Compound 206.YaibEGTFTSDLSIALEKEAVK(x20)DFVNWLLAGGPSSGAPPPS-NH2 Compound 207.YaibEGTFTSDLSIQLEKEAVRLFIEWLIAGGPSK(x20)-NH2 Compound 208.YaibEGTFTSDLSIYLEKEAVRLFIEWLLK(x18)GGPSSGA-NH2 Compound 209.YaibEGTFTSDLSIALEKEAVC(x18)LFIEWLIAGGPSSGAPPPS-NH2 Compound 210.YaibEGTFTSDLSIALEKEAVRLFIC(x18)WLLAGGPSSGAPPPS-NH2 Compound 211.YaibEGTFTSDLSIQLEKEAVRLFIEWLKAGGPSSG-NH2 Compound 212.YaibEGTFTSDLSIALEKEAVC(x20)LFIEWLIAGGPSSGAPPPS-NH2 Compound 213.YaibEGTFTSDLSIaibLEKK(x18)AVRLFIEWLLAGGPSS-NH2 Compound 214.YaibEGTFTSDLSIALEKEAVRLFIEWLLC(x20)GGPSSGAPPPS-NH2 Compound 215.YaibEGTFTSDLSIYLEKEAVRLFIEWLLC(x18)GGPSS-NH2 Compound 216.YaibEGTFTSDLSIALEKC(x20)AVRLFIEWLIAGGPSSGAPPPS-NH2 Compound 217.YaibEGTFTSDLSIYLEKEAVK(x20)LFIEWLLAGGPSSGAPPPS-NH2 Compound 218.YaibEGTFTSDLSIQLEKEAVRLFIEWLKAGGPSS-NH2 Compound 219.YaibEGTFTSDYSIYLEKEAVRLFIC(x20)WLLAGGPSSGAPPPS-NH2 Compound 220.YaibEGTFTSDLSIYLEKEAVK(x20)LFIEWLKAGGPS-NH2 Compound 221.YaibEGTFTSDLSIaibLEKEAVRLFIEWLK(x20)AGGPSSGA-NH2 Compound 222.YaibEGTFTSDLSIaibLEKEAVRLFIK(x18)WLKAGGPSS-NH2 Compound 223.YaibEGTFTSDLSIALEKC(x18)AVRLFIEWLIAGGPSSGAPPPS-NH2 Compound 224.YaibEGTFTSDLSIQLEKEAVRLFIEWLKAGGPS-NH2 Compound 225.YaibEGTFTSDLSIYLEKEAVK(x18)LFIEWLIAGGPSSGAPPPS-NH2 Compound 226.YaibEGTFTSDLSIaibLEK(x20)EAVRLFIEWLIAGGPSSGAPPPS-NH2 Compound 227.YaibEGTFTSDLSIYLEKEAVK(x18)LFIEWLLAGGPSSG-NH2 Compound 228.YaibEGTFTSDLSIYLEKEAVRLFIEWLLC(x20)GGPSS-NH2 Compound 229. YaibEGTFTSDLSIALEKEAVRLFIK(x20)WLKAGGPSSGA-NH2 Compound 230.YaibEGTFTSDLSIaibLEKEAVRLFIEWLLC(x20)GGPSS-NH2 Compound 231. YaibEGTFTSDLSIaibLEKEAVK(x18)LFIEWLKAGGPSSGA-NH2 Compound 232. YaibEGTFTSDLSIALEKEAVRLFIK(x20)WLKAGGPSS-NH2 Compound 233.YaibEGTFTSDLSIALEKEAVKEFIAWLK(x20)AGGPSSGAPPPS-NH2 Compound 234.YaibEGTFTSDLSIYLEKEAVRLFIEWLKAGGPS-NH2 Compound 235.YaibEGTFTSDLSIQLEKEAVK(x18)LFIEWLLAGGPSSGAPPPS-NH2 Compound 236.YaibEGTFTSDLSIYLEK(x20)EAVRLFIEWLIAGGPSSGAPPPS-NH2 Compound 237.YaibEGTFTSDLSIaibLEKEAVRLFIEWLIAGGPSSGAK(x20)-NH2 Compound 238.YaibEGTFTSDLSIQLEKEAVRLFIEWLK(x20)AGGPSSGAPPPS-NH2 Compound 239. YaibEGTFTSDLSIALEKEAVRLFIK(x18)WLKAGGPSS-NH2 Compound 240.YaibEGTFTSDLSIaibLEKEAVRLFIEWLLC(x18)GGPSSGAPPPS-NH2 Compound 241. YaibEGTFTSDYSIYLEKEAVRLFIC(x18)WLLAGGPSSG-NH2 Compound 242.YaibEGTFTSDLSIaibLEKEAVRLFIEWLLC(x20)GGPSSGA-NH2 Compound 243.YaibEGTFTSDLSIQLEKEAVRLFIC(x20)WLLAGGPSSGAPPPS-NH2 Compound 244.YaibEGTFTSDLSIaibLEKEAVRLFIEWLIAGGPSSGK(x18)-NH2 Compound 245.YaibEGTFTSDYSIYLEKEAVRLFIEWLK(x20)AGGPSSGAPPPS-NH2 Compound 246.YaibEGTFTSDLSIQLEKEAVRLFIK(x18)WLIAGGPS-NH2 Compound 247.YaibEGTFTSDLSIALEK(x18)EAVRLFIEWLLAGGPSSGAPPPS-NH2 Compound 248.YaibEGTFTSDLSIaibLEKEAVRLFIEWLLC(x18)GGPSSGA-NH2 Compound 249. YaibEGTFTSDLSIQLEK(x18)EAVRLFIEWLLAGGPSSG-NH2 Compound 250.YaibEGTFTSDLSIALEKEAVRLFIK(x18)WLKAGGPSSGA-NH2 Compound 251. YaibEGTFTSDLSIQLEK(x18)EAVRLFIEWLLAGGPS-NH2 Compound 252.YaibEGTFTSDYSIYLEKEAVRLFIC(x18)WLLAGGPSSGAPPPS-NH2 Compound 253.YaibEGTFTSDLSIaibLEKEAVRLFIEWLKK(x18)GGPSSGAPPPS-NH2 Compound 254.YaibEGTFTSDLSIYLEKEAVRLFIEWLKAGGPSSGAPPPS-NH2 Compound 255.YaibEGTFTSDLSIaibLEKEAVRLFIK(x20)WLIAGGPSSGA-NH2 Compound 256.YaibEGTFTSDLSIQLEKEAVK(x18)LFIEWLLAGGPSSG-NH2 Compound 257.YaibEGTFTSDLSIaibLEKEAVRLFIK(x18)WLIAGGPSS-NH2 Compound 258.YaibEGTFTSDLSIYLEKEAVRLFIEWLLC(x20)GGPSSGA-NH2 Compound 259.YaibEGTFTSDLSIQLEKK(x20)AVRLFIEWLIAGGPSSGAPPPS-NH2 Compound 260.YaibEGTFTSDLSIaibLEKEAVRLFIK(x20)WLKAGGPSSGAPPPS-NH2 Compound 261. YaibEGTFTSDLSIQLEKEAVK(x18)LFIEWLIAGGPS-NH2 Compound 262.YaibEGTFTSDLSIaibLEKEAVRLFIC(x20)WLLAGGPSSGAPPPS-NH2 Compound 263.YaibEGTFTSDLSIQLEKEAVRLFIEWLIC(x20)GGPSSG-NH2 Compound 264.YaibEGTFTSDLSIYLEKEAVRLFIEWLKAGGPSSGAPP-NH2 Compound 265.YaibEGTFTSDLSIQLEKEAVRLFIEWLK(x20)AGGPSSGA-NH2 Compound 266.YaibEGTFTSDLSIaibLEKEAVRLFIC(x20)WLKAGGPSSGAPPPS-NH2 Compound 267. YaibEGTFTSDLSIALEKEAVRLFIEWLIK(x20)GGPSSGA-NH2 Compound 268.YaibEGTFTSDLSIQLEKEAVRLFIC(x18)WLLAGGPSSGAPPPS-NH2 Compound 269.YaibEGTFTSDLSIALEKEAVRLFIEWLLC(x18)GGPSSGAPPPS-NH2 Compound 270.YaibEGTFTSDLSIYLEKEAVRLFIEWLKAGGPSSGAP-NH2 Compound 271.YaibEGTFTSDLSIaibLEKEAVRLFIC(x18)WLKAGGPSSGAPPPS-NH2 Compound 272..YaibEGTFTSDLSIQLEKEAVRLFIEWLK(x18)AGGPSS-NH2 Compound 273.YaibEGTFTSDLSIALEKEAVRLFIEWLKAGGPSSGAK(x20)-NH2 Compound 274..YaibEGTFTSDLSIQLEKEAVRLFIEWLC(x18)AGGPSSGAPPPS-NH2 Compound 275.YaibEGTFTSDLSIYLEKEAVRLFIEWLKAGGPSSGA-NH2 Compound 276.YaibEGTFTSDLSIQLEKEAVRLFIK(x18)WLLAGGPSSGAPPPS-NH2 Compound 277.YaibEGTFTSDLSIaibLEKEAVK(x18)LFIEWLKAGGPSS-NH2 Compound 278.YaibEGTFTSDLSIYLEKEAVRLFIEWLLC(x18)GGPSSGAPPPS-NH2 Compound 279.YaibEGTFTSDLSIQLEKEAVRLFIK(x18)WLIAGGPSSG-NH2 Compound 280.YaibEGTFTSDLSIQLEKEAVRLFIEWLIC(x18)GGPSSGAPPPS-NH2 Compound 281.YaibEGTFTSDLSIaibLEKEAVRLFIEWLKAGGPSS-NH2 Compound 282.YaibEGTFTSDLSIQLEKEAVRLFIK(x18)WLKAGGPSSGAPPPS-NH2 Compound 283.YaibEGTFTSDLSIaibLEKEAVK(x20)LFIEWLLAGGPSSGAPPPS-NH2 Compound 284.YaibEGTFTSDLSIQLEKEAVRLFIK(x18)WLKAGGPSSGA-NH2 Compound 285.YaibEGTFTSDLSIALEKEAVRLFIK(x18)WLKAGGPSSGAPPPS-NH2 Compound 286.YaibEGTFTSDLSIQLEKEAVRLFIEWLC(x20)AGGPSSGA-NH2 Compound 287.YaibEGTFTSDLSIaibLEKEAVRLFIK(x18)WLKAGGPSSGA-NH2 Compound 288.YaibEGTFTSDLSIALEKEAVRLFIEWLC(x18)AGGPSSGAPPPS-NH2 Compound 289.YaibEGTFTSDLSIQLEKEAVRLFIEWLIAGGPSSK(x20)-NH2 Compound 290.YaibEGTFTSDLSIALEKEAVRLFIK(x20)WLLAGGPSSGA-NH2 Compound 291. YaibEGTFTSDLSIaibLEKEAVRLFIEWLK(x18)AGGPSSGA-NH2 Compound 292.YaibEGTFTSDLSIQLEKEAVRLFIK(x20)WLKAGGPSSGAPPPS-NH2 Compound 293.YaibEGTFTSDLSIYLEKEAVRLFIEWLLK(x20)GGPSSGA-NH2 Compound 294. YaibEGTFTSDLSIALEKEAVRLFIK(x20)WLLAGGPSS-NH2 Compound 295.YaibEGTFTSDLSIaibLEKEAVRLFIEWLK(x18)AGGPSS-NH2 Compound 296.YaibEGTFTSDLSIYLEKEAVRLFIEWLLC(x18)GGPSSGA-NH2 Compound 297.YaibEGTFTSDLSIaibLEKEAVRLFIEWLKAGGPSSGAPP-NH2 Compound 298. YaibEGTFTSDLSIALEKEAVRLFIEWLLC(x20)GGPSSGA-NH2 Compound 299. YaibEGTFTSDLSIALEKEAVRLFIK(x18)WLKAGGPS-NH2 Compound 300.YaibEGTFTSDLSIALEKEAVRLFIC(x18)WLKAGGPSSGAPPPS-NH2 Compound 301.YaibEGTFTSDLSIALEKEAVRLFIEWLKK(x18)GGPSSGAPPPS-NH2 Compound 302.YaibEGTFTSDLSIaibLEKEAVRLFIK(x20)WLKAGGPSSGA-NH2 Compound 303.YaibEGTFTSDLSIQLEKK(x18)AVRLFIEWLIAGGPSSGA-NH2 Compound 304.YaibEGTFTSDLSIaibLEKEAVRLFIEWLKK(x20)GGPSSGAPPPS-NH2 Compound 305.YaibEGTFTSDLSIALEKEAVRLFIC(x20)WLKAGGPSSGAPPPS-NH2 Compound 306.YaibEGTFTSDLSIYLEKEAVRLFIEWLKAGGPSSG-NH2 Compound 307.YaibEGTFTSDLSIQLEKEAVRLFIEWLC(x20)AGGPSSGAPPPS-NH2 Compound 308.YaibEGTFTSDK(x20)SIaibLEKEAVKEFIAWLLAGGPSSGAPPPS-NH2 Compound 309.YaibEGTFTSDLSIALEKEAVRLFIEWLKAGGPSSGK(x20)-NH2 Compound 310.YaibEGTFTSDLSK(x18)aibLEKEAVKEFIAWLIAGGPSSGAPPPS-NH2 Compound 311.YaibEGTFTSDLSIALEKEAVRLFIC(x20)WLLAGGPSSGAPPPS-NH2 Compound 312.YaibEGTFTSDLSIYLEKEAVRLFIEWLK(x20)AGGPSSGAPPPS-NH2 Compound 313.YaibEGTFTSDLSIaibLEKEAVK(x18)LFIEWLKAGGPSSGAPPPS-NH2 Compound 314. YaibEGTFTSDLSIQLEKEAVRLFIEWLIC(x20)GGPSSGAPPPS-NH2 Compound 315. YaibEGTFTSDLSIaibLEKEAVRLFIK(x20)WLKAGGPSS-NH2 Compound 316.YaibEGTFTSDLSIQLEKEAVQDFVNWLIK(x18)GGPSSGAPPPS-NH2 Compound 317.YaibEGTFTSDLSIaibLEKEAVRLFIEWLKAGGPSK(x18)-NH2 Compound 318.YaibEGTFTSDLSIYLEKEAVRLFIEWLC(x18)AGGPSSGAPPPS-NH2 Compound 319. YaibEGTFTSDLSIQLEEEAVK(x18)EFIAWLLKGG-NH2 Compound 320.YaibEGTFTSDLSIaibLEKEAVRLFIEWLIAGGPSSGAPPPK(x18)-NH2 Compound 321.YaibEGTFTSDLSIQLEKEAVKLFVNWLK(x20)AGGPSSGAPPPS-NH2 Compound 322.YaibEGTFTSDLSIALEKEAVRLFIEWLKAGGPSSGAP-NH2 Compound 323.YaibEGTFTSDLSIaibLEKEAVRLFIEWLIAGGPSSGAK(x18)-NH2 Compound 324.YaibEGTFTSDLSIQLEKEAVQDFVNWLK(x18)AGGPSSGAPPPS-NH2 Compound 325.YaibEGTFTSDLSIYLEKEAVKLFIEWLIAGGPSK(x18)-NH2 Compound 326.YaibEGTFTSDLSIaibLEKEAVRLFIK(x18)WLKAGGPSSGAPPPS-NH2 Compound 327.YaibEGTFTSDLSIQLEKEAVRLFIEWLC(x18)AGGPSSGA-NH2 Compound 328. YaibEGTFTSDK(x18)SIQLEKEAVRLFIEWLLAGGPSS-NH2 Compound 329. YaibEGTFTSDLSIALEKEAVRLFIEWLK(x18)AGGPSS-NH2 Compound 330.Y(aib)EGTFTSDLSIQLEKEAVRLFIEWLIAGGPSSGAK(x18)-NH2 Compound 331. YaibEGTFTSDLSIALEKEAVRLFIEWLLC(x18)GGPSSGA-NH2 Compound 332.YaibEGTFTSDLSIQLEKK(x18)AVRLFIEWLIAGGPSS-NH2 Compound 333.YaibEGTFTSDLSIALEKEAVRLFIEWLC(x20)AGGPSS-NH2 Compound 334.Y(aib)EGTFTSDLSIaibLEKEAVRLFIEWLKAGGPSSK(x18)-NH2 Compound 335. YaibEGTFTSDLSIALEKEAVRLFIEWLC(x18)AGGPSS-NH2 Compound 336.YaibEGTFTSDLSIaibLEKEAVRLFIEWLKAGGPSSGAP-NH2 Compound 337.YaibEGTFTSDYSIYLEKEAVRLFIEWLLK(x18)GGPSSGAPPPS-NH2 Compound 338.Y(aib)EGTFTSDLSIQLEKEAVRLFIEWLIAGGPSSGK(x18)-NH2 Compound 339.YaibEGTFTSDLSIYLEKEAVRLFIEWLLK(x20)GGPSS-NH2 Compound 340.YaibEGTFTSDK(x18)SIALEKEAVRLFIEWLLAGGPSSGA-NH2 Compound 341.YaibEGTFTSDLSIQLEKEAVRLFIEWLKK(x20)GGPSSGAPPPS-NH2 Compound 342.YaibEGTFTSDLSIQLEKEAVRLFIEWLIAGGPSSGAK(x20)-NH2 Compound 343.YaibEGTFTSDLSIYLEKEAVRLFIC(x20)WLLAGGPSSGAPPPS-NH2 Compound 344. YaibEGTFTSDLSK(x18)QLEKEAVRLFIEWLLAGGPSSGA-NH2 Compound 345. YaibEGTFTSDLSIQLEKEAVRLFIEWLIC(x18)GGPS-NH2 Compound 346.YaibEGTFTSDLSIALEKEAVRLFIEWLKAGGPSSGAPP-NH2 Compound 347.YaibEGTFTSDLSIYLEKEAVRLFIEWLC(x20)AGGGPSSGAPPPS-NH2 Compound 348.YaibEGTFTSDLSIALEKEAVRLFIEWLIAGGPSSGAPPK(x20)-NH2 Compound 349.YaibEGTFTSDLSIQLEKEAVRLFIK(x20)WLKAGGPSSGAPP-NH2 Compound 350.Y(aib)EGTFTSDLSIALEKEAVRLFIEWLKAGGPSK(x18)-NH2 Compound 351.Y(aib)EGTFTSDLSIaibleKEAVRLFIEWLIAGGPSSGK(x20)-NH2 Compound 352.YaibEGTFTSDLSIaibleKEAVRLFIEWLLC(x18)GGPSS-NH2 Compound 353.YaibEGTFTSDLSIYLEKEAVRLFIC(x18)WLLAGGPSSGAPPPS-NH2 Compound 354.YaibEGTFTSDLSSYLEKEAVRLFVQWLKRGGPSSGAPC(x20)-NH2 Compound 355.YaibEGTFTSDLSIaibleKEAVRLFIEWLLC(x20)GGPSSGAPPPS-NH2 Compound 356.YaibEGTFTSDLSIQLEKEAVRLFIK(x20)WLIAGGPSSGAP-NH2 Compound 357. YaibEGTFTSDLSIYLEEEAAK(x18)EFIAWLLKGGP-NH2 According to any of the foregoing aspects, the peptide compound contains only natural amino acids.

[0159] In one aspect, the present invention relates to a pharmaceutical composition comprising the aforementioned peptide compound or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient.

[0160] In one aspect, this invention relates to methods for treating or preventing the following diseases or conditions: impaired glucose tolerance (IGT), hyperglycemia, type 1 diabetes, type 2 diabetes, obesity, metabolic syndrome, and neurodegenerative diseases, particularly for delaying or preventing disease progression in type 2 diabetes, delaying the progression from impaired glucose tolerance to type 2 diabetes; delaying the progression from type 2 diabetes to insulin-dependent diabetes; treating metabolic syndrome by regulating appetite, inducing satiety, reducing food intake, and increasing energy expenditure; treating obesity or preventing overweight; preventing weight rebound after successful weight loss; treating diseases or conditions associated with overweight or obesity; treating bulimia; treating binge eating; treating dyslipidemia, atherosclerosis, hypertension, coronary heart disease, beta-blocker toxicity; and non-alcoholic fatty liver disease (NAFLD). (Can be classified as simple fatty liver (SFL), non-alcoholic steatohepatitis (NASH) and its associated cirrhosis); used to inhibit gastrointestinal motility, for use in conjunction with gastrointestinal surveys using techniques such as X-ray, CT and NMR scanning; the method includes administering to a patient an effective amount of any of the aforementioned peptide compounds or pharmaceutically acceptable salts or solvates or pharmaceutical compositions thereof.

[0161] In one aspect, the present invention relates to the use of peptide compounds or pharmaceutically acceptable salts or solvates thereof or pharmaceutical compositions thereof in the preparation of medicaments for lowering blood sugar or treating diabetes.

[0162] In one aspect, the present invention relates to the use of peptide compounds or pharmaceutically acceptable salts or solvates thereof or pharmaceutical compositions thereof in the preparation of medicaments for weight loss.

[0163] In one aspect, this invention relates to the use of peptide compounds or pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for lowering blood lipids. Preferably, the medicament lowers blood lipid components selected from: cholesterol, triglycerides, free fatty acids, and low-density lipoprotein cholesterol.

[0164] In one aspect, the present invention relates to a method for preparing peptide compounds according to any of the foregoing aspects, wherein the preparation method is a chemical synthesis method.

[0165] The inventors have obtained a novel class of peptide compounds by performing a series of structural modifications on GLP-1 receptor agonist peptide derivatives, including selecting specific amino acids, introducing new amino acids at the C-terminus of the peptide, or substituting amino acid residues at the C-terminus of the peptide, and linking unique long-acting groups to the peptide via the thiol side chain of cysteine ​​residues or the amino side chain of lysine residues at the C-terminus of the peptide. Unexpected technical effects have been achieved. Attached Figure Description

[0166] Figure 1 Compounds 12 and 15 of this invention reduce blood glucose in db / db mice.

[0167] Figure 2 Compounds 55, 58 and 243 of this invention reduce body weight in DIO mice. Detailed Implementation

[0168] Unless otherwise stated, the following definitions apply throughout this invention. Undefined terms may be understood according to industry conventions.

[0169] "Amino acid" refers to a molecule that contains both amino and carboxyl functional groups. In α-amino acids, the amino and carboxyl groups are attached to the same carbon atom (α-carbon). The α-carbon may have 1-2 additional organic substituents. Amino acids include L- and D-isomers and racemic mixtures. Unless otherwise specified, the amino acid residues in the polypeptide sequence of this invention are all L-isomers, i.e., L-amino acids. D-amino acids are indicated by adding a lowercase "d" before the amino acid name or abbreviation, such as dK.

[0170] The amino acid sequences of this invention contain conventional single-letter or three-letter codes for naturally occurring amino acids, as well as universally accepted three-letter codes for other amino acids, such as Tic (1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid), Aib (α-aminoisobutyric acid), or GABA (γ-aminobutyric acid). Commonly used abbreviation codes for molecular structures include: hGlu is high in glutamic acid; α-hGlu is an L isomer of -HNCH(CO-)CH2CH2CH2COOH; δ-hGlu is an L isomer of -HNCH(COOH)CH2CH2CH2CO-; α-Glu is an L isomer of -HNCH(CO-)CH2CH2COOH; γ-Glu or gGlu is an L isomer of -HNCH(COOH)CH2CH2CO-; α-Asp is an L isomer of -HNCH(CO-)CH2COOH; β-Asp is an L isomer of -HNCH(COOH)CH2CO-; β-Ala is -HN-CH2-CH2-COOH; PEG2 is 2-(2-(2-aminoethoxy)ethoxy)acetic acid (CAS No. 134978-97-5).

[0171] In this invention, the amino acid composition of the polypeptide can be altered without significantly affecting its biological activity. For example, a polypeptide sequence may contain one or more conserved amino acid substitutions. A conserved amino acid substitution is the replacement of one amino acid residue with another amino acid residue having a similar side chain. The literature classifies amino acid residues based on the nature of their side chains. Amino acid residues containing basic side chains include lysine, arginine, and histidine; amino acid residues containing acidic side chains and amide side chains include aspartic acid, glutamic acid, asparagine, and glutamine; amino acid residues with small aliphatic, nonpolar, or weakly polar side chains include glycine, alanine, threonine, serine, and proline; amino acid residues with large aliphatic, nonpolar side chains include leucine, isoleucine, and valine; aromatic amino acid residues include phenylalanine, tryptophan, and tyrosine; and amino acid residues with sulfur-containing side chains include cysteine ​​and methionine.

[0172] In some embodiments, the derivative comprises a substituent containing a lipophilic moiety and optionally a moiety with 1-3 negative charges, wherein one of the negatively charged moieties is distal to the lipophilic moiety. In some embodiments, the substituent is attached to the side chain of an amino acid at the C-terminus of the sequence. If the C-terminus is a lysine, it is attached to the ε-amino group of the lysine residue.

[0173] As used herein, "expression vector" includes a vector capable of expressing DNA operatively linked to a regulatory sequence, such as a promoter region, capable of influencing the expression of such DNA fragments. Such additional fragments may include promoter and terminator sequences and optionally include one or more origins of replication, one or more selection markers, enhancers, polyadenylation signals, etc. Expression vectors are generally derived from plasmid or viral DNA, or may contain elements of both. Thus, an expression vector refers to a recombinant DNA or RNA construct, such as a plasmid, bacteriophage, recombinant virus, or other vector, which, when introduced into a suitable host cell, results in the expression of clonal DNA. Suitable expression vectors are well known to those skilled in the art and include reproducible expression vectors in eukaryotic and / or prokaryotic cells, as well as expression vectors that remain free or are integrated into the host cell genome. In one embodiment, i.e., when the compound contains genetically encoded amino acid residues, the invention further provides a nucleic acid (which may be DNA or RNA) encoding the compound, a vector containing such nucleic acid, and a host cell containing such nucleic acid or expression vector.

[0174] As used herein, the term "treatment" includes suppressing, slowing, stopping, or reversing existing symptoms or the progression or severity of a patient's condition. Therefore, treatment encompasses prevention, treatment, and / or cure. Prevention refers to preventing underlying disease and / or preventing the worsening of symptoms or the development of disease.

[0175] As used in this article, “therapeutic effect” refers to the effect resulting from treatment of an individual, which alters, usually improves or enhances the symptoms of a disease or condition, or cures a disease or condition.

[0176] As used herein, "therapeutic effective amount" or "therapeutic effective dose" refers to an amount of substance, compound, material, or composition containing a compound that, when applied to a subject, is at least sufficient to produce a therapeutic effect. Therefore, it is the amount necessary to prevent, cure, improve, block, or partially block the symptoms of a disease or condition.

[0177] As used herein, "preventive effective amount" or "preventive effective dose" refers to the amount of a substance, compound, material, or composition containing a compound that, when applied to a subject, would have the intended preventive effect, such as preventing or delaying the onset or recurrence of a disease or symptom, or reducing the likelihood of the onset or recurrence of a disease or symptom. A fully preventive effective dose does not necessarily occur through the administration of a single dose and can occur only after a series of doses have been administered. Therefore, a preventive effective amount can be administered in one or more applications.

[0178] As used in this article, the term "patient" refers to mammals, such as humans.

[0179] Holst (Holst, JJ Physiol. Rev. 2007, 87, 1409) and Meier (Meier, JJ Nat. Rev. Endocrinol. 2012, 8, 7 28) described GLP-1 receptor agonists such as GLP-1, liraglutide, and lizard exotropic peptide-4.

[0180] Some compounds of the present invention are generally effective over a wide dose range. For example, a once-weekly dose can range from about 0.05 to about 30 mg per person per week. Some compounds of the present invention can be administered daily. Additionally, some compounds of the present invention can be administered once weekly.

[0181] It should be understood that the therapeutic agent according to the described embodiment will be administered together with pharmaceutically acceptable suitable carriers, excipients, and other agents incorporated into the formulation to provide improved transfer, delivery, tolerability, etc. A large number of suitable formulations can be found in all pharmacopoeias known to medicinal chemists: Remington's Pharmaceutical Sciences (15th edition, Mack Publishing Company, Easton, Pa. (1975)), particularly Chapter 87 of Blaug and Seymour. These formulations include, for example, powders, pastes, ointments, gels, waxes, oils, lipids, lipid-containing (cationic or anionic) carriers (e.g., Lipofectin™), DNA conjugates, anhydrous slurries, oil-in-water and water-in-oil emulsions, emulsion polyethylene glycol (polyethylene glycol of various molecular weights), semi-solid gels, and semi-solid mixtures containing polyethylene glycol. Any of the foregoing mixtures may be used for the treatment or therapy according to the invention, provided that the active ingredient in the formulation is not inactivated by the formulation and the formulation is physiologically compatible and tolerable to the route of administration.

[0182] As used herein, the term "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delayers compatible with drug administration. Suitable carriers are described in the latest edition of Remington's Pharmaceutical Sciences, the standard bibliography in the art, which is incorporated herein by reference. Preferred examples of such carriers or diluents include, but are not limited to, water, saline, Ringer's solution, glucose solution, and 5% human serum albumin. Liposomes and non-aqueous carriers, such as immobilized oils, may also be used. The use of such media and reagents for pharmaceutically active substances is well known in the art.

[0183] Preparations intended for clinical in vivo administration must be sterile. This can be easily achieved through filtration using sterile membrane filters.

[0184] The compounds of this invention can react with any of a variety of inorganic or organic acids to form pharmaceutically acceptable acid addition salts. Pharmaceutically acceptable salts and common methods for preparing them are well known in the art. See, for example, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Second Revised Edition (Wiley-VCH, 2011); SMBerge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January 1977. Commonly used pharmaceutically acceptable salts include trifluoroacetates, phosphates, acetates, citrates, hydrochlorides, etc.

[0185] The compounds of this invention can react with any of a variety of inorganic or organic bases to form pharmaceutically acceptable salts, commonly including sodium salts, potassium salts, ammonium salts, etc.

[0186] The pharmaceutical composition of the embodiments described herein is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, such as intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (i.e., local), transmucosal, and rectal administration. Solutions or suspensions for parenteral, intradermal, or subcutaneous administration may include the following components: sterile diluents for injection, such as water, saline solutions, fixative oils, polyethylene glycols, glycerol, propylene glycol, or other synthetic solvents; antibacterial agents, such as benzyl alcohol, methylparaben, phenol, or m-cresol; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid (EDTA); buffers, such as acetates, citrates, or phosphates; and osmotic pressure adjusting agents, such as sodium chloride or dextran. pH may be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. Parenteral formulations may be packaged in ampoules, vials, disposable syringes, glass or plastic multi-dose vials, or injection pens. There are two main types of injection pens: one is a disposable pre-filled pen containing medication, which can be discarded after use without needing to replace the medication cartridge; the other is a more commonly used durable injection pen, which consists of an injection pen and a medication cartridge, and can be used again after the cartridge is replaced.

[0187] Suitable pharmaceutical compositions for injection include sterile aqueous solutions (in this case, water-soluble) or dispersions, as well as sterile powders for immediate preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, antibacterial water, Cremophor EL™ (BASF, Parsippany, NJ), or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and its flowability should be sufficient for easy injection. It must be stable under manufacturing and storage conditions and must be resistant to contamination by microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. Suitable flowability can be maintained, for example, by using a coating such as lecithin to maintain the desired particle size in the case of dispersions, and by using surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, m-cresol, ascorbic acid, thimerosal, etc. In many cases, it is preferable to include isotonic agents in the composition, such as sugars, polyols (e.g., mannitol, sorbitol), and sodium chloride. Prolonged absorption of the injectable composition can be achieved by including absorption-retarding agents such as aluminum monostearate and gelatin in the composition.

[0188] As needed, sterile injectable solutions can be prepared by incorporating the compounds of the present invention in desired amounts into a suitable solvent having one or a combination of the components listed above (as desired), followed by filtration sterilization. Generally, dispersions are prepared by incorporating the compounds of the present invention into a sterile carrier containing a dispersion medium and the other desired components listed above. For sterile powders used to prepare sterile injectable solutions, the preparation method involves obtaining powders by vacuum drying and freeze-drying, the powders containing the active ingredient and any other desired components derived from a sterile filtered solution of these aforementioned components.

[0189] For inhalation administration, the compound is delivered in the form of an aerosol spray from a pressurized container or dispenser or nebulizer containing a suitable propellant such as carbon dioxide.

[0190] Systemic administration can also be achieved via mucosal or transdermal routes. For mucosal or transdermal administration, a penetrant suitable for the permeability barrier is used in the formulation. Such penetrants are generally known in the art and include detergents, bile salts, and fusidic acid derivatives, such as those used for mucosal administration. Mucosal administration can be achieved by using nasal sprays or suppositories. For transdermal administration, one or more of the compounds of the present invention can be formulated into ointments, ointments, gels, or creams as commonly known in the art.

[0191] The compound can also be prepared in the form of suppositories (e.g., having a conventional suppository base, such as cocoa butter or other glycerides) or retention enemas for rectal delivery.

[0192] In one embodiment, the compounds of the present invention can be prepared using a carrier that prevents their rapid elimination from the body, such as a sustained-release / controlled-release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene-vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such formulations will be apparent to those skilled in the art.

[0193] For example, these active ingredients can be encapsulated in microcapsules, such as those prepared by coagulation technology or interfacial polymerization, for example, hydroxymethyl cellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or macroemulsions.

[0194] Sustained-release formulations can be prepared. Examples of suitable sustained-release formulations include semi-permeable matrices of solid hydrophobic polymers containing the compounds of the present invention, which are in the form of molded articles such as membranes or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methylpropionate), or poly(vinyl alcohol)), polylactides (US Patent No. 3,773,919), copolymers of L-glutamic acid and γ-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic-glycolic acid copolymers such as LUPRON DEPOT™ (injectable microspheres composed of lactic-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid. While polymers such as ethylene-vinyl acetate and lactic-glycolic acid can release molecules for more than 100 days, some hydrogels release proteins for shorter periods. Polylactic acid (PLA) and polylactic-glycolic acid copolymer (PLGA) have been hot topics in recent years. In addition, there are albumin microspheres, chitosan microspheres, gelatin microspheres, etc.

[0195] Liposome suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example as described in U.S. Patent No. 4,522,811.

[0196] Particularly advantageous is the formulation of parenteral compositions in unit dosage form for ease of administration and dosage consistency. As used herein, unit dosage form refers to physically separable units suitable as unit doses for use in the subject to be treated; each unit contains a predetermined amount of one or more of the compounds of the invention calculated to bind with the desired drug carrier to produce the desired therapeutic effect. The specifications of the unit dosage form of the embodiments are indicated by and directly depend on: the unique characteristics of the compounds of the invention and the specific therapeutic effect to be achieved, and the inherent limitations in the field of formulation of such compounds of the invention for the individual to be treated.

[0197] The pharmaceutical composition may be placed in a container, package, or dispenser together with the instructions for use.

[0198] This invention provides a method for treating type 2 diabetes in patients, comprising administering an effective amount of the compound of the invention or a pharmaceutically acceptable salt thereof to a patient requiring such treatment. This invention also provides a method for treating type 2 diabetes in patients, comprising administering an effective amount of the compound of the invention or a pharmaceutically acceptable salt thereof to a patient requiring such treatment, wherein the administration is subcutaneous. This invention further provides a method for treating type 2 diabetes in patients, comprising administering an effective amount of the compound of the invention or a pharmaceutically acceptable salt thereof to a patient requiring such treatment, and simultaneously, separately, or sequentially administering effective amounts of one or more other active ingredients. In one embodiment, the other one or more active ingredients are currently available glucose-lowering drugs derived from drugs considered as standards of care prior to administration (as determined by industry guidelines such as those of the American Diabetes Association).

[0199] This invention also provides methods for treating or preventing the following diseases or conditions: impaired glucose tolerance (IGT), hyperglycemia, type 1 diabetes, type 2 diabetes, obesity, metabolic syndrome, and neurodegenerative diseases, particularly for delaying or preventing disease progression in type 2 diabetes, delaying the progression from impaired glucose tolerance to type 2 diabetes; delaying the progression from type 2 diabetes to insulin-dependent diabetes; treating metabolic syndrome by regulating appetite, inducing satiety, reducing food intake, increasing energy expenditure, treating obesity or preventing overweight; preventing weight rebound after successful weight loss; treating diseases or conditions associated with overweight or obesity; treating bulimia; treating binge eating; treating dyslipidemia, atherosclerosis, hypertension, coronary heart disease, beta-blocker poisoning; non-alcoholic fatty liver disease (NAFLD) (which can be divided into simple fatty liver (SFL), non-alcoholic steatohepatitis (NASH), and related cirrhosis); and for inhibiting gastrointestinal motility, for use in conjunction with gastrointestinal surveys using techniques such as X-ray, CT, and NMR scanning. The method includes administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof or a solvate thereof to a patient in need of such treatment, and simultaneously, separately, or sequentially administering effective amounts of one or more other active ingredients.

[0200] Further preferred medicinal uses include the treatment or prevention of degenerative diseases, particularly neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, ataxia (e.g., spinocerebellar ataxia), Kennedy's disease, myotonic dystrophy, Lewy body dementia, multiple systemic atrophy, amyotrophic lateral sclerosis (ALS), primary ALS, spinal muscular atrophy, prion-related diseases (e.g., Creutzfeldt-Jacob disease), multiple sclerosis, capillary aplasia, Batten's disease, corticobasal degeneration, subacute combined degeneration of the spinal cord, tabes dorsalis, and Tay-Sachs disease. Diseases, toxic encephalopathy, infantile Refsum disease, neuroacanthosis, Niemann-Pick disease, Lyme disease, Machado-Joseph disease, Sandhoff disease, Shy-Drager syndrome, wobbly hedgehog syndrome, primary disease (proteopathy), cerebral β-amyloid angiopathy, retinal ganglion cell degeneration in glaucoma, synucleinopathies, tauopathies, frontotemporal lobe degeneration (FTLD), dementia, Cadasil syndrome, hereditary cerebral hemorrhage with amyloidosis, Alexander disease, seipinopathies, familial amyloid neuropathy, senile systemic amyloidosis. Amyloidosis, serpinopathies, AL (light chain) amyloidosis (primary systemic amyloidosis), AH (heavy chain) amyloidosis, AA (secondary) amyloidosis, and intra-aortic amyloidosis (aortic medial)Amyloidosis, ApoAI amyloidosis, ApoAII amyloidosis, ApoAIV amyloidosis, Finnish familial amyloidosis (FAF), lysozyme amyloidosis, fibrinogen amyloidosis, dialysis amyloidosis, inclusion body myositis / myopathy, cataract, retinitis pigmentosa with rhodopsin mutation, medullary thyroid carcinoma, atrial amyloidosis, pituitary prolactinoma, hereditary latticecorneal dystrophy, cutaneous lichenoid amyloidosis, Mallory bodies, corneal lactoferrin amyloidosis, pulmonary alveolar proteinosis, pindborg tumor amyloidosis, cystic fibrosis, sickle cell disease, or critical illness myopathy (CIM). Further medical applications include treating bone-related conditions such as osteoporosis or osteoarthritis, where increased bone formation and reduced bone resorption may be beneficial.

[0201] Abbreviations Protective base: Aloc or AOC, allyloxycarbonyl: allyloxycarbonyl; Bom, benzyloxymethyl: benzyloxymethyl; 2-Br-Z, 2-bromobenzyloxycarbonyl: 2-bromobenzyloxycarbonyl; tBu, t-butyl: tert-butyl; Bz, benzoyl: benzoyl; Bzl, benzyl: benzyl; Boc, tert-butoxycarbonyl: tert-butoxycarbonyl; CHO, formyl: formyl; cHx, cyclohexyl: cyclohexyl; Cbz or Z, benzyloxycarbonyl: benzyloxycarbonyl; 2-Cl-Z, 2-chlorobenzyloxycarbonyl: 2-chlorobenzyloxycarbonyl; Fm, 9-fluorenylmethyl: 9-fluorenylmethyl; Fmoc, 9-fluorenylmethoxycarbonyl: 9-fluorenylmethoxycarbonyl; Mtt, 4-methyltrityl: 4-methyltriphenylmethyl; Pmc, (2,2,5,7,8-pentamethylchroman-6-sulphonyl: 2,2,5,7,8-pentamethyl-6-hydroxychromanyl; Tos, 4-toluenesulphonyl: p-toluenesulfonyl; Trt, triphenylmethyl: triphenylmethyl; Xan,xanthyl: xanthyl, xanthyl.)

[0202] Reagents and solvents: ACN, acetonitrile: acetonitrile; BOP, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate: benzotriazol-1-tris(trimethylamino)-hexafluorophosphate (Carter's condensing agent); DCC, N,N'-Dicyclohexylcarbodiimide: dicyclohexylcarbodiimide; DCM: dichloromethane; DEPBT, 3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one: 3-(diethoxy-o-acyloxy)-1,2,3-benzotriazine-4-one; DIC, N,N'-Diisopropylcarbodiimide: N,N'-diisopropylcarbodiimide; DIPEA (or DIEA), diisopropylethylamine: diisopropylethylamine; DMF: N,N-dimethylformamide; DMSO: dimethyl sulfoxide; EDC or EDCI, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride: 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; EtOAc: ethyl acetate; HATU, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate: 1-[di(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HBTU, O-(1H-benzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate: benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate; HOAT, 1-Hydroxy-7-azabenzotriazole: 1-hydroxy-7-azabenzotriazole; HOBT, 1-hydroxybenzotriazole: 1-hydroxy-benzotriazole; Cl-HOBT: 6-chloro-1-hydroxy-benzotriazole; NMM, N-Methylmorpholine: N-methylmorpholine; NMP, N-methylpyrrolidinone: N-methylpyrrolidone; Su, succinimide: succinimide; TBTU, 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate: O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate; TEA, triethylamine: triethylamine; TFA, trifluoroacetic acid; TIS, triisopropylsilane: triisopropylsilane; TMP, 2,2,6,6-Tetramethylpiperidine: 2.2,6,6-tetramethylpiperidine.

[0203] Polypeptide chemical synthesis methods Solid-phase chemical synthesis of peptides is a well-developed methodology, as can be found in references such as R.C. Sheppard, Solid Phase Peptide Synthesis. A Practical Approach, Oxford-IRL Press, New York, 1989.

[0204] Linear peptides are synthesized using either the Boc solid-phase peptide synthesis method or the Fmoc solid-phase peptide synthesis method. For Fmoc chemical synthesis of peptides with a C-terminal carboxyl group, Wang resin is typically used; for C-terminal amide peptides, Rink amide resin (including Rink Amide-AM resin, Rink Amide-MBHA resin, and similar resins) is typically used. For Boc chemical synthesis of peptides with a C-terminal carboxyl group, Pam resin is typically used; for C-terminal amide peptides, MBHA resin is typically used. Commonly used condensing agents and activators are DIC and HOBT; other optional peptide bond condensing agents include EDC, BOP, HBTU, DEPBT, and TBTU. Depending on the reaction complexity, amino acids can be used in 1.1-10 equivalents, with reaction times ranging from 15 minutes to 24 hours. Peptides can be synthesized manually or using a peptide solid-phase synthesizer.

[0205] The Fmoc protecting group was removed using 20% ​​piperidine / DMF. The Boc protecting group was removed using TFA. The peptide bond condensation reaction was monitored using ninhydrin (2,2-Dihydroxyindane-1,3-dione) reagent.

[0206] Solid-phase synthesis can use resins pre-loaded with C-terminal amino acids or resins without amino acid loading.

[0207] The method for loading the first amino acid onto Rink Amide resin can be found in industry practice. A common method is briefly described below: Weigh an appropriate amount of resin and remove the Fmoc protecting group in a solid-phase synthesis tube using 20% ​​piperidine / DMF (15 mL / g resin, 30 min x 2). Wash the resin with DMF. Weigh an amount of Fmoc amino acid equivalent to 5 times the resin amino group, HATU, HOAT, and NMM equivalent to 10 times the resin amino group. Add DMF, mix well, and transfer to a solid-phase synthesis tube. React overnight, then wash the resin with DMF. Add a 1:1 acetic anhydride / pyridine (v / v) mixture to the solid-phase synthesis tube, drain after 30 minutes, and wash the resin with DMF. The first amino acid is now loaded.

[0208] The commonly used amino acids and protecting groups in Fmoc solid-phase peptide synthesis are as follows: Fmoc-Cys(Trt)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-His(Trt)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Asn(Trt)-O H, Fmoc-Gln(Trt)-OH, Fmoc-Arg(Pmc)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Trp(Boc)-OH, Fmoc-Tyr(tBu)-OH The synthesis utilizes appropriately protected structural units, such as the aforementioned standard amino acids, Fmoc-8-amino-3,6-dioxanoic acid (CAS No. 166108-71-0), and Fmoc-Glu-OtBu (CAS No. 84793-07-7). The introduction of the fatty acid moiety can be achieved using structural units, such as, but not limited to, eicosanoic acid monotert-butyl ester. After each coupling step, the unreacted peptide intermediate can be capped with acetic anhydride (10 equivalents) and excess chlorhexidine (20 equivalents).

[0209] After solid-phase Fmoc chemical synthesis of peptides, the commonly used cleavage reagent is TFA. Dry resin is placed in a shake flask, and an appropriate amount of cleavage buffer containing 90:4:2:2:2 (v / v) trifluoroacetic acid:triisopropylsilane:1,2-ethylenedithiol:water:benzyl sulfide (10-25 mL / g resin) is added. The flask is capped, and the mixture is subjected to intermittent rotary shaking at room temperature. After 2 hours, the resin is filtered, and washed 2-3 times with fresh TFA. The filtrates are combined, and 8-10 times their volume of ice-cold diethyl ether is added dropwise. Finally, the precipitated crude peptide is collected by centrifugation.

[0210] The following amino acids and protecting groups are commonly used in Boc solid-phase peptide synthesis: Boc-Cys(4-MeBzl)-OH, Boc-Asp(OcHx)-OH, Boc-Glu(OcHx)-OH, Boc-His(Bom)-OH, Boc-Lys(2-Cl-Z)-OH, Boc- Asn(Xan)-OH, Boc-Arg(Tos)-OH, Boc-Ser(Bzl)-OH, Boc-Thr(Bzl)-OH, Boc-Trp(CHO)-OH and Boc-Tyr(2-Br-Z)-OH If the side-chain amino group of lysine is used for the synthesis of lactams or acylation reactions, the side-chain amino group of lysine can be protected with an allyloxycarbonyl (aloc) or Fmoc. If the side-chain carboxyl group of aspartic acid or glutamic acid is used for the synthesis of lactams or acylation reactions, the carboxyl group should be converted to an allyl ester or 9-fluorenylmethyl for protection, such as Boc-Glu(OAllyl)-OH or Boc-Glu(Ofm)-OH.

[0211] After solid-phase Boc chemical synthesis of peptides, HF cleavage is typically performed on PAM and MBHA resins. 5 mL of HF is added for every 0.1 mmol of resin, along with reagents such as p-cresol, p-mercaptophenol, or anisole. The mixture is stirred in an ice bath for 1 hour. After vacuum drying of the HF, the peptides are precipitated with ice-cold diethyl ether. The precipitate is collected by centrifugation, purified by HPLC, and then freeze-dried to obtain the final product.

[0212] purification The crude peptide was dissolved in a suitable mixture of water and acetonitrile (e.g., water / acetonitrile (3:1)) and purified by reversed-phase preparative HPLC (e.g., AKTA purifier, Shimadzu LC-20AR, etc.). Different packing materials and column sizes were selected based on the amount of crude peptide loaded and its polarity, such as C8 or C18 semi-preparative or preparative columns. Buffer A was 0.1% TFA aqueous solution, and buffer B was 0.1% TFA and 100% acetonitrile. Elution was performed using a gradient uplift of buffer B. The relevant fraction was examined by analytical HPLC using a ZORBAX 300 SB-C18 (4.6 x 250 mm, 5 µM) column with 0.1% TFA aqueous solution in buffer A and 0.1% TFA and 100% acetonitrile in buffer B. The flow rate was 1 ml / min, and detection was performed at 210 nm. The fractions containing the target peptide of acceptable purity were mixed and freeze-dried to obtain a white solid polypeptide. The product was aliquoted into glass vials for storage.

[0213] Preparation method (1) The compound of this invention is a linear peptide. Each amino acid can be sequentially coupled from the C-terminus to the N-terminus of the polypeptide sequence to obtain the polypeptide backbone. The process is as follows: First, an amino acid with one amino group protected by a blocking group is covalently linked to a solid support. The amino protecting group of the first amino acid is then removed, thus attaching the first amino acid to the solid support. Next, the carboxyl group of the second amino acid with its amino group blocked is activated and reacts with the amino group of the first amino acid already attached to the solid support to form a peptide bond, thereby generating a dipeptide with a protecting group on the solid support. This peptide bond formation reaction is repeated to elongate the peptide chain from the C-terminus to the N-terminus until the desired peptide chain is formed. Finally, the polypeptide is cleaved and separated from the resin, purified, and lyophilized to obtain the polypeptide product.

[0214] Some compounds of this invention are synthesized by conjugating long-acting groups or modifying groups to the side chains of amino acids containing amino or thiol groups. Compound 12 is used as an example to illustrate the synthetic route and method.

[0215] The synthesis of compound 12 includes the following steps: Step A: Fmoc-Lys(PG)-OH is coupled with resin to obtain Fmoc-Lys(PG)-resin, where PG is the protecting group of the amino group on the lysine side chain; Step B: Fmoc-Lys(PG)-resin is first stepwise coupled with amino acids or amino acid derivatives to obtain a first peptide resin with the sequence shown in the main peptide chain of compound 12. Step C: Remove the side chain protecting group PG of the Lys terminal of the main peptide chain in the first peptide resin, as shown in the main peptide chain of compound 12, and then perform a second stepwise coupling with 2-(2-(2-aminoethoxy)ethoxy)acetic acid, 2-(2-(2-aminoethoxy)ethoxy)acetic acid, γ-Glu and eicosanoic acid to obtain the second peptide resin. Step D: The second peptide resin was cleaved, purified, and lyophilized to obtain compound 12.

[0216] Preferably, the resin in step A can be a Rink Amide resin (including Rink Amide-AM resin, Rink Amide-MBHA resin, and similar resins). Preferably, the side chain protecting group of Lys is aloc, Mmt, Mtt, Dde, or ivDde.

[0217] Preferably, the reagents used for coupling are selected from DIC+A, B+A+C or B+C, wherein A is selected from HOAt or HOBt, B is selected from EDC, HATU, BOP, PyBOP, PyAOP, HBTU, TBTU or DEPBT, and C is selected from DIPEA, TEA, NMM or TMP.

[0218] For example, the coupling agents used in the first stepwise coupling in step B and the second stepwise coupling in step C include condensing agents and reaction solvents. The condensing agent can be a mixture of DIC and HOBt, a mixture of PyBOP, HOBt, and DIEA, or a mixture of HATU, HOAt, and DIEA, or a mixture of DEPBT and DIEA, or a mixture of HBTU and DIEA. The reaction solvent is one, two, or a mixture of more than two of DMF, DCM, NMP, or DMSO.

[0219] In step B, during the first stepwise coupling, based on the sequence of compound 12, Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc-Ala-OH, Fmoc-Gly-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Gly-OH, Fmoc-Gly-OH, Fmoc-Ala-OH, Fmoc-Leu-OH, Fmoc-Leu-OH, Fmoc-Trp(Boc)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Ile–OH, Fmoc-Phe-OH, Fmoc-Leu-OH, and Fmoc-Arg(Pbf)-OH are sequentially coupled. Fmoc-Val-OH, Fmoc-Ala-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Leu-OH, Fmoc-Ala-OH, Fmoc-Ile–OH, Fmoc-Ser(tBu)-OH, Fmoc-Leu-O H, Fmoc-Asp(OtBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Phe-OH, Fmoc-Thr(tBu)-OH, Fmoc-Gly-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Aib-OH and Boc-Tyr(tBu)-OH.

[0220] When PG is alooc, the reagent used for deprotection in step C is 1-20 equivalents of morpholine (or 1-20 equivalents of benzylsilane instead of morpholine) and 0.05-3 equivalents of Pd(PPh3)4. Preferably, the alooc protecting group is removed using 5-10 equivalents of morpholine (or 5-10 equivalents of benzylsilane instead of morpholine) and 0.1-0.3 equivalents of Pd(PPh3)4. The protecting group removal reaction can be carried out twice, each time for 10-30 minutes, with CH2Cl2 preferably used as the solvent.

[0221] Another method for removing the Aloc protecting group is to stir for 2 hours at room temperature under argon atmosphere with a catalytic amount of tetra(triphenylphosphine)palladium(0) and a 37:2:1 ratio of DCM, glacial acetic acid, and NMM (15 mL / g resin). After the reaction, each gram of resin is washed with 0.5% DIPEA / DMF (10 mL), 0.5% sodium diethyldithiocarbamate / DMF (3 x 10 mL), and 1:1 DCM:DMF (5 x 10 mL).

[0222] When PG is Dde or ivDde, the reagent used for deprotection in step C is a hydrazine hydrate / DMF mixture. Prepare a 2% (w / v) hydrazine hydrate DMF solution (25 mL / g resin), add it to the resin, dry it after 5 minutes, and wash the resin with DMF. Repeat the process of deprotection with 2% hydrazine hydrate / DMF and washing with DMF three times.

[0223] When PG is Mmt or Mtt, the reagent used to remove the protecting group in step C is a 1-2% TFA / DCM mixture.

[0224] In step C, during the second stepwise coupling, Fmoc-8-amino-3,6-dioxanoic acid (CAS No. 166108-71-0), Fmoc-8-amino-3,6-dioxanoic acid, Fmoc-Glu-OtBu (CAS No. 84793-07-7), and HOOC-(CH2) monotert-butyl eicosanoate are stepwise coupled according to the sequence of compound 12. 18 -COOtBu. The reagents used for pyrolysis in step D include TFA and one, two, or a mixture of more than two of PhSMe, PhOMe, EDT, H2O, TIS, and PhOH. For example, the reagent used for pyrolysis is a mixture of TFA, anisole, dimethyl sulfide, and EDT, with a volume ratio of 90:5:3:2. Preferably, the reagent used for pyrolysis is a mixture of TFA, H2O, and TIS, with a volume ratio of 95:2.5:2.5.

[0225] Preparation method (2) In this invention, some compounds are coupled with long-acting groups or modifying groups via the side-chain amino or thiol groups of amino acids containing amino or thiol groups. The compounds can be sequentially coupled with each amino acid from the C-terminus to the N-terminus of the polypeptide sequence until the amino acid residue X requiring the long-acting or modifying group is coupled. Without affecting the protecting group of the α-amino group of amino acid residue X, the side-chain protecting group of amino acid residue X is removed to complete the synthesis of the long-acting or modifying group. Then, the protecting group of the α-amino group of amino acid residue X is removed, and each remaining amino acid in the polypeptide backbone is sequentially coupled to obtain the complete polypeptide. Finally, the polypeptide is cleaved and separated from resin, purified, and lyophilized to obtain the polypeptide product.

[0226] The synthetic route and method are illustrated using compound 12 as an example. The synthesis of compound 12 includes the following steps: Step A: Couple PG1-Lys(PG2)-OH with resin to obtain PG1-Lys(PG2)-resin, where PG1 is the protecting group of lysine α-amino and PG2 is the protecting group of lysine side chain amino. Step B: Remove the side chain protecting group PG2 of lysine from the PG1-Lys(PG2)-resin, and then proceed with a second stepwise coupling of 2-(2-(2-aminoethoxy)ethoxy)acetic acid, 2-(2-(2-aminoethoxy)ethoxy)acetic acid, γ-Glu and eicosanoic acid to obtain the third peptide resin; Step C: Remove the protecting group PG1 of the α-amino group of the lysine, and then couple an amino acid or amino acid derivative through a first stepwise coupling to obtain a fourth peptide resin with the sequence shown in compound 12. Step D: The fourth peptide resin was cleaved, purified, and lyophilized to obtain compound 12.

[0227] Preferably, the resin used in step A can be Rink Amide resin (including Rink Amide-AM resin, Rink Amide-MBHA resin, and similar resins).

[0228] Preferably, the protecting group PG2 of the Lys side chain is Fmoc, aloc, Mmt, Mtt, Dde, or ivDde. The protecting group PG1 of the α-amino group of Lys is aloc, Mmt, Mtt, Dde, or ivDde. PG1 and PG2 must be orthogonal. Examples of PG1-Lys(PG2)-OH used for the synthesis of compound 12 include Dde-Lys(Fmoc)-OH, Alloc-Lys(Fmoc)-OH, etc. For the removal of protecting groups, refer to the preparation method (1), examples, or literature on solid-phase synthesis of peptides.

[0229] Preferably, the reagents used for coupling are selected from DIC+A, B+A+C or B+C, wherein A is selected from HOAt or HOBt, B is selected from EDC, HATU, BOP, PyBOP, PyAOP, HBTU, TBTU or DEPBT, and C is selected from DIPEA, TEA, NMM or TMP.

[0230] In step B, during the second stepwise coupling, based on the sequence of compound 12, Fmoc-8-amino-3,6-dioxanoic acid (CAS No. 166108-71-0), Fmoc-8-amino-3,6-dioxanoic acid, Fmoc-Glu-OtBu (CAS No. 84793-07-7), and HOOC-(CH2) monotert-butyl eicosanoate are stepwise coupled. 18 -COOtBu.

[0231] In step C, during the first stepwise coupling, based on the sequence of compound 12, Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc-Ala-OH, Fmoc-Gly-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Gly-OH, Fmoc-Gly-OH, Fmoc-Ala-OH, Fmoc-Leu-OH, Fmoc-Leu-OH, Fmoc-Trp(Boc)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Ile–OH, Fmoc-Phe-OH, Fmoc-Leu-OH, and Fmoc-Arg(Pbf)-OH are sequentially coupled. Fmoc-Val-OH, Fmoc-Ala-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Leu-OH, Fmoc-Ala-OH, Fmoc-Ile–OH, Fmoc-Ser(tBu)-OH, Fmoc-Leu-O H, Fmoc-Asp(OtBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Phe-OH, Fmoc-Thr(tBu)-OH, Fmoc-Gly-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Aib-OH and Boc-Tyr(tBu)-OH.

[0232] Preferably, the pyrolysis method in step D is the same as the reagents and preparation method (1).

[0233] This invention also includes novel intermediates and methods for synthesizing the compounds of the invention or pharmaceutically acceptable salts thereof. The intermediates and compounds of the invention can be prepared by a variety of methods known in the art. In particular, the following examples illustrate methods using chemical synthesis. The specific synthetic steps of each described route can be combined in different ways to prepare the compounds of the invention or salts thereof. Reagents and raw materials are readily available to those skilled in the art.

[0234] Example The invention is further illustrated with reference to the embodiments. These embodiments are not intended to limit the scope of the claimed invention. Those skilled in the art can draw upon the content of this invention, appropriately modify process parameters, and make modifications or appropriate changes and combinations to the methods and applications described in this invention to implement and apply the technology of this invention. All similar substitutions and modifications will be apparent to those skilled in the art, and they are all considered to be included in this invention.

[0235] Amino acid raw materials and condensation reagents were purchased from Jier Biochemical (Shanghai) Co., Ltd. Rink Amide resin was purchased from Shangyu Puer Company and Tianjin Nankai Hecheng Technology Co., Ltd.

[0236] Example 1: Synthesis of Compound 58 Pre-loaded Fmoc-Ser(tBu)-Rink Amide resin was selected, and the Fmoc protecting group was removed with 20% piperidine / DMF (2 x 10 min). The resin was washed three times with DMF. The Fmoc solid-phase peptide synthesis method was used. Amino acids (10 equivalents relative to the resin amino acid loading) were dissolved in DMF, and then HOBT and DIC (10 equivalents relative to the resin amino acid loading) were added. After mixing, the mixture was added to the resin, and coupling was carried out at room temperature for 120 min. The solution in the solid-phase reaction tube was drained, and the resin was washed three times with DMF. This completes the coupling of one synthetic unit. Each synthetic unit of the peptide from the C-terminus to the N-terminus used the same coupling method. Amino acid residues used the protecting groups commonly used in Fmoc solid-phase synthesis listed in the "Solid-Phase Chemical Synthesis Methods of Peptides" and the preparation method section, or other protecting groups suitable for this sequence. The tyrosine residue at the N-terminus of the main peptide chain was Boc-Tyr(tBu)-OH. The 24th amino acid from the N-terminus, Lys24, is represented by Fmoc-Lys(Dde)-OH.

[0237] After the main peptide chain was synthesized, the Dde protecting group on the Lys24 side chain was removed using 2% hydrazine hydrate / DMF. A 2% (w / v) hydrazine hydrate DMF solution (25 mL / g resin) was prepared, added to the resin, dried under vacuum after 10 minutes, and then washed with DMF. The process of deprotection with 2% hydrazine hydrate / DMF and washing with DMF was repeated three times.

[0238] The Lys24 side chain substituents were synthesized using the structural units Fmoc-8-amino-3,6-dioxanoic acid (CAS No. 166108-71-0), Fmoc-Glu-OtBu (CAS No. 84793-07-7), and HOOC-(CH2) monotert-butyl eicosanoate. 18 -COOtBu. The amount of side chain substituents used in each structural unit is 10 equivalents of the resin amino acid loading, and the coupling time for each step is 4 hours.

[0239] After peptide synthesis, the resin was washed with DCM, and a cleavage buffer containing 90:4:2:2:2 (v / v) trifluoroacetic acid:triisopropylsilane:1,2-ethylenedithiol:water:benzyl sulfide (10-25 mL / g resin) was added. The mixture was shaken at room temperature for 2 hours and precipitated with ice-cold diethyl ether. The crude peptide was dissolved in an aqueous solution of 0.1% TFA and 30% acetonitrile and eluted by semi-preparative or preparative RP-HPLC using, for example, a Luna C18 30 x 250 mm, 5 µM reversed-phase column. Buffer A was a 0.1% TFA aqueous solution, and buffer B was 0.1% TFA and 100% acetonitrile. Buffer B was used for elution with a gradient increase, and the correct fractions were combined and freeze-dried at low temperature to obtain a white solid. The structure of the peptide was determined by mass spectrometry and amino acid sequencing. Compounds with a serine residue at the C-terminus in this invention can be synthesized according to the method of Example 1.

[0240] Example 2 Synthesis of Compound 15 Pre-loaded Fmoc-Lys(Aloc)-Rink Amide resin (e.g., 0.29 mmol / g) was selected. Each synthetic unit of the peptide from the C-terminus to the N-terminus was synthesized using the coupling method described in Example 1. Amino acid residues other than the C-terminal lysine and the N-terminal Boc-Tyr(tBu)-OH were protected using the protecting groups commonly used in Fmoc solid-phase synthesis or other protecting groups suitable for this sequence, as listed in the "Solid-Phase Chemical Synthesis of Peptides" and "Preparation Methods" sections. After the main peptide chain synthesis, the allyloxycarbonyl group of the C-terminal lysine side chain was removed by stirring tetrakis(triphenylphosphine)palladium(0) with DCM, glacial acetic acid, and NMM (15 mL / g resin) in a 37:2:1 ratio at room temperature under argon atmosphere for 2 hours. The tetrakis(triphenylphosphine)palladium(0) could be used in amounts up to 1 equivalent. After the reaction, each gram of resin was washed with 0.5% DIPEA / DMF (10 mL), 0.5% sodium diethyldithiocarbamate / DMF (3 x 10 mL), and 1:1 DCM:DMF (5 x 10 mL). The Aloc protecting group can also be removed with 5-10 equivalents of morpholine (or 5-10 equivalents of benzenesilane) and 0.1-0.3 equivalents of Pd(PPh3)4. The protecting group removal reaction can be carried out twice, 30 minutes each time, using CH2Cl2 as the solvent. After removing the Aloc protecting group from the side chain, the synthesis method and steps of this lysine side chain substituent are as described in Example 1.

[0241] Another method involves using pre-loaded Fmoc-Lys(ivDde)-Rink Amide resin. The synthesis method of the main peptide chain is the same as the method using Fmoc-Lys(Aloc)-Rink Amide resin in the previous section. After the main peptide chain is synthesized, the ivDde protecting group of the C-terminal lysine side chain is removed using 2% hydrazine hydrate / DMF. A 2% (w / v) hydrazine hydrate DMF solution (25 mL / g resin) is prepared, added to the resin, dried under vacuum after 10 minutes, and the resin is washed with DMF. The process of removing the protecting group with 2% hydrazine hydrate / DMF and washing with DMF is repeated three times. The synthesis method and steps of this lysine side chain substituent are similar to those in Example 1.

[0242] When PG is Mmt or Mtt, the reagent used to remove the protecting group in step C is a 1-2% TFA / DCM mixture.

[0243] In this invention, compounds with a C-terminus of lysine and a side chain amino group connected to a long-acting group can be synthesized using the method of Example 2, or by using the synthetic route and method of compound 12 in the "Preparation Method" section.

[0244] Example 3 Synthesis of Compound 11 Pre-loaded Fmoc-Cys(Trt)-Rink Amide resin was selected. The remaining synthesis methods and steps were similar to those in Example 1. Compounds with a cysteine ​​residue at the C-terminus in this invention can be synthesized according to the method in Example 3.

[0245] Example 4: Synthesis of Compound 65 Pre-loaded Fmoc-Ala-Rink Amide resin was selected. The remaining synthesis methods and steps were similar to those in Example 1. Compounds with an alanine terminal in this invention can be synthesized according to the method in Example 4.

[0246] Example 5: Synthesis of Compound 279 Pre-loaded Fmoc-Gly-Rink Amide resin was selected. The remaining synthesis methods and steps were similar to those in Example 1. Compounds with glycine at the C-terminus in this invention can be synthesized according to the method in Example 5.

[0247] Example 6 Synthesis of Compound 356 Pre-loaded Fmoc-Pro-Rink Amide resin was selected. The remaining synthesis methods and steps were similar to those in Example 1. Compounds with a proline terminal in this invention can be synthesized according to the method in Example 6.

[0248] Table 1 lists the calculated and measured molecular weights of some of the compounds in this invention.

[0249] Table 1 Mass spectrometry molecular weight and amino acid sequencing results confirmed the correct peptide structure.

[0250] The peptides were dissolved in physiological saline (pH 7.4) to prepare a stock solution. The peptide concentration in the stock solution was quantified using conventional methods such as the Bradford method and ultraviolet spectrophotometry. Before animal efficacy studies, a stock solution containing the required dose of peptides was prepared and diluted with phosphate-buffered saline (PBS, pH 7.4) to prepare an injection solution. The optimal injection volume per animal was 5 ml / kg body weight. This can be used to calculate the required volume of injection solution.

[0251] All data from animal experiments will be entered into an Excel document and expressed as mean ± SEM. Differences among multiple groups will be compared using GraphPad Prism 6 software using Dunnett's one-way analysis of variance (ANOVA). Differences between two groups will be compared using an unpaired T-test. A p-value less than 0.05 is considered statistically significant.

[0252] Example 7 The in vivo efficacy of the peptides of this invention can be determined in any suitable animal model known in the art, as well as in clinical trials. For example, the db / db mouse is a suitable animal model for diabetes.

[0253] db / db mice were housed in strictly controlled environments, with the temperature maintained at 20–24°C and humidity at 40–70%. Temperature and humidity were monitored in real-time using a thermometer and hygrometer, and recorded twice daily (once in the morning and once in the afternoon). Lighting in the enclosures was controlled by an electronic timer system, with lights on for 12 hours and off for 12 hours daily (starting at 7:00 AM and ending at 7:00 PM). During the experiment, animals were housed individually, with toys provided to each cage. Animals had free access to water. Male db / db mice (7 weeks old) were acclimatized to the experimental environment for one week. Baseline blood glucose and body weight were recorded for the first three days of the experiment (days -3 to -1). Based on these three-day blood glucose and body weight data, mice were randomly assigned to groups of six. Mice were subcutaneously injected with physiological saline (5 ml / kg, control group) or peptide compounds 12 and 15 (10 nmol / kg). Blood samples were collected at 0 hours before administration and at 1, 4, 8, 24, 36, and 48 hours after administration. Blood glucose levels were measured using a Johnson & Johnson OneTouch blood glucose meter and matching test strips. Blood glucose curves were plotted with time on the x-axis and blood glucose values ​​at different time points on the y-axis. The area under the curve (AUC) was calculated to compare the time and efficacy of the peptide compounds in lowering blood glucose.

[0254] The results are as follows Figure 1 As shown, peptide compounds 12 and 15 significantly reduced blood glucose levels in type 2 diabetic mice, showing a statistically significant difference compared to the control group. These two compounds have the potential to serve as long-acting therapeutic agents for diabetes.

[0255] Example 8 The in vivo efficacy of the peptides of this invention can be determined in any suitable animal model known in the art. Diet-induced obese (DIO) mice are commonly used animal models for obesity, insulin resistance, and hyperlipidemia.

[0256] Five-week-old male C57BL / 6 mice were housed in an animal enclosure with strictly controlled environmental conditions. The temperature was maintained at 20–24 °C, and the humidity at 30–70%. Temperature and humidity were monitored in real-time using a thermometer and hygrometer, and recorded twice daily, once in the morning and once in the afternoon. Lighting in the enclosure was controlled by an electronic timed lighting system, with lights on for 12 hours and off for 12 hours daily (starting at 6:00 AM and ending at 6:00 PM). During the experiment, animals were housed individually, and each mouse was provided with toys. Animals were fed a high-fat diet from six weeks of age (the weight ratio of nutrients was 26.2% protein, 26.3% carbohydrates, and 36.9% fat, providing 20%, 20%, and 60% of the total calories, respectively). Animals had free access to water. Two-six-week-old male DIO mice with an average weight of approximately 50 grams were selected for the experiment. Animals underwent one week of acclimatization by handling and subcutaneous injection. Animals were weighed and fed for three consecutive days before the experiment. Blood glucose levels were measured one day before the experiment. Animals were then grouped into groups of eight based on their blood glucose and weight.

[0257] During the experiment, the control group received subcutaneous injections of PBS every 2 days. The liraglutide group received subcutaneous injections of liraglutide (60 nmol / kg) every 2 days. The other three groups received subcutaneous injections of peptides 55, 58, and 243 (20 nmol / kg) every 2 days, respectively, for a total of 11 administrations. Animal weight was measured on day 23. Percentage change in body weight = [(final body weight - initial body weight) / initial body weight] * 100%.

[0258] The results are as follows Figure 2 As shown, peptide compounds 55, 58, and 243 all significantly reduced the body weight of DIO mice compared to the control group, and were significantly superior to liraglutide. These compounds have the potential to be used as long-acting weight-loss drugs.

[0259] Example 9 Pharmacokinetic Study Eight SD rats (half male and half female), aged 8 weeks and weighing 200-300g, were used in each group to study the pharmacokinetic characteristics of the compounds of this invention after a single subcutaneous injection in rats. Compounds 12, 15, and the control compound (peptide compound 27 described in PCT / CN2020 / 070697) were dissolved in PBS to prepare 1 mg / mL solutions. These solutions were subcutaneously injected at a dose of 75 μg / kg. Whole blood samples (0.2 ml) were collected at 0, 0.5, 2, 4, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours and transferred to EDTA-K2 anticoagulant tubes. The tubes were centrifuged at 1200-1500 ×g for 10-15 minutes at 2-8℃. The plasma was separated into clean tubes, labeled, and stored at -60 to -90℃. The peptide concentration in each sample was determined using LC-MS / MS on a QTRAP® 6500 (Applied Biosystems / Sciex) mass spectrometer. Pharmacokinetic parameters were calculated using a non-compartmental model with WinNonLin v 6.4 (Pharsight Inc.) software. The half-life of compound 12 was 9.82 ± 0.49 h, the half-life of compound 15 was 10.46 ± 0.71 h, and the half-life of the control compound was 7.93 ± 0.72 h.

Claims

1. A peptide compound of formula (I) or a pharmaceutically acceptable salt thereof, Y-aib-EGTFTSD-X1-S-X11-X2-X12-E-X3-X4-A-X5-X6-X13-F-X7-X8-WL-X9-X14-G-X10 (I) in, X1 represents L amino acid residue; X3 represents K amino acid residue; X4 represents E amino acid residue; X5 represents V amino acid residue; X6 represents R amino acid residue; X7 represents I amino acid residue; X10 represents GPSSGAPPP, with an S amino acid residue added to the C-terminus of X10; X11 represents I amino acid residue; X12 represents L amino acid residue; X13 represents L amino acid residue; X14 represents A amino acid residue. X2 represents an amino acid residue of Y, X9 represents an amino acid residue of I, and X8 represents an amino acid residue of K, or X2 represents an amino acid residue of A, X9 represents an amino acid residue of K, and X8 represents an amino acid residue of K, wherein the K represented by X8 has its side chain amino acid modified by a long-acting group of formula (IV). Alternatively, X2 represents the amino acid residue of Q, X9 represents the amino acid residue of L, and X8 represents the amino acid residue of C; the C amino acid residue is modified with a long-acting group of formula (IV) on its side chain thiol group, wherein the connection relationship between the cysteine ​​side chain thiol group and the long-acting group is: cysteine ​​side chain thiol group - thiol reactive group - optional linking group L - long-acting group. The long-lasting group has the structure of formula (IV): O1-O2-O3-O4-O5-O6-O7-O8- (IV), Where O1 represents the structure of formula (V): （V） Where n2 is an integer between 16 and 22; The wavy line represents the linking point of an amino group to an adjacent group, and O2-O3-O4-O5-O6-O7-O8- represents a linker, wherein each of O2 to O8 is independently represented by any one of the following amino acid residues or long chain structures: α-Glu, γ-Glu, α-Asp, β-Asp, α-hGlu, δ-hGlu, Gly, Ala, β-Ala, GABA or PEG2, or one or more of O2 to O8 are absent, provided that at least two of O2 to O8 are present, and O2 to O8 contain at least one negatively charged moiety.

2. The peptide compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein O2-O3-O4-O5-O6-O7-O8- represents a linker selected from the group consisting of: γGlu-PEG2-γGlu-, γGlu-PEG2-2×γGlu-, γGlu-PEG2-, γGlu-2×PEG2-, γGlu-3×PEG2-, γGlu-PEG2-γGlu-PEG2, γGlu-2×PEG2-γGlu-, γGlu-2×PEG2-2×γGlu-, 2×γGlu-, 2×γGlu-PEG2-, 2×γGlu-PEG2-γGlu-, 2×γGlu-PEG2-γGlu-, 2×γGlu-2×PEG2-, 2×γGlu-2×PEG2-γGlu, 2×γGlu-2×PEG2-2×γGlu-.

3. The peptide compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the C amino acid residue has its side chain thiol group modified by a long-acting group of formula (IV), the side chain thiol group of said C amino acid residue being connected to one end of the linking group L via a Michael reaction acceptor or a thiol reactive group, the other end of said linking group L being further covalently connected to the long-acting group of formula (IV) via an amino or carboxyl group, said linking group L being selected from: -NH-(CH2) n5 -(CH2CH2O) n6 -(CH2) n7 -,-NH-(CH2) n5 -(CH2CH2O) n6 -(CH2) n7 -NH-, -NH-(CH2) n5 -(CH2CH2O) n6 -(CH2) n7 -CO-, -NH-(CH2) n5 -(CH2CH2O) n6 -(CH2) n7 -NHCO-(CH2) n8 -,-NH-(CH2) n5 -(CH2CH2O) n6 -(CH2) n7 -NHCO-(CH2) n8 -NH- or any combination thereof, where n5, n6, n7, and n8 are each integers from 0 to 10.

4. The peptide compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein the linking group L is -NH-CH2-(CH2CH2O)3-(CH2)3-NH- or -NH-(CH2). n5 -(CH2CH2O) n6 -(CH2) n7 -NHCO-(CH2) n8 - 5. The peptide compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the lysine side chain amino-conjugated long-acting group K(x18), K(x18) having the structure of formula (VII): (VII); Alternatively, the lysine side chain may be conjugated with a long-lasting amino group K(x20), where K(x20) has the structure of formula (VIII): (VIII); The wavy line represents the connection point to the adjacent amino acid residue.

6. The peptide compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the cysteine ​​side chain thiol-conjugated long-acting group C(x18), C(x18) having the structure of formula (IX): (IX); Alternatively, the cysteine ​​side chain thiol group is conjugated with a long-lasting group C(x20), where C(x20) has the structure of formula (X): (X)； The wavy line represents the connection point to the adjacent group.

7. A peptide compound or a pharmaceutically acceptable salt thereof, wherein the peptide compound is selected from: Compound 12. ； Compound 15. ； Compound 55. ； Compound 58. ； Compound 243.YaibEGTFTSDLSIQLEKEAVRLFI-C(x20)-WLLAGGPSSGAPPPS-NH 2， in, C(x20) has the structure of formula (X): (X) ； The wavy line represents the connection point to the adjacent group.

8. A pharmaceutical composition comprising a peptide compound of any one of claims 1-7 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

9. Use of the peptide compound of any one of claims 1-7 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 8, in the preparation of a medicament for treating a disease or condition, wherein, The disease or condition mentioned is selected from type 2 diabetes, obesity, and non-alcoholic fatty liver disease.

10. The use according to claim 9, wherein, Nonalcoholic fatty liver disease can be divided into simple fatty liver, nonalcoholic steatohepatitis, and related cirrhosis.

11. Use of the peptide compound of any one of claims 1-7 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 8 in the preparation of a medicament for weight loss.

12. The use according to claim 9, wherein the use includes delaying or preventing disease progression in type 2 diabetes.

13. The use according to claim 9, wherein the use includes delaying the progression from impaired glucose tolerance to type 2 diabetes.

14. The use according to claim 9, wherein the use includes delaying the progression from type 2 diabetes to insulin-dependent diabetes.

15. Use of the peptide compound of any one of claims 1-7 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 8 in the preparation of a medicament for lowering blood lipids, wherein the blood lipid components selected from the group consisting of cholesterol, triglycerides, and free fatty acids are lowered.

16. The use according to claim 15, wherein the cholesterol comprises low-density lipoprotein cholesterol.

17. A method for preparing the peptide compound according to any one of claims 1-7, wherein the preparation method is a chemical synthesis method.

18. Use of the peptide compound of any one of claims 1-7 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 8, in the preparation of a medicament for treating a disease or condition, wherein, The disease or condition mentioned is selected from hyperglycemia.

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