Polypeptide compound and use thereof

Abstract

Provided are a compound having activity against both human glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, a pharmaceutical composition comprising said compound, and a therapeutic use.

Description

A polypeptide compound and its application

[0001] This disclosure claims priority to the following applications:

[0002] Chinese Patent Application No. 202411449910.8, entitled "A polypeptide compound and its application", was filed with the China National Intellectual Property Administration on October 17, 2024; Chinese Patent Application No. 202511193394.1, entitled "A polypeptide compound and its application", was filed with the China National Intellectual Property Administration on August 25, 2025; the entire contents of these documents are incorporated herein by reference. Technical Field

[0003] This disclosure relates to the field of biomedical technology, specifically to a polypeptide compound and such compounds for the treatment and / or prevention of GLP1R / GIPR-mediated diseases and symptoms.

[0004] Background Introduction

[0005] Incretin hormones are hormones that provide glycemic control in response to food intake. Glucose-dependent insulinotropic polypepide (GIP) and glucagon-like peptide-1 (GLP-1) are the main incretin hormones secreted by L cells and K cells in the small intestine, respectively, upon ingestion of glucose or nutrients, to stimulate insulin secretion from β cells in the pancreas. GIP and GLP-1 undergo degradation via dipeptidyl peptidase-4 (DPP-4) and rapidly lose their biological activity (see, for example, Y. Sieno et al., Journal of Diabetes Investigation 2013, 4, 108-130).

[0006] The effects of GIP and GLP-1 are believed to be mediated by their specific receptors, namely the GIP receptor (GIPR) and the GLP-1 receptor (GLP-1R), both belonging to the G-protein-coupled receptor family and manifested in pancreatic β-cells as well as various tissues and organs. GLP-1 activity includes, but is not limited to, stimulating insulin synthesis and secretion, inhibiting glucagon secretion, and suppressing food intake. GIP activity includes, but is not limited to, stimulating glucose-dependent insulin secretion, increasing β-cell clusters, stimulating glucagon secretion, and reducing gastric acid secretion. See, for example, WO 2016 / 131893.

[0007] Peptide compounds are playing an increasingly important role in the pharmaceutical field due to their unique biological activities and therapeutic potential. These compounds offer new strategies for treating a variety of diseases by mimicking or enhancing the functions of natural peptides in the human body. In particular, peptide compounds show broad application prospects in the treatment of diseases such as diabetes, obesity, cardiovascular disease, and metabolic syndrome.

[0008] In the field of diabetes treatment, peptide compounds such as GLP-1 receptor agonists have been widely used to increase insulin secretion, lower blood glucose, and have shown cardiovascular protective effects. These peptides, by binding to their corresponding receptors, play a crucial role in regulating blood glucose, promoting insulin secretion, protecting pancreatic β-cells, and controlling weight. Through structural optimization strategies, such as introducing non-natural amino acids, introducing long-chain side chains (e.g., fatty acid modification), and polyethylene glycol conversion, the stability and half-life of these peptides have been significantly improved, enabling them to be used in clinical treatment with longer-acting effects. Furthermore, the development of GIP / GLP-1 dual receptor agonists has provided new therapeutic options for improving glucose-lowering effects and promoting weight loss.

[0009] In the field of weight loss, the application of peptide compounds is also noteworthy. By increasing satiety and reducing food intake, they offer new strategies for the treatment of obesity. GIP / GLP-1 dual receptor agonists have shown superior efficacy in weight loss compared to single agonists, providing new treatment options for obese patients.

[0010] Peptide compounds have also shown potential in the treatment of other metabolic diseases. For example, they offer novel strategies for the treatment of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) by modulating hepatic lipid metabolism and reducing inflammatory responses.

[0011] In the cardiovascular field, the application of peptide compounds is constantly being explored. Some peptides have the effects of lowering blood pressure, preventing atherosclerosis, and improving cardiac function, providing new possibilities for the treatment of cardiovascular diseases.

[0012] Furthermore, the applications of peptide compounds in neurodegenerative diseases, tumors, and inflammatory diseases are under continuous research. They exhibit anti-tumor activity by targeting tumor cells or modulating the immune system. In inflammatory diseases, peptide compounds alleviate inflammatory responses by inhibiting the release of inflammatory mediators.

[0013] With a deeper understanding of the structure and function of these peptide compounds, and continuous advancements in drug design and formulation technologies, we can expect to develop more safe, effective, and long-acting therapeutics to meet the clinical needs for treating metabolic diseases. These peptide compounds, possessing dual agonist activity against both the GLP-1 receptor (GLP1R) and glucose-dependent insulinotropic peptide receptor (GIPR), offer new avenues for treating and / or preventing GLP1R / GIPR-mediated diseases and symptoms. Through precise molecular design and optimization, these compounds hold the promise of becoming effective means of treating a variety of diseases, improving patients' quality of life, and bringing revolutionary changes to the pharmaceutical field.

[0014] Invention Overview

[0015] This disclosure provides a compound having strong affinity and agonistic activity for GLP-1 and GIP receptors, a pharmaceutical composition thereof, and therapeutic uses thereof.

[0016] On the one hand, this disclosure provides a polypeptide compound of formula (I),

[0017] R1-Y-X1-EGTFTSDYSI-X2-LDKIAQ-X3-A-X4-VQWLIAGGPSSGAPPPS-R2

[0018] (I)

[0019] Or its pharmaceutically acceptable salts, esters or solvates,

[0020] in,

[0021] R1 is selected from H, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl, or is not present;

[0022] R2 is selected from -NH2, -OH, or is not present;

[0023] X1 is selected from Aib or Aib(d6);

[0024] X2 is selected from Aib or Aib(d6);

[0025] X3 is K, and the ε-amino group of its side chain is modified with a structure having the following formula (II);

[0026] in,

[0027] R3 and R4 are each independently selected from isosteres of hydrogen, carboxylic acid, phosphoric acid, sulfonic acid, or carboxylic acid.

[0028] L1 is selected from -C(O)- or -S(O)2-;

[0029] L2 is selected from non-existent, carbon-carbon triple bond, carbon-carbon double bond, or 5-membered heteroaryl group containing 3 N atoms;

[0030] n and m are each independently selected from any integer from 1 to 18, and p is 0, 1, 2 or 3;

[0031] * indicates that if there is a chiral center, * represents S or R;

[0032] X4 is selected from F or non-natural amino acids;

[0033] Furthermore, when X1 and X2 are both Aib and X4 is F, equation (II) must satisfy any of the following conditions:

[0034] (1) At least one of R3 and R4 is not a carboxylic acid or phosphoric acid;

[0035] (2) L1 is -S(O)2-;

[0036] (3) L2 is a carbon-carbon triple bond, a carbon-carbon double bond, or a 5-membered heteroaryl group containing 3 N atoms;

[0037] The amino acid sequence number corresponding to the polypeptide compound of formula (I) is any one of the following: SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46.

[0038] On the other hand, this application relates to a composition comprising the disclosed compound or a pharmaceutically acceptable salt, ester or solvate thereof, and a pharmaceutically acceptable excipient.

[0039] On the other hand, this application relates to a method for treating GLP1R / GIPR-mediated diseases or symptoms, comprising the steps of administering to a subject an effective amount of the disclosed compound or a pharmaceutically acceptable salt, ester or solvate thereof, or administering to a subject an effective amount of the disclosed composition.

[0040] On the other hand, this application provides the use of a compound as described in this application or a pharmaceutically acceptable salt, ester or solvate thereof, or a pharmaceutical composition disclosed herein, in the preparation of a medicament for treating GLP1R / GIPR-mediated diseases or symptoms.

[0041] The diseases or symptoms mediated by GLP1R / GIPR are selected from: T1DM, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-associated diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, nephropathy, diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea, long-term weight management, obesity, overweight, eating disorders, weight gain due to other medications, excessive sugar consumption, dyslipidemia, hyperinsulinemia, NAFLD, NASH, fibrosis, cirrhosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, post-angioplasty. Restenosis, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral artery disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, restenosis, impaired glucose metabolism, impaired fasting glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue diseases, psoriasis, foot ulcers, ulcerative colitis, hyperapolipoprotein B lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome or substance addiction, weight management, long-term weight management, chronic kidney disease, atherosclerotic cardiovascular disease, heart failure, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, diabetes prevention or obstructive sleep apnea. Attached Figure Description

[0042] Figure 1 shows the MS spectrum of polypeptide compound 1.

[0043] Figure 2 shows the MS spectrum of polypeptide compound 3.

[0044] Figure 3 shows the MS spectrum of polypeptide compound 4.

[0045] Figure 4 shows the MS spectrum of polypeptide compound 5.

[0046] Figure 5 shows the MS spectrum of polypeptide compound 23.

[0047] Figure 6 shows the MS spectrum of polypeptide compound 25.

[0048] Figure 7 shows the MS spectrum of polypeptide compound 29.

[0049] Figure 8 shows the MS spectrum of polypeptide compound 30.

[0050] Figure 9 shows the MS spectrum of polypeptide compound 31.

[0051] Invention Details

[0052] The following description includes certain specific details to provide a comprehensive understanding of the various disclosed embodiments. However, those skilled in the art will recognize that the embodiments can be implemented without employing one or more of these specific details, but using other methods, components, materials, etc.

[0053] Unless otherwise required in this disclosure, throughout the specification and the claims, the words “comprising” and “including” shall be interpreted in an open-ended, inclusive sense, meaning “including but not limited to”.

[0054] When used in this disclosure and the appended claims, a singular designation without a quantity indication includes a plural designation unless the context clearly specifies otherwise.

[0055] Throughout this specification, the phrases "in some embodiments," "in one embodiment," "in another embodiment," or "in certain embodiments" mean that at least one embodiment includes a specific reference element, structure, or feature related to that embodiment. Therefore, the phrases "in some embodiments," "in one embodiment," "in another embodiment," or "in certain embodiments" appearing in different places throughout the specification do not necessarily all refer to the same embodiment. Furthermore, specific elements, structures, or features may be combined in one or more embodiments in any suitable manner.

[0056] It should be understood that the article “a” (corresponding to the English “a”, “an”, and “the”) used in this disclosure and the appended claims can be used to refer to one or more (i.e., at least one) grammatical objects of the article, including plural objects, unless otherwise expressly stated in the text. Therefore, for example, a sustained-release tablet containing “a pharmaceutically acceptable excipient” includes one pharmaceutically acceptable excipient, or two or more pharmaceutically acceptable excipients.

[0057] definition

[0058] Unless otherwise stated, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art, and in particular, the terms used alone or in combination in the specification and claims have the following meanings.

[0059] GLP-1 / GIP receptor agonists refer to the same active agent, such as the polypeptide compound provided in this application, which has good agonistic activity against both GLP-1 and GIP receptors.

[0060] “GLP1R / GIPR mediated diseases” or “GLP1R and / or GIPR and / or GCGR mediated diseases” refers to diseases or conditions mediated by any one or both of GLP1R and GIPR.

[0061] In this disclosure, the different terms such as "X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", and "X is A, B, and C" all express the same meaning, that is, X can be any one or more of A, B, and C.

[0062] The "-" at the beginning or end of a chemical group is used to conveniently indicate the connection point with the parent compound; a chemical group may or may not be described with one or more "-" without losing its ordinary meaning.

[0063] The numerical ranges used in this article include the endpoints and any values ​​in between. For example, "0-3" can include 0, 1, 2, or 3, and "1-3" can include 1, 2, or 3.

[0064] The term "modification" of an amino acid refers to the substitution, addition, replacement, or removal of specific groups from the C-terminal carboxyl group and / or N-terminal amino group and / or side chain of a natural or non-natural amino acid, thereby producing an amino acid derivative. For example, in one embodiment, a structure having formula (II) is conjugated to the Xth... 3， That is, the ε-amino group of the K side chain is conjugated to acylation.

[0065] The term "peptide" encompasses the category of peptides with modified amino and carboxyl terms. For example, amino acid chains containing terminal carboxylic acids with amide groups substituted are also included in the amino acid sequences named as natural amino acids.

[0066] The term "treatment" includes suppressing, slowing down, stopping, or reversing existing symptoms or the progression or severity of a patient's condition.

[0067] The term "amino acid" refers to both naturally occurring and non-natural amino acids. When these constitute an amino acid sequence or polypeptide, the amino acid refers to the corresponding amino acid residue. The amino acid sequences disclosed herein contain standard single-letter or three-letter codes for twenty amino acids. Unless explicitly stated otherwise, all amino acid residues in this disclosure are preferably configured in the L-type.

[0068] "Natural amino acids" refers to 20 common amino acids, namely alanine (Ala), cysteine ​​(Cys), aspartic acid (D, Asp), glutamic acid (E, Glu), phenylalanine (F, Phe), glycine (G, Gly), histidine (H, His), isoleucine (I, Ile), lysine (K, Lys), leucine (L, Leu), methionine (M, Met), asparagine (N, Asn), proline (P, Pro), glutamine (Q, Gln), arginine (R, Arg), serine (S, Ser), threonine (T, Thr), valine (V, Val), tryptophan (W, Trp), and tyrosine (Y, Tyr). The three-letter and single-letter codes for amino acids used in this disclosure are as described in J. Biol. Chem., 243, p3558 (1968). "Non-natural amino acids" refer to amino acids that are not naturally encoded or not found in the genetic code of any organism. For example, non-natural amino acids can be purely synthetic compounds. Examples of non-natural amino acids include, but are not limited to, hydroxyproline, γ-carboxyglutamic acid, O-phosphoserine, azacyclobutanecarboxylic acid, 2-aminohexanoic acid, 3-aminohexanoic acid, β-alanine, 2-aminobutyric acid, 4-aminobutyric acid, 6-aminohexanoic acid, 2-aminoheptanoic acid, 2-aminoisobutyric acid, 3-aminoisobutyric acid, 2-aminopimelic acid, tert-butylglycine, 2,3-diaminopropionic acid (Dap), desmosine, 2,6-diaminopimelic acid, 2,4-diaminobutyric acid (Dab), N-ethylglycine, N-methylglycine. Acids, N-ethylasparagine, homoproline, hydroxylysine, allo-hydroxylysine, 3-hydroxyproline, 4-hydroxyproline, isodesmosine, alloleucine, N-methylalanine, N-methylisoleucine, N-methylvaline, naphthylalanine, n-valine, n-leucine, ornithine (Orn), D-ornithine, D-arginine, p-aminophenylalanine, pentylglycine, thioproline, and various deuterated amino acids. Furthermore, the term also includes derivatives obtained by chemically modifying the C-terminal carboxyl group (or N-terminal amino group and / or its side chain functional groups) of natural amino acids (or non-natural amino acids). Preferred examples of non-natural amino acids in this disclosure include, but are not limited to, the following structures and their abbreviations:

[0069] Table 1 shows the abbreviations of non-natural amino acids and their corresponding Chinese and English names.

[0070] Table 1 Abbreviations and English / Chinese names of non-natural amino acids

[0071] In the text, when "carboxylic acid" is used as a group, it refers to the compound group formed by removing one hydrogen atom from carbonic acid, with the structure "-COOH"; when "phosphoric acid" is used as a group, it refers to the compound group formed by removing one hydrogen atom from phosphoric acid, "-PO(OH)2"; when "sulfonic acid" is used as a group, it refers to the compound group formed by removing one hydrogen atom from sulfuric acid, "-S(O)2H"; for example, R4 is selected from carboxylic acid, phosphoric acid or sulfonic acid, and can also be represented as R4 being selected from hydrogen, -COOH, -PO(OH)2 or -S(O)2H.

[0072] In the text, "carbon-carbon triple bond" refers to a compound group in which two carbon atoms are connected by a triple bond, with the structure: A carbon-carbon double bond is a compound group in which two carbon atoms are connected by a double bond, with the following structure: Unless otherwise specified, the α-carboxyl group of the above-mentioned amino acids and the α-amino (or imino) group of another amino acid participate in the formation of the peptide chain. For example, the amino acid residues formed by αMePro are... The amino-terminal residues formed by Dab are

[0073] The compounds of embodiments disclosed herein, or their pharmaceutically acceptable salts, may contain one or more asymmetric centers, thus potentially yielding enantiomers, diastereomers, and other stereoisomers that are (R)- or (S)- in absolute stereochemistry, or, for amino acids, (D)- or (L)-. This statement is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R) and (S), or (D) and (L)- isomers can be prepared using chiral synthesis or chiral reagents, or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of racemic mixtures (or racemic mixtures of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other geometrically asymmetric centers, these compounds are intended to include E and Z geometric isomers unless otherwise specified. Similarly, all isomer forms are included. When a compound is represented in its chiral form, it should be understood that the embodiment includes, but is not limited to, a specific diastereomer or enantiomer-enriched form. If chirality is not specified but present, it can be understood that the embodiment is for a specific diastereomer or enantiomer-enriched form; or a racemic or scalar mixture of such a compound. As used herein, a "scalar mixture" means a mixture of stereoisomers in a non-1:1 ratio.

[0074] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, such as an alkyl group containing 1 to 8 carbon atoms, an alkyl group containing 1 to 6 carbon atoms, or an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. Alkyl groups can be, for example, lower alkyl groups containing 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any accessible connection point. The substituent can be one or more groups independently selected from: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester. The substituted alkyl group disclosed herein can be methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuteralkyl, alkoxy-substituted alkyl, or hydroxy-substituted alkyl.

[0075] The term "carboxylic acid isosteres" refers to molecular or atomic groups that have similar electronic or stereoconfigurations to carboxylic acids, including but not limited to hydroxamic acid, sulfonamide, acetylsulfonamide, sulfonamide, sulfonylurea, tetrazolium, oxazolidinedione, square acid, isoxazole, 5-oxadiazole, sulfadiazine, trifluoromethyl alcohol, and trifluoromethyl ketone.

[0076] In this disclosure, the different terms such as "X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", and "X is A, B, and C" all express the same meaning, that is, X can be any one or more of A, B, and C.

[0077] The term "substitution" of amino acids as used in this disclosure refers to the replacement of one amino acid residue with another amino acid residue in a protein or polypeptide compound.

[0078] The term "substitution" of an amino acid residue as used in this disclosure refers to the substitution of an amino acid residue by a different substance.

[0079] The term "fatty acid" refers to a carboxylic acid with a long fatty acid tail (chain), which can be saturated or unsaturated; in this disclosure, fatty acids are those with a C4-C6 tail. 30 Carboxylic acids with straight-chain or branched aliphatic groups.

[0080] The term "peptide" encompasses the category of peptides with modified amino and carboxyl terms. For example, amino acid chains containing terminal carboxylic acids with amide groups substituted are also included in the amino acid sequences named as natural amino acids.

[0081] All hydrogen atoms described in this disclosure can be replaced by their isotopes (protium, deuterium, tritium), and any hydrogen atom in the compounds disclosed herein can also be replaced by isotopic atoms.

[0082] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of such event or environment. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

[0083] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms, that are independently substituted by substituents. Substituents are only present in their possible chemical positions, and those skilled in the art can determine (experimentally or theoretically) the possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene). "Pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0084] "Pharmaceutically acceptable salt" refers to the salt of the compounds of this invention, prepared by reacting a compound with a specific substituent discovered in this invention with a relatively non-toxic acid or base. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When the compounds of this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; as well as salts of amino acids (such as arginine) and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

[0085] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0086] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmaceutical salts or prodrugs, along with other chemical components, such as physiologically / pharmaceutical carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0087] Unless otherwise specified, the solvent in the solution form of the pharmaceutical compositions described in this disclosure is water.

[0088] "Lyophilized formulation" refers to a formulation or pharmaceutical composition obtained by a vacuum freeze-drying step after a liquid or solution form of a pharmaceutical composition or solution preparation.

[0089] As used herein, the terms “about” or “approximately” mean a numerical value within the acceptable error range of a specific value determined by a person skilled in the art, the numerical value depending in part on how it is measured or determined (i.e., the limits of the measurement system). For example, in every practice in the art, “about” may mean within or above 1 standard deviation. Alternatively, “about” or “substantially includes” may mean a range of up to ±20%, for example, about 5.5 pH means pH 5.5 ± 1.1. Furthermore, particularly for biological systems or processes, the term may mean up to an order of magnitude or up to 5 times the numerical value. Unless otherwise stated, when a specific value appears in this disclosure and claims, the meaning of “about” or “substantially includes” should be assumed to be within the acceptable error range of that specific value.

[0090] The three-letter and single-letter codes for amino acids used in this disclosure are as described in J. biol. chem, 243, p3558 (1968).

[0091] compound

[0092] On the one hand, this application discloses a polypeptide compound of formula (I),

[0093] R1-Y-X1-EGTFTSDYSI-X2-LDKIAQ-X3-A-X4-VQWLIAGGPSSGAPPPS-R2

[0094] (I)

[0095] Or its pharmaceutically acceptable salts, esters or solvates,

[0096] in,

[0097] R1 is selected from H, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl, or is not present;

[0098] R2 is selected from -NH2, -OH, or is not present;

[0099] X1 is selected from Aib or Aib(d6);

[0100] X2 is selected from Aib or Aib(d6);

[0101] X3 is K, and the ε-amino group of its side chain is modified with a structure having the following formula (II);

[0102] in,

[0103] R3 and R4 are each independently selected from isosteres of hydrogen, carboxylic acid, phosphoric acid, sulfonic acid, or carboxylic acid.

[0104] L1 is selected from -C(O)- or -S(O)2-;

[0105] L2 is selected from non-existent, carbon-carbon triple bond, carbon-carbon double bond, or 5-membered heteroaryl group containing 3 N atoms;

[0106] n and m are each independently selected from any integer from 1 to 18, and p is 0, 1, 2 or 3;

[0107] * indicates that if there is a chiral center, * represents S or R;

[0108] X4 is selected from F or non-natural amino acids;

[0109] Furthermore, when X1 and X2 are both Aib and X4 is F, equation (II) must satisfy any of the following conditions:

[0110] (1) At least one of R3 and R4 is not a carboxylic acid or phosphoric acid;

[0111] (2) L1 is -S(O)2-;

[0112] (3) L2 is a carbon-carbon triple bond, a carbon-carbon double bond, or a 5-membered heteroaryl group containing 3 N atoms;

[0113] The amino acid sequence number corresponding to the polypeptide compound of formula (I) is any one of the following: SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46.

[0114] In some implementations, R1 is selected from H and R2 is selected from -NH2.

[0115] In some implementations, * indicates that if there is a chiral center, * is S.

[0116] In some implementations, p is 1.

[0117] In some embodiments, the non-natural amino acids are selected from...

[0118] In some implementations, at least one of X1 and X2 is Aib(d6).

[0119] In some implementations, X4 is selected from

[0120] In some implementations, R3 and R4 are selected from the group consisting of:

[0121] (1) R3 is a carboxylic acid, and R4 is H;

[0122] (2) R3 is phosphoric acid, and R4 is H;

[0123] (3) R3 is H, and R4 is a carboxylic acid;

[0124] (4) R3 is H, and R4 is phosphoric acid;

[0125] (5) R3 is H, and R4 is sulfonic acid;

[0126] (6) R3 is a carboxylic acid, and R4 is a sulfonic acid;

[0127] (7) R3 is phosphoric acid, and R4 is sulfonic acid;

[0128] (8) R3 is sulfonic acid, and R4 is phosphoric acid;

[0129] (9) R3 is sulfonic acid, R4 is carboxylic acid, or

[0130] (10) R3 is sulfonic acid, and R4 is H.

[0131] In some implementations, L1 is -S(O)2-.

[0132] In some implementations, L2 is selected from carbon-carbon triple bonds, carbon-carbon double bonds, or 5-membered heteroaryl groups containing 3 N atoms.

[0133] In some embodiments, formula (II) has the structure of formula (II-1).

[0134] in,

[0135] R3 and R4 are each independently selected from isosteres of hydrogen, carboxylic acid, phosphoric acid, sulfonic acid, or carboxylic acid.

[0136] o is any integer from 1 to 29.

[0137] In some embodiments, formula (II) has the structure of formula (II-2).

[0138] R3 and R4 are each independently selected from isosteres of hydrogen, carboxylic acid, phosphoric acid, sulfonic acid, or carboxylic acid.

[0139] o is any integer from 1 to 29.

[0140] In some implementations, o is any integer from 14 to 20.

[0141] In some embodiments, formula (II) has the structure of formula (II-3).

[0142] R3 and R4 are each independently selected from isosteres of hydrogen, carboxylic acid, phosphoric acid, sulfonic acid, or carboxylic acid.

[0143] L2 is selected from carbon-carbon triple bonds, carbon-carbon double bonds, or 5-membered heteroaryl groups containing 3 nitrogen atoms.

[0144] n and m are each selected from any integer from 1 to 18.

[0145] In some implementations, in the structure shown in equation (II-3), n is any integer from 3 to 10, and m is any integer from 3 to 10.

[0146] In some implementations, X1 is selected from Aib, X2 is selected from Aib, X4 is selected from F, and R3 and R4 are selected from the group consisting of:

[0147] (1) R3 is a carboxylic acid, and R4 is H;

[0148] (2) R3 is phosphoric acid, and R4 is H;

[0149] (3) R3 is H, and R4 is a carboxylic acid;

[0150] (4) R3 is H, and R4 is phosphoric acid;

[0151] (5) R3 is H, and R4 is sulfonic acid;

[0152] (6) R3 is a carboxylic acid, and R4 is a sulfonic acid;

[0153] (7) R3 is phosphoric acid, and R4 is sulfonic acid;

[0154] (8) R3 is sulfonic acid, and R4 is phosphoric acid;

[0155] (9) R3 is sulfonic acid, and R4 is carboxylic acid;

[0156] (10) R3 is sulfonic acid, and R4 is H;

[0157] L1 is selected from -C(O)- or -S(O)2-;

[0158] L2 is selected from non-existent, carbon-carbon triple bond, carbon-carbon double bond, or 5-membered heteroaryl group containing 3 N atoms.

[0159] In some implementations, X1 is selected from Aib, X2 is selected from Aib, X4 is selected from F, L1 is -S(O)2-, L2 is selected from non-existent, carbon-carbon triple bond, carbon-carbon double bond or 5-membered heteroaryl containing 3 N atoms, and R3 and R4 are each independently selected from hydrogen, carboxylic acid, phosphoric acid, sulfonic acid or carboxylic acid isosteric.

[0160] In some embodiments, X1 is selected from Aib, X2 is selected from Aib, X4 is selected from F, L2 is a carbon-carbon triple bond, a carbon-carbon double bond, or a 5-membered heteroaryl group containing 3 N atoms, L1 is selected from -C(O)- or -S(O)2-, and R3 and R4 are each independently selected from hydrogen, carboxylic acid, phosphoric acid, sulfonic acid, or isosteric groups of carboxylic acid.

[0161] In some implementations, n is any integer from 3 to 10, and m is any integer from 3 to 10.

[0162] In some implementations, n is any integer from 7 to 8, and m is any integer from 7 to 8.

[0163] In some embodiments, the polypeptide compound of formula (I) has the amino acid sequence shown in SEQ ID NO:47, and the polypeptide compound of formula (I) has the structure shown in formula (III-1):

[0164] in,

[0165] X4 is selected from F(2F), F(2Cl), F(2Me), F(2CN), F(3F), F(3Cl), F(3Me), F(3CN), F(4F), F(4Cl), F(4Me), F(4CN), 2Pal, 3Pal, 4Pal or other non-natural amino acid residues;

[0166] r is selected from any integer between 14 and 25;

[0167] s is selected from 0, 1 or 2.

[0168] In some embodiments, the polypeptide compound of formula (I) has an amino acid sequence as shown in SEQ ID NO:48, and the polypeptide compound of formula (I) has a structure as shown in formula (III-2):

[0169] in,

[0170] X4 is selected from F(2F), F(2Cl), F(2Me), F(2CN), F(3F), F(3Cl), F(3Me), F(3CN), F(4F), F(4Cl), F(4Me), F(4CN), 2Pal, 3Pal, 4Pal or other non-natural amino acid residues;

[0171] r is selected from any integer between 14 and 25;

[0172] s is selected from 0, 1 or 2.

[0173] In some embodiments, the compounds described in this disclosure are selected from:

[0174] The compounds described in this disclosure are shown in Table 2.

[0175] Table 2. Compounds disclosed herein

[0176] Or its pharmaceutically acceptable salts, esters or solvates.

[0177] amino acid sequence

[0178] The amino acid sequence corresponding to the polypeptide compound No. 1 is SEQ ID NO: 1, where amino acid at position 2 is Aib; amino acid at position 13 is Aib; and K at position 20 is obtained by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-γGlu-CO-(CH2). 18 -CO2H is chemically modified by conjugating to the ε-amino group of the K side chain; the amino acid at position 22 is 4-fluoro-L-phenylalanine; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0179] The amino acid sequence number corresponding to the polypeptide compound No. 2 is SEQ ID NO: 2, where the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; and the K at position 20 is obtained by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-γGlu-CO-(CH2). 18-CO2H is chemically modified by conjugating to the ε-amino group of the K side chain; the amino acid at position 22 is 3-fluoro-L-phenylalanine; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0180] The amino acid sequence corresponding to the polypeptide compound No. 3 is SEQ ID NO:3, where the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; and the K at position 20 is obtained by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-γGlu-CO-(CH2). 18 -CO2H is chemically modified by conjugating to the ε-amino group of the K side chain; the amino acid at position 22 is 2-fluoro-L-phenylalanine; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0181] The amino acid sequence number corresponding to the polypeptide compound No. 4 is SEQ ID NO:4, where the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; and the K at position 20 is obtained by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-γGlu-CO-(CH2). 18 -CO2H is chemically modified by conjugating to the ε-amino group of the K side chain; the amino acid at position 22 is L-3-(4-pyridyl)-alanine; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0182] The amino acid sequence number corresponding to the polypeptide compound No. 5 is SEQ ID NO:5, where the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; and the K at position 20 is obtained by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-γGlu-CO-(CH2). 18 -CO2H is chemically modified by conjugating to the ε-amino group of the K side chain; the amino acid at position 22 is L-3-(3-pyridyl)-alanine; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0183] The amino acid sequence corresponding to the polypeptide compound No. 6 is SEQ ID NO: 6, where the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; and the K at position 20 is obtained by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-γGlu-CO-(CH2). 18-CO2H is chemically modified by conjugating to the ε-amino group of the K side chain; the amino acid at position 22 is L-3-(2-pyridyl)-alanine; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0184] The amino acid sequence corresponding to the polypeptide compound No. 7 is SEQ ID NO:7, where the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; and the K at position 20 is obtained by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-γGlu-CO-(CH2). 18 -CO2H is chemically modified by conjugating to the ε-amino group of the K side chain; the amino acid at position 22 is L-phenylalanine-2,3,4,5,6-d5; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0185] The amino acid sequence corresponding to the polypeptide compound No. 8 is SEQ ID NO:8, where the amino acid at position 2 is 2-aminoisobutyric acid-d6 (2-Methylalanine-d6); the amino acid at position 13 is Aib; and K at position 20 is obtained by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-γGlu-CO-(CH2). 18 -CO2H is chemically modified by conjugating to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0186] The amino acid sequence corresponding to the polypeptide compound No. 9 is SEQ ID NO: 9, where the amino acid at position 2 is Aib; the amino acid at position 13 is 2-aminoisobutyric acid-d6 (2-Methylalanine-d6); and the K at position 20 is obtained by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-γGlu-CO-(CH2). 18 -CO2H is chemically modified by conjugating to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0187] The amino acid sequence corresponding to the polypeptide compound No. 10 is SEQ ID NO:10, where the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; and the K at position 20 is obtained by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-γGlu-CO-(CH2). 18 -SO3H is chemically modified by conjugating to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0188] The amino acid sequence corresponding to the polypeptide compound No. 11 is SEQ ID NO:11, where the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; and at position 20, K is obtained by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-γGlu-CO-(CH2). 15 -SO3H is chemically modified by conjugating to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0189] The amino acid sequence corresponding to the polypeptide compound No. 12 is SEQ ID NO:12, wherein the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; K at position 20 is chemically modified by conjugating (S)-22-carboxyl-10,19,24-trioxo-42-(1H-tetrazole-5-yl)-3,6,12,15-tetroxa-9,18,23-triazatetane-2-carbonyl to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0190] The amino acid sequence number corresponding to the polypeptide compound No. 13 is SEQ ID NO:13, wherein the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; K at position 20 is chemically modified by conjugating (S)-42-carboxy-10,19,24-trioxo-22-(1H-tetrazole-5-yl)-3,6,12,15-tetroxa-9,18,23-triazatetane-2-carbonyl to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0191] The amino acid sequence number corresponding to the polypeptide compound No. 14 is SEQ ID NO:14, where the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; K at position 20 is chemically modified by conjugating (S,E)-22,42-dicarboxy-19,24-dioxo-3,6,12,15-tetraoxa-9,18,23-triazatetane-33-enoyl to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0192] The amino acid sequence number corresponding to the polypeptide compound No. 15 is SEQ ID NO:15, wherein the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; K at position 20 is chemically modified by conjugating (S)-22,42-dicarboxy-10,19,24-trioxo-3,6,12,15-tetraoxa-9,18,23-triazatetane-33-acetylacetyl to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0193] The amino acid sequence number corresponding to the polypeptide compound No. 16 is SEQ ID NO:16, where the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; K at position 20 is chemically modified by conjugating (S)-22-carboxyl-10,19,24-trioxo-3,6,12,15-tetraoxa-9,18,23-triazatetane-33-acetylacetyl to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0194] The amino acid sequence corresponding to the polypeptide compound No. 17 is SEQ ID NO:17, wherein the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; K at position 20 is chemically modified by conjugating (S)-22-carboxy-26-(1-(13-carboxytadexyl)-1H-1,2,3-triazol-4-yl)-10,19,24-trioxo-3,6,12,15-tetraoxa-9,18,23-triazahexacarbonyl to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0195] The amino acid sequence corresponding to the polypeptide compound No. 18 is SEQ ID NO:18, where the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; and at position 20, K is obtained by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-γGlu-CO-(CH2). 18 -SO3H is chemically modified by conjugating to the ε-amino group of the K side chain; the amino acid at position 22 is 2-fluoro-L-phenylalanine; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0196] The amino acid sequence corresponding to the polypeptide compound No. 19 is SEQ ID NO:19, where the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; and the K at position 20 is obtained by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-γGlu-CO-(CH2). 18 -SO3H is chemically modified by conjugating to the ε-amino group of the K side chain; the amino acid at position 22 is L-3-(4-pyridyl)-alanine; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0197] The amino acid sequence corresponding to the polypeptide compound No. 20 is SEQ ID NO:20, where the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; and at position 20, K is obtained by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-γGlu-SO2-(CH2). 18 -CO2H is chemically modified by conjugating to the ε-amino group of the K side chain; the amino acid at position 22 is L-3-(2-pyridyl)-alanine; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0198] The amino acid sequence number corresponding to the polypeptide compound No. 21 is SEQ ID NO:21, where the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; K at position 20 is chemically modified by conjugating (S)-22-carboxyl-10,19,24-trioxo-42-(1H-tetrazole-5-yl)-3,6,12,15-tetroxa-9,18,23-triazatetane-2-carbonyl to the ε-amino group of the K side chain; the amino acid at position 22 is 3-fluoro-L-phenylalanine (L-3-Fluorophenylalanine); and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0199] The amino acid sequence number corresponding to the polypeptide compound No. 22 is SEQ ID NO:22, where the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; K at position 20 is chemically modified by conjugating (S)-42-carboxy-10,19,24-trioxo-22-(1H-tetrazol-5-yl)-3,6,12,15-tetraoxa-9,18,23-triazatetane-2-carbonyl to the ε-amino group of the K side chain; the amino acid at position 22 is 4-fluoro-L-phenylalanine (L-4-Fluorophenylalanine); and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0200] The amino acid sequence corresponding to the polypeptide compound No. 23 is SEQ ID NO:23, where the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; and the K at position 20 is obtained by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-γGlu-CO-(CH2). 18 -PO(OH)2 is chemically modified by conjugating to the ε-amino group of the K side chain; the amino acid at position 22 is 4-fluoro-L-phenylalanine; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0201] The amino acid sequence corresponding to the polypeptide compound No. 24 is SEQ ID NO:24, where the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; and the K at position 20 is obtained by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-γGlu-CO-(CH2). 18 -PO(OH)2 is chemically modified by conjugating to the ε-amino group of the K side chain; the amino acid at position 22 is 2-fluoro-L-phenylalanine; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0202] The amino acid sequence corresponding to the polypeptide compound No. 25 is SEQ ID NO:25, where the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; and the K at position 20 is obtained by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-γGlu-CO-(CH2). 18 -CO2H is chemically modified by conjugating to the ε-amino group of the K side chain; the amino acid at position 22 is 2-chloro-L-phenylalanine; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0203] The amino acid sequence corresponding to the polypeptide compound No. 26 is SEQ ID NO:26, where the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; and the K at position 20 is obtained by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-γGlu-CO-(CH2). 18 -CO2H is chemically modified by conjugating to the ε-amino group of the K side chain; the amino acid at position 22 is 2-methyl-L-phenylalanine; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0204] The amino acid sequence corresponding to the polypeptide compound No. 27 is SEQ ID NO:27, where the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; and the K at position 20 is obtained by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-γGlu-CO-(CH2). 18 -CO2H is chemically modified by conjugating to the ε-amino group of the K side chain; the amino acid at position 22 is 4-methyl-L-phenylalanine; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0205] The amino acid sequence corresponding to the polypeptide compound No. 28 is SEQ ID NO:28, where the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; and the K at position 20 is obtained by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-γGlu-CO-(CH2). 22 -CO2H is chemically modified by conjugating to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0206] The amino acid sequence corresponding to the polypeptide compound No. 29 is SEQ ID NO:29, where the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; and the K at position 20 is obtained by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-γGlu-CO-(CH2). 19 -PO(OH)2 is chemically modified by conjugating the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to form a C-terminal primary amide.

[0207] The amino acid sequence corresponding to the polypeptide compound No. 30 is SEQ ID NO:30, where the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; and at position 20, K is [2-(2-amino-ethoxy)-ethoxy]-acetyl)2-γGlu-CO-(CH2). 20 -PO(OH)2 is chemically modified by conjugating the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to form a C-terminal primary amide.

[0208] The amino acid sequence corresponding to the polypeptide compound No. 31 is SEQ ID NO:31, where the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; and the K at position 20 is obtained by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-γGlu-CO-(CH2). 17 -PO(OH)2 is chemically modified by conjugating the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to form a C-terminal primary amide.

[0209] The amino acid sequence corresponding to the polypeptide compound No. 32 is SEQ ID NO:32, where the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; and the K at position 20 is obtained by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-γGlu-CO-(CH2). 17 -PO(OH)2 is chemically modified by conjugating to the ε-amino group of the K side chain; the amino acid at position 22 is 2-chloro-L-phenylalanine; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0210] The amino acid sequence corresponding to the polypeptide compound No. 33 is SEQ ID NO:33, where the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; and the K at position 20 is obtained by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-γGlu-CO-(CH2). 18 -PO(OH)2 is chemically modified by conjugating to the ε-amino group of the K side chain; the amino acid at position 22 is 2-chloro-L-phenylalanine; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0211] The amino acid sequence corresponding to the polypeptide compound No. 34 is SEQ ID NO:34, where the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; and the K at position 20 is obtained by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-γGlu-CO-(CH2). 19 -PO(OH)2 is chemically modified by conjugating to the ε-amino group of the K side chain; the amino acid at position 22 is 2-chloro-L-phenylalanine; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0212] The amino acid sequence corresponding to the polypeptide compound No. 35 is SEQ ID NO:35, where the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; and the K at position 20 is obtained by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-γGlu-CO-(CH2). 17 -PO(OH)2 is chemically modified by conjugating to the ε-amino group of the K side chain; the amino acid at position 22 is 2-fluoro-L-phenylalanine; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0213] The amino acid sequence corresponding to the polypeptide compound No. 36 is SEQ ID NO:36, where the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; and the K at position 20 is obtained by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-γGlu-CO-(CH2). 19 -PO(OH)2 is chemically modified by conjugating to the ε-amino group of the K side chain; the amino acid at position 22 is 2-fluoro-L-phenylalanine; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0214] The amino acid sequence corresponding to the polypeptide compound No. 37 is SEQ ID NO:37, where the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; and the K at position 20 is obtained by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-γGlu-CO-(CH2). 17 -PO(OH)2 is chemically modified by conjugating to the ε-amino group of the K side chain; the amino acid at position 22 is 3-chloro-L-phenylalanine; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0215] The amino acid sequence corresponding to the polypeptide compound No. 38 is SEQ ID NO:38, where the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; and the K at position 20 is obtained by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-γGlu-CO-(CH2). 18 -PO(OH)2 is chemically modified by conjugating to the ε-amino group of the K side chain; the amino acid at position 22 is 3-chloro-L-phenylalanine; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0216] The amino acid sequence corresponding to the polypeptide compound No. 39 is SEQ ID NO:39, where the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; and the K at position 20 is obtained by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-γGlu-CO-(CH2). 19 -PO(OH)2 is chemically modified by conjugating to the ε-amino group of the K side chain; the amino acid at position 22 is 3-chloro-L-phenylalanine; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0217] The amino acid sequence corresponding to the polypeptide compound No. 40 is SEQ ID NO:40, wherein the N-terminal group of the amino acid at position 1 is replaced by R1, where R1 is selected from H, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl, or is absent; the amino acid at position 2 is selected from Aib or Aib(d6); the amino acid at position 13 is selected from Aib or Aib(d6); and K at position 20 is replaced by a group having the general formula ([2-(2-amino-ethoxy)-ethoxy]-acetyl)-([2-(2-amino-ethoxy)-ethoxy]-acetyl) p -CO-(CH2)2-(*)R3-NH-L1-CH2-(CH2) n -L2-CH2-(CH2) m-R4 is chemically modified by conjugating the ε-amino group of the K side chain, wherein R3 and R4 are each independently selected from hydrogen, carboxylic acid, phosphoric acid, sulfonic acid, or carboxylic acid isosteres, L1 is selected from -C(O)- or -S(O)2-, L2 is selected from non-existent, carbon-carbon triple bond, carbon-carbon double bond, or a 5-membered heteroaryl group containing 3 N atoms, n and m are each independently selected from any integer from 1 to 18, p is 0, 1, 2, or 3, * indicates that if there is a chiral center, * is S or R; the amino acid at position 22 is selected from non-natural amino acids; and the C-terminus of the amino acid at position 39 is replaced by an R2 group, R2 is selected from -NH2, -OH, or non-existent.

[0218] The amino acid sequence corresponding to the polypeptide compound No. 41 is SEQ ID NO:41, wherein the N-terminal group of the amino acid at position 1 is replaced by R1, where R1 is selected from H, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl, or is absent; the amino acid at position 2 is Aib (d6); the amino acid at position 13 is Aib; and K at position 20 is substituted with the general formula ([2-(2-amino-ethoxy)-ethoxy]-acetyl)-([2-(2-amino-ethoxy)-ethoxy]-acetyl) p -CO-(CH2)2-(*)R3-NH-L1-CH2-(CH2) n -L2-CH2-(CH2) m -R4 is chemically modified by conjugating the ε-amino group of the K side chain, wherein R3 and R4 are each independently selected from hydrogen, carboxylic acid, phosphoric acid, sulfonic acid, or carboxylic acid isosteres, L1 is selected from -C(O)- or -S(O)2-, L2 is selected from non-existent, carbon-carbon triple bond, carbon-carbon double bond, or a 5-membered heteroaryl group containing 3 N atoms, n and m are each independently selected from any integer from 1 to 18, p is 0, 1, 2, or 3, * indicates that if there is a chiral center, * is S or R; and the C-terminus of the amino acid at position 39 is replaced by the R2 group, R2 is selected from -NH2, -OH, or non-existent.

[0219] The amino acid sequence corresponding to the polypeptide compound No. 42 is SEQ ID NO:42, wherein the N-terminal group of the amino acid at position 1 is replaced by R1, where R1 is selected from H, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl, or is absent; the amino acid at position 2 is Aib; the amino acid at position 13 is Aib(d6); and K at position 20 is substituted by a group having the general formula ([2-(2-amino-ethoxy)-ethoxy]-acetyl)-([2-(2-amino-ethoxy)-ethoxy]-acetyl) p -CO-(CH2)2-(*)R3-NH-L1-CH2-(CH2) n -L2-CH2-(CH2) m-R4 is chemically modified by conjugating the ε-amino group of the K side chain, wherein R3 and R4 are each independently selected from hydrogen, carboxylic acid, phosphoric acid, sulfonic acid, or carboxylic acid isosteres, L1 is selected from -C(O)- or -S(O)2-, L2 is selected from non-existent, carbon-carbon triple bond, carbon-carbon double bond, or a 5-membered heteroaryl group containing 3 N atoms, n and m are each independently selected from any integer from 1 to 18, p is 0, 1, 2, or 3, * indicates that if there is a chiral center, * is S or R; and the C-terminus of the amino acid at position 39 is replaced by the R2 group, R2 is selected from -NH2, -OH, or non-existent.

[0220] The amino acid sequence corresponding to the polypeptide compound No. 43 is SEQ ID NO:43, wherein the N-terminal group of the amino acid at position 1 is replaced by R1, where R1 is selected from H, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl, or is absent; the amino acid at position 2 is Aib(d6); the amino acid at position 13 is Aib(d6); and K at position 20 is substituted by a group having the general formula ([2-(2-amino-ethoxy)-ethoxy]-acetyl)-([2-(2-amino-ethoxy)-ethoxy]-acetyl) p -CO-(CH2)2-(*)R3-NH-L1-CH2-(CH2) n -L2-CH2-(CH2) m -R4 is chemically modified by conjugating the ε-amino group of the K side chain, wherein R3 and R4 are each independently selected from hydrogen, carboxylic acid, phosphoric acid, sulfonic acid, or carboxylic acid isosteres, L1 is selected from -C(O)- or -S(O)2-, L2 is selected from non-existent, carbon-carbon triple bond, carbon-carbon double bond, or a 5-membered heteroaryl group containing 3 N atoms, n and m are each independently selected from any integer from 1 to 18, p is 0, 1, 2, or 3, * indicates that if there is a chiral center, * is S or R; and the C-terminus of the amino acid at position 39 is replaced by the R2 group, R2 is selected from -NH2, -OH, or non-existent.

[0221] The amino acid sequence corresponding to the polypeptide compound No. 44 is SEQ ID NO:44, wherein the N-terminal group of the amino acid at position 1 is replaced by R1, where R1 is selected from H, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl, or is absent; the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; and K at position 20 is substituted with the general formula ([2-(2-amino-ethoxy)-ethoxy]-acetyl)-([2-(2-amino-ethoxy)-ethoxy]-acetyl) p -CO-(CH2)2-(*)R3-NH-L1-CH2-(CH2) n -L2-CH2-(CH2) m-R4 is chemically modified by conjugating the ε-amino group of the K side chain, wherein R3 and R4 are each independently selected from hydrogen, carboxylic acid, phosphoric acid, sulfonic acid, or isosteric acid, and at least one of R3 and R4 is not a carboxylic acid or phosphoric acid; L1 is selected from -C(O)- or -S(O)2-; L2 is selected from non-existent, carbon-carbon triple bond, carbon-carbon double bond, or a 5-membered heteroaryl group containing 3 N atoms; n and m are each independently selected from any integer from 1 to 18; p is 0, 1, 2, or 3; * indicates that if there is a chiral center, * is S or R; and the C-terminus of the amino acid at position 39 is replaced by an R2 group, where R2 is selected from -NH2, -OH, or non-existent.

[0222] The amino acid sequence corresponding to the polypeptide compound No. 45 is SEQ ID NO:45, wherein the N-terminal group of the amino acid at position 1 is replaced by R1, where R1 is selected from H, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl, or is absent; the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; and K at position 20 is substituted with the general formula ([2-(2-amino-ethoxy)-ethoxy]-acetyl)-([2-(2-amino-ethoxy)-ethoxy]-acetyl) p -CO-(CH2)2-(*)R3-NH-L1-CH2-(CH2) n -L2-CH2-(CH2) m -R4 is chemically modified by conjugating the ε-amino group of the K side chain, wherein R3 and R4 are each independently selected from hydrogen, carboxylic acid, phosphoric acid, sulfonic acid, or carboxylic acid isosteres, L1 is -S(O)2-, L2 is selected from non-existent, carbon-carbon triple bond, carbon-carbon double bond, or a 5-membered heteroaryl group containing 3 N atoms, n and m are each independently selected from any integer from 1 to 18, p is 0, 1, 2, or 3, * indicates that if there is a chiral center, * is S or R; and the C-terminus of the amino acid at position 39 is replaced by the R2 group, R2 is selected from -NH2, -OH, or non-existent.

[0223] The amino acid sequence corresponding to the polypeptide compound No. 46 is SEQ ID NO:46, wherein the N-terminal group of the amino acid at position 1 is replaced by R1, where R1 is selected from H, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl, or is absent; the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; and K at position 20 is substituted with the general formula ([2-(2-amino-ethoxy)-ethoxy]-acetyl)-([2-(2-amino-ethoxy)-ethoxy]-acetyl) p -CO-(CH2)2-(*)R3-NH-L1-CH2-(CH2) n -L2-CH2-(CH2) m-R4 is chemically modified by conjugating the ε-amino group of the K side chain, wherein R3 and R4 are each independently selected from hydrogen, carboxylic acid, phosphoric acid, sulfonic acid, or isosteric acid, L1 is selected from -C(O)- or -S(O)2-, L2 is a carbon-carbon triple bond, a carbon-carbon double bond, or a 5-membered heteroaryl group containing 3 N atoms, n and m are each independently selected from any integer from 1 to 18, p is 0, 1, 2, or 3, * indicates that if there is a chiral center, * is S or R; and the C-terminus of the amino acid at position 39 is replaced by the R2 group, R2 is selected from -NH2, -OH, or is absent.

[0224] The amino acid sequence number corresponding to the polypeptide compound No. 47 is SEQ ID NO:47, where the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; and at position 20, K is obtained by passing through a compound with the general formula ([2-(2-amino-ethoxy)-ethoxy]-acetyl)-([2-(2-amino-ethoxy)-ethoxy]-acetyl) s -γGlu-CO-(CH2) r The -CO2H structure is chemically modified by conjugating it to the ε-amino group of the K side chain, wherein r is selected from any integer from 14 to 25, and s is selected from 0, 1, or 2; the amino acid at position 22 is selected from F(2F), F(2Cl), F(2Me), F(2CN), F(3F), F(3Cl), F(3Me), F(3CN), F(4F), F(4Cl), F(4Me), F(4CN), 2Pal, 3Pal, 4Pal, or other non-natural amino acid residues; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0225] The amino acid sequence number corresponding to the polypeptide compound No. 48 is SEQ ID NO:48, where the amino acid at position 2 is Aib; the amino acid at position 13 is Aib; and at position 20, K is obtained by passing through a compound with the general formula ([2-(2-amino-ethoxy)-ethoxy]-acetyl)-([2-(2-amino-ethoxy)-ethoxy]-acetyl) s -γGlu-CO-(CH2) r The structure of -PO(OH)2 is chemically modified by conjugating it to the ε-amino group of the K side chain, wherein r is selected from any integer from 14 to 25, and s is selected from 0, 1, or 2; the amino acid at position 22 is selected from F(2F), F(2Cl), F(2Me), F(2CN), F(3F), F(3Cl), F(3Me), F(3CN), F(4F), F(4Cl), F(4Me), F(4CN), 2Pal, 3Pal, 4Pal, or other non-natural amino acid residues; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0226] In this paper, the sequence structure "-NH2" refers to the amidation of the -COOH group at the C-terminus of an amino acid to -CONH2. For example, the "-NH2" on the right side of compound 1 indicates that the free carboxyl group -COOH in the C-terminal serine S is amidated to -CONH2.

[0227] Regardless of whether the compounds in this application are in the form of amino acid sequences combined with compound groups or in the form of compound structural formulas, those skilled in the art can make relevant conversions using common general knowledge. For example, the following two structures represent the same compound:

[0228] Drug formulation

[0229] In some embodiments, this disclosure provides a pharmaceutical composition comprising a compound of the disclosure (e.g., a compound of formula (I) or a pharmaceutically acceptable salt, ester, or solvate thereof) and a pharmaceutically acceptable excipient.

[0230] Pharmaceutical compositions comprising the compounds disclosed herein or their pharmaceutically acceptable salts, esters, or solvates may be prepared using one or more pharmaceutically acceptable excipients, which may be selected according to conventional practice. Tablets may contain excipients, including gliding agents, fillers, binders, etc. Aqueous compositions may be prepared aseptically and are typically isotonic when intended for delivery by means other than oral administration.

[0231] In some embodiments, the composition may comprise excipients, such as those described in Rowe et al., *Handbook of Pharmaceutical Excipients, 6th edition, American Pharmacists Association, 2009*. Excipients may include ascorbic acid and other antioxidants, chelating agents such as ethylenediaminetetraacetic acid, carbohydrates such as dextrin, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid, etc. In some embodiments, the composition is provided in a solid dosage form, including a solid oral dosage form.

[0232] This composition includes those suitable for various routes of administration, including oral administration. The composition may be present in unit dose form and can be prepared by any method known in the pharmaceutical field. These methods involve the step of combining an active ingredient (e.g., a compound of this disclosure or a pharmaceutical salt thereof) with one or more pharmaceutically acceptable excipients. The composition can be prepared by uniformly and tightly combining the active ingredient with a liquid excipient or finely chopped solid excipients, or both, and then, if desired, shaping the product. Techniques and formulations can generally be found in *Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.*

[0233] The compositions described herein suitable for oral administration may be available in discrete units (unit dosage forms), including but not limited to capsules, sachets, or tablets, each containing a predetermined amount of the active ingredient. In one embodiment, the pharmaceutical composition disclosed herein is a tablet.

[0234] The pharmaceutical compositions disclosed herein comprise one or more of the compounds disclosed herein or pharmaceutically acceptable salts thereof, along with pharmaceutically acceptable excipients and optional other therapeutic agents. Pharmaceutical compositions containing an active ingredient can be in any form suitable for the intended method of administration. When intended for oral use, for example, they can be prepared as tablets, lozenges, tablets, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs. Compositions for oral use can be prepared according to any method known in the art for manufacturing pharmaceutical compositions, and such compositions may contain one or more excipients, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable formulation. Tablets containing an active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for tablet production are acceptable. These excipients can be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium phosphate, or sodium phosphate; granulating and disintegrants such as corn starch or alginate; binders such as cellulose, microcrystalline cellulose, starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets can be uncoated or can be coated using known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract, thereby providing a longer duration of action. For example, delaying materials such as glyceryl monostearate or glyceryl distearate can be used alone or in combination with waxes.

[0235] The amount of active ingredient that can combine with an inactive ingredient to produce a dosage form can vary depending on the intended treatment subjects and the route of administration. For example, in some embodiments, a dosage form for oral administration to humans may contain about 1 to 1000 mg of the active substance, formulated with an appropriate and convenient amount of pharmaceutically acceptable excipients. In some embodiments, pharmaceutically acceptable excipients comprise about 5% to about 95% (by weight) of the total composition.

[0236] In some embodiments, in one variant, compositions comprising compounds of the present disclosure or pharmaceutically acceptable salts thereof do not contain agents that affect the metabolic rate of the active ingredient. Therefore, it should be understood that, in one aspect, compositions comprising compounds of the present invention do not contain agents that affect (e.g., slow down, inhibit, or delay) the metabolism of the compounds of the present invention or any other active ingredient administered separately, sequentially, or simultaneously with the compounds of the present invention. It should also be understood that, in one aspect, any methods, kits, articles, etc., detailed herein do not contain agents that affect (e.g., slow down, inhibit, or delay) the metabolism of the compounds of the present disclosure or any other active ingredient administered separately, sequentially, or simultaneously with the compounds of the present disclosure.

[0237] In some embodiments, the above-described pharmaceutical composition is used in humans or animals.

[0238] This disclosure also includes compounds of the disclosure administered as a single active ingredient in a pharmaceutically acceptable composition, which can be prepared by conventional methods known in the art, such as by conjugating the active ingredient to a pharmaceutically acceptable, therapeutically inert organic and / or inorganic carrier or excipient, or by mixing with it.

[0239] In one aspect, this document provides for the use of the compounds of this disclosure as a second or other active ingredient that has a synergistic effect with other active ingredients in known pharmaceutical products, or for administration of the compounds of this disclosure together with such pharmaceutical products.

[0240] The compounds disclosed herein may also be used in the form of prodrugs or in other suitable modified forms that release the active ingredient in vivo.

[0241] route of administration

[0242] On the other hand, this application provides the use of a compound as described in this application or a pharmaceutically acceptable salt, ester or solvate thereof, or a pharmaceutical composition disclosed herein, in the preparation of a medicament for treating GLP1R / GIPR-mediated diseases or symptoms.

[0243] The diseases or symptoms mediated by GLP1R / GIPR are selected from: T1DM, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-associated diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, nephropathy, diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea, long-term weight management, obesity, eating disorders, weight gain due to other medications, excessive sugar consumption, dyslipidemia, hyperinsulinemia, NAFLD, NASH, fibrosis, cirrhosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction. Death, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral artery disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, restenosis, impaired glucose metabolism, impaired fasting glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue diseases, psoriasis, foot ulcers, ulcerative colitis, hyperapolipoprotein B lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome, or substance addiction.

[0244] The compounds disclosed herein (also referred to herein as the active ingredients) can be administered via any route suitable for the condition to be treated. Suitable routes include oral, rectal, nasal, local (including oral and sublingual), transdermal, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intratumoral, intrathecal, and epidural). It is understood that preferred routes may vary depending on, for example, the condition of the recipient. An advantage of some of the compounds disclosed herein is that they are orally bioavailable and can be administered orally.

[0245] The compounds disclosed herein can be administered to an individual for a desired period of time or duration according to an effective dosing regimen, such as at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer. In one embodiment, the compound is administered daily or intermittently over the duration of an individual's life.

[0246] The dosage or frequency of administration of the compounds disclosed herein can be adjusted during treatment based on the judgment of the administering physician.

[0247] This compound can be administered to an individual (e.g., a human) in an effective amount. In some embodiments, the compound is administered once daily.

[0248] This compound can be administered by any useful route and means, such as oral or parenteral (e.g., intravenous) administration. Therapeutic amounts of this compound may range from about 0.00001 mg / kg body weight per day to about 10 mg / kg body weight per day, for example, from about 0.0001 mg / kg body weight per day to about 10 mg / kg body weight per day, or from about 0.001 mg / kg body weight per day to about 1 mg / kg body weight per day, or from about 0.01 mg / kg body weight per day to about 1 mg / kg body weight per day, or from about 0.05 mg / kg body weight per day to about 0.5 mg / kg body weight per day, or from about 0.3 mg to about 30 mg per day, or from about 30 mg to about 300 mg per day.

[0249] The compounds disclosed herein may be combined with one or more additional therapeutic agents in any dosage amount of the compounds disclosed herein (e.g., from 1 mg to 1000 mg of the compounds). Therapeuticly effective amounts may include from about 1 mg per dose to about 1000 mg per dose, such as from about 50 mg per dose to about 500 mg per dose, or from about 100 mg per dose to about 400 mg per dose, or from about 150 mg per dose to about 350 mg per dose, or from about 200 mg per dose to about 300 mg per dose. Other therapeutically effective amounts of the compounds disclosed herein are about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, or about 500 mg per dose. Other therapeutically effective amounts of the compounds disclosed herein are about 100 mg per dose, or about 125, 150, 175, 200, 225, 250, 275, 300, 350, 400, 450, or about 500 mg per dose. A single dose may be administered hourly, daily, or weekly. For example, a single dose may be administered every 1 hour, 2, 3, 4, 6, 8, 12, 16, or 24 hours. A single dose may also be administered every 1 day, 2, 3, 4, 5, 6, or 7 days. A single dose may also be administered every 1 week, 2, 3, or 4 weeks. In some embodiments, a single dose may be administered weekly. A single dose may also be administered monthly.

[0250] Kits comprising compounds of this disclosure, or enantiomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising any of the foregoing, are also included in this disclosure. In one embodiment, a kit further includes instructions for use. In one aspect, a kit comprises compounds of this disclosure, or pharmaceutically acceptable salts thereof, isomers, mixtures of stereoisomers, the active ingredient, or deuterated analogs thereof, and labeling and / or instructions for use of the compound in treating the indications described herein, such as diseases or conditions. In one embodiment, a kit is provided comprising compounds of this disclosure or pharmaceutically acceptable salts thereof with one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents.

[0251] This document also provides articles comprising the compounds of this disclosure or pharmaceutically acceptable salts, isomers, mixtures of stereoisomers, active ingredients, or deuterated analogs thereof in a suitable container. The container may be a vial, jar, ampoule, pre-filled syringe, or intravenous bag.

[0252] synthesis

[0253] This invention also includes novel intermediates and methods for synthesizing the compounds of the present invention or pharmaceutically acceptable salts thereof. The intermediates and compounds of the present 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 present invention or salts thereof. Reagents and starting materials are readily available to those skilled in the art. It should be understood that these examples are not intended to limit the scope of the invention in any way.

[0254] General methods for synthesizing side chains

[0255] According to typical embodiments of the compounds disclosed herein, synthesis can be performed using the general reaction schemes and / or examples described below. Given the description herein, it is apparent that the general scheme can be modified by substituting the starting materials with other materials having similar structures, thereby producing correspondingly different products. The subsequent synthetic descriptions provide numerous examples illustrating how variations in starting materials can yield corresponding products. Starting materials are typically available from commercial sources or synthesized using published synthetic methods for synthesizing the compounds of the embodiments of this disclosure. The nature of each substituent can be determined by analyzing the structure of the compound to be synthesized, and, in conjunction with the examples herein, the properties of the final product generally clearly indicate the nature of the desired starting material. Group labels (such as R1, R2) used in the reaction schemes herein are for illustrative purposes only and, unless otherwise stated, do not necessarily correspond in name or function to labels used elsewhere to describe formula (I), the compound, or a portion or fragment thereof.

[0256] Synthesis reaction parameters

[0257] The compounds disclosed herein can be prepared using readily available starting materials by, for example, the general methods and procedures described below. It will be understood that, where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, other process conditions may be used unless otherwise specified. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art through conventional optimization procedures.

[0258] Furthermore, conventional protecting groups may be necessary for those skilled in the art to prevent certain functional groups from undergoing undesirable reactions. Protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting specific functional groups, are well known in the art. For example, many protecting groups are described in TW Greene and GMWuts (1999), Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and the references cited therein.

[0259] Furthermore, the compounds disclosed herein may contain one or more chiral centers. Therefore, such compounds can be prepared or isolated as chiral pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as mixtures enriched with stereoisomers, if desired. Unless otherwise stated, all such stereoisomers (and mixtures enriched with stereoisomers) are included within the scope of this statement. Chiral pure stereoisomers (or mixtures enriched with stereoisomers) can be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Additionally, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral dissociation agents, etc.

[0260] The starting materials for the following reactions are generally known compounds, or can be prepared by known procedures or obvious modifications thereof. For example, many starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). Others can be prepared by procedures described in standard references or obvious modifications thereof, such as Fieser's *Organic Synthetic Reagents*, Volumes 1-15 (John Wiley and Sons, 1991); Rodd's *Chemistry of Carbon Compounds*, Volumes 1-5, and Supplements (Elsevier Science Press, 1989); *Organic Reactions*, Volumes 1-40 (John Wiley and Sons, 1991); and March's *Advanced Organic Chemistry* (John Wiley and Sons, 1991). thEdition, 2001), and Larock's Comprehensive Organic Transformation (VCH Publishing, 1989).

[0261] The terms "solvent," "inert organic solvent," or "inert solvent" refer to an inert solvent under the associated reaction conditions (e.g., including benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), N,N-dimethylformamide ("DMF"), chloroform, dichloromethane, diethyl ether, methanol, pyridine, etc.). Unless otherwise specified, the solvents used in the reactions of this disclosure are inert organic solvents, and the reactions are carried out under an inert gas, preferably nitrogen.

[0262] The term "qs" refers to the amount added sufficient to achieve the stated function, for example, to bring the solution to the desired volume (i.e., 100%).

[0263] Preparation of side chain A1:

[0264] Step 1: Sulfuric acid (12.9 g, 132 mmol, 7.06 mL, 1.0 eq) was added to a solution of 19-bromononadecanoic acid (50.0 g, 132 mmol, 1.0 eq) in methanol (500 mL). The mixture was stirred at 80 °C for 8 hours. The reaction mixture was concentrated under vacuum. The crude product was diluted with water and ethyl acetate, and the pH of the aqueous phase was adjusted to 7 with saturated sodium bicarbonate solution. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound A1-1 (55.0 g, crude product) as a white solid. 1 H NMR (400MHz, CDCl3) δ: 3.66 (s, 3H), 3.40 (t, J = 6.8 Hz, 2H), 2.29 (t, J = 7.6 Hz, 2H), 1.88-1.81 (m, 2H), 1.65-1.54 (m, 2H), 1.43-1.22 (m, 28H).

[0265] Step 2: Dibenzyl phosphite (14.7 g, 56.2 mmol, 1.1 eq) was added dropwise to a 200 mL solution of DMF containing cesium carbonate (33.2 g, 102 mmol, 2.0 eq) and tetraethylammonium iodide (13.1 g, 51.0 mmol, 1.0 eq) at 20 °C. Compound A1-1 (20.0 g, 51.0 mmol, 1.0 eq) was then added to the solution, and the reaction mixture was stirred at 35 °C for 8 hours. The reaction mixture was filtered, the filtrate was quenched with water, and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound A1-2 (30.0 g, 50.1 mmol, 98.2% yield) as a white solid. m / z = [M + H]+ =573.3, 1 H NMR(400MHz, CDCl3)δ7.36-7.29(m,10H),5.11-4.89(m,4H),3.65(s,3H),2.2 9(t,J=7.6Hz,2H),1.87-1.68(m,2H),1.62-1.49(m,4H),1.27-1.21(m,28H).

[0266] Step 3: To a solution of compound A1-2 (15.0 g, 25.0 mmol, 1.0 eq) in tetrahydrofuran (140 mL), lithium hydroxide monohydrate (3.15 g, 75.2 mmol, 3.0 eq) and water (140 mL) were added. The mixture was stirred at 35 °C for 8 hours. The reaction mixture was quenched by adding 1 M hydrochloric acid and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound A1 (11.0 g, 78% yield) as a white solid. m / z = [M + H] + =559.3, 1 H NMR(400MHz,DMSO-d6)δ11.9(s,1H),7.39-7.30(m,10H),5.03-4.91(m,4H),2. 17(t,J=7.6Hz,2H),1.80-1.72(m,2H),1.48-1.34(m,4H),1.30-1.18(m,28H).

[0267] Preparation of side chain A2:

[0268] Step 1: Sulfuric acid (1.25 g, 12.7 mmol, 1.0 eq) was added to a methanol (50 mL) solution of compound 20-bromoeicosanoic acid (5.0 g, 12.7 mmol, 681 μL, 1 eq). The mixture was stirred at 80 °C for 12 hours. TLC showed that the reaction was complete. The reaction mixture was concentrated under vacuum. The crude product was diluted with water and ethyl acetate, and the pH of the aqueous phase was adjusted to 7 with saturated sodium bicarbonate solution. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound A2-1 (4.90 g, crude product) as a white solid. 1 H NMR (400MHz, CDCl3) δ: 3.67 (s, 3H), 3.41 (t, J = 6.90Hz, 2H), 2.31 (t, J = 7.60Hz, 2 H),1.92-1.78(m,2H),1.65-1.54(m,2H),1.48-1.37(m,2H),1.31-1.22(m,28H).

[0269] Step 2: To a 50 mL solution of DMF containing cesium carbonate (7.87 g, 24.2 mmol, 2.0 eq) and tetraethylammonium iodide (3.10 g, 12.1 mmol, 1.0 eq), dibenzyl phosphite (3.48 g, 13.3 mmol, 1.1 eq) was added dropwise at 20 °C. Then, compound A2-1 (4.90 g, 12.1 mmol, 1.0 eq) was added to the solution, and the reaction mixture was stirred at 35 °C for 12 hours. The reaction was confirmed by LC-MS. The reaction mixture was filtered, the filtrate was quenched with water, and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound A2-2 (6.8 g, crude product) as a white solid. m / z = [M + H] + =587.4.

[0270] Step 3: Lithium hydroxide monohydrate (1.46 g, 34.8 mmol, 3.0 eq) was added to a solution of compound A2-2 (6.80 g, 11.6 mmol, 1.0 eq) in tetrahydrofuran (60 mL) and water (60 mL). The mixture was stirred at 20 °C for 12 hours. The pH of the mixture was adjusted to 3–4 with hydrochloric acid (1 N), followed by extraction with dichloromethane. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative high-performance liquid chromatography to give compound A2 (0.22 g, yield 3.28%) as a white solid. m / z = [M + H] + =573.4. 1 H NMR(400MHz, CDCl3)δ:7.40-7.30(m,10H),5.10-5.03(m,2H),5.02-4.93(m,2H), 2.35(t,J=7.50Hz,2H),1.82-1.70(m,2H),1.69-1.51(m,4H),1.35-1.18(m,30H).

[0271] Preparation of side chain A3:

[0272] Step 1: Sulfuric acid (1.0 mL) was added to a solution of compound 21-bromotetracosic acid (1.00 g, 2.47 mmol, 1.0 eq) in methanol (10 mL). The mixture was stirred at 70 °C for 15 hours. TLC showed product formation. The reaction mixture was concentrated under vacuum, and the crude product was diluted with water and ethyl acetate. The pH of the aqueous phase was adjusted to 7 with saturated sodium bicarbonate solution. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound A3-1 (1.0 g, 96.7% yield) as a white solid.1 H NMR (400MHz, CDCl3) δ: 3.67 (s, 3H), 3.41 (t, J = 6.90Hz, 2H), 2.31 (t, J = 7.60Hz, 2 H),1.88-1.86(m,2H),1.64-1.62(m,2H),1.43-1.60(m,2H),1.28-1.26(m,30H).

[0273] Step 2: To a 20 mL solution of DMF containing cesium carbonate (1.55 g, 4.77 mmol, 2.0 eq) and tetraethylammonium iodide (674 mg, 2.62 mmol, 1.1 eq), dibenzyl phosphite (687 mg, 2.62 mmol, 1.1 eq) was added dropwise at 20 °C. Then, compound A3-1 (1.0 g, 2.38 mmol, 1.0 eq) was added to the solution, and the reaction mixture was stirred at 35 °C for 15 hours. The reaction mixture was filtered, the filtrate was quenched with water, and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound A3-2 (1.0 g, 69.8% yield) as a white solid. m / z = [M + H] + =601.4. 1 H NMR (400MHz, CDCl3) 1 H NMR (400MHz, CDCl3) δ7.36-7.32(m,10H),5.08-4.94(m,4H),3.67(s,3H),2.3 1(t,J=7.6Hz,2H),1.84-1.67(m,2H),1.60-1.48(m,4H),1.32-1.22(m,32H).

[0274] Step 3: Lithium hydroxide monohydrate (230 mg, 5.49 mmol, 3.0 eq) was added to a solution of compound A3-2 (1.1 g, 1.83 mmol, 1.0 eq) in tetrahydrofuran (30 mL) and water (30 mL). The mixture was stirred at 25 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran. The pH of the mixture was adjusted to 6 with 1 M hydrochloric acid, and then extracted with ethyl acetate (30 mL × 3). The mixture was filtered and concentrated under reduced pressure. The crude product was purified by reversed-phase liquid chromatography to give compound A3 (200 mg, yield 11.4%) as a white solid. m / z = [M + H] + = 587.5. 1H NMR(400MHz, CDCl3)δ11.95(s,1H),7.56-7.15(m,10H),5.18-4.74(m,4H),2. 17(t,J=7.4Hz,2H),1.81-1.72(m,2H),1.56-1.40(m,4H),1.31-1.17(m,32H).

[0275] Preparation of side chain A4

[0276] Step 1: To a solution of undecyl-10-yn-1-ol (5.0 g, 22.4 mmol, 1.0 eq) in 50.0 mL of THF, add TsOH (385 mg, 2.24 mmol, 0.10 eq) at 0 °C. After stirring for 5 minutes, slowly add 3,4-dihydro-2H-pyran (3.60 g, 42.7 mmol, 3.91 mL, 1.91 eq). Stir the mixture at 25 °C for 1 hour. C showed that undecyl-10-yn-1-ol was completely consumed. Triethylamine (2.0 mL) was added to neutralize TsOH, and the reaction mixture was then diluted with water (50 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography. The final product was compound A4-1 (6.0 g, yield 87.1%), as a colorless oily liquid. 1 H NMR(400MHz, CDCl3)δ:4.56-4.54(m,1H),3.88-3.82(m,1H),3.74-3.68(m,1H),3.50-3.45(m,1H),3.39-3.33(m,1H), 2.18-2.13(m,2H),1.92(t,J=2.4Hz,1H),1.85-1.77(m,1H),1.73-1.66(m,1H),1.59-1.46(m,8H),1.38-1.28(m,10H).

[0277] Step 2: To a solution of 9-bromononane-1-ol (9.0 g, 53.4 mmol, 1.0 eq) in THF (90.0 mL), TsOH (921 mg, 5.34 mmol, 0.10 eq) was added at 0 °C. After stirring for 0.5 hours, 3,4-dihydro-2H-pyran (8.99 g, 106 mmol, 9.78 mL, 2.0 eq) was slowly added, and the mixture was stirred at 25 °C for 1 hour. TLC showed that 9-bromononane-1-ol reacted completely. TsOH was quenched with triethylamine (5 mL), and the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give compound A4-2 (10.8 g, 80% yield) as a colorless oily liquid. 1 H NMR(400MHz, CDCl3)δ:4.57-4.56(m,1H),3.89-3.84(m,1H),3.75-3.69(m,1H),3.52-3.47(m,1H) ,3.41-3.34(m,3H),1.88-1.79(m,3H),1.74-1.68(m,1H),1.60-1.49(m,6H),1.43-1.30(m,10H).

[0278] Step 3: Compound A4-2 (500 mg, 1.98 mmol, 1.0 eq) was added to a solution of THF (10.0 mL) at -50 °C. Butyllithium (2.50 M, 792 μL, 1.0 eq) and HMPA (2.49 g, 13.9 mmol, 2.43 mL, 7.02 eq) was slowly added, and the mixture was stirred for 30 minutes under a nitrogen atmosphere. Then, compound A4-1 (669 mg, 2.17 mmol, 1.1 eq) was slowly added, followed by stirring at 25 °C for 12 hours. The reaction mixture was diluted with ice water (50 mL) and extracted with ethyl acetate (80 mL × 3). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give compound A4-3 (500 mg, yield 42.6%) as a yellow oily liquid. 1 H NMR(400MHz, CDCl3)δ:4.58-4.57(m,2H),3.90-3.84(m,2H),3.76-3.70(m,2H),3.53-3.48(m,2H) ,3.41-3.35(m,2H),2.23-2.11(m,4H),1.83-1.71(m,4H),1.61-1.45(m,16H),1.36-1.26(m,20H).

[0279] Step 4: Hydrochloric acid / methanol solution (2M, 4.46 mL, 17.0 eq) was added to a methanol (5.0 mL) solution of compound A4-3 (500 mg, 522 μmol, 1.0 eq), and the mixture was stirred at 25 °C for 12 hours. TLC showed that compound A1-3 was consumed. The solution was concentrated under reduced pressure to give compound A4-4 (362 mg, yield 85.6%) as a white powder. 1 HNMR (400MHz, CDCl3) δ: 3.64 (t, J = 6.8Hz, 4H), 2.16-2.12 (m, 4H), 1.60-1.30 (m, 30H).

[0280] Step 5, Preparation of Solution 1: Sulfuric acid (3.31 g, 33.7 mmol, 437 μL, 7.32 eq) was slowly added to a solution of dichromic anhydride (1.18 g, 11.8 mmol, 437 μL, 7.32 eq) in water (8.2 mL) at 0 °C. Compound A4-4 (362 mg, 1.61 mmol, 1.0 eq) was slowly added to Solution 1 at 0 °C, and the mixture was stirred at 0 °C for 0.5 hours. The reaction mixture was diluted with ice water (50 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography to give compound A4 (250 mg, yield 65.4%) as a slightly white solid. 1 H NMR (400MHz, DMSO-d6) δ: 11.96 (s, 2H), 2.20–2.18 (m, 4H), 2.16–2.10 (m, 4H), 1.48–1.24 (m, 24H).

[0281] Preparation of side chain A5

[0282] Undecenoic acid (1.50 g, 8.14 mmol, 1.0 eq) was added to a solution of dichloromethane (60 mL) with Grubbs 2nd catalyst (255 mg, 407 μmol, 0.05 eq). The reaction mixture was stirred at 40 °C for 2 hours. TLC analysis showed product formation. The reaction mixture was concentrated under vacuum to obtain a residue. The residue was purified by column chromatography to give compound A5 (300 mg, yield 10.8%) as a white solid. m / z = 363.1 [M + Na] + , 1H NMR (400MHz, CDCl3) δ: 5.39-5.37 (m, 2H), 2.37-2.34 (t, J = 8.0Hz, 4H), 1.98-1.97 (m, 4H), 1.67-1.60 (m, 4H), 1.33-1.29 (m, 20H).

[0283] General synthetic methods for polypeptide compounds

[0284] The polypeptide compounds of this invention can be prepared using the standard Fmoc solid-phase peptide synthesis (SPPS) chemical method, and the following steps are performed:

[0285] Polypeptide synthesis:

[0286] 1) Resin preparation: The peptide was synthesized by solid-phase synthesis using a suitable resin; for example, for a synthesis scale of 0.20 mmol, 0.66 g MBHA resin (loading = 0.3 mmol / g) was used.

[0287] 2) Deprotection: Add 20% piperidine / DMF solution to the resin and stir with N2 at 23°C for 30 min. Then wash the resin with DMF and collect the resin by filtration.

[0288] 3) Coupling: A DMF solution containing HATU and Fmoc-amino acids was added to the resin, followed by DIEA, and the mixture was stirred with N2 at 23°C for 0.5 h. The resin was then washed with DMF.

[0289] 4) Repeat steps 2 to 3 above to couple the remaining amino acids in sequence.

[0290] Peptide cleavage and purification:

[0291] 1) Add lysis buffer (20.0 mL, 92.5% TFA / 2.50% TIS / 2.50% H2O / 2.5% DTT) to a resin-containing flask and stir at room temperature for 2 h.

[0292] 2) Precipitate the peptide with cold isopropyl ether (100.0 mL), filter, and collect the filter cake. Wash the filter cake with isopropyl ether (100.0 mL × 2 times). Dry the crude peptide under vacuum for 2 h to obtain the crude product. The crude peptide was confirmed by LC-MS.

[0293] 3) The crude peptide was purified by preparative HPLC (TFA system: A: 0.1% TFA aqueous solution, B: acetonitrile; AcOH system: A: 0.5% acetic acid aqueous solution, B: acetonitrile) to obtain the target polypeptide compound.

[0294] Peptide purity detection and mass spectrometry analysis:

[0295] The purity of the obtained polypeptide compounds was determined by analytical reversed-phase HPLC, and their mass spectrometric characteristic peaks were confirmed by LC / MS.

[0296] The structural formula of compound 1 in Example 1 is as follows:

[0297] The amino acid sequence of compound 1:

[0298] YAibEGTFTSDYSIAibLDKIAQKAF(4F)VQWLIAGGPSSGAPPPS-NH2;

[0299] Synthesis procedure: Rink amide MBHA resin was used, Fmoc was removed with 20% piperidine / DMF, HOBT / DIC was used as the coupling agent, DMF was used as the reaction solvent, and the reaction was monitored by ninhydrin detection method.

[0300] Step 1: Weigh 1.43 g of Rink amide MBHA resin (degree of substitution 0.35 mmol / g) and place it in a reactor. Add 10 mL of DCM and soak for 2 hours. Wash the resin three times with 10 mL of DMF. Then remove the Fmoc protecting group with 20% piperidine / DMF and wash six times with 5 mL of DMF. Weigh 0.96 g of Fmoc-Ser(tBu)-OH and 0.41 g of HOBt, dissolve them in 5 mL of DMF, add 0.35 g of DIC at 0°C, activate for 5 minutes, add to the reactor, and react for 2 hours. Then remove the Fmoc protecting group with 20% piperidine / DMF. Repeat the above steps to complete the coupling of other amino acids according to the amino acid sequence of compound 1, where Lys20 is coupled using Fmoc-Lys(Alloc)-OH.

[0301] Step 2: After the above condensation is completed, wash the resin three times with DCM. Then add phenylsilane (0.98 g) and DCM, react for 5 minutes, then add Pd(PPh3)4 (0.26 g) to remove the alloc protecting group from Lys20, and react for 1 hour. Then wash the resin three times with DCM, three times with DMF, and then three more times with DCM to obtain a peptide resin with selectively removed alloc.

[0302] Step 3: Weigh 1.0 g of Fmoc-AEEA-OH and 0.41 g of HOBt, dissolve them in DMF, add 0.52 g of DIC at 0°C, activate for 5 minutes, add the previously obtained alloc-free peptide resin, react for 2 hours, and then remove the Fmoc protecting group with 20% piperidine / DMF. Repeat the above operation to couple Fmoc-AEEA-OH, Fmoc-Glu-OtBu, and tert-butyl eicosanoate sequentially according to the sequence. After the reaction is complete, wash 5 times with DMF, 3 times with DCM, and 2 times with methanol, and dry under reduced pressure at room temperature to obtain the target peptide resin.

[0303] Step 4: Add the obtained peptide resin to the pre-prepared lysis buffer (TFA:EDT:TIS:H2O, volume ratio 94:2:2:2), react at room temperature for 3 hours, filter off the resin, collect the filtrate, wash the resin three times with a small amount of TFA, combine the filtrates and concentrate under reduced pressure, add methyl tert-butyl ether to precipitate, a white solid is precipitated, centrifuge, wash three times with methyl tert-butyl ether, dry under reduced pressure to obtain crude product, purify the crude product by HPLC and freeze dry to obtain target polypeptide compound 1.

[0304] The purity of compound 1 was determined by analytical reversed-phase HPLC (95.8%), and its characteristic phase (M+2H) was confirmed by LC / MS. + ) / 2=2516.3,(M+3H + ) / 3=1610.9,(M+4H + ) / 4 = 1209.0. The MS spectrum of compound 1 is shown in Figure 1.

[0305] The structural formula of compound 2 in Example 2 is as follows:

[0306] The amino acid sequence of compound 2:

[0307] YAibEGTFTSDYSIAibLDKIAQKAF(3F)VQWLIAGGPSSGAPPPS-NH2;

[0308] Similar to the solid-phase synthesis steps described in Example 1, the target polypeptide compound 2 was synthesized based on the provided amino acid sequence of compound 2 and side chain modifications.

[0309] The structural formula of compound 3 in Example 3 is as follows:

[0310] The amino acid sequence of compound 3:

[0311] YAibEGTFTSDYSIAibLDKIAQKAF(2F)VQWLIAGGPSSGAPPPS-NH2;

[0312] Similar to the solid-phase synthesis steps described in Example 1, the target polypeptide compound 3 was synthesized based on the provided amino acid sequence of compound 3 and side chain modifications.

[0313] The purity of compound 3 was determined by analytical reversed-phase HPLC (97.3%), and its characteristics (M+3H) were confirmed by LC / MS. + ) / 3 = 1611.8, (M+4H + ) / 4 = 1208.6. The MS spectrum of compound 3 is shown in Figure 2.

[0314] The structural formula of compound 4 in Example 4 is as follows:

[0315] The amino acid sequence of compound 4:

[0316] YAibEGTFTSDYSIAibLDKIAQKA4PalVQWLIAGGPSSGAPPPS-NH2;

[0317] Similar to the solid-phase synthesis steps described in Example 1, the target polypeptide compound 4 was synthesized based on the provided amino acid sequence of compound 4 and side chain modifications.

[0318] The purity of compound 4 was determined by analytical reversed-phase HPLC (98.0%), and its characteristics (M+3H) were confirmed by LC / MS. + ) / 3=1605.6,(M+4H + ) / 4 = 1204.6. The MS spectrum of compound 4 is shown in Figure 3.

[0319] The structural formula of compound 5 in Example 5 is as follows:

[0320] The amino acid sequence of compound 5:

[0321] YAibEGTFTSDYSIAibLDKIAQKA3PalVQWLIAGGPSSGAPPPS-NH2;

[0322] Similar to the solid-phase synthesis steps described in Example 1, the target polypeptide compound 5 was synthesized based on the provided amino acid sequence of compound 5 and side chain modifications.

[0323] The purity of compound 5 was determined by analytical reversed-phase HPLC (98.5%), and its characteristics (M+3H) were confirmed by LC / MS. + ) / 3=1605.2,(M+4H + ) / 4 = 1204.7. The MS spectrum of compound 5 is shown in Figure 4.

[0324] The structural formula of compound 6 in Example 6 is as follows:

[0325] The amino acid sequence of compound 6:

[0326] YAibEGTFTSDYSIAibLDKIAQKA2PalVQWLIAGGPSSGAPPPS-NH2;

[0327] Similar to the solid-phase synthesis steps described in Example 1, the target polypeptide compound 6 was synthesized based on the provided amino acid sequence of compound 6 and side chain modifications.

[0328] Example 7 Compound 14

[0329] Similar to the solid-phase synthesis steps described in Example 1, the target polypeptide compound 14 was synthesized based on the amino acid sequence of compound 14 and side chain modifications.

[0330] The purity of compound 14 was determined by analytical reversed-phase HPLC (94.8%), and its characteristics (M+2H) were confirmed by LC / MS. + ) / 2=2406.1,(M+3H + ) / 3 = 1604.6.

[0331] Example 7 Compound 15

[0332] Similar to the solid-phase synthesis steps described in Example 1, the target polypeptide compound 15 was synthesized based on the amino acid sequence of compound 15 and side chain modifications.

[0333] The purity of compound 15 was determined by analytical reversed-phase HPLC (95.0%), and its characteristics (M+2H) were confirmed by LC / MS. + ) / 2=2405.7,(M+3H + ) / 3 = 1604.9.

[0334] Example 8 Compound 23

[0335] Similar to the solid-phase synthesis steps described in Example 1, the target polypeptide compound 23 was synthesized based on the amino acid sequence of compound 23 and side chain modifications.

[0336] The purity of compound 23 was determined by analytical reversed-phase HPLC (97.4%), and its characteristics (M+3H) were confirmed by LC / MS. + ) / 3 = 1623.4, (M+4H + ) / 4 = 1217.7. The MS spectrum of compound 23 is shown in Figure 5.

[0337] Example 9 Compound 25

[0338] Similar to the solid-phase synthesis steps described in Example 1, the target polypeptide compound 25 was synthesized based on the amino acid sequence of compound 25 and side chain modifications.

[0339] The purity of compound 25 was determined by analytical reversed-phase HPLC (95.1%), and its characteristic phase (M+2H) was confirmed by LC / MS. + ) / 2=2424.6,(M+3H + ) / 3 = 1617.7, (M+4H + ) / 4 = 1212.5. The MS spectrum of compound 25 is shown in Figure 6.

[0340] Example 10 Compound 26

[0341] Similar to the solid-phase synthesis steps described in Example 1, the target polypeptide compound 26 was synthesized based on the amino acid sequence of compound 26 and side chain modifications.

[0342] The purity of compound 26 was determined by analytical reversed-phase HPLC (95.3%), and its characteristics (M+3H) were confirmed by LC / MS. + ) / 3=1610.7,(M+4H + ) / 4 = 1207.7.

[0343] Example 11 Compound 27

[0344] Similar to the solid-phase synthesis procedure described in Example 1, the target polypeptide compound 27 was synthesized based on the amino acid sequence of compound 27 and side chain modifications.

[0345] The purity of compound 27 was determined by analytical reversed-phase HPLC (99.1%), and its characteristics (M+3H) were confirmed by LC / MS. + ) / 3=1610.5,(M+4H + ) / 4 = 1207.6.

[0346] Example 12 Compound 28

[0347] Similar to the solid-phase synthesis steps described in Example 1, the target polypeptide compound 28 was synthesized based on the amino acid sequence of compound 28 and side chain modifications.

[0348] The purity of compound 28 was determined by analytical reversed-phase HPLC (92.0%), and its characteristics (M+3H) were confirmed by LC / MS.+ ) / 3 = 1624.5, (M+4H + ) / 4 = 1218.7.

[0349] Example 13 Compound 29

[0350] Similar to the solid-phase synthesis steps described in Example 1, the target polypeptide compound 29 was synthesized based on the amino acid sequence of compound 29 and side chain modifications.

[0351] The purity of compound 29 was determined by analytical reversed-phase HPLC (95.3%), and its characteristics (M+3H) were confirmed by LC / MS. + ) / 3 = 1622.0, (M+4H + ) / 4 = 1216.2. The MS spectrum of compound 29 is shown in Figure 7.

[0352] Example 14 Compound 30

[0353] Similar to the solid-phase synthesis steps described in Example 1, the target polypeptide compound 30 was synthesized based on the amino acid sequence of compound 30 and side chain modifications.

[0354] The purity of compound 30 was determined by analytical reversed-phase HPLC (95.1%), and its characteristic phase (M+2H) was confirmed by LC / MS. + ) / 2=2439.7,(M+3H + ) / 3 = 1626.7, (M+4H + ) / 4 = 1220.8. The MS spectrum of compound 30 is shown in Figure 8.

[0355] Example 15 Compound 31

[0356] Similar to the solid-phase synthesis steps described in Example 1, the target polypeptide compound 31 was synthesized based on the amino acid sequence of compound 31 and side chain modifications.

[0357] The purity of compound 31 was determined by analytical reversed-phase HPLC (96.9%), and its characteristics (M+2H) were confirmed by LC / MS. + ) / 2=2418.7,(M+3H + ) / 3 = 1612.5, (M+4H + ) / 4 = 1209.6. The MS spectrum of compound 31 is shown in Figure 9.

[0358] Example 16 Compound 33

[0359] Similar to the solid-phase synthesis steps described in Example 1, the target polypeptide compound 33 was synthesized based on the amino acid sequence of compound 33 and side chain modifications.

[0360] The purity of compound 33 was determined by analytical reversed-phase HPLC (95.6%), and its characteristics (M+3H) were confirmed by LC / MS. + ) / 3 = 1628.9.

[0361] Biological experiments

[0362] Test Example 1: Evaluation of human GLP-1 receptor agonist activity

[0363] GLP-1 receptor (GLP-1R) functional activity was determined by cAMP formation in the HEK293 immortalized cell line Flp-In-293-GLP1R (constructed by Pharmaron) expressing human GLP-1R.

[0364] Flp-In-293-GLP1R immortalized cells were seeded in 384-well plates of DMEM medium supplemented with 10% FBS, 1× penicillin-streptomycin, and 200 μg / mL HB and incubated overnight to allow adherence. A 4× working solution of the test compound was prepared using assay buffer (1×HBSS + 20 mM HEPES + 0.1% BSA + 500 μM IBMX). 5 μL of the 4× working solution was added to the cell plate and incubated at 37°C for 30 min. The increase in intracellular cAMP was quantified using the CisBio cAMP Dynamic 2HTRF assay kit. In short, intracellular cAMP levels were detected by adding the cAMP-d2 conjugate to cell lysis buffer (10 μL), followed by the addition of anti-cAMP-Eu3+-Cryptate antibody to the cell lysis buffer (10 μL). The resulting competitive detection system was incubated at room temperature for at least 60 min, and then detected using a microplate reader with excitation wavelengths of 320 nm and emission wavelengths of 665 nm and 620 nm. The emission peak area was inversely proportional to the amount of cAMP present, and this was converted to the cAMP concentration per well using a cAMP standard curve. The amount of cAMP generated in each well was then converted to the percentage of the observed maximum response. (Relative EC) 50 The value and percentage upper limit (Emax) were obtained through nonlinear regression analysis, using the maximum response percentage to fit the concentration of the added compound to a four-parameter logistic equation.

[0365] The disclosed compounds exhibit agonistic activity against human GLP-1R (EC). 50 <0.1 nM, where the specific EC values ​​of some of the compounds in the examples are... 50 The components are shown in Table 3.

[0366] Table 3. Agonistaltic activity of the disclosed compounds against human GLP-1R.

[0367] Conclusion: The compound disclosed herein has strong agonistic activity against human GLP-1R.

[0368] Test Example 2: Evaluation of Human GIP Receptor Agonistaltic Activity

[0369] GIP receptor (GIPR) functional activity was determined by cAMP formation in the HEK293 immortalized cell line Flp-In-293-GIPR (constructed by Pharmaron) expressing human GIPR.

[0370] Flp-In-293-GIPR immortalized cells were seeded in 384-well plates of DMEM medium supplemented with 10% FBS, 1× penicillin-streptomycin, and 200 μg / mL HB and incubated overnight to allow adherence. A 4× working solution of the test compound was prepared using assay buffer (1×HBSS + 20 mM HEPES + 0.1% BSA + 500 μM IBMX). 5 μL of the 4× working solution was added to the cell plate and incubated at 37°C for 30 min. The increase in intracellular cAMP was quantified using the CisBio cAMP Dynamic 2HTRF assay kit. In short, intracellular cAMP levels were detected by adding the cAMP-d2 conjugate to cell lysis buffer (10 μL), followed by the addition of anti-cAMP-Eu3+-Cryptate antibody to the cell lysis buffer (10 μL). The resulting competitive detection system was incubated at room temperature for at least 60 min, and then detected using a microplate reader with excitation wavelengths of 320 nm and emission wavelengths of 665 nm and 620 nm. The emission peak area was inversely proportional to the amount of cAMP present, and this was converted to the cAMP concentration per well using a cAMP standard curve. The amount of cAMP generated in each well was then converted to the percentage of the observed maximum response. (Relative EC) 50 The value and percentage upper limit (Emax) were obtained through nonlinear regression analysis, using the maximum response percentage to fit the concentration of the added compound to a four-parameter logistic equation.

[0371] The disclosed compounds exhibit agonistic activity against human GIPR (EC). 50 <0.1 nM, where the specific EC values ​​of some of the compounds in the examples are... 50 The components are shown in Table 4.

[0372] Table 4. Agonistaltic activity of the disclosed compounds on human GIPR

[0373] Conclusion: The compound disclosed herein exhibits strong agonistic activity against human GIPR.

[0374] Test Example 3: GLP-1R / GIPR cAMP assay of peptide compounds

[0375] 1. Experimental Materials

[0376] (1) Reagents

[0377] cAMP assay kit, Cisbio (Cat#62AM4PEJ); 1M HEPES buffer, Invitrogen (Cat#15630-106); 1×HBSS buffer, Invitrogen (Cat#14025); milk-derived casein solution, Sigma (Cat#C3400-500g); IBMX, Sigma (Cat#I5879)

[0378] (2) Instruments and equipment

[0379] OptiPlate-384 white microplate, PerkinElmer (Cat#6007290); Echo-specific 384-well plate, Labcyte (Cat#P-05525); EnVision multi-label analyzer, PerkinElmer; Vi-cell cell counter, Beckman (Cat#Vi-CELL™ XR Cell ViabilityAnalyzer)

[0380] (3) Cell lines

[0381] The cell lines were constructed by WuXi AppTec, and detailed information is shown in Table 5.

[0382] Table 5. Detailed information on cell lines

[0383] 2. Experimental Methods

[0384] a) Preparation of compound source plate

[0385] The reference and test compounds were diluted 4-fold at 10 concentration points using a Bravo automated workstation, starting from the working concentration, and completely dissolved in buffer solution.

[0386] b) Preparation of cell suspension

[0387] 1) Quickly place one frozen cell in a 37°C water bath to thaw.

[0388] 2) Transfer the cell suspension to a 15mL conical tube and add 10mL of HBSS.

[0389] 3) Centrifuge at 1000 rpm at room temperature for 5 min to precipitate the cells.

[0390] 4) Carefully aspirate the supernatant, being careful not to aspirate the cells.

[0391] 5) Gently tap the bottom of the tube to loosen the cell clumps, then resuspend them in 10 mL of HBSS; use a sterile pipette to blow up and down to break up the cell clumps.

[0392] 6) Use a Vi-cell counter to determine cell concentration and assess cell viability.

[0393] 7) Resuspend GLP-1R and GIPR cells in detection buffer to a final concentration of 2.0 × 10⁻⁶. 5 cells / mL and 4.0×10 5 cells / mL.

[0394] 8) Take 5 μL of cell suspension and add it to an OptiPlate-384 white microplate.

[0395] c) Compound transfer: Using a Bravo automated workstation, 5 μL of the diluted compound was added to the corresponding well of the OptiPlate-384 plate.

[0396] d) HTRF cAMP agonist detection

[0397] 1) Incubate at 23℃ for 30 minutes before adding the test reagent.

[0398] 2) Add 10 μL of test reagent to each well using an electric multichannel pipette.

[0399] 3) Seal the plate with TopSeal-A film and incubate at 23°C in the dark for 60 minutes;

[0400] After peeling off the film, the fluorescence signal was read on EnVision.

[0401] 3. Experimental Results

[0402] The experimental results are shown in Tables 6 and 7.

[0403] Table 6. Experimental results of GLP-1R using cAMP.

[0404] Table 7. Experimental results of GIPR using cAMP

[0405] 4. Experimental Conclusions

[0406] The peptide compounds of this invention, through the design and modification of the peptide amino acid sequence and fatty acid side chains, exhibit comparable or stronger GLP1R agonist activity and more potent GIPR agonist activity compared to the known GLP1R / GIPR dual agonist Tirzepatide. Furthermore, compared to Tirzepatide, the compounds of this invention possess a more balanced GLP1R and GIPR agonist activity. Therefore, the peptide compounds of this invention are expected to have better therapeutic potential in humans for GLP1R and / or GIPR-mediated diseases.

[0407] Test Example 4: Pharmacokinetic Study of Compounds in Rats

[0408] 1. Experimental objective:

[0409] The purpose of this experiment was to study the pharmacokinetic behavior of this compound in rats (plasma) after a single tail vein injection, using SD rats as the test animals.

[0410] 2. Experimental Methods:

[0411] Male SD rats weighing approximately 200-300g and aged 6-10 weeks were purchased from Viton Lever Laboratories. The test peptide compound was prepared to a concentration of 0.04 mg / mL using a solvent (20 mM citrate buffer, pH 7.0). The drug was administered via tail vein injection at a volume of 5 mL / kg of animal body weight. Approximately 0.15 mL of blood was collected from the jugular sinus before administration and at 0.25, 0.5, 1, 2, 4, 8, 12, 24, 36, 48, and 72 hours after administration. All whole blood samples were placed in EDTA-K2 anticoagulant tubes, thoroughly mixed by inverting several times, and placed on wet ice before centrifugation (1500g, 4℃) for 10 min. After plasma separation, all samples were stored at -90 to -60℃ until analysis. The plasma concentration of the drug was determined by LC-MS / MS, and the pharmacokinetic parameters were calculated using a non-compartmental model in Phoenix 8.3 software.

[0412] 3. Experimental Results:

[0413] The specific data obtained through the above experimental methods are shown in Table 8.

[0414] Table 8 Specific data from animal experiments

[0415] Data show that the disclosed compound exhibits excellent pharmacokinetic characteristics after intravenous administration in rats. Compound 29 has a very low plasma clearance (CL), while its key pharmacokinetic parameter AUC... (0-72h)The concentration is very high, 1.85 times that of Tirzepatide. Therefore, the disclosed compound is expected to have better clinical therapeutic potential.

[0416] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A polypeptide compound of formula (I), R1-Y-X1-EGTFTSDYSI-X2-LDKIAQ-X3-A-X4-VQWLIAGGPSSGAPPPS-R2 (I) Or its pharmaceutically acceptable salts, esters or solvates, in, R1 is selected from H, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl, or is not present; R2 is selected from -NH2, -OH, or is not present; X1 is selected from Aib or Aib(d6); X2 is selected from Aib or Aib(d6); X3 is K, and the ε-amino group of its side chain is modified with a structure having the following formula (II); in, R3 and R4 are each independently selected from isosteres of hydrogen, carboxylic acid, phosphoric acid, sulfonic acid, or carboxylic acid. L1 is selected from -C(O)- or -S(O)2-; L2 is selected from non-existent, carbon-carbon triple bond, carbon-carbon double bond, or 5-membered heteroaryl group containing 3 N atoms; n and m are each independently selected from any integer from 1 to 18. p is 0, 1, 2 or 3; * indicates that if there is a chiral center, * represents S or R; X4 is selected from F or non-natural amino acids; Furthermore, when X1 and X2 are both Aib and X4 is F, equation (II) must satisfy any of the following conditions: (1) At least one of R3 and R4 is not a carboxylic acid or phosphoric acid; (2) L1 is -S(O)2-; (3) L2 is a carbon-carbon triple bond, a carbon-carbon double bond, or a 5-membered heteroaryl group containing 3 N atoms.

2. The compound according to claim 1, wherein, R1 is selected from H, and R2 is selected from -NH2.

3. The compound according to any one of claims 1-2, wherein, * indicates that if there is a chiral center, * represents S.

4. The compound according to any one of claims 1-3, wherein, p is 1.

5. The compound according to any one of claims 1-4, wherein, The non-natural amino acids mentioned are selected from 6. The compound according to any one of claims 1-5, wherein, At least one of X1 and X2 is Aib(d6).

7. The compound according to any one of claims 1-6, wherein, X4 is selected from 8. The compound according to any one of claims 1-7, wherein, R3 and R4 are selected from the following groups: (1) R3 is a carboxylic acid, and R4 is H; (2) R3 is phosphoric acid, and R4 is H; (3) R3 is H, and R4 is a carboxylic acid; (4) R3 is H, and R4 is phosphoric acid; (5) R3 is H, and R4 is sulfonic acid; (6) R3 is a carboxylic acid, and R4 is a sulfonic acid; (7) R3 is phosphoric acid, and R4 is sulfonic acid; (8) R3 is sulfonic acid, and R4 is phosphoric acid; (9) R3 is sulfonic acid, R4 is carboxylic acid, or (10) R3 is sulfonic acid, and R4 is H.

9. The compound according to any one of claims 1-7, wherein, L1 is -S(O)2-.

10. The compound according to any one of claims 1-7, wherein, L2 is selected from carbon-carbon triple bonds, carbon-carbon double bonds, or 5-membered heteroaryl groups containing 3 N atoms.

11. The compound according to any one of claims 1-7, wherein, The aforementioned formula (II) has the structure of formula (II-1). in, R3 and R4 are each independently selected from isosteres of hydrogen, carboxylic acid, phosphoric acid, sulfonic acid, or carboxylic acid. o is any integer from 1 to 29.

12. The compound according to claims 1-7, wherein, Equation (II) has the structure of Equation (II-2). R3 and R4 are each independently selected from isosteres of hydrogen, carboxylic acid, phosphoric acid, sulfonic acid, or carboxylic acid. o is any integer from 1 to 29.

13. The compound according to claims 11-12, wherein, o is any integer between 14 and 20.

14. The compound according to claims 1-7, wherein, Equation (II) has the structure of Equation (II-3). R3 and R4 are each independently selected from isosteres of hydrogen, carboxylic acid, phosphoric acid, sulfonic acid, or carboxylic acid. L2 is selected from carbon-carbon triple bonds, carbon-carbon double bonds, or 5-membered heteroaryl groups containing 3 nitrogen atoms. n and m are each selected from any integer from 1 to 18.

15. The compound according to claim 14, wherein, n is any integer from 3 to 10, and m is any integer from 3 to 10.

16. The compound according to claims 1-4, wherein, X1 is selected from Aib, X2 is selected from Aib, X4 is selected from F, and R3 and R4 are selected from the group consisting of the following: (1) R3 is a carboxylic acid, and R4 is H; (2) R3 is phosphoric acid, and R4 is H; (3) R3 is H, and R4 is a carboxylic acid; (4) R3 is H, and R4 is phosphoric acid; (5) R3 is H, and R4 is sulfonic acid; (6) R3 is a carboxylic acid, and R4 is a sulfonic acid; (7) R3 is phosphoric acid, and R4 is sulfonic acid; (8) R3 is sulfonic acid, and R4 is phosphoric acid; (9) R3 is sulfonic acid, and R4 is carboxylic acid; (10) R3 is sulfonic acid, and R4 is H; L1 is selected from -C(O)- or -S(O)2-; L2 is selected from non-existent, carbon-carbon triple bond, carbon-carbon double bond, or 5-membered heteroaryl group containing 3 N atoms.

17. The compound according to claims 1-4, wherein, X1 is selected from Aib, X2 is selected from Aib, X4 is selected from F, L1 is -S(O)2-, L2 is selected from non-existent, carbon-carbon triple bond, carbon-carbon double bond or 5-membered heteroaryl containing 3 N atoms, and R3 and R4 are each independently selected from hydrogen, carboxylic acid, phosphoric acid, sulfonic acid or carboxylic acid isosteric.

18. The compound according to claims 1-4, wherein, X1 is selected from Aib, X2 is selected from Aib, X4 is selected from F, L2 is a carbon-carbon triple bond, a carbon-carbon double bond or a 5-membered heteroaryl group containing 3 N atoms, L1 is selected from -C(O)- or -S(O)2-, and R3 and R4 are each independently selected from hydrogen, carboxylic acid, phosphoric acid, sulfonic acid or carboxylic acid isosteric groups.

19. The compound according to claims 1-4, wherein, n is any integer from 3 to 10, and m is any integer from 3 to 10.

20. The compound according to claim 19, wherein, n is any integer between 7 and 8, and m is any integer between 7 and 8.

21. The compound according to claim 1, wherein, The polypeptide compound of formula (I) has the structure shown in formula (III-1): in, X4 is selected from F(2F), F(2Cl), F(2Me), F(2CN), F(3F), F(3Cl), F(3Me), F(3CN), F(4F), F(4Cl), F(4Me), F(4CN), 2Pal, 3Pal, 4Pal or other non-natural amino acid residues; r is selected from any integer between 14 and 25; s is selected from 0, 1 or 2.

22. The compound according to claim 1, wherein, The polypeptide compound of formula (I) has the structure shown in formula (III-2): in, X4 is selected from F(2F), F(2Cl), F(2Me), F(2CN), F(3F), F(3Cl), F(3Me), F(3CN), F(4F), F(4Cl), F(4Me), F(4CN), 2Pal, 3Pal, 4Pal or other non-natural amino acid residues; r is selected from any integer between 14 and 25; s is selected from 0, 1 or 2.

23. The compound according to claim 1, wherein the compound is selected from any one of the following compounds: Or its pharmaceutically acceptable salts, esters or solvates.

24. A composition comprising a compound as claimed in any one of claims 1-23, or a pharmaceutically acceptable salt, ester, or solvate thereof, and at least one pharmaceutically acceptable excipient.

25. A method for treating GLP1R / GIPR-mediated diseases or symptoms, wherein the method comprises the following steps: The effective amount of the compound as described in any one of claims 1-23, and its pharmaceutically acceptable salt, ester or solvate, or the effective amount of the composition as described in claim 24, is administered to the subject.

26. Use of the compound of any one of claims 1-23, and its pharmaceutically acceptable salt, ester or solvate, or the composition of claim 24 in the preparation of a medicament for treating GLP1R / GIPR-mediated diseases or symptoms.

27. The method of claim 25 or the use of claim 26, wherein, The diseases or symptoms mediated by GLP1R / GIPR are selected from: T1DM, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-associated diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, nephropathy, diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea, long-term weight management, obesity, overweight, eating disorders, weight gain due to other medications, excessive sugar consumption, dyslipidemia, hyperinsulinemia, NAFLD, NASH, fibrosis, cirrhosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, post-angioplasty. Restenosis, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral artery disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, restenosis, impaired glucose metabolism, impaired fasting glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue diseases, psoriasis, foot ulcers, ulcerative colitis, hyperapolipoprotein B lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome or substance addiction, weight management, long-term weight management, chronic kidney disease, atherosclerotic cardiovascular disease, heart failure, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, diabetes prevention or obstructive sleep apnea.

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