Use of GLP-1r / GIPR double-target agonist in preparing animal drug

Abstract

Use of a GLP-1R / GIPR double-target agonist compound in preparing a drug for preventing or treating diseases in non-primate and non-rodent animals.

Description

Use of GLP-1R / GIPR dual-target agonists in the preparation of animal medicines Technical Field

[0001] The present invention belongs to the field of animal therapeutic drugs, and specifically relates to the use of a glucagon-like peptide-1 receptor / glucose-dependent insulinotropic polypeptide receptor (GLP-1R / GIPR) dual-target agonist in the preparation of drugs for preventing or treating diseases in non-primates and non-rodents. Background Art

[0002] With the development of social economy, more and more residents are starting to keep pets, and keeping pets has become an indispensable part of their lives. The number of domestic pets is increasing significantly, especially the number of dogs and cats, which has led to a rapid increase in the demand for pet products and animal products.

[0003] There are very few domestically produced pet-specific medications in China. As of 2017, only 187 veterinary drugs approved by the Ministry of Agriculture were specifically for pets, including 180 chemical drugs and 7 biological products. Although the Regulations on Veterinary Drug Administration prohibit the use of human medications for pets, due to the scarcity of pet-specific medications, many pets in my country still use human medications. Furthermore, some human medications are ineffective in pets. Consequently, various problems have arisen in animal clinics, most notably the misuse of human medications. The mixed use of drugs between humans and animals can lead to serious harm. Due to differences in physiological mechanisms and metabolic characteristics between humans and animals, and the significant differences in drug tolerance between different species, some human medications may be ineffective or ineffective when given to animals. Some may also produce unexpected side effects or even lead to the death of pets. For example, the use of human antimicrobial drugs in animals can easily lead to the development of drug-resistant bacteria, posing immeasurable risks and losses to public health.

[0004] Obesity is a common problem for pets. Obesity leads to metabolic disorders in pets, increasing the risk of diabetes, cardiovascular disease, arthritis, skin diseases, and other conditions, seriously affecting their physical health. Currently, pet weight loss prescription food is one of the options for managing overweight pets. In terms of drug treatment, Slentrol (deltapaide) and Yarvitan (mitatapaide) have been approved for marketing. Yarvitan is the first weight loss drug developed specifically for pet dogs, which can achieve a monthly weight loss of approximately 6.4 kg. Slentrol and Yarvitan are both selective inhibitors of microsomal triglyceride transfer protein (MTP). Both act on intestinal epithelial cells, preventing lipid absorption and having a local effect on satiety.

[0005] Diabetes mellitus is a common endocrine disease in pets, such as cats and dogs. Veterinary medicine currently classifies pet diabetes into four types, based on the mechanisms of human diabetes and pancreatic beta-cell failure: type I, type II, gestational, and other specific types. Type I diabetes is characterized by immune-mediated beta-cell destruction, leading to absolute insulin deficiency, and is relatively rare in pets. Type II diabetes remains the most common type of diabetes in pets. Insufficient insulin secretion leads to decreased glucose utilization, clinically manifesting as a positive urine glucose test. Increased blood glucose levels stimulate the hypothalamic feeding center, increasing appetite. Furthermore, increased blood glucose levels increase plasma osmolality, leading to increased vascular permeability and clinically manifesting as osmotic diuresis. Simultaneously, the body's ability to break down glucose is reduced, preventing it from being utilized as an energy source. This leads to increased energy expenditure, glucose excretion in the urine, and increased water loss, ultimately resulting in increased thirst, weight loss, and weight loss. Clinical manifestations include polyuria, polydipsia, polyphagia, and weight loss. In severe cases, a fruity breath odor may develop. Dogs may also develop cataracts, hepatomegaly, and hepatic fat deposits. The goal of treating pet diabetes is to relieve symptoms as much as possible while minimizing the risk of hypoglycemia. Currently, most pet diabetes treatments use insulin products, such as porcine insulin zinc suspension ( Intervet, Netherlands; Vetsulin, Merck), protamine zinc recombinant human insulin ( Boehringer Ingelheim) and administer insulin rationally based on its onset and duration of action.

[0006] Incretin hormones influence pancreatic β-cells and play a crucial role in glucose homeostasis. The incretin hormones GIP and GLP-1 are crucial for increasing insulin secretion and regulating glucagon secretion following nutrient-induced intestinal secretion. GIP is primarily secreted by K cells in the duodenum and upper jejunum, while GLP-1 is secreted by L cells in the intestine. The GLP-1 receptor (GLP-1R) is expressed in multiple brain nuclei involved in appetite regulation and can suppress appetite and energy intake in both normal-weight and obese individuals. In animal models of obesity, including minipigs and rodents, GLP-1 analogs reduce feeding frequency and meal size. GLP-1 can also promote satiety and reduce appetite by reducing gastric emptying rate. The active forms of GIP and GLP-1 are degraded into inactive forms by dipeptidyl peptidase 4 (DPP-4, also known as Cd26) and neutral endopeptidase 24.11 (NEP-24.11). DPP-4 and NEP are ubiquitous in tissues, and DPP-4 is also present in a soluble form in the blood. Therefore, after intravenous administration, the active forms of GLP-1 and GIP are rapidly degraded to inactive forms and cleared rapidly by the kidneys, resulting in short half-lives for the active forms of GLP-1 (1–2 minutes) and GIP (5 minutes). Although the half-lives of GLP-1 and GIP in cats and dogs are unknown, the activity of DPP-4 in healthy cats has been indirectly demonstrated: administration of DPP-4 inhibitors to healthy cats has been associated with increased insulin concentrations and decreased glucagon concentrations after intravenous glucose challenge; in another study, administration of DPP-4 inhibitors was associated with increased GLP-1 concentrations.

[0007] The distribution of L and K cells in the intestine varies across species, which, to some extent, determines the importance of different stimuli for GLP-1 and GIP secretion. Quantitative immunohistochemical studies of the intestines of dogs, rats, pigs, and humans have demonstrated that L and K cell density gradients are generally opposite: L cells are few, if any, in the distal duodenum, their density gradually increases along the jejunum, reaching a maximum in the ileum and colon. In contrast, K cells are most dense in the duodenum and decrease along the jejunum. K cells are absent in the ileum and colon of dogs, rats, pigs, and humans. Furthermore, the extent to which different nutrients stimulate GIP and GLP-1 varies across species (New approaches to feline diabetes mellitus Glucagon-like peptide-1 analogs). Fat and carbohydrates are potent stimulators of GIP secretion in humans, dogs, pigs, and rodents. In humans and dogs, fat stimulates GIP secretion more strongly than carbohydrates, but the opposite is true in rodents and pigs. In cats, fat stimulates GIP secretion more effectively than amino acids, but oral glucose administration has no effect on GIP secretion. Postprandial GLP-1 secretion is generally biphasic and stimulated by ingested lipids, carbohydrates, and proteins. In a study of healthy cats, lipids, carbohydrates, and amino acids had similar overall effects on total GLP-1 secretion, although the temporal patterns differed.

[0008] Currently, there are no GLP-1R agonist drugs for animal obesity and / or hyperglycemia, let alone GLP-1R / GIPR dual-target agonist pet drugs. Therefore, it is necessary to develop GLP-1R / GIPR dual-target agonist animal drugs to provide safe, effective, and long-acting medication for animals, especially to provide a variety of options for medication for overweight, obesity and / or diabetes in pets. Summary of the Invention

[0009] One object of the present invention is to provide the use of certain long-acting GLP-1R / GIPR dual-target agonist compounds in the preparation of animal medicines, in particular, in the preparation of drugs for the prevention or treatment of diseases in non-primates and non-rodents. The compounds of the present invention have excellent GIPR / GLP-1R dual agonist activity in various genera of animals, including but not limited to dogs, cats, rabbits, pigs, alpacas, horses, sheep and cattle. Compared with known GIPR / GLP-1R dual agonist compounds, the compounds of the present invention have a longer half-life and / or a more sustained duration of action. The compounds of the present invention have a stronger hypoglycemic effect and a more significant weight loss effect. The compounds of the present invention have lower side effects, including but not limited to gastrointestinal reactions and cardiac safety risks. The compounds of the present invention can adopt a shorter titration strategy. The compounds of the present invention have a larger safety window. In addition, the compounds of the present invention have a protective effect on the liver.

[0010] As part of the present invention, applicants have discovered that the selection of the length, composition and attachment position of the fatty acid chain, as well as the linker between the peptide and the fatty acid chain, has an unexpected effect on extending the half-life of the polypeptide.

[0011] One embodiment of the present invention is to provide a use of a compound of formula (AI) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal:

[0012] Y-X1-EGT-X2-TSDY-A11-A12-A13-LDK-A17-AQ-A20-EFVKWLLK-A29-GPSSGAPPPSK Formula (AI);

[0013] wherein X1 is Aib; X2 is αMePhe;

[0014] A11 is Aib or Ala;

[0015] A12 is Ala, Ile, Lys, Phe, or Pya (4);

[0016] A13 is Aib, Cha, Leu, αMePhe, or αMeTyr;

[0017] A17 is Gln or Ile;

[0018] A20 is Ala or Ser;

[0019] A29 is Gln or Gly;

[0020] 1 K, 2 K, 3 K or 4 K positions are selected from the 16th, 24th, 28th and 40th positions by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -Z is chemically modified by being conjugated to the ε-amino group of the K side chain, wherein each a is independently an integer from 0 to 5, each b is independently an integer from 0 to 5, and each c is independently an integer from 10 to 24, wherein Z is independently selected from -CH3, carboxylic acid or carboxylic acid bioisostere, phosphonate / ester or sulfonate / ester.

[0021] In another embodiment, the present invention provides the use of a compound of formula (AI) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal, wherein:

[0022] X1 is Aib; X2 is αMePhe;

[0023] A11 is Aib or Ala;

[0024] A12 is Ala, Ile, Lys, Phe, or Pya (4);

[0025] A13 is Aib, Cha, Leu, αMePhe, or αMeTyr;

[0026] A17 is Gln or Ile;

[0027] A20 is Ala or Ser;

[0028] A29 is Gln or Gly,

[0029] 1 K, 2 K, 3 K or 4 K positions are selected from the 16th, 24th, 28th and 40th positions by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -Z is chemically modified by being conjugated to the ε-amino group of the K side chain, wherein a is independently selected from an integer of 1, 2, 3, 4 or 5, b is independently selected from an integer of 1, 2, 3, 4 or 5, and c is independently selected from an integer of 12 to 22; wherein Z is independently selected from -CH3, carboxylic acid or carboxylic acid bioisostere, phosphonate / ester or sulfonate / ester; and compounds wherein c is independently selected from 14, 16, 18 or 20 are also provided.

[0030] In some embodiments, in the peptide of formula (AI) or a pharmaceutically acceptable salt thereof, A11 is Aib; or / and

[0031] In the peptide of the above formula (AI) or a pharmaceutically acceptable salt thereof, A12 is Ile; or / and

[0032] In the above peptide of formula (AI) or a pharmaceutically acceptable salt thereof, A13 is Aib; or / and

[0033] In the peptide of the above formula (AI) or a pharmaceutically acceptable salt thereof, A17 is Gln; or / and

[0034] In the peptide of the above formula (AI) or a pharmaceutically acceptable salt thereof, A20 is Ala; or / and

[0035] In the peptide of the above formula (AI) or a pharmaceutically acceptable salt thereof, A29 is Gly.

[0036] One embodiment of the present invention is to provide the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal:

[0037] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK Formula (I);

[0038] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; 1, 2, 3 or 4 K positions are selected from positions 16, 24, 28 and 40, by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -Z is chemically modified by conjugation to the ε-amino group of the K side chain, wherein each a is independently an integer from 0 to 5, each b is independently an integer from 0 to 5, and each c is independently an integer from 10 to 24, wherein Z is independently selected from -CH3, carboxylic acid or carboxylic acid bioisostere, phosphonate / ester or sulfonate / ester; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0039] In some embodiments, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, one K position is selected from among the K at positions 16, 24, 28, and 40 by replacing the K with ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c-Z is chemically modified by conjugating to the ε-amino group of the K side chain. For example, at the position of K at position 16, by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -Z is chemically modified by conjugating to the ε-amino group of the K side chain; for example, at the 24-position of K, by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -Z is chemically modified by conjugating to the ε-amino group of the K side chain; for example, at position 28 of K, by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -Z is chemically modified by conjugating to the ε-amino group of the K side chain; for example, at position 40 of K, by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -Z is chemically modified by conjugating to the ε-amino group of the K side chain.

[0040] In some embodiments, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, two K positions are selected from among K at positions 16, 24, 28, and 40 by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -Z is conjugated to the ε-amino group of the K side chain to perform chemical modification of two modified chains. For example, at the positions of K at position 16 and K at position 24, ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -Z is conjugated to the ε-amino group of the K side chain to perform chemical modification of two modified chains; for example, at the positions of K at position 16 and K at position 28, by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -Z is conjugated to the ε-amino group of the K side chain to perform chemical modification of two modified chains; for example, at the positions of K at position 16 and K at position 40, by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b-CO-(CH2) c -Z is conjugated to the ε-amino group of the K side chain to perform chemical modification of two modified chains; for example, at the positions of K at position 24 and K at position 28, by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -Z is conjugated to the ε-amino group of the K side chain to perform chemical modification of two modified chains; for example, at the positions of K at position 24 and K at position 40, by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -Z is conjugated to the ε-amino group of the K side chain to perform chemical modification of two modified chains; for example, at the positions of K at position 28 and K at position 40, by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -Z is conjugated to the ε-amino group of the K side chain to perform chemical modification of the two modified chains.

[0041] In some embodiments, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, three K positions are selected from among K at positions 16, 24, 28, and 40 by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -Z is conjugated to the ε-amino group of the K side chain to perform chemical modification of three modified chains. For example, at the positions of K at position 16, K at position 24, and K at position 28, ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -Z is conjugated to the ε-amino group of the K side chain to perform chemical modification of three modified chains; for example, at the positions of K at 16, K at 24, and K at 40, by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -Z is conjugated to the ε-amino group of the K side chain to perform chemical modification of three modified chains; for example, at the positions of K at position 16, K at position 28, and K at position 40, by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c-Z is conjugated to the ε-amino group of the K side chain to perform chemical modification of three modified chains; for example, at the positions of K at position 24, K at position 28, and K at position 40, by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -Z is conjugated to the ε-amino group of the K side chain to perform chemical modification of three modified chains.

[0042] In some embodiments, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, the positions of 4 K are selected from among the K at positions 16, 24, 28, and 40 by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -Z was conjugated to the ε-amino group of the K side chain to perform chemical modification of the four modified chains.

[0043] In some embodiments, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, Z is independently selected from -CH3, carboxylic acid or carboxylic acid bioisostere, phosphonate / ester or sulfonate / ester, for example, but not limited to, the Z may include carboxylic acid (-CO2H) or carboxylic acid bioisostere (e.g. ), phosphonic acid (-P(O)(OH)2) or sulfonic acid (-SO2OH) groups, preferably -CO2H.

[0044] Suitable carboxylic acid bioisosteres are known in the art. Preferably, the bioisostere has a pK a Examples of suitable bioisosteres may include, but are not limited to, tetrazoles, acylsulfonamides, acylhydroxylamines, and squaric acid derivatives, as shown below:

[0045] R is Me or CF3.

[0046] In some embodiments, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, a is independently selected from an integer of 1, 2, 3, 4 or 5, preferably 1, 2 or 3, b is independently selected from an integer of 1, 2, 3, 4 or 5, preferably 1, 2 or 3, and c is independently selected from an integer of 12 to 22; in addition, the present invention provides a compound wherein c is 14, 16, 18 or 20.

[0047] One embodiment of the present invention is to provide the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal:

[0048] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK Formula (I);

[0049] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; one or two K positions are selected from positions 16, 24, 28, and 40, by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -Z is chemically modified by conjugation to the ε-amino group of the K side chain, wherein Z is independently selected from -CH3, carboxylic acid or carboxylic acid bioisostere, phosphonate / ester or sulfonate / ester, preferably -CO2H, each a is independently an integer from 0 to 5, each b is independently an integer from 0 to 5, and each c is independently an integer from 10 to 24; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0050] In another embodiment, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal, wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; and one or two K positions are selected from positions 16, 24, 28, and 40, by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -Z is chemically modified by being conjugated to the ε-amino group of the K side chain, wherein Z is independently selected from -CH3, carboxylic acid or carboxylic acid bioisostere, phosphonate / ester or sulfonate / ester, preferably -CO2H, a is independently selected from an integer of 1, 2, 3, 4 or 5, b is independently selected from an integer of 1, 2, 3, 4 or 5, and c is independently selected from an integer of 12 to 22; preferably, wherein c is 14, 16, 18 or 20.

[0051] One embodiment of the present invention is to provide the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal:

[0052] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK Formula (I);

[0053] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 24 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain and chemically modified, wherein a is independently selected from an integer from 0 to 5, b is independently selected from an integer from 0 to 5, and c is independently selected from an integer from 10 to 24; and the C-terminal amino acid is amidated to form a C-terminal primary amide.

[0054] In another embodiment, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal, wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 24 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is chemically modified by conjugating to the ε-amino group of the K side chain, wherein a is independently selected from an integer of 1, 2, 3, 4 or 5, b is independently selected from an integer of 1, 2, 3, 4 or 5, and c is independently selected from an integer of 12 to 22; preferably, c is 14, 16, 18 or 20.

[0055] In another embodiment, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal, wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; and at position 24, K is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is chemically modified by conjugating to the ε-amino group of the K side chain, wherein each a is independently selected from an integer of 2 or 3, each b is independently 1, and each c is independently selected from an integer of 16, 18, or 20, and wherein Z is independently selected from a carboxylic acid.

[0056] Another embodiment of the present invention is to provide the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal:

[0057] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK Formula (I);

[0058] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain and chemically modified, wherein a is independently selected from an integer from 0 to 5, b is independently selected from an integer from 0 to 5, and c is independently selected from an integer from 10 to 24; and the C-terminal amino acid is amidated to form a C-terminal primary amide.

[0059] In another embodiment, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal, wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is chemically modified by conjugating to the ε-amino group of the K side chain, wherein a is independently selected from an integer of 1, 2, 3, 4 or 5, b is independently selected from an integer of 1, 2, 3, 4 or 5, and c is independently selected from an integer of 12 to 22; preferably, c is 14, 16, 18 or 20.

[0060] In another embodiment, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal, wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; and at position 28, K is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is chemically modified by conjugating to the ε-amino group of the K side chain, wherein each a is independently selected from an integer of 2 or 3, each b is independently selected from an integer of 1 or 3, each c is independently selected from an integer of 16 or 20, and Z is independently selected from a carboxylic acid.

[0061] In another embodiment, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal, wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; and at position 28, K is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is chemically modified by conjugating to the ε-amino group of the K side chain, wherein each a is independently selected from an integer of 2 or 3, each b is independently selected from an integer of 1 or 3, each c is independently selected from an integer of 16 or 20, and Z is independently selected from a carboxylic acid.

[0062] Another embodiment of the present invention is to provide the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal:

[0063] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK Formula (I);

[0064] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 16 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain and chemically modified, wherein a is independently selected from an integer from 0 to 5, b is independently selected from an integer from 0 to 5, and c is independently selected from an integer from 10 to 24; and the C-terminal amino acid is amidated to form a C-terminal primary amide.

[0065] In another embodiment, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal, wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 16 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c-CO2H is chemically modified by conjugating to the ε-amino group of the K side chain, wherein a is independently selected from an integer of 1, 2, 3, 4 or 5, b is independently selected from an integer of 1, 2, 3, 4 or 5, and c is independently selected from an integer of 12 to 22; preferably, c is 14, 16, 18 or 20.

[0066] Another embodiment of the present invention is to provide the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal:

[0067] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK Formula (I);

[0068] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 40 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain and chemically modified, wherein a is independently selected from an integer from 0 to 5, b is independently selected from an integer from 0 to 5, and c is independently selected from an integer from 10 to 24; and the C-terminal amino acid is amidated to form a C-terminal primary amide.

[0069] In another embodiment, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal, wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 40 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is chemically modified by conjugating to the ε-amino group of the K side chain, wherein a is independently selected from an integer of 1, 2, 3, 4 or 5, b is independently selected from an integer of 1, 2, 3, 4 or 5, and c is independently selected from an integer of 12 to 22; preferably, c is 14, 16, 18 or 20.

[0070] Another embodiment of the present invention is to provide the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal:

[0071] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK Formula (I);

[0072] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at positions 24 and 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain to perform chemical modification of two modified chains, wherein each a is independently an integer from 0 to 5, each b is independently an integer from 0 to 5, and each c is independently an integer from 10 to 22; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0073] In another embodiment, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal, wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at positions 24 and 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain to perform chemical modification of two modified chains, wherein a is independently selected from an integer of 1, 2, 3, 4 or 5, b is independently selected from an integer of 1, 2, 3, 4 or 5, and c is independently selected from an integer of 12 to 22; preferably, c is 14, 16, 18 or 20.

[0074] Another embodiment of the present invention is to provide the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal:

[0075] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK Formula (I);

[0076] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at positions 16 and 24 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2)c -CO2H is conjugated to the ε-amino group of the K side chain to perform chemical modification of two modified chains, wherein each a is independently an integer from 0 to 5, each b is independently an integer from 0 to 5, and each c is independently an integer from 10 to 22; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0077] In another embodiment, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal, wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at positions 16 and 24 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain to perform chemical modification of two modified chains, wherein a is independently selected from an integer of 1, 2, 3, 4 or 5, b is independently selected from an integer of 1, 2, 3, 4 or 5, and c is independently selected from an integer of 12 to 22; preferably, c is 14, 16, 18 or 20.

[0078] Another embodiment of the present invention is to provide the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal:

[0079] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK Formula (I);

[0080] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at positions 16 and 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain to perform chemical modification of two modified chains, wherein each a is independently an integer from 0 to 5, each b is independently an integer from 0 to 5, and each c is independently an integer from 10 to 22; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0081] In another embodiment, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal, wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at positions 16 and 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain to perform chemical modification of two modified chains, wherein a is independently selected from an integer of 1, 2, 3, 4 or 5, b is independently selected from an integer of 1, 2, 3, 4 or 5, and c is independently selected from an integer of 12 to 22; preferably, c is 14, 16, 18 or 20.

[0082] Another embodiment of the present invention is to provide the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal:

[0083] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK Formula (I);

[0084] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at positions 16 and 40 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain to perform chemical modification of two modified chains, wherein each a is independently an integer from 0 to 5, each b is independently an integer from 0 to 5, and each c is independently an integer from 10 to 22; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0085] In another embodiment, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal, wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at positions 16 and 40 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c-CO2H is conjugated to the ε-amino group of the K side chain to perform chemical modification of two modified chains, wherein a is independently selected from an integer of 1, 2, 3, 4 or 5, b is independently selected from an integer of 1, 2, 3, 4 or 5, and c is independently selected from an integer of 12 to 22; preferably, c is 14, 16, 18 or 20.

[0086] Another embodiment of the present invention is to provide the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal:

[0087] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK Formula (I);

[0088] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at positions 24 and 40 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain to perform chemical modification of two modified chains, wherein each a is independently an integer from 0 to 5, each b is independently an integer from 0 to 5, and each c is independently an integer from 10 to 22; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0089] In another embodiment, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal, wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at positions 24 and 40 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain to perform chemical modification of two modified chains, wherein a is independently selected from an integer of 1, 2, 3, 4 or 5, b is independently selected from an integer of 1, 2, 3, 4 or 5, and c is independently selected from an integer of 12 to 22; preferably, c is 14, 16, 18 or 20.

[0090] Another embodiment of the present invention is to provide the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal:

[0091] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK Formula (I);

[0092] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at positions 28 and 40 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain to perform chemical modification of two modified chains, wherein each a is independently an integer from 0 to 5, each b is independently an integer from 0 to 5, and each c is independently an integer from 10 to 22; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0093] In another embodiment, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal, wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at positions 28 and 40 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain to perform chemical modification of two modified chains, wherein a is independently selected from an integer of 1, 2, 3, 4 or 5, b is independently selected from an integer of 1, 2, 3, 4 or 5, and c is independently selected from an integer of 12 to 22; preferably, c is a compound of 14, 16, 18 or 20.

[0094] In all embodiments described above, each a is independently an integer from 1 to 3, each b is independently an integer from 1 to 3, and each c is independently an integer from 12 to 22; in addition, the present invention provides the use of a compound of formula (AI) or formula (I) wherein c is 14, 16, 18, or 20 in the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal. In all embodiments described above, preferably, one modified chain is chemically modified at K at position 24 or 28.

[0095] In one embodiment, the present invention provides the use of a compound of the following formula or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal:

[0096] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0097] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 24 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)1-CO-(CH2) 16 The K side chain was chemically modified by conjugating -CO2H to the ε-amino group; and the C-terminal amino acid was amidated to a C-terminal primary amide (SEQ ID NO: 7).

[0098] In one embodiment, the present invention provides the use of a compound of the following formula or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal:

[0099] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0100] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 24 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)1-CO-(CH2) 18 The K side chain was chemically modified by conjugating -CO2H to the ε-amino group; and the C-terminal amino acid was amidated to a C-terminal primary amide (SEQ ID NO: 13).

[0101] In one embodiment, the present invention provides the use of a compound of the following formula or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal:

[0102] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0103] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 24 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)1-CO-(CH2) 20The K side chain was chemically modified by conjugating -CO2H to the ε-amino group; and the C-terminal amino acid was amidated to a C-terminal primary amide (SEQ ID NO: 14).

[0104] In one embodiment, the present invention provides the use of a compound of the following formula or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal:

[0105] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0106] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 24 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)3-CO-(CH2) 16 The K side chain was chemically modified by conjugating -CO2H to the ε-amino group; and the C-terminal amino acid was amidated to a C-terminal primary amide (SEQ ID NO: 15).

[0107] In one embodiment, the present invention provides the use of a compound of the following formula or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal:

[0108] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0109] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 24 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)3-(γ-Glu)1-CO-(CH2) 20 The K side chain was chemically modified by conjugating -CO2H to the ε-amino group; and the C-terminal amino acid was amidated to a C-terminal primary amide (SEQ ID NO: 16).

[0110] In one embodiment, the present invention provides the use of a compound of the following formula or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal:

[0111] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0112] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)1-CO-(CH2) 16 The K side chain was chemically modified by conjugating -CO2H to the ε-amino group; and the C-terminal amino acid was amidated to a C-terminal primary amide (SEQ ID NO: 8).

[0113] In one embodiment, the present invention provides the use of a compound of the following formula or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal:

[0114] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0115] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)1-CO-(CH2) 20 The K side chain was chemically modified by conjugating -CO2H to the ε-amino group; and the C-terminal amino acid was amidated to a C-terminal primary amide (SEQ ID NO: 17).

[0116] In one embodiment, the present invention provides the use of a compound of the following formula or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal:

[0117] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0118] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)3-CO-(CH2) 16The K side chain was chemically modified by conjugating -CO2H to the ε-amino group; and the C-terminal amino acid was amidated to a C-terminal primary amide (SEQ ID NO: 18).

[0119] In one embodiment, the present invention provides the use of a compound of the following formula or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal:

[0120] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0121] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)3-(γ-Glu)1-CO-(CH2) 16 The K side chain was chemically modified by conjugating -CO2H to the ε-amino group; and the C-terminal amino acid was amidated to a C-terminal primary amide (SEQ ID NO: 19).

[0122] In one embodiment, the present invention provides the use of a compound of the following formula or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal:

[0123] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0124] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)3-(γ-Glu)1-CO-(CH2) 20 The K side chain was chemically modified by conjugating -CO2H to the ε-amino group; and the C-terminal amino acid was amidated to a C-terminal primary amide (SEQ ID NO: 20).

[0125] Another object of the present invention is to provide some GLP-1R / GIPR dual-target agonist compounds for preventing or treating diseases in non-primates and non-rodents. The compounds described in any one of the above embodiments or pharmaceutically acceptable salts thereof are suitable for the purpose of the present invention.

[0126] Another object of the present invention is to provide methods for preventing or treating diseases in non-primates and non-rodents, comprising administering to an animal in need thereof a GLP-1R / GIPR dual-target agonist compound of the present invention. The compounds described in any of the above embodiments, or pharmaceutically acceptable salts thereof, are suitable for the purposes of the present invention.

[0127] The present invention also provides a method for increasing the duration of action of a GLP-1R / GIPR dual-target agonist in non-primates and non-rodents, characterized by using the GLP-1R / GIPR dual-target agonist provided by the present invention as described above.

[0128] In one embodiment, the present invention provides a composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0129] One embodiment provides the use of a compound according to any one of the above embodiments or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing the following diseases in non-primates and non-rodents, wherein the diseases are hyperglycemia, impaired glucose tolerance, diabetes (including type I diabetes and type II diabetes), obesity, hypertension, dyslipidemia, cognitive impairment, atherosclerosis, myocardial infarction, coronary heart disease and other cardiovascular diseases, stroke, inflammatory bowel syndrome, dyspepsia and gastric ulcer.

[0130] One embodiment provides the use of a compound according to any one of the above embodiments, wherein the compound or a pharmaceutically acceptable salt thereof is used to prepare a medicament for preventing, delaying or treating type II diabetes in non-primates and non-rodents.

[0131] One embodiment provides the use of a compound according to any one of the above embodiments, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for reducing food intake, reducing β-cell apoptosis, increasing β-cell function and β-cell mass, and / or restoring glucose sensitivity of β-cells in non-primates and non-rodents.

[0132] In one embodiment, the present invention provides a method for preventing or treating type II diabetes in non-primates and non-rodents, comprising administering to an animal in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0133] In one embodiment, the present invention provides a method for improving glycemic control in non-primates and non-rodents with type 2 diabetes, comprising administering to the animal in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof as an adjunct to diet and exercise.

[0134] In one embodiment, the present invention provides a method for long-term weight management in an overweight or obese animal, comprising administering to an animal in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof as an adjunct to a reduced calorie diet and increased physical activity.

[0135] In one embodiment, the present invention provides a method for treating metabolic syndrome, comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a non-primate and non-rodent in need. In another embodiment, the present invention provides a method for preventing or treating dyslipidemia, obesity and / or hepatic steatosis associated with insulin resistance and diabetes in non-primates and non-rodents, comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to an animal in need. In addition, the present invention provides a method for preventing or treating weakness in non-primates and non-rodents or increasing bone strength in the animals, comprising administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to an animal in need. In another embodiment, the present invention provides a method for treating osteopenia and bone / joint diseases in non-primates and non-rodents, such as a method for treating knee osteoarthritis, hip osteoarthritis, deforming spondylitis, and low back pain, comprising administering an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof to an animal in need.

[0136] In one embodiment, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use as an adjunct to diet and exercise for glycemic control in non-primates and non-rodents with type 2 diabetes. In one embodiment, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use as an adjunct to a reduced-calorie diet and increased physical activity in overweight or obese non-primates and non-rodents for long-term weight management.

[0137] One embodiment provides the use according to any one of the above embodiments for preparing a medicament for treating or preventing the above diseases in cats, dogs, rabbits, pigs, alpacas, horses, sheep, and cattle.

[0138] The above-mentioned activation effect of the compounds of the present invention on GLP-1 receptors and GIP receptors suggests that the compounds of the present invention or pharmaceutically acceptable salts thereof can be used as drugs for preventing or treating the following diseases: for example, symptomatic obesity, obesity based on simple obesity, disease states or diseases related to obesity, eating disorders, diabetes (for example, type I diabetes, type II diabetes, gestational diabetes, obesity-related diabetes), hyperlipidemia (for example, hypertriglyceridemia, hypercholesterolemia, high LDL-cholesterolemia, low HDL-cholesterolemia, postprandial hyperlipidemia), hypertension , heart failure, complications of diabetes (e.g., neuropathy, nephropathy, retinopathy, diabetic cardiomyopathy, cataracts, macroangiopathy, osteopenia, hyperosmolar diabetic coma), infectious diseases (e.g., respiratory tract infection, urinary tract infection, gastrointestinal infection, superficial soft tissue infection, lower limb infection), diabetic gangrene, xerostomia, hearing loss, cerebrovascular disorders, peripheral blood circulation disorders, metabolic syndrome (a disease state having three or more selected from hypertriglyceridemia, low HDL cholesterolemia, hypertension, abdominal obesity and impaired glucose tolerance), and / or muscle loss, etc.

[0139] Examples of symptomatic obesity include endocrine obesity (e.g., Cushing's syndrome, hypothyroidism, insulinoma, obese type II diabetes, pseudohypoparathyroidism, hypogonadism), central obesity (e.g., hypothalamic obesity, frontal lobe syndrome, Klebsiella pneumoniae syndrome), genetic obesity (e.g., Prader-Willi syndrome, Lawrence-Moore syndrome), drug-induced obesity (e.g., obesity induced by steroids, phenothiazines, insulin, sulfonylurea drugs, beta-blockers), and the like.

[0140] Examples of disease states or diseases associated with obesity include: glucose tolerance disorders, diabetes (especially type II diabetes, obese diabetes), lipid metabolism disorders (synonymous with the above-mentioned hyperlipidemia), hypertension, heart failure, hyperuricemia, fatty liver (including non-alcoholic hepatitis), coronary heart disease (myocardial infarction, angina pectoris), cerebral infarction (cerebral thrombosis, transient ischemic attack), bone / joint diseases (knee osteoarthritis, hip osteoarthritis, ankylosing spondylitis, low back pain), sleep apnea syndrome / Pickwick syndrome, menstrual disorders (abnormal menstrual cycle, amenorrhea, abnormal menstrual symptoms), metabolic syndrome, etc.

[0141] The compound provided by the present invention has GLP-1R / GIPR dual-target agonist activity, a long half-life, and exhibits a longer duration of drug effect.

[0142] The compounds of the present invention can react with any of a variety of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. Pharmaceutically acceptable salts and common methods for preparing them are well known in the art.

[0143] In one embodiment, the compounds of the present invention are administered in the form of a formulation. In addition to the compounds described herein, the formulations also contain pharmaceutically acceptable carriers, diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water-soluble vehicles, emulsifiers, buffers, wetting agents, moisturizers, solubilizers, and preservatives. The formulations described herein can be in the form of solutions, suspensions, emulsions, tablets, pills, granules, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, aerosols, sprays, or any other form suitable for use. Saline solutions and aqueous solutions of glucose and glycerol can be used as liquid carriers, particularly for injectable solutions.

[0144] The compounds of the invention may be administered in any conventional manner by any route in which they are active, for example, systemically or topically. For example, they may be administered by inhalation, by depot injection, or by implantation, and may be administered, but is not limited to, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, buccal, sublingual, or ocular.

[0145] The compounds of the present invention can be used in combination therapy with at least one other therapeutic agent. In some embodiments, the compounds of the present invention can be co-administered with additional diabetes medications, weight loss medications, blood pressure medications, and / or cholesterol medications. The compounds of the present invention and other therapeutic agents can act additively or synergistically. The other therapeutic agents can be included in the same composition as the compounds of the present invention, or they can be included in different compositions. The composition containing the compounds of the present invention and the other therapeutic agent can be administered simultaneously or sequentially. In another embodiment, the composition containing the compounds of the present invention is administered before or after the administration of the other therapeutic agent.

[0146] In some embodiments, the compounds of the present invention are used to treat type II diabetes, overweight and / or obesity in cats or dogs.

[0147] In some embodiments, the compounds of the invention are administered as a solution or suspension.

[0148] In some embodiments, the compounds described herein are administered as subcutaneous injections.

[0149] In some embodiments, the compounds described herein are administered in cats and dogs at an amount of 0.003 to 2.5 mg / kg.

[0150] In some embodiments, the compounds described herein are administered in amounts of 0.003 to 0.6 mg / kg to cats and dogs.

[0151] In some embodiments, the amount of the compound of the present invention or a pharmaceutically acceptable salt thereof administered to a cat or dog is about 0.005 to about 0.1 mg / kg, about 0.1 to about 0.125 mg / kg, about 0.1 to about 0.15 mg / kg, about 0.15 to about 0.25 mg / kg, about 0.125 to about 0.25 mg / kg, about 0.005 to about 2 mg / kg, about 0.005 to about 1.5 mg / kg, about 0.005 to about 1 mg / kg, about 0.005 to about 0.5 mg / kg, about 0.1 to about 2 mg / kg, about 0.1 to about 1.5 mg / kg, about 0.1 to about 1 mg / kg, about 0.1 to about 0.5 mg / kg, about 0.15 to about 2. 5mg / kg, about 0.15 to about 2mg / kg, about 0.15 to about 1.5mg / kg, about 0.15 to about 1mg / kg, about 0.15 to about 0.5mg / kg, about 0.2 to about 2.5mg / kg, about 0.2 to about 2mg / kg, about 0.2 to about 1.5mg / kg, about 0.2 to about 1mg / kg, about 0.2 to about 0.5mg / kg, about 0.25 to about 2.5mg / kg, about 0.25 to about 2mg / kg, about 0.25 to about 1.5mg / kg, about 0.25 to about 1mg / kg, about 0.25 to about 0.5mg / kg, about 0.3 to about 2.5mg / kg, about 0.3 to about 2mg / kg, about 0.3 to about 1. 5mg / kg, about 0.3 to about 1mg / kg, about 0.3 to about 0.5mg / kg, about 0.301 to 2.001mg / kg, about 0.35 to about 2.5mg / kg, about 0.35 to about 2mg / kg, about 0.35 to about 1.5mg / kg, about 0.35 to about 1mg / kg, about 0.35 to about 0.5mg / kg, about 0.4 to about 2.5mg / kg, about 0.4 to about 2mg / kg, about 0.4 to about 1.5mg / kg, about 0.4 to about 1mg / kg, about 0.4 to about 0.5mg / kg, about 0.5 to about 2.5mg / kg, about 0.5 to about 2mg / kg, about 0.5 to about 1.5mg / kg, about 0.5 to about 1 mg / kg, about 2.5 mg / kg, about 2.0 mg / kg, about 1.95 mg / kg, about 1.9 mg / kg, about 1.85 mg / kg, about 1.8 mg / kg, about 1.75 mg / kg, about 1.7 mg / kg, about 1.65 mg / kg, about 1.6 mg / kg, about 1.55 mg / kg, about 1.5 mg / kg, about 1.45 mg / kg, about 1.4 mg / kg, about 1.35 mg / kg, about 1.3 mg / kg, about 1.25 mg / kg, about 1.2 mg / kg, about 1.15 mg / kg, about 1.1 mg / kg, about 1.05 mg / kg, about 1.0 mg / kg, about 0.95 mg / kg, about 0.9 mg / kg, about 0.85 mg / kg, about 0.8 mg / kg, about 0.75 mg / kg, about 0.7 mg / kg, about 0.65 mg / kg, about 0.6 mg / kg, about 0.55 mg / kg, about 0.5 mg / kg, about 0.45 mg / kg, about 0.4 mg / kg, about 0.35 mg / kg, about 0.3 mg / kg, about 0.25 mg / kg, about 0.2 mg / kg, about 0.15 mg / kg, or about 0.1 mg / kg.

[0152] In some embodiments, the compounds described herein are administered once weekly (QW) in cats and dogs.

[0153] In some embodiments, the dosage regimen of the compound of the present invention or a pharmaceutically acceptable salt thereof in cats or dogs is about 0.003 to about 2.5 mg / kg QW, preferably about 0.01 to about 2 mg / kg QW, more preferably about 0.25 to about 2.0 mg / kg QW, and / or about 0.1 to about 2.0 mg / kg QW, further preferably about 0.5 to about 2.0 mg / kg QW. For example, the compound of the present invention or a pharmaceutically acceptable salt thereof is administered to cats or dogs in an amount of about 0.01 to about 2 mg / kg QW, about 0.01 to about 1.5 mg / kg QW, about 0.01 to about 1 mg / kg QW, about 0.01 to about 0.5 mg / kg QW, about 0.02 to about 2.5 mg / kg QW, about 0.02 to about 2 mg / kg QW, about 0.02 to about 1.5 mg / kg QW, about 0.02 to about 1 mg / kg QW, about 0.02 to about 0.5 mg / kg QW, about 0.021 to about 0.499 mg / kg QW, about 0.03 to about 2.5 mg / kg QW, about 0.03 to about 2 mg / kg QW, about 0.03 to about 1.5 mg / kg QW, about 0.03 to about 1 mg / kg QW, about 0.03 to about 0.5 mg / kg QW, about 0.04 to about 2.5 mg / kg QW, about 0.04 to about 2 mg / kg QW, about 0.04 to about 1.5 mg / kg QW, about 0.04 to about 1 mg / kg QW, about 0.04 to about 0.5 mg / kg QW, about 0.05 to about 2.5 mg / kg QW, about 0.05 to about 2 mg / kg QW, about 0.05 to about 1.5 mg / kg QW, about 0.05 to about 1 mg / kg QW, about 0.05 to about 0.5 mg / kg QW, about 0.06 to about 2.5 mg / kg QW, about 0.06 to about 2 mg / kg QW, about 0.06 to about 1.5 mg / kg QW, about 0.06 to about 1 mg / kg QW, about 0.06 to about 0.5 mg / kg QW, about 0.062 to 2.001 mg / kg QW, about 0.07 to about 2.5 mg / kg QW, about 0.07 to about 2 mg / kg QW, about 0.07 to about 1.5 mg / kg QW, about 0.07 to about 1 mg / kg QW, about 0.07 to about 0.5 mg / kg QW, about 0.073 to 0.998 mg / kg QW, about 0.08 to about 2.5 mg / kg QW, about 0.08 to about 2 mg / kg QW, about 0.08 to about 1.5 mg / kg QW, about 0.08 to about 1 mg / kg QW, about 0.08 to about 0.5 mg / kg QW, about 0.09 to about 2.5 mg / kg QW, about 0.09 to about 2 mg / kg QW, about 0.09 to about 1.5 mg / kg QW, about 0.0.9 to about 1 mg / kg QW, about 0.09 to about 0.5 mg / kg QW, about 0.1 to about 2.5 mg / kg QW, about 0.1 to about 2 mg / kg QW, about 0.1 to about 1.5 mg / kg QW, about 0.1 to about 1 mg / kg QW, about 0.1 to about 0.5 mg / kg QW, about 0.15 to about 2.5 mg / kg QW, about 0.15 to about 2 mg / kg QW, about 0.15 to about 1.5 mg / kg QW, about 0.15 to about 1 mg / kg QW, about 0.15 to about 0.5 mg / kg QW, about 0.2 to about 2.5 mg / kg QW, about 0.2 to about 2 mg / kg QW, about 0.2 to about 1.5 mg / kg QW, about 0.2 to about 1 mg / kg QW, about 0.2 to about 0.5 mg / kg QW, about 0.25 to about 2.5 mg / kg QW, about 0.25 to about 2 mg / kg QW, about 0.25 to about 1.5 mg / kg QW, about 0.25 to about 1 mg / kg QW, about 0.25 to about 0.5 mg / kg QW, about 0.3 to about 2.5 mg / kg QW, about 0.3 to about 2 mg / kg QW, about 0.3 to about 1.5 mg / kg QW, about 0.3 to about 1 mg / kg QW, about 0.3 to about 0.5 mg / kg QW, about 0.301 to 2.001 mg / kg QW, about 0.35 to about 2.5 mg / kg QW, about 0.35 to about 2 mg / kg QW, about 0.35 to about 1.5 mg / kg QW, about 0.35 to about 1 mg / kg QW, about 0.35 to about 0.5 mg / kg QW, about 0.4 to about 2.5 mg / kg QW, about 0.4 to about 2 mg / kg QW, about 0.4 to about 1.5 mg / kg QW, about 0.4 to about 1 mg / kg QW, about 0.4 to about 0.5 mg / kg QW, about 0.5 to about 2 mg / kg QW, about 0.5 to about 1.5 mg / kg QW, about 0.5 to about 1 mg / kg QW, about 2.5 mg / kg QW, about 2.0 mg / kg QW, about 1.95 mg / kg QW, about 1.9 mg / kg QW, about 1.85 mg / kg QW, about 1.8 mg / kg QW, about 1.75 mg / kg QW, about 1.7 mg / kg QW, about 1.65 mg / kg QW, about 1.6 mg / kg QW, about 1.55 mg / kg QW, about 1.5 mg / kg QW, about 1.45 mg / kg QW, about 1.4 mg / kg QW, about 1.35 mg / kg QW, about 1.3 mg / kg QW, about 1.25 mg / kg QW, about 1.2 mg / kg QW, about 1.15 mg / kg QW, about 1.1 mg / kg QW, about 1.0.5 mg / kg QW, about 1.0 mg / kg QW, about 0.95 mg / kg QW, about 0.9 mg / kg QW, about 0.85 mg / kg QW, about 0.8 mg / kg QW, about 0.75 mg / kg QW, about 0.7 mg / kg QW, about 0.65 mg / kg QW, about 0.6 mg / kg QW, about 0.55 mg / kg QW, about 0.5 mg / kg QW, about 0.45 mg / kg QW, about 0.4 mg / kg QW, about 0.35 mg / kg QW, about 0.3 mg / kg QW, about 0.25 mg / kg QW, or about 0.2 mg / kg QW.

[0154] In some embodiments, the compound of the present invention or a pharmaceutically acceptable salt thereof is administered to a cat or dog once a week, with the administration period determined according to the needs of the subject, and the administration period may be 4-8 weeks, or 8-20 weeks, for example, 4, 5, 6, 7, or 8 weeks. The doses of each administration may be the same or different.

[0155] In some of the regimens, the compound of the invention or a pharmaceutically acceptable salt thereof is administered to dogs once a week for 6 weeks. The dosage of each administration may be the same or different.

[0156] In some of the regimens, the compound of the invention or a pharmaceutically acceptable salt thereof is administered to cats once a week for 5 weeks. The dosage of each administration may be the same or different.

[0157] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered to a cat or dog in increasing doses.

[0158] In some embodiments, a compound of the invention, or a pharmaceutically acceptable salt thereof, is administered to a cat at the following dosage:

[0159] The doses of the first and second administrations are the same, both being a first dose of about 0.02 to about 0.35 mg / kg QW.

[0160] The third dose is a second dose of about 0.2 to about 1 mg / kg QW, wherein the second dose is about 1.2 to about 50 times the first dose, preferably about 10 to about 15 times, for example about 12 times,

[0161] The fourth and fifth administrations are the same dose, which is the third dose of about 0.49 to about 2.5 mg / kg QW, wherein the third dose is about 1.75 to about 2.5 times the second dose, preferably about 1.95 to about 2.05 times, more preferably about 2 times.

[0162] Preferably, the compound of the present invention or a pharmaceutically acceptable salt thereof is administered to cats at the following dosage:

[0163] The first dose is about 0.019 mg / kg QW,

[0164] The second dose is about 0.25 mg / kg QW,

[0165] The third dose is about 0.50 mg / kg QW.

[0166] Preferably, the compound of the present invention or a pharmaceutically acceptable salt thereof is administered to cats at the following dosage:

[0167] The first dose is about 0.075 mg / kg QW,

[0168] The second dose is about 0.50 mg / kg QW,

[0169] The third dose is about 1.00 mg / kg QW.

[0170] Preferably, the compound of the present invention or a pharmaceutically acceptable salt thereof is administered to cats at the following dosage:

[0171] The first dose is about 0.30 mg / kg QW,

[0172] The second dose is about 1.00 mg / kg QW,

[0173] The third dose is about 2.00 mg / kg QW.

[0174] In some embodiments, a compound of the invention, or a pharmaceutically acceptable salt thereof, is administered to a cat according to the following dosing regimen:

[0175] The dosage is about 0.25 to about 2.5 mg / kg;

[0176] Dosing frequency is QW;

[0177] The dosing cycle is 5 weeks.

[0178] In some embodiments, a compound of the invention, or a pharmaceutically acceptable salt thereof, is administered to a cat according to the following dosing regimen:

[0179] The dosage is about 0.25 to about 2.5 mg per injection;

[0180] Dosing frequency is QW;

[0181] The dosing cycle is 5 weeks.

[0182] In some embodiments, a compound of the invention or a pharmaceutically acceptable salt thereof is administered to a dog at the following dosages:

[0183] The doses of the first and second administrations are the same, both being a first dose of about 0.015 to about 0.07 mg / kg QW.

[0184] The third dose is a second dose of about 0.02 to about 0.14 mg / kg QW, preferably about 0.03 to about 0.1 mg / kg QW, and the second dose is about 1.4 to 2 times the first dose, preferably about 1.45 to about 1.6 times, more preferably about 1.5 times,

[0185] The doses for the fourth to sixth administrations are the same, which are all the third dose of about 0.49 to about 2.5 mg / kg QW, preferably about 0.495 to about 2.1 mg / kg QW, and the third dose is about 13 to about 25 times the second dose, more preferably about 16 to about 21 times.

[0186] Preferably, the compound of the present invention or a pharmaceutically acceptable salt thereof is administered to dogs at the following dosages:

[0187] The first dose is about 0.02 mg / kg QW,

[0188] The second dose is about 0.03 mg / kg QW,

[0189] The third dose is about 0.50 mg / kg QW.

[0190] Preferably, the compound of the present invention or a pharmaceutically acceptable salt thereof is administered to dogs at the following dosages:

[0191] The first dose is about 0.06 mg / kg QW,

[0192] The second dose is about 0.10 mg / kg QW,

[0193] The third dose is about 2.00 mg / kg QW.

[0194] In some embodiments, a compound of the invention or a pharmaceutically acceptable salt thereof is administered to a dog at the following dosages:

[0195] The dosage is about 0.1-2.5 mg / kg;

[0196] The dosing cycle is QW;

[0197] Dosing frequency is 6 weeks.

[0198] In some embodiments, a compound of the invention or a pharmaceutically acceptable salt thereof is administered to a dog at the following dosages:

[0199] The dosage is about 0.1-2.5 mg per injection;

[0200] Dosing frequency is QW;

[0201] The dosing cycle is 6 weeks.

[0202] In some embodiments, a fixed dose may be used instead of the mg / kg doses described above.

[0203] In some embodiments, the dosing regimen of a compound of the invention, or a pharmaceutically acceptable salt thereof, in cats is a fixed dose QW of about 0.25-2.5 mg per injection. Preferably, the dosing regimen of the compound of the present invention or a pharmaceutically acceptable salt thereof in cats is a fixed dose per injection of about 0.25 to about 2.5 mg QW, about 0.25 to about 2 mg QW, about 0.25 to about 1.5 mg QW, about 0.25 to about 1 mg QW, about 0.25 to about 0.5 mg QW, about 0.3 to about 2.5 mg QW, about 0.3 to about 2 mg QW, about 0.3 to about 1.5 mg QW, about 0.3 to about 1 mg QW, about 0.3 to about 0.5 mg QW, about 0.301 to 2.001 mg QW, about 0.35 to about 2.5 mg QW, about 0.35 to about 2 mg QW, about 0.35 to about 1.5 mg QW, about 0.35 to about 1 mg QW, about 0.35 to about 0.5 mg QW, about 0.4 to about 2.5 mg QW, about 0.4 to about 2 mg QW, about 0.4 to about 1.5 mg QW, about 0.4 to about 1 mg QW, about 0.4 to about 0.5 mg QW, about 0.5 to about 2 mg QW, about 0.5 to about 1.5 mg QW, about 0.5 to about 1 mg QW, about 2.5 mg QW, about 2.0 mg QW, about 1.95 mg QW, about 1.9 mg QW, about 1.85 mg QW, about 1.8 mg QW, about 1.75 mg QW, about 1.7 mg QW, about 1.65 mg QW, about 1.6 mg QW, about 1.55 mg QW, about 1.5 mg QW, about 1.45 mg QW, about 1.4 mg QW, about 1.35 mg QW, about 1.3 mg QW, about 1.25 mg QW, about 1.2 mg QW, about 1.15 mg QW, about 1.1 mg QW, about 1.05 mg QW, about 1.0 mg QW, about 0.95 mg QW, about 0.9 mg QW, about 0.85 mg QW, about 0.8 mg QW, about 0.75 mg QW, about 0.7 mg QW, about 0.65 mg QW, about 0.6 mg QW, about 0.55 mg QW, about 0.5 mg QW, about 0.45 mg QW, about 0.4 mg QW, about 0.35 mg QW, about 0.3 mg QW, or about 0.25 mg QW.

[0204] In some embodiments, the dosing regimen for a compound of the invention, or a pharmaceutically acceptable salt thereof, in dogs is a fixed dose QW of about 0.1-2.5 mg per injection.Preferably, the dosing regimen of the compound of the present invention or a pharmaceutically acceptable salt thereof in cats is a fixed dose per injection of about 0.1 to about 2 mg QW, about 0.1 to about 1.5 mg QW, about 0.1 to about 1 mg QW, about 0.1 to about 0.5 mg QW, about 0.15 to about 2.5 mg QW, about 0.15 to about 2 mg QW, about 0.15 to about 1.5 mg QW, about 0.15 to about 1 mg QW, about 0.15 to about 0.5 mg QW, about 0.2 to about 2.5 mg QW, about 0.2 to about 2 mg QW, about 0.2 to about 1.5 mg QW, about 0.2 to about 1 mg QW, about 0.2 to about 0.5 mg QW, about 0.25 to about 2.5 mg QW, about 0.25 to about 2 mg QW, about 0.25 to about 1.5 mg QW, about 0.25 to about 1 mg QW, about 0.25 to about 0.5 mg QW, about 0.3 to about 2.5 mg QW, about 0.3 to about 2 mg QW, about 0.3 to about 1.5 mg QW, about 0.3 to about 1 mg QW, about 0.3 to about 0.5 mg QW, about 0.301 to 2.001 mg QW, about 0.35 to about 2.5 mg QW, about 0.35 to about 2 mg QW, about 0.35 to about 1.5 mg QW, about 0.35 to about 1 mg QW, about 0.35 to about 0.5 mg QW, about 0.4 to about 2.5 mg QW, about 0.4 to about 2 mg QW, about 0.4 to about 1.5 mg QW, about 0.4 to about 1 mg QW, about 0.4 to about 0.5 mg QW, about 0.5 to about 2 mg QW, about 0.5 to about 1.5 mg QW, about 0.5 to about 1 mg QW, about 2.5 mg QW, about 2.0 mg QW, about 1.95 mg QW, about 1.9 mg QW, about 1.85 mg QW, about 1.8 mg QW, about 1.75 mg QW, about 1.7 mg QW, about 1.65 mg QW, about 1.6 mg QW, about 1.55 mg QW, about 1.5 mg QW, about 1.45 mg QW, about 1.4 mg QW, about 1.35 mg QW, about 1.3 mg QW, about 1.25 mg QW, about 1.2 mg QW, about 1.15 mg QW, about 1.1 mg QW, about 1.05 mg QW, about 1.0 mg QW, about 0.95 mg QW, about 0.9 mg QW, about 0.85 mg QW, about 0.8 mg QW, about 0.75 mg QW, about 0.7 mg QW, about 0.65 mg QW, about 0.6 mg QW, about 0.55 mg QW, about 0.5 mg QW, about 0.45 mg QW, about 0.4 mg QW, about 0.35 mg QW, about 0.3 mg QW, or about 0.25 mg QW.

[0205] According to the dosage regimen of the present invention, the body weight, feed intake, BMI, SFV, TFV, AC and BCS of dogs, cats, rabbits, pigs, alpacas, horses, sheep and cattle, especially dogs and cats, are significantly reduced.

[0206] In the context of this article, "canine" and "dog" are synonymous and can be used interchangeably.

[0207] The amino acid sequences of the present invention contain the standard one-letter or three-letter codes for the twenty naturally occurring amino acids. Additionally, "Aib" is α-aminoisobutyric acid, "αMePhe" is α-methylphenylalanine, "Pya(4)" is 4-pyridylalanine, "Cha" is cyclohexylalanine, and "αMeTyr" is α-methyltyrosine.

[0208] The "AEEA" of the present invention is the abbreviation of 2-(2-amino-ethoxy)-ethoxy]-acetyl. The "Ste" of the present invention represents an octadecane dioic acid-C(O)-C 16 H 32 -C(O)-.

[0209] An "effective amount" or "therapeutically effective amount" as used herein is an amount or dosage of a compound of the invention or a pharmaceutically acceptable salt thereof that, when administered in single or multiple doses to an animal, provides the desired effect in the animal being diagnosed or treated.

[0210] The "effective dose" as used herein refers to the minimum dose that produces a pharmacological effect. Specifically, in the db / db mouse multiple-dose efficacy study, it refers to the minimum dose that produces a significant difference (P < 0.05) in blood glucose AUC in the test group compared to the vehicle group.

[0211] The term "efficacy dose" as used herein refers to the dose that produces a pharmacologically effective effect. Specifically, in the db / db mouse multiple-dose efficacy study, it refers to the dose at which the blood glucose AUC in the test group shows a significant difference (P < 0.05) compared to the vehicle group.

[0212] The "Vehicle group" described in the present invention refers to the vehicle control group.

[0213] The "AUC" in this invention refers to the area under the drug-time curve, which is the area enclosed by the drug concentration curve over the time axis. This parameter is an important indicator for evaluating the degree of drug absorption and reflects the drug's exposure characteristics in the body.

[0214] The "MRT" mentioned in the present invention refers to the mean residence time, which is the average time that drug molecules stay in the body, and represents the time required to eliminate 63.2% of the drug from the body.

[0215] The "MTD" mentioned in the present invention refers to the maximum tolerated dose, which is the highest dose that does not cause the death of the test animals.

[0216] The "internal standard" mentioned in the present invention refers to a known amount of a pure compound added to a sample to correct errors caused by instrument signal fluctuations, human operation, etc.

[0217] The "blood glucose AUC inhibition rate" of the present invention is the percentage of blood glucose AUC reduction in the test substance administration group compared with the vehicle group. Blood glucose AUC inhibition rate = (blood glucose AUC Vehicle - Blood glucose AUC 受试物 ) / blood glucose AUC Vehicle

[0218] The "weight change rate" in the present invention is the percentage of weight change of the test substance administration group after administration compared with that before administration, reflecting the extent of the effect of the test substance on body weight. For example, the weight change rate on day 28 (D28) = (weight 给药后D28 -weight 给药前 ) / weight 给药前 × 100% The "percentage of weight loss" in the present invention is the percentage of weight loss in the test substance administration group after administration compared with that before administration, reflecting the extent of weight loss of the test substance. For example, the percentage of weight loss on D28 = (weight 给药前 -weight 给药后D28 ) / weight 给药前 ×100%

[0219] The "titration strategy" described in the present invention is a method of increasing the dose, that is, after the initial dose, the frequency of the dose increase and the amount of administration are adjusted to obtain the optimal dosage.

[0220] As used herein, "treating" includes attenuating, inhibiting, reversing, slowing, delaying or stopping the progression or severity of an existing condition, disease, disorder or symptom. As used herein, "preventing" includes reducing the risk of acquiring a particular disease, condition or disorder.

[0221] Unless otherwise specified or clearly contradictory, "animals" as used herein means non-primates and non-rodents, that is, excluding humans and non-human primates and rodents. "Animals" as used herein include pets. Unless otherwise specified or clearly contradictory, "pets" as used herein mean non-primate and non-rodent pets, that is, excluding primates and rodents. "Primates" as used herein include monkeys, such as cynomolgus macaques. "Rodents" as used herein include rats and mice. Unless otherwise specified or clearly contradictory, "animals," "non-primates and non-rodents," "pets," and "non-primate and non-rodent pets" as used herein are used interchangeably and include dogs, cats, rabbits, pigs, alpacas, horses, sheep, and cattle.

[0222] The "modified chain" of the present invention is ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -Z, wherein each a is independently an integer from 0 to 5, each b is independently an integer from 0 to 5, and each c is independently an integer from 10 to 22; further wherein a is independently selected from an integer from 1, 2, 3, 4 or 5, b is independently selected from an integer from 1, 2, 3, 4 or 5, and c is independently selected from an integer from 12 to 22; in addition, the present invention provides compounds wherein c is 14, 16, 18 or 20, wherein Z is independently selected from -CH3, carboxylic acid or carboxylic acid bioisostere, phosphonate / ester or sulfonate / ester, for example, but not limited to, the Z may include carboxylic acid (-CO2H) or carboxylic acid bioisostere (for example ), phosphonic acid (-P(O)(OH)2) or sulfonic acid (-SO2OH) groups, preferably -CO2H.

[0223] Carboxylic acid bioisosteres, suitable carboxylic acid bioisosteres are known in the art. Preferably, the bioisostere has a pK a Examples of suitable bioisosteres may include, but are not limited to, tetrazoles, acylsulfonamides, acylhydroxylamines, and squaric acid derivatives, as shown below:

[0224] R is Me or CF3.

[0225] For the peptides mentioned herein, according to conventional peptide notation, the left end is the N-terminus (amino terminus) and the right end is the C-terminus (carboxyl terminus). The C-terminus of the peptide can be an amide (e.g., primary amide -CONH2), a carboxyl group (-COOH), a carboxylate group (-COO - ), any of alkylamides (-CONHR') and esters (-COOR'), R' is C1-8 An alkyl group. In particular, an amide (-CONH2) is preferred.

[0226] The "coupling" or "accessioning" in the preparation method of the present invention refers to the process of adding new amino acids to the bound amino acids or peptides.

[0227] In the context of this document, the numerical value modified by "about" may have a deviation of ±10%. For example, "about 10" means that the value may fluctuate within the range of 9 to 11.

[0228] In the context of this article, "increasing dose" means that in two adjacent administrations, the dose of the latter administration is equal to or greater than the dose of the previous administration. "Increasing" is relative to "decreasing", and "increasing" includes the situation where two or more adjacent administrations are performed with the same dose.

[0229] In the context of this article, "overweight" refers to the weight of non-primate and non-rodent species with a BCS ≥ 6. Specific implementation plan

[0230] 1. Use of a compound of the following formula (AI), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal:

[0231] Y-X1-EGT-X2-TSDY-A11-A12-A13-LDK-A17-AQ-A20-EFVKWLLK-A29-GPSSGAPPPSK Formula (AI);

[0232] wherein X1 is Aib; X2 is αMePhe;

[0233] A11 is Aib or Ala;

[0234] A12 is Ala, Ile, Lys, Phe, or Pya (4);

[0235] A13 is Aib, Cha, Leu, αMePhe, or αMeTyr;

[0236] A17 is Gln or Ile;

[0237] A20 is Ala or Ser;

[0238] A29 is Gln or Gly,

[0239] 1 K, 2 K, 3 K or 4 K positions are selected from the 16th, 24th, 28th and 40th positions by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a-(γ-Glu) b -CO-(CH2) c -Z is chemically modified by being conjugated to the ε-amino group of the K side chain, wherein each a is independently an integer from 0 to 5, each b is independently an integer from 0 to 5, and each c is independently an integer from 10 to 24, wherein Z is independently selected from -CH3, carboxylic acid or carboxylic acid bioisostere, phosphonate / ester or sulfonate / ester.

[0240] 2. The use according to embodiment 1, wherein

[0241] A11 is Aib; or / and

[0242] A12 is Ile; or / and

[0243] A13 is Aib; or / and

[0244] A17 is Gln; or / and

[0245] A20 is Ala; or / and

[0246] A29 is Gly; or / and

[0247] a is independently selected from an integer of 1, 2, 3, 4 or 5, b is independently selected from an integer of 1, 2, 3, 4 or 5, c is independently selected from an integer of 12 to 22; further, c is independently selected from 14, 16, 18 or 20.

[0248] 3. Use of a compound of the following formula (I), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for preventing or treating diseases in non-primates and non-rodents:

[0249] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK Formula (I);

[0250] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; 1, 2, 3 or 4 K positions are selected from positions 16, 24, 28 and 40, by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c-Z is chemically modified by conjugation to the ε-amino group of the K side chain, wherein each a is independently an integer from 0 to 5, each b is independently an integer from 0 to 5, and each c is independently an integer from 10 to 24, wherein Z is independently selected from -CH3, carboxylic acid or carboxylic acid bioisostere, phosphonate / ester or sulfonate / ester; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0251] 4. The use according to embodiment 3, wherein the compound is:

[0252] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK Formula (I), or a pharmaceutically acceptable salt thereof,

[0253] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; one or two K positions are selected from positions 16, 24, 28, and 40, by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -Z is chemically modified by conjugation to the ε-amino group of the K side chain, wherein Z is independently selected from -CH3, carboxylic acid or carboxylic acid bioisostere, phosphonate / ester or sulfonate / ester, preferably -CO2H, each a is independently an integer from 0 to 5, each b is independently an integer from 0 to 5, and each c is independently an integer from 10 to 22; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0254] 5. The use according to embodiment 4, wherein

[0255] At position 16, K is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain for chemical modification; or

[0256] At position 24, K is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain for chemical modification; or

[0257] At position 28, K is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a-(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain for chemical modification; or

[0258] At position 40, K is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H was conjugated to the ε-amino group of the K side chain for chemical modification.

[0259] 6. The use according to embodiment 4, wherein

[0260] K at positions 24 and 28 is synthesized by replacing the 2-(2-amino-ethoxy)-ethoxy]-acetyl group with a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain to perform chemical modification of the two modified chains; or

[0261] K at positions 16 and 24 is synthesized by replacing the acetyl group with ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain to perform chemical modification of the two modified chains; or

[0262] K at positions 16 and 28 was synthesized by replacing ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain to perform chemical modification of the two modified chains; or

[0263] K at positions 16 and 40 is synthesized by replacing the acetyl group with ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain to perform chemical modification of the two modified chains; or

[0264] K at positions 24 and 40 is synthesized by replacing the 2-(2-amino-ethoxy)-ethoxy]-acetyl group with a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain to perform chemical modification of the two modified chains; or

[0265] K at positions 28 and 40 is synthesized by replacing the 2-(2-amino-ethoxy)-ethoxy]-acetyl group with a -(γ-Glu) b -CO-(CH2) c -CO2H was conjugated to the ε-amino group of the K side chain to perform chemical modification of the two modified chains.

[0266] 7. The use according to any one of embodiments 3 to 6, wherein

[0267] a is independently selected from an integer of 1, 2, 3, 4 or 5, b is independently selected from an integer of 1, 2, 3, 4 or 5, c is independently selected from an integer of 12 to 22; further, c is independently selected from 14, 16, 18 or 20; and / or

[0268] Z is -CO2H.

[0269] 8. The use according to embodiment 4, wherein the compound is

[0270] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK Formula (I);

[0271] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 24 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is chemically modified by conjugation to the ε-amino group of the K side chain, wherein a is independently selected from an integer from 0 to 5, b is independently selected from an integer from 0 to 5, and c is independently selected from an integer from 10 to 24; and the C-terminal amino acid is amidated to a C-terminal primary amide;

[0272] Preferably, wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; at position 24, K is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is chemically modified by conjugating to the ε-amino group of the K side chain, wherein each a is independently selected from an integer of 2 or 3, each b is independently 1, and each c is independently selected from an integer of 16, 18, or 20, and wherein Z is independently selected from a carboxylic acid.

[0273] 9. The use according to embodiment 4, wherein the compound is

[0274] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK Formula (I);

[0275] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is chemically modified by conjugation to the ε-amino group of the K side chain, wherein a is independently selected from an integer from 0 to 5, b is independently selected from an integer from 0 to 5, and c is independently selected from an integer from 10 to 24; and the C-terminal amino acid is amidated to a C-terminal primary amide;

[0276] Preferably, wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; at position 28, K is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is chemically modified by conjugating to the ε-amino group of the K side chain, wherein each a is independently selected from an integer of 2 or 3, each b is independently selected from an integer of 1 or 3, each c is independently selected from an integer of 16 or 20, and Z is independently selected from a carboxylic acid.

[0277] 10. The use according to any one of embodiments 8-9, wherein

[0278] a is independently selected from an integer of 1, 2, 3, 4 or 5, b is independently selected from an integer of 1, 2, 3, 4 or 5, c is independently selected from an integer of 12 to 22; further, c is independently selected from 14, 16, 18 or 20.

[0279] 11. The use according to embodiment 4, wherein the compound is

[0280] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0281] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 24 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)1-CO-(CH2) 16 -CO2H is chemically modified by conjugation to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide (SEQ ID NO: 7); or

[0282] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0283] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 24 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)1-CO-(CH2) 18 -CO2H is chemically modified by conjugation to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide (SEQ ID NO: 13); or

[0284] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0285] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 24 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)1-CO-(CH2) 20 -CO2H is chemically modified by conjugation to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide (SEQ ID NO: 14); or

[0286] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0287] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 24 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)3-CO-(CH2) 16-CO2H is chemically modified by conjugation to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide (SEQ ID NO: 15); or

[0288] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0289] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 24 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)3-(γ-Glu)1-CO-(CH2) 20 -CO2H is chemically modified by conjugation to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide (SEQ ID NO: 16); or

[0290] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0291] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)1-CO-(CH2) 16 -CO2H is chemically modified by conjugation to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide (SEQ ID NO: 8); or

[0292] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0293] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)1-CO-(CH2) 20 -CO2H is chemically modified by conjugation to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide (SEQ ID NO: 17); or

[0294] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0295] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)3-CO-(CH2) 16 -CO2H is chemically modified by conjugation to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide (SEQ ID NO: 18); or

[0296] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0297] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)3-(γ-Glu)1-CO-(CH2) 16 -CO2H is chemically modified by conjugation to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide (SEQ ID NO: 19); or

[0298] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0299] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)3-(γ-Glu)1-CO-(CH2) 20 The K side chain was chemically modified by conjugating -CO2H to the ε-amino group; and the C-terminal amino acid was amidated to a C-terminal primary amide (SEQ ID NO: 20).

[0300] 12. The use according to embodiment 4, wherein the compound is

[0301] or a pharmaceutically acceptable salt thereof.

[0302] 13. The use according to any one of embodiments 1 to 12, wherein the disease comprises hyperglycemia, impaired glucose tolerance, diabetes (including type 1 diabetes, type 2 diabetes), obesity, hypertension, dyslipidemia, cognitive impairment, atherosclerosis, myocardial infarction, coronary heart disease and other cardiovascular diseases, stroke, inflammatory bowel syndrome, dyspepsia and gastric ulcer.

[0303] 14. The use according to any one of embodiments 1-12, wherein the drug is a drug for preventing, delaying or treating type 2 diabetes.

[0304] 15. The use according to any one of embodiments 1-12, wherein the compound or a pharmaceutically acceptable salt thereof is used to prepare a medicament for reducing food intake, reducing β-cell apoptosis, increasing β-cell function and β-cell mass, and / or restoring glucose sensitivity of β-cells in an animal.

[0305] 16. The use according to any one of embodiments 1-12, wherein the disease comprises a metabolic disorder, dyslipidemia associated with insulin resistance and diabetes, obesity and / or hepatic steatosis.

[0306] 17. The use according to any one of embodiments 1-12, wherein the disease comprises osteopenia, bone / joint disease, such as knee osteoarthritis, hip osteoarthritis, and / or deforming spondylitis.

[0307] 18. The use according to any one of embodiments 1-12, wherein the compound or a pharmaceutically acceptable salt thereof is used in an overweight or obese animal as an adjunct to a hypocaloric diet and increased physical activity for long-term weight management.

[0308] 19. The use according to any one of embodiments 1-12, wherein the disease comprises: symptomatic obesity, obesity based on simple obesity, disease states or diseases related to obesity, eating disorders, diabetes (e.g., type I diabetes, type II diabetes, gestational diabetes, obese diabetes), hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, high LDL-cholesterolemia, low HDL-cholesterolemia, postprandial hyperlipidemia), hypertension, heart failure, complications of diabetes (e.g. , neuropathy, nephropathy, retinopathy, diabetic cardiomyopathy, cataract, macroangiopathy, osteopenia, hyperosmolar diabetic coma), infectious diseases (e.g., respiratory tract infection, urinary tract infection, gastrointestinal infection, superficial soft tissue infection, lower limb infection), diabetic gangrene, xerostomia, hearing loss, cerebrovascular disorders, peripheral blood circulation disorders, metabolic syndrome (a disease state having three or more selected from hypertriglyceridemia, low HDL cholesterolemia, hypertension, abdominal obesity and impaired glucose tolerance), and / or sarcopenia.

[0309] 20. The use according to any one of embodiments 1-19, wherein the animal is a pet or companion animal.

[0310] 21. The use according to embodiment 20, wherein the pet is selected from the group consisting of dogs, cats, rabbits, pigs, alpacas, horses, sheep and cattle.

[0311] 22. The use according to any one of embodiments 1-21, wherein the animal is a dog or a cat.

[0312] 23. The use according to any one of embodiments 1-22, wherein the compound or a pharmaceutically acceptable salt thereof is used to treat type 2 diabetes, overweight and / or obesity in cats or dogs.

[0313] 24. The use according to any one of embodiments 1 to 23, wherein the compound or a pharmaceutically acceptable salt thereof is administered in the form of a solution or a suspension.

[0314] 25. The use according to any one of embodiments 1-24, wherein the compound or a pharmaceutically acceptable salt thereof is administered by subcutaneous injection;

[0315] Preferably, the compound or a pharmaceutically acceptable salt thereof is administered once a week (QW) to cats and dogs.

[0316] 26. The use according to any one of embodiments 1 to 25, wherein the compound or a pharmaceutically acceptable salt thereof is administered in an amount of about 0.003 to about 2.5 mg / kg, or about 0.003 to about 0.6 mg / kg in cats and dogs, such as about 0.005 to about 0.1 mg / kg, about 0.1 to about 0.125 mg / kg, about 0.1 to about 0.15 mg / kg, about 0.15 to about 0.25 mg / kg, about 0.125 to about 0.25 mg / kg, about 0.005 to about 2 mg / kg, about 0.005 to about 1.5 mg / kg, about 0.005 to about 1 mg / kg, about 0.005 to about 0.5 mg / kg, about 0.1 to about 2 mg / kg , about 0.1 to about 1.5 mg / kg, about 0.1 to about 1 mg / kg, about 0.1 to about 0.5 mg / kg, about 0.15 to about 2.5 mg / kg, about 0.15 to about 2 mg / kg, about 0.15 to about 1.5 mg / kg, about 0.15 to about 1 mg / kg, about 0.15 to about 0.5 mg / kg, about 0.2 to about 2.5 mg / kg, about 0.2 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.2 to about 1 mg / kg, about 0.2 to about 0.5 mg / kg, about 0.25 to about 2.5 mg / kg, about 0.25 to about 2 mg / kg, about 0.25 to about 1.5 mg / kg, about 0.25 to about 1 mg / kg , about 0.25 to about 0.5 mg / kg, about 0.3 to about 2.5 mg / kg, about 0.3 to about 2 mg / kg, about 0.3 to about 1.5 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.5 mg / kg, about 0.301 to 2.001 mg / kg, about 0.35 to about 2.5 mg / kg, about 0.35 to about 2 mg / kg, about 0.35 to about 1.5 mg / kg, about 0.35 to about 1 mg / kg, about 0.35 to about 0.5 mg / kg, about 0.4 to about 2.5 mg / kg, about 0.4 to about 2 mg / kg, about 0.4 to about 1.5 mg / kg, about 0.4 to about 1 mg / kg, about 0.4 to about 0.5 mg / kg kg, about 0.5 to about 2.5 mg / kg, about 0.5 to about 2 mg / kg, about 0.5 to about 1.5 mg / kg, about 0.5 to about 1 mg / kg, about 2.5 mg / kg, about 2.0 mg / kg, about 1.95 mg / kg, about 1.9 mg / kg, about 1.85 mg / kg, about 1.8 mg / kg, about 1.75 mg / kg, about 1.7 mg / kg, about 1.65 mg / kg, about 1.6 mg / kg, about 1.55 mg / kg, about 1.5 mg / kg, about 1.45 mg / kg, about 1.4 mg / kg, about 1.35 mg / kg, about 1.3 mg / kg, about 1.25 mg / kg, about 1.2 mg / kg, about 1.15 mg / kg, about 1.1 mg / kg, about 1.05 mg / kg, about 1.0 mg / kg, about 0.95 mg / kg, about 0.9 mg / kg, about 0.85 mg / kg, about 0.8 mg / kg, about 0.75 mg / kg, about 0.7 mg / kg, about 0.65 mg / kg, about 0.6 mg / kg, about 0.55 mg / kg, about 0.5 mg / kg, about 0.45 mg / kg, about 0.4 mg / kg, about 0.35 mg / kg, about 0.3 mg / kg, about 0.25 mg / kg, about 0.2 mg / kg, about 0.15 mg / kg, or about 0.1 mg / kg.

[0317] 27. The compound or pharmaceutically acceptable salt thereof according to any one of embodiments 1-25, wherein the compound or pharmaceutically acceptable salt thereof is administered in cats or dogs at a dosage of about 0.003 to about 2.5 mg / kg QW, preferably about 0.01 to about 2 mg / kg QW, more preferably about 0.25 to about 2.0 mg / kg QW, and / or about 0.1 to about 2.0 mg / kg QW, further preferably about 0.5 to about 2.0 mg / kg QW, for example, about 0.01 to about 2 mg / kg QW, about 0.01 to about 1.5 mg / kg QW, about 0.01 to about 1 mg / kg QW, about 0.01 to about 0.5 mg / kg QW, about 0.02 to about 2.5 mg / kg QW, about 0.02 to about 2 mg / kg QW, about 0.02 to about 1.5 mg / kg QW, about 0.02 to about 1 mg / kg QW, about 0.02 to about 0.5 mg / kg QW, about 0.021 to about 0.499 mg / kg QW, about 0.03 to about 2.5 mg / kg QW, about 0.03 to about 2 mg / kg QW, about 0.03 to about 1.5 mg / kg QW, about 0.03 to about 1 mg / kg QW, about 0.03 to about 0.5 mg / kg QW, about 0.04 to about 2.5 mg / kg QW, about 0.04 to about 2 mg / kg QW, about 0.04 to about 1.5 mg / kg QW, about 0.04 to about 1 mg / kg QW, about 0.04 to about 0.5 mg / kg QW, about 0.05 to about 2.5 mg / kg QW, about 0.05 to about 2 mg / kg QW, about 0.05 to about 1.5 mg / kg QW, about 0.05 to about 1 mg / kg QW, about 0.05 to about 0.5 mg / kg QW, about 0.06 to about 2.5 mg / kg QW, about 0.06 to about 2 mg / kg QW, about 0.06 to about 1.5 mg / kg QW, about 0.06 to about 1 mg / kg QW, about 0.06 to about 0.5 mg / kg QW, about 0.062 to 2.001 mg / kg QW, about 0.07 to about 2.5 mg / kg QW, about 0.07 to about 2 mg / kg QW, about 0.07 to about 1.5 mg / kg QW, about 0.07 to about 1 mg / kg QW, about 0.07 to about 0.5 mg / kg QW, about 0.073 to 0.998 mg / kg QW, about 0.08 to about 2.5 mg / kg QW, about 0.08 to about 2 mg / kg QW, about 0.08 to about 1.5 mg / kg QW, about 0.08 to about 1 mg / kg QW, about 0.08 to about 0.5 mg / kg QW, about 0.09 to about 2.5 mg / kg QW, about 0.09 to about 2 mg / kg QW, about 0.09 to about 1.5 mg / kg QW, about 0.0.9 to about 1 mg / kg QW, about 0.09 to about 0.5 mg / kg QW, about 0.1 to about 2.5 mg / kg QW, about 0.1 to about 2 mg / kg QW, about 0.1 to about 1.5 mg / kg QW, about 0.1 to about 1 mg / kg QW, about 0.1 to about 0.5 mg / kg QW, about 0.15 to about 2.5 mg / kg QW, about 0.15 to about 2 mg / kg QW, about 0.15 to about 1.5 mg / kg QW, about 0.15 to about 1 mg / kg QW, about 0.15 to about 0.5 mg / kg QW, about 0.2 to about 2.5 mg / kg QW, about 0.2 to about 2 mg / kg QW, about 0.2 to about 1.5 mg / kg QW, about 0.2 to about 1 mg / kg QW, about 0.2 to about 0.5 mg / kg QW, about 0.25 to about 2.5 mg / kg QW, about 0.25 to about 2 mg / kg QW, about 0.25 to about 1.5 mg / kg QW, about 0.25 to about 1 mg / kg QW, about 0.25 to about 0.5 mg / kg QW, about 0.3 to about 2.5 mg / kg QW, about 0.3 to about 2 mg / kg QW, about 0.3 to about 1.5 mg / kg QW, about 0.3 to about 1 mg / kg QW, about 0.3 to about 0.5 mg / kg QW, about 0.301 to 2.001 mg / kg QW, about 0.35 to about 2.5 mg / kg QW, about 0.35 to about 2 mg / kg QW, about 0.35 to about 1.5 mg / kg QW, about 0.35 to about 1 mg / kg QW, about 0.35 to about 0.5 mg / kg QW, about 0.4 to about 2.5 mg / kg QW, about 0.4 to about 2 mg / kg QW, about 0.4 to about 1.5 mg / kg QW, about 0.4 to about 1 mg / kg QW, about 0.4 to about 0.5 mg / kg QW, about 0.5 to about 2 mg / kg QW, about 0.5 to about 1.5 mg / kg QW, about 0.5 to about 1 mg / kg QW, about 2.5 mg / kg QW, about 2.0 mg / kg QW, about 1.95 mg / kg QW, about 1.9 mg / kg QW, about 1.85 mg / kg QW, about 1.8 mg / kg QW, about 1.75 mg / kg QW, about 1.7 mg / kg QW, about 1.65 mg / kg QW, about 1.6 mg / kg QW, about 1.55 mg / kg QW, about 1.5 mg / kg QW, about 1.45 mg / kg QW, about 1.4 mg / kg QW, about 1.35 mg / kg QW, about 1.3 mg / kg QW, about 1.25 mg / kg QW, about 1.2 mg / kg QW, about 1.15 mg / kg QW, about 1.1 mg / kg QW, about 1.0.5 mg / kg QW, about 1.0 mg / kg QW, about 0.95 mg / kg QW, about 0.9 mg / kg QW, about 0.85 mg / kg QW, about 0.8 mg / kg QW, about 0.75 mg / kg QW, about 0.7 mg / kg QW, about 0.65 mg / kg QW, about 0.6 mg / kg QW, about 0.55 mg / kg QW, about 0.5 mg / kg QW, about 0.45 mg / kg QW, about 0.4 mg / kg QW, about 0.35 mg / kg QW, about 0.3 mg / kg QW, about 0.25 mg / kg QW, or about 0.2 mg / kg QW.

[0318] 28. The use according to any one of embodiments 1-25, wherein the compound or a pharmaceutically acceptable salt thereof is continuously administered to a cat or dog at a frequency of once a week, and the dosing cycle is determined according to the needs of the subject, and the dosing cycle can be 4-8 weeks, or 8-20 weeks, for example 4, 5, 6, 7 or 8 weeks.

[0319] 29. The use according to embodiments 1-26, wherein the compound of the present invention or a pharmaceutically acceptable salt thereof is administered to dogs once a week for 6 weeks, with each administration being the same or different in dose.

[0320] 30. The use according to embodiments 1-26, wherein the compound of the present invention or a pharmaceutically acceptable salt thereof is administered to cats once a week for 5 weeks, with each administration being the same or different.

[0321] 31. The use according to embodiment 29 or 30, wherein the compound or a pharmaceutically acceptable salt thereof is administered to the cat or dog in increasing doses.

[0322] 32. The use according to any one of embodiments 28-31, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a cat at the following dosage:

[0323] The doses of the first and second administrations are the same, both being a first dose of about 0.02 to about 0.35 mg / kg QW.

[0324] The third dose is a second dose of about 0.49 to about 1 mg / kg QW, and the second dose is about 1.2 to 50 times the first dose, preferably about 10 to about 15 times, for example about 12 times,

[0325] The fourth and fifth administrations have the same dose, which is the third dose of about 0.49 to about 2.5 mg / kg QW. The third dose is about 1.75 to about 2.5 times the second dose, preferably about 1.95 to 2.05 times, more preferably about 2 times.

[0326] 33. The use according to any one of embodiments 28-32, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a cat at the following dosage:

[0327] The first dose is about 0.019 mg / kg QW,

[0328] The second dose is about 0.25 mg / kg QW,

[0329] The third dose is about 0.50 mg / kg QW.

[0330] 34. The use according to any one of embodiments 28-32, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a cat at the following dosage:

[0331] The first dose is about 0.075 mg / kg QW,

[0332] The second dose is about 0.50 mg / kg QW,

[0333] The third dose is about 1.00 mg / kg QW.

[0334] 35. The use according to any one of embodiments 28-32, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a cat at the following dosage:

[0335] The first dose is about 0.30 mg / kg QW,

[0336] The second dose is about 1.00 mg / kg QW,

[0337] The third dose is about 2.00 mg / kg QW.

[0338] 36. The use according to any one of embodiments 28-32, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a cat according to the following dosing regimen:

[0339] The dosage is about 0.25-2.5 mg / kg; alternatively, the dosage is about 0.25-2.5 mg per injection;

[0340] Dosing frequency is QW;

[0341] The dosing cycle is 5 weeks.

[0342] 37. The use according to any one of embodiments 28-31, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a dog at the following dosage:

[0343] The doses of the first and second administrations are the same, both being a first dose of about 0.015 to about 0.07 mg / kg QW.

[0344] The third dose is a second dose of about 0.02 to about 0.14 mg / kg QW, preferably about 0.03 to about 0.1 mg / kg QW, and the second dose is about 1.4 to 2 times the first dose, preferably about 1.45 to about 1.6 times, more preferably about 1.5 times,

[0345] The doses for the fourth to sixth administrations are the same, which are all the third dose of about 0.49 to about 2.5 mg / kg QW, preferably about 0.495 to about 2.1 mg / kg QW, and the third dose is about 13 to about 25 times the second dose, more preferably about 16 to about 21 times.

[0346] 38. The use according to embodiment 36, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a dog at the following dosage:

[0347] The first dose is about 0.02 mg / kg QW,

[0348] The second dose is about 0.03 mg / kg QW,

[0349] The third dose is about 0.50 mg / kg QW.

[0350] 39. The use according to embodiment 36, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a dog at the following dosage:

[0351] The first dose is about 0.06 mg / kg QW,

[0352] The second dose is about 0.10 mg / kg QW,

[0353] The third dose is about 2.00 mg / kg QW.

[0354] 40. The use according to embodiment 36, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a dog according to the following dosing regimen:

[0355] The dosage is about 0.1-2.5 mg / kg; alternatively, the dosage is about 0.1-2.5 mg per injection;

[0356] The dosing cycle is QW;

[0357] Dosing frequency is 6 weeks.

[0358] 41. The use according to any one of embodiments 1-40, wherein the compound is selected from SEQ ID NO: 14, SEQ ID NO: 16 and SEQ ID NO: 20, preferably SEQ ID NO: 16.

[0359] 42. A compound of the following formula (AI) or a pharmaceutically acceptable salt thereof for use in preventing or treating non-primate and non-rodent diseases:

[0360] Y-X1-EGT-X2-TSDY-A11-A12-A13-LDK-A17-AQ-A20-EFVKWLLK-A29-GPSSGAPPPSK Formula (AI);

[0361] wherein X1 is Aib; X2 is αMePhe;

[0362] A11 is Aib or Ala;

[0363] A12 is Ala, Ile, Lys, Phe, or Pya (4);

[0364] A13 is Aib, Cha, Leu, αMePhe, or αMeTyr;

[0365] A17 is Gln or Ile;

[0366] A20 is Ala or Ser;

[0367] A29 is Gln or Gly,

[0368] 1 K, 2 K, 3 K or 4 K positions are selected from the 16th, 24th, 28th and 40th positions by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -Z is chemically modified by being conjugated to the ε-amino group of the K side chain, wherein each a is independently an integer from 0 to 5, each b is independently an integer from 0 to 5, and each c is independently an integer from 10 to 24, wherein Z is independently selected from -CH3, carboxylic acid or carboxylic acid bioisostere, phosphonate / ester or sulfonate / ester.

[0369] 43. The compound according to embodiment 42, or a pharmaceutically acceptable salt thereof, wherein

[0370] A11 is Aib; or / and

[0371] A12 is Ile; or / and

[0372] A13 is Aib; or / and

[0373] A17 is Gln; or / and

[0374] A20 is Ala; or / and

[0375] A29 is Gly; or / and

[0376] a is independently selected from an integer of 1, 2, 3, 4 or 5, b is independently selected from an integer of 1, 2, 3, 4 or 5, c is independently selected from an integer of 12 to 22; further, c is independently selected from 14, 16, 18 or 20.

[0377] 44. A compound of the following formula (I) or a pharmaceutically acceptable salt thereof for use in preventing or treating non-primate and non-rodent diseases:

[0378] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK Formula (I);

[0379] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; 1, 2, 3 or 4 K positions are selected from positions 16, 24, 28 and 40, by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -Z is chemically modified by conjugation to the ε-amino group of the K side chain, wherein each a is independently an integer from 0 to 5, each b is independently an integer from 0 to 5, and each c is independently an integer from 10 to 24, wherein Z is independently selected from -CH3, carboxylic acid or carboxylic acid bioisostere, phosphonate / ester or sulfonate / ester; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0380] 45. The compound according to embodiment 42 or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is:

[0381] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK Formula (I), or a pharmaceutically acceptable salt thereof,

[0382] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; one or two K positions are selected from positions 16, 24, 28, and 40, by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c-Z is chemically modified by conjugation to the ε-amino group of the K side chain, wherein Z is independently selected from -CH3, carboxylic acid or carboxylic acid bioisostere, phosphonate / ester or sulfonate / ester, preferably -CO2H, each a is independently an integer from 0 to 5, each b is independently an integer from 0 to 5, and each c is independently an integer from 10 to 22; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0383] 46. ​​The compound according to embodiment 42, or a pharmaceutically acceptable salt thereof, wherein

[0384] At position 16, K is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain for chemical modification; or

[0385] At position 24, K is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain for chemical modification; or

[0386] At position 28, K is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain for chemical modification; or

[0387] At position 40, K is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H was conjugated to the ε-amino group of the K side chain for chemical modification.

[0388] 47. The compound according to embodiment 42, or a pharmaceutically acceptable salt thereof, wherein

[0389] K at positions 24 and 28 is synthesized by replacing the 2-(2-amino-ethoxy)-ethoxy]-acetyl group with a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain to perform chemical modification of the two modified chains; or

[0390] K at positions 16 and 24 is synthesized by replacing the acetyl group with ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain to perform chemical modification of the two modified chains; or

[0391] K at positions 16 and 28 was synthesized by replacing ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain to perform chemical modification of the two modified chains; or

[0392] K at positions 16 and 40 is synthesized by replacing the acetyl group with ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain to perform chemical modification of the two modified chains; or

[0393] K at positions 24 and 40 is synthesized by replacing the 2-(2-amino-ethoxy)-ethoxy]-acetyl group with a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain to perform chemical modification of the two modified chains; or

[0394] K at positions 28 and 40 is synthesized by replacing the 2-(2-amino-ethoxy)-ethoxy]-acetyl group with a -(γ-Glu) b -CO-(CH2) c -CO2H was conjugated to the ε-amino group of the K side chain to perform chemical modification of the two modified chains.

[0395] 48. A compound according to any one of embodiments 42-45, or a pharmaceutically acceptable salt thereof, wherein

[0396] a is independently selected from an integer of 1, 2, 3, 4 or 5, b is independently selected from an integer of 1, 2, 3, 4 or 5, c is independently selected from an integer of 12 to 22; further, c is independently selected from 14, 16, 18 or 20; and / or

[0397] Z is -CO2H.

[0398] 49. The compound according to embodiment 42 or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is

[0399] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK Formula (I);

[0400] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 24 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is chemically modified by conjugation to the ε-amino group of the K side chain, wherein a is independently selected from an integer from 0 to 5, b is independently selected from an integer from 0 to 5, and c is independently selected from an integer from 10 to 24; and the C-terminal amino acid is amidated to a C-terminal primary amide;

[0401] Preferably, wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; at position 24, K is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is chemically modified by conjugating to the ε-amino group of the K side chain, wherein each a is independently selected from an integer of 2 or 3, each b is independently 1, and each c is independently selected from an integer of 16, 18, or 20, and wherein Z is independently selected from a carboxylic acid.

[0402] 50. The compound according to embodiment 42 or a pharmaceutically acceptable salt thereof, wherein the compound is

[0403] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK Formula (I);

[0404] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is chemically modified by conjugation to the ε-amino group of the K side chain, wherein a is independently selected from an integer from 0 to 5, b is independently selected from an integer from 0 to 5, and c is independently selected from an integer from 10 to 24; and the C-terminal amino acid is amidated to a C-terminal primary amide;

[0405] Preferably, wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; at position 28, K is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is chemically modified by conjugating to the ε-amino group of the K side chain, wherein each a is independently selected from an integer of 2 or 3, each b is independently selected from an integer of 1 or 3, each c is independently selected from an integer of 16 or 20, and Z is independently selected from a carboxylic acid.

[0406] 51. A compound according to any one of embodiments 46-47, or a pharmaceutically acceptable salt thereof, wherein

[0407] a is independently selected from an integer of 1, 2, 3, 4 or 5, b is independently selected from an integer of 1, 2, 3, 4 or 5, c is independently selected from an integer of 12 to 22; further, c is independently selected from 14, 16, 18 or 20.

[0408] 52. The compound according to embodiment 42 or a pharmaceutically acceptable salt thereof, wherein the compound is

[0409] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0410] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 24 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)1-CO-(CH2) 16 -CO2H is chemically modified by conjugation to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide (SEQ ID NO: 7); or

[0411] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0412] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 24 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)1-CO-(CH2) 18-CO2H is chemically modified by conjugation to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide (SEQ ID NO: 13); or

[0413] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0414] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 24 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)1-CO-(CH2) 20 -CO2H is chemically modified by conjugation to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide (SEQ ID NO: 14); or

[0415] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0416] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 24 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)3-CO-(CH2) 16 -CO2H is chemically modified by conjugation to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide (SEQ ID NO: 15); or

[0417] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0418] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 24 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)3-(γ-Glu)1-CO-(CH2) 20 -CO2H is chemically modified by conjugation to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide (SEQ ID NO: 16); or

[0419] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0420] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)1-CO-(CH2) 16 -CO2H is chemically modified by conjugation to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide (SEQ ID NO: 8); or

[0421] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0422] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)1-CO-(CH2) 20 -CO2H is chemically modified by conjugation to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide (SEQ ID NO: 17); or

[0423] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0424] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)3-CO-(CH2) 16 -CO2H is chemically modified by conjugation to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide (SEQ ID NO: 18); or

[0425] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0426] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)3-(γ-Glu)1-CO-(CH2) 16 -CO2H is chemically modified by conjugation to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide (SEQ ID NO: 19); or

[0427] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0428] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)3-(γ-Glu)1-CO-(CH2) 20 The K side chain was chemically modified by conjugating -CO2H to the ε-amino group; and the C-terminal amino acid was amidated to a C-terminal primary amide (SEQ ID NO: 20).

[0429] 53. The compound according to embodiment 42 or a pharmaceutically acceptable salt thereof, wherein the compound is

[0430] or a pharmaceutically acceptable salt thereof.

[0431] 54. A compound according to any one of embodiments 42 to 53, or a pharmaceutically acceptable salt thereof, wherein the disease includes animal hyperglycemia, impaired glucose tolerance, diabetes (including type I diabetes, type II diabetes), obesity, hypertension, dyslipidemia, cognitive impairment, atherosclerosis, myocardial infarction, coronary heart disease and other cardiovascular diseases, stroke, inflammatory bowel syndrome, dyspepsia and gastric ulcer.

[0432] 55. The compound according to any one of embodiments 42-53 or a pharmaceutically acceptable salt thereof, wherein the drug is a drug for preventing, delaying or treating type 2 diabetes.

[0433] 56. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 42-53, wherein the compound or a pharmaceutically acceptable salt thereof is used to reduce animal food intake, reduce β-cell apoptosis, increase β-cell function and β-cell mass and / or restore β-cell glucose sensitivity.

[0434] 57. A compound according to any one of embodiments 42-53, or a pharmaceutically acceptable salt thereof, wherein the disease comprises a metabolic disorder, including dyslipidemia associated with insulin resistance and diabetes, obesity and / or hepatic steatosis.

[0435] 58. The compound according to any one of embodiments 42-53, or a pharmaceutically acceptable salt thereof, wherein the disease comprises osteopenia, bone / joint diseases such as knee osteoarthritis, hip osteoarthritis, and / or deforming spondylitis.

[0436] 59. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 42-53, wherein the compound or a pharmaceutically acceptable salt thereof is used in overweight or obese animals as an adjunct to a hypocaloric diet and increased physical activity for long-term weight management.

[0437] 60. A compound according to any one of embodiments 42-53 or a pharmaceutically acceptable salt thereof, wherein the disease includes: symptomatic obesity, obesity based on simple obesity, disease states or diseases related to obesity, eating disorders, diabetes (e.g., type I diabetes, type II diabetes, gestational diabetes, obese diabetes), hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, high LDL-cholesterolemia, low HDL-cholesterolemia, postprandial hyperlipidemia), hypertension, heart failure, diabetic Complications (e.g., neuropathy, nephropathy, retinopathy, diabetic cardiomyopathy, cataracts, macroangiopathy, osteopenia, hyperosmolar diabetic coma), infectious diseases (e.g., respiratory tract infection, urinary tract infection, gastrointestinal infection, superficial soft tissue infection, lower limb infection), diabetic gangrene, xerostomia, hearing loss, cerebrovascular disorders, peripheral blood circulation disorders, metabolic syndrome (a disease state having three or more selected from hypertriglyceridemia, low HDL cholesterol, hypertension, abdominal obesity and impaired glucose tolerance), and / or sarcopenia.

[0438] 61. The compound of any one of embodiments 42-60, or a pharmaceutically acceptable salt thereof, wherein the animal is a pet or companion animal.

[0439] 62. The compound of embodiment 61 or a pharmaceutically acceptable salt thereof, wherein the pet is selected from the group consisting of dogs, cats, rabbits, pigs, alpacas, horses, sheep, and cattle.

[0440] 63. The compound of any one of embodiments 42-62, or a pharmaceutically acceptable salt thereof, wherein the animal is a dog or a cat.

[0441] 64. A compound according to any one of embodiments 42-63, or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is used to treat type 2 diabetes, overweight and / or obesity in cats or dogs.

[0442] 65. The compound or pharmaceutically acceptable salt thereof according to any one of embodiments 42-64, wherein the compound or pharmaceutically acceptable salt thereof is administered in the form of a solution or suspension.

[0443] 66. The compound or pharmaceutically acceptable salt thereof according to any one of embodiments 42-65, wherein the compound or pharmaceutically acceptable salt thereof is administered by subcutaneous injection;

[0444] Preferably, the compound or a pharmaceutically acceptable salt thereof is administered to cats and dogs once a week.

[0445] 67. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 42-66, wherein the compound or a pharmaceutically acceptable salt thereof is administered in an amount of about 0.003 to about 2.5 mg / kg in cats and dogs, or about 0.003 to about 0.6 mg / kg, such as about 0.005 to about 0.1 mg / kg, about 0.1 to about 0.125 mg / kg, about 0.1 to about 0.15 mg / kg, about 0.15 to about 0.25 mg / kg, about 0.125 to about 0.25 mg / kg, about 0.005 to about 2 mg / kg, about 0.005 to about 1.5 mg / kg, about 0.005 to about 1 mg / kg, about 0.005 to about 0.5 mg / kg, about 0.1 to about 2 mg / kg, about 0.1 to about 1.5 mg / kg, about 0.1 to about 1 mg / kg, about 0.1 to about 0.5 mg / kg, about 0.15 to about 2.5 mg / kg, about 0.15 to about 2 mg / kg, about 0.15 to about 1.5 mg / kg, about 0.15 to about 1 mg / kg, about 0.15 to about 0.5 mg / kg, about 0.2 to about 2.5 mg / kg, about 0.2 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.2 to about 1 mg / kg, about 0.2 to about 0.5 mg / kg, about 0.25 to about 2.5 mg / kg, about 0.25 to about 2 mg / kg, about 0.25 to about 1.5 mg / kg, about 0 .25 to about 1 mg / kg, about 0.25 to about 0.5 mg / kg, about 0.3 to about 2.5 mg / kg, about 0.3 to about 2 mg / kg, about 0.3 to about 1.5 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.5 mg / kg, about 0.301 to 2.001 mg / kg, about 0.35 to about 2.5 mg / kg, about 0.35 to about 2 mg / kg, about 0.35 to about 1.5 mg / kg, about 0.35 to about 1 mg / kg, about 0.35 to about 0.5 mg / kg, about 0.4 to about 2.5 mg / kg, about 0.4 to about 2 mg / kg, about 0.4 to about 1.5 mg / kg, about 0.4 to about 1 mg / kg, about 0.4 to about 0.5 mg / kg, about 0.5 to about 2.5 mg / kg, about 0.5 to about 2 mg / kg, about 0.5 to about 1.5 mg / kg, about 0.5 to about 1 mg / kg, about 2.5 mg / kg, about 2.0 mg / kg, about 1.95 mg / kg, about 1.9 mg / kg, about 1.85 mg / kg, about 1.8 mg / kg, about 1.75 mg / kg, about 1.7 mg / kg, about 1.65 mg / kg, about 1.6 mg / kg, about 1.55 mg / kg, about 1.5 mg / kg, about 1.45 mg / kg, about 1.4 mg / kg, about 1.35 mg / kg, about 1.3 mg / kg, about 1.25 mg / kg, about 1.2 mg / kg, about 1.15 mg / kg, about 1.1 mg / kg, about 1.05 mg / kg, about 1.0 mg / kg, about 0.95 mg / kg, about 0.9 mg / kg, about 0.85 mg / kg, about 0.8 mg / kg, about 0.75 mg / kg, about 0.7 mg / kg, about 0.65 mg / kg, about 0.6 mg / kg, about 0.55 mg / kg, about 0.5 mg / kg, about 0.45 mg / kg, about 0.4 mg / kg, about 0.35 mg / kg, about 0.3 mg / kg, about 0.25 mg / kg, about 0.2 mg / kg, about 0.15 mg / kg, or about 0.1 mg / kg. . .

[0446] 68. The compound or pharmaceutically acceptable salt thereof according to any one of embodiments 42-66, wherein the compound or pharmaceutically acceptable salt thereof is administered in cats or dogs at a dosage of about 0.003 to about 2.5 mg / kg QW, preferably about 0.01 to about 2 mg / kg QW, more preferably about 0.25 to about 2.0 mg / kg QW, and / or about 0.1 to about 2.0 mg / kg QW, further preferably about 0.5 to about 2.0 mg / kg QW, for example, about 0.01 to about 2 mg / kg QW, about 0.01 to about 1.5 mg / kg QW, about 0.01 to about 1 mg / kg QW, about 0.01 to about 0.5 mg / kg QW, about 0.02 to about 2.5 mg / kg QW, about 0.02 to about 2 mg / kg QW, about 0.02 to about 1.5 mg / kg QW, about 0.02 to about 1 mg / kg QW, about 0.02 to about 0.5 mg / kg QW, about 0.021 to about 0.499 mg / kg QW, about 0.03 to about 2.5 mg / kg QW, about 0.03 to about 2 mg / kg QW, about 0.03 to about 1.5 mg / kg QW, about 0.03 to about 1 mg / kg QW, about 0.03 to about 0.5 mg / kg QW, about 0.04 to about 2.5 mg / kg QW, about 0.04 to about 2 mg / kg QW, about 0.04 to about 1.5 mg / kg QW, about 0.04 to about 1 mg / kg QW, about 0.04 to about 0.5 mg / kg QW, about 0.05 to about 2.5 mg / kg QW, about 0.05 to about 2 mg / kg QW, about 0.05 to about 1.5 mg / kg QW, about 0.05 to about 1 mg / kg QW, about 0.05 to about 0.5 mg / kg QW, about 0.06 to about 2.5 mg / kg QW, about 0.06 to about 2 mg / kg QW, about 0.06 to about 1.5 mg / kg QW, about 0.06 to about 1 mg / kg QW, about 0.06 to about 0.5 mg / kg QW, about 0.062 to 2.001 mg / kg QW, about 0.07 to about 2.5 mg / kg QW, about 0.07 to about 2 mg / kg QW, about 0.07 to about 1.5 mg / kg QW, about 0.07 to about 1 mg / kg QW, about 0.07 to about 0.5 mg / kg QW, about 0.073 to 0.998 mg / kg QW, about 0.08 to about 2.5 mg / kg QW, about 0.08 to about 2 mg / kg QW, about 0.08 to about 1.5 mg / kg QW, about 0.08 to about 1 mg / kg QW, about 0.08 to about 0.5 mg / kg QW, about 0.09 to about 2.5 mg / kg QW, about 0.09 to about 2 mg / kg QW, about 0.09 to about 1.5mg / kg QW, about 0.09 to about 1mg / kg QW, about 0.09 to about 0.5mg / kg QW, about 0.1 to about 2.5mg / kg QW, about 0.1 to about 2mg / kg QW, about 0.1 to about 1.5mg / kg QW, about 0.1 to about 1mg / kg QW, about 0.1 to about 0.5mg / kg QW, about 0.15 to about 2.5mg / kg QW, about 0.15 to about 2mg / kg QW, about 0.15 to about 1.5mg / kg QW, about 0.15 to about 1mg / kg QW, about 0.15 to about 0.5mg / kg QW, about 0.2 to about 2.5mg / kg QW, about 0.2 to about 2mg / kg QW, about 0.2 to about 1.5mg / kg QW, about 0.2 to about 1mg / kg QW, about 0.2 to about 0.5 mg / kg QW, about 0.25 to about 2.5 mg / kg QW, about 0.25 to about 2 mg / kg QW, about 0.25 to about 1.5 mg / kg QW, about 0.25 to about 1 mg / kg QW, about 0.25 to about 0.5 mg / kg QW, about 0.3 to about 2.5 mg / kg QW, about 0.3 to about 2 mg / kg QW, about 0.3 to about 1.5 mg / kg QW, about 0.3 to about 1 mg / kg QW, about 0.3 to about 0.5 mg / kg QW, about 0.301 to 2.001 mg / kg QW, about 0.35 to about 2.5 mg / kg QW, about 0.35 to about 2 mg / kg QW, about 0.35 to about 1.5 mg / kg QW, about 0.35 to about 1 mg / kg QW, about 0.35 to about 0.5 mg / kg QW, about 0.4 to about 2.5 mg / kg QW, about 0.4 to about 2 mg / kg QW, about 0.4 to about 1.5 mg / kg QW, about 0.4 to about 1 mg / kg QW, about 0.4 to about 0.5 mg / kg QW, about 0.5 to about 2 mg / kg QW, about 0.5 to about 1.5 mg / kg QW, about 0.5 to about 1 mg / kg QW, about 2.5 mg / kg QW, about 2.0 mg / kg QW, about 1.95 mg / kg QW, about 1.9 mg / kg QW, about 1.85 mg / kg QW, about 1.8 mg / kg QW, about 1.75 mg / kg QW, about 1.7 mg / kg QW, about 1.65 mg / kg QW, about 1.6 mg / kg QW, about 1.55 mg / kg QW, about 1.5 mg / kg QW, about 1.45 mg / kg QW, about 1.4 mg / kg QW, about 1.35 mg / kg QW, about 1.3 mg / kg QW, about 1.25 mg / kg QW, about 1.2 mg / kg QW, about 1.15 mg / kg QW, about 1.1 mg / kg QW, about 1.05 mg / kg QW, about 1.0 mg / kg QW, about 0.95 mg / kg QW, about 0.9 mg / kg QW, about 0.85 mg / kg QW, about 0.8 mg / kg QW, about 0.75 mg / kg QW, about 0.7 mg / kg QW, about 0.65 mg / kg QW, about 0.6 mg / kg QW, about 0.55 mg / kg QW, about 0.5 mg / kg QW, about 0.45 mg / kg QW, about 0.4 mg / kg QW, about 0.35 mg / kg QW, about 0.3 mg / kg QW, about 0.25 mg / kg QW, or about 0.2 mg / kg QW.

[0447] 69. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 42-68, wherein the compound or a pharmaceutically acceptable salt thereof is continuously administered to cats or dogs at a frequency of once a week, and the dosing cycle is determined according to the needs of the subject, and the dosing cycle can be 48 weeks, or 8-20 weeks, for example 4, 5, 6, 7 or 8 weeks.

[0448] 70. The compound according to any one of embodiments 42-68 or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is administered to dogs once a week for 6 weeks, with each administration being the same or different.

[0449] 71. The compound or pharmaceutically acceptable salt thereof according to embodiments 42-68, wherein the compound or pharmaceutically acceptable salt thereof is administered to cats once a week for 5 weeks, with each administration being the same or different.

[0450] 72. The compound or pharmaceutically acceptable salt thereof according to embodiment 68 or 69, wherein the compound or pharmaceutically acceptable salt thereof is administered to a cat or dog in increasing doses.

[0451] 73. The compound or pharmaceutically acceptable salt thereof according to any one of embodiments 68-72, administered to a cat at the following dose:

[0452] The doses of the first and second administrations are the same, both being a first dose of about 0.02 to about 0.35 mg / kg QW.

[0453] The third dose is a second dose of about 0.49 to about 1 mg / kg QW, and the second dose is about 1.2 to 50 times the first dose, preferably about 10 to about 15 times, for example about 12 times,

[0454] The fourth and fifth administrations have the same dose, which is the third dose of about 0.49 to about 2.5 mg / kg QW. The third dose is about 1.75 to about 3.5 times the second dose, preferably about 1.95 to 2.05 times, more preferably about 2 times.

[0455] 74. The compound or pharmaceutically acceptable salt thereof according to any one of embodiments 68-73, administered to a cat at the following dose:

[0456] The first dose is about 0.019 mg / kg QW,

[0457] The second dose is about 0.25 mg / kg QW,

[0458] The third dose is about 0.50 mg / kg QW.

[0459] 75. The compound or pharmaceutically acceptable salt thereof according to any one of embodiments 68-73, administered to a cat at the following dose:

[0460] The first dose is about 0.075 mg / kg QW,

[0461] The second dose is about 0.50 mg / kg QW,

[0462] The third dose is about 1.00 mg / kg QW.

[0463] 76. The compound or pharmaceutically acceptable salt thereof according to any one of embodiments 68-73, administered to a cat at the following dose:

[0464] The first dose is about 0.30 mg / kg QW,

[0465] The second dose is about 1.0 mg / kg QW,

[0466] The third dose is about 2.0 mg / kg QW.

[0467] 77. The compound or pharmaceutically acceptable salt thereof according to any one of embodiments 65-70, administered to a cat at the following dose:

[0468] The dosage is about 0.25-2.5 mg / kg; alternatively, the dosage is about 0.25-2.5 mg per injection;

[0469] Dosing frequency is QW;

[0470] The dosing cycle is 5 weeks.

[0471] 78. The compound or pharmaceutically acceptable salt thereof according to any one of embodiments 68-72, administered to a dog at the following dose:

[0472] The doses of the first and second administrations are the same, both being a first dose of about 0.015 to about 0.07 mg / kg QW.

[0473] The third dose is a second dose of about 0.02 to about 0.14 mg / kg QW, preferably about 0.03 to about 0.1 mg / kg QW, and the second dose is about 1.4 to 2 times the first dose, preferably about 1.45 to about 1.6 times, more preferably about 1.5 times,

[0474] The doses for the fourth to sixth administrations are the same, which are all the third dose of about 0.49 to about 2.5 mg / kg QW, preferably about 0.495 to about 2.1 mg / kg QW, and the third dose is about 13 to about 25 times the second dose, more preferably about 16 to about 21 times.

[0475] 79. The compound according to embodiment 78, or a pharmaceutically acceptable salt thereof, administered to a dog at the following dose:

[0476] The first dose is about 0.02 mg / kg QW,

[0477] The second dose is about 0.03 mg / kg QW,

[0478] The third dose is about 0.5 mg / kg QW.

[0479] 80. The compound according to embodiment 78, or a pharmaceutically acceptable salt thereof, administered to a dog at the following dose:

[0480] The first dose is about 0.06 mg / kg QW,

[0481] The second dose is about 0.10 mg / kg QW,

[0482] The third dose is about 2.00 mg / kg QW.

[0483] 81. The compound according to embodiment 78, or a pharmaceutically acceptable salt thereof, administered to a dog at the following dose:

[0484] The dosage is about 0.1-2.5 mg / kg; alternatively, the dosage is about 0.1-2.5 mg per injection;

[0485] The dosing cycle is QW;

[0486] Dosing frequency is 6 weeks.

[0487] 82. The compound according to any one of embodiments 42-81, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from SEQ ID NO: 14, SEQ ID NO: 16 and SEQ ID NO: 20, preferably SEQ ID NO: 16.

[0488] 83. A method for preventing or treating a disease in a non-primate or non-rodent animal, comprising administering to an animal in need thereof an effective amount of a compound of the following formula (AI), or a pharmaceutically acceptable salt thereof:

[0489] Y-X1-EGT-X2-TSDY-A11-A12-A13-LDK-A17-AQ-A20-EFVKWLLK-A29-GPSSGAPPPSK Formula (AI);

[0490] wherein X1 is Aib; X2 is αMePhe;

[0491] A11 is Aib or Ala;

[0492] A12 is Ala, Ile, Lys, Phe, or Pya (4);

[0493] A13 is Aib, Cha, Leu, αMePhe, or αMeTyr;

[0494] A17 is Gln or Ile;

[0495] A20 is Ala or Ser;

[0496] A29 is Gln or Gly,

[0497] 1 K, 2 K, 3 K or 4 K positions are selected from the 16th, 24th, 28th and 40th positions by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -Z is chemically modified by being conjugated to the ε-amino group of the K side chain, wherein each a is independently an integer from 0 to 5, each b is independently an integer from 0 to 5, and each c is independently an integer from 10 to 24, wherein Z is independently selected from -CH3, carboxylic acid or carboxylic acid bioisostere, phosphonate / ester or sulfonate / ester.

[0498] 84. The method according to embodiment 83, wherein

[0499] A11 is Aib; or / and

[0500] A12 is Ile; or / and

[0501] A13 is Aib; or / and

[0502] A17 is Gln; or / and

[0503] A20 is Ala; or / and

[0504] A29 is Gly; or / and

[0505] a is independently selected from an integer of 1, 2, 3, 4 or 5, b is independently selected from an integer of 1, 2, 3, 4 or 5, c is independently selected from an integer of 12 to 22; further, c is independently selected from 14, 16, 18 or 20.

[0506] 85. A method for preventing or treating a disease in a non-primate or non-rodent animal, comprising administering to an animal in need thereof an effective amount of a compound of the following formula (I), or a pharmaceutically acceptable salt thereof:

[0507] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK Formula (I);

[0508] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; 1, 2, 3 or 4 K positions are selected from positions 16, 24, 28 and 40, by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -Z is chemically modified by conjugation to the ε-amino group of the K side chain, wherein each a is independently an integer from 0 to 5, each b is independently an integer from 0 to 5, and each c is independently an integer from 10 to 24, wherein Z is independently selected from -CH3, carboxylic acid or carboxylic acid bioisostere, phosphonate / ester or sulfonate / ester; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0509] 86. The method of embodiment 83, wherein the compound is:

[0510] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK Formula (I), or a pharmaceutically acceptable salt thereof,

[0511] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; one or two K positions are selected from positions 16, 24, 28, and 40, by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -Z is chemically modified by conjugation to the ε-amino group of the K side chain, wherein Z is independently selected from -CH3, carboxylic acid or carboxylic acid bioisostere, phosphonate / ester or sulfonate / ester, preferably -CO2H, each a is independently an integer from 0 to 5, each b is independently an integer from 0 to 5, and each c is independently an integer from 10 to 22; and the C-terminal amino acid is amidated to a C-terminal primary amide.

[0512] 87. The method of embodiment 84, wherein

[0513] At position 16, K is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain for chemical modification; or

[0514] At position 24, K is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain for chemical modification; or

[0515] At position 28, K is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain for chemical modification; or

[0516] At position 40, K is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H was conjugated to the ε-amino group of the K side chain for chemical modification.

[0517] 88. The method of embodiment 84, wherein

[0518] K at positions 24 and 28 is synthesized by replacing the 2-(2-amino-ethoxy)-ethoxy]-acetyl group witha -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain to perform chemical modification of the two modified chains; or

[0519] K at positions 16 and 24 is synthesized by replacing the acetyl group with ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain to perform chemical modification of the two modified chains; or

[0520] K at positions 16 and 28 was synthesized by replacing ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain to perform chemical modification of the two modified chains; or

[0521] K at positions 16 and 40 is synthesized by replacing the acetyl group with ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain to perform chemical modification of the two modified chains; or

[0522] K at positions 24 and 40 is synthesized by replacing the 2-(2-amino-ethoxy)-ethoxy]-acetyl group with a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain to perform chemical modification of the two modified chains; or

[0523] K at positions 28 and 40 is synthesized by replacing the 2-(2-amino-ethoxy)-ethoxy]-acetyl group with a -(γ-Glu) b -CO-(CH2) c -CO2H was conjugated to the ε-amino group of the K side chain to perform chemical modification of the two modified chains.

[0524] 89. The method of any one of embodiments 83-86, wherein

[0525] a is independently selected from an integer of 1, 2, 3, 4 or 5, b is independently selected from an integer of 1, 2, 3, 4 or 5, c is independently selected from an integer of 12 to 22; further, c is independently selected from 14, 16, 18 or 20; and / or

[0526] Z is -CO2H.

[0527] 90. The method according to embodiment 84, wherein the compound is

[0528] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK Formula (I);

[0529] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 24 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is chemically modified by conjugation to the ε-amino group of the K side chain, wherein a is independently selected from an integer from 0 to 5, b is independently selected from an integer from 0 to 5, and c is independently selected from an integer from 10 to 24; and the C-terminal amino acid is amidated to a C-terminal primary amide;

[0530] Preferably, wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; at position 24, K is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is chemically modified by conjugating to the ε-amino group of the K side chain, wherein each a is independently selected from an integer of 2 or 3, each b is independently 1, and each c is independently selected from an integer of 16, 18, or 20, and wherein Z is independently selected from a carboxylic acid.

[0531] 91. The method according to embodiment 84, wherein the compound is

[0532] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK Formula (I);

[0533] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c-CO2H is chemically modified by conjugation to the ε-amino group of the K side chain, wherein a is independently selected from an integer from 0 to 5, b is independently selected from an integer from 0 to 5, and c is independently selected from an integer from 10 to 24; and the C-terminal amino acid is amidated to a C-terminal primary amide;

[0534] Preferably, wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; at position 28, K is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is chemically modified by conjugating to the ε-amino group of the K side chain, wherein each a is independently selected from an integer of 2 or 3, each b is independently selected from an integer of 1 or 3, each c is independently selected from an integer of 16 or 20, and Z is independently selected from a carboxylic acid.

[0535] 92. The method of any one of embodiments 88-89, wherein

[0536] a is independently selected from an integer of 1, 2, 3, 4 or 5, b is independently selected from an integer of 1, 2, 3, 4 or 5, c is independently selected from an integer of 12 to 22; further, c is independently selected from 14, 16, 18 or 20.

[0537] 93. The method according to embodiment 84, wherein the compound is

[0538] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0539] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 24 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)1-CO-(CH2) 16 -CO2H is chemically modified by conjugation to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide (SEQ ID NO: 7); or

[0540] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0541] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 24 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)1-CO-(CH2) 18 -CO2H is chemically modified by conjugation to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide (SEQ ID NO: 13); or

[0542] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0543] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 24 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)1-CO-(CH2) 20 -CO2H is chemically modified by conjugation to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide (SEQ ID NO: 14); or

[0544] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0545] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 24 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)3-CO-(CH2) 16 -CO2H is chemically modified by conjugation to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide (SEQ ID NO: 15); or

[0546] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0547] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 24 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)3-(γ-Glu)1-CO-(CH2) 20-CO2H is chemically modified by conjugation to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide (SEQ ID NO: 16); or

[0548] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0549] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)1-CO-(CH2) 16 -CO2H is chemically modified by conjugation to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide (SEQ ID NO: 8); or

[0550] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0551] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)1-CO-(CH2) 20 -CO2H is chemically modified by conjugation to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide (SEQ ID NO: 17); or

[0552] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0553] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)3-CO-(CH2) 16 -CO2H is chemically modified by conjugation to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide (SEQ ID NO: 18); or

[0554] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0555] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)3-(γ-Glu)1-CO-(CH2) 16 -CO2H is chemically modified by conjugation to the ε-amino group of the K side chain; and the C-terminal amino acid is amidated to a C-terminal primary amide (SEQ ID NO: 19); or

[0556] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0557] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)3-(γ-Glu)1-CO-(CH2) 20 The K side chain was chemically modified by conjugating -CO2H to the ε-amino group; and the C-terminal amino acid was amidated to a C-terminal primary amide (SEQ ID NO: 20).

[0558] 94. The method according to embodiment 84, wherein the compound is

[0559] or a pharmaceutically acceptable salt thereof.

[0560] 95. A method according to any one of embodiments 83-94, wherein the disease includes animal hyperglycemia, impaired glucose tolerance, diabetes (including type I diabetes, type II diabetes), obesity, hypertension, dyslipidemia, cognitive impairment, atherosclerosis, myocardial infarction, coronary heart disease and other cardiovascular diseases, stroke, inflammatory bowel syndrome, dyspepsia and gastric ulcer.

[0561] 96. The method of any one of embodiments 83-94, wherein the drug is a drug for preventing, delaying or treating type 2 diabetes.

[0562] 97. A method according to any one of embodiments 83-94, wherein the compound or a pharmaceutically acceptable salt thereof is used as a drug to reduce animal food intake, reduce β-cell apoptosis, increase β-cell function and β-cell mass and / or restore glucose sensitivity of β-cells.

[0563] 98. A method according to any one of embodiments 83-94, wherein the disease comprises an animal metabolic disorder including dyslipidemia, obesity and / or hepatic steatosis associated with insulin resistance and diabetes.

[0564] 99. The method according to any one of embodiments 83-94, wherein the disease comprises osteopenia, bone / joint disease, such as knee osteoarthritis, hip osteoarthritis and / or deforming spondylitis.

[0565] 100. The method of any one of embodiments 83-94, wherein the compound or a pharmaceutically acceptable salt thereof is used in an overweight or obese animal as an adjunct to a reduced calorie diet and increased physical activity for long-term weight management.

[0566] 101. The method according to any one of embodiments 83-94, wherein the disease comprises: symptomatic obesity, obesity based on simple obesity, disease states or diseases related to obesity, eating disorders, diabetes (e.g., type I diabetes, type II diabetes, gestational diabetes, obesity-related diabetes), hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, high LDL-cholesterolemia, low HDL-cholesterolemia, postprandial hyperlipidemia), hypertension, heart failure, complications of diabetes (e.g., For example, neuropathy, nephropathy, retinopathy, diabetic cardiomyopathy, cataracts, macroangiopathy, osteopenia, hyperosmolar diabetic coma), infectious diseases (e.g., respiratory tract infection, urinary tract infection, gastrointestinal infection, superficial soft tissue infection, lower limb infection), diabetic gangrene, xerostomia, hearing loss, cerebrovascular disorders, peripheral blood circulation disorders, metabolic syndrome (a disease state having three or more selected from hypertriglyceridemia, low HDL cholesterolemia, hypertension, abdominal obesity and impaired glucose tolerance), and / or sarcopenia.

[0567] 102. The method of any one of embodiments 83-101, wherein the animal is a pet or companion animal.

[0568] 103. The method of embodiment 102, wherein the pet is selected from the group consisting of dogs, cats, rabbits, pigs, alpacas, horses, sheep, and cattle.

[0569] 104. The method of any one of embodiments 83-101, wherein the animal is a dog or a cat.

[0570] 105. The method of any one of embodiments 83-104, wherein the compound or a pharmaceutically acceptable salt thereof is used to treat type 2 diabetes, overweight, or obesity in a cat or dog.

[0571] 106. The method of any one of embodiments 83-105, wherein the compound or a pharmaceutically acceptable salt thereof is administered in the form of a solution or a suspension.

[0572] 107. The method of any one of embodiments 83-106, wherein the compound or a pharmaceutically acceptable salt thereof is administered by subcutaneous injection.

[0573] 108. The method of any one of embodiments 82-106, wherein the compound or a pharmaceutically acceptable salt thereof is administered in an amount of about 0.003 to about 2.5 mg / kg, or about 0.003 to about 0.6 mg / kg, such as about 0.005 to about 0.1 mg / kg, about 0.1 to about 0.125 mg / kg, about 0.1 to about 0.15 mg / kg, about 0.15 to about 0.25 mg / kg, about 0.125 to about 0.25 mg / kg, about 0.005 to about 2 mg / kg, about 0.005 to about 1.5 mg / kg, about 0.005 to about 1 mg / kg, about 0.005 to about 0.5 mg / kg, about 0.1 to about 2 mg / kg g / kg, about 0.1 to about 1.5 mg / kg, about 0.1 to about 1 mg / kg, about 0.1 to about 0.5 mg / kg, about 0.15 to about 2.5 mg / kg, about 0.15 to about 2 mg / kg, about 0.15 to about 1.5 mg / kg, about 0.15 to about 1 mg / kg, about 0.15 to about 0.5 mg / kg, about 0.2 to about 2.5 mg / kg, about 0.2 to about 2 mg / kg, about 0.2 to about 1.5 mg / kg, about 0.2 to about 1 mg / kg, about 0.2 to about 0.5 mg / kg, about 0.25 to about 2.5 mg / kg, about 0.25 to about 2 mg / kg, about 0.25 to about 1.5 mg / kg, about 0.25 to about 1 mg / kg, about 0.25 to about 0.5 mg / kg, about 0.3 to about 2.5 mg / kg, about 0.3 to about 2 mg / kg, about 0.3 to about 1.5 mg / kg, about 0.3 to about 1 mg / kg, about 0.3 to about 0.5 mg / kg, about 0.301 to 2.001 mg / kg, about 0.35 to about 2.5 mg / kg, about 0.35 to about 2 mg / kg, about 0.35 to about 1.5 mg / kg, about 0.35 to about 1 mg / kg, about 0.35 to about 0.5 mg / kg, about 0.4 to about 2.5 mg / kg, about 0.4 to about 2 mg / kg, about 0.4 to about 1.5 mg / kg, about 0.4 to about 1 mg / kg, about 0.4 to about 0.5 mg / kg, about 0.5 to about 2.5 mg / kg, about 0.5 to about 2 mg / kg, about 0.5 to about 1.5 mg / kg, about 0.5 to about 1 mg / kg, about 2.5 mg / kg, about 2.0 mg / kg, about 1.95 mg / kg, about 1.9 mg / kg, about 1.85 mg / kg, about 1.8 mg / kg, about 1.75 mg / kg, about 1.7 mg / kg, about 1.65 mg / kg, about 1.6 mg / kg, about 1.55 mg / kg, about 1.5 mg / kg, about 1.45 mg / kg, about 1.4 mg / kg, about 1.35 mg / kg, about 1.3 mg / kg, about 1.25 mg / kg, about 1.2 mg / kg, about 1.15 mg / kg, about 1.1 mg / kg, about 1.05 mg / kg, about 1.0 mg / kg, about 0.95 mg / kg, about 0.9 mg / kg, about 0.85 mg / kg, about 0.8 mg / kg, about 0.75 mg / kg, about 0.7 mg / kg, about 0.65 mg / kg, about 0.6 mg / kg, about 0.55 mg / kg, about 0.5 mg / kg, about 0.45 mg / kg, about 0.4 mg / kg, about 0.35 mg / kg, about 0.3 mg / kg, about 0.25 mg / kg, about 0.2 mg / kg, about 0.15 mg / kg, or about 0.1 mg / kg. . .

[0574] 109. The method of any one of embodiments 82-106, wherein the compound or a pharmaceutically acceptable salt thereof is administered once a week in cats and dogs.

[0575] 110. The method according to any one of embodiments 82-106, wherein the compound or a pharmaceutically acceptable salt thereof is administered in cats or dogs at a dosage of about 0.003 to about 2.5 mg / kg QW, preferably about 0.01 to about 2 mg / kg QW, more preferably about 0.25 to about 2.0 mg / kg QW, and / or about 0.1 to about 2.0 mg / kg QW, further preferably about 0.5 to about 2.0 mg / kg QW, for example, about 0.01 to about 2 mg / kg QW, about 0.01 to about 1.5 mg / kg QW, about 0.01 to about 1 mg / kg QW, about 0.01 to about 0.5 mg / kg QW, about 0.02 to about 2.5 mg / kg QW, about 0.02 to about 2 mg / kg QW, about 0.02 to about 1.5 mg / kg QW, about 0.02 to about 1 mg / kg QW QW, about 0.02 to about 0.5 mg / kg QW, about 0.021 to about 0.499 mg / kg QW, about 0.03 to about 2.5 mg / kg QW, about 0.03 to about 2 mg / kg QW, about 0.03 to about 1.5 mg / kg QW, about 0.03 to about 1 mg / kg QW, about 0.03 to about 0.5 mg / kg QW, about 0.04 to about 2.5 mg / kg QW, about 0.04 to about 2 mg / kg QW, about 0.04 to about 1.5 mg / kg QW, about 0.04 to about 1 mg / kg QW, about 0.04 to about 0.5 mg / kg QW, about 0.05 to about 2.5 mg / kg QW, about 0.05 to about 2 mg / kg QW, about 0.05 to about 1.5 mg / kg QW, about 0.05 to about 1 mg / kg QW, about 0.05 to about 0.5 mg / kg QW, about 0.06 to about 2.5 mg / kg QW, about 0.06 to about 2 mg / kg QW, about 0.06 to about 1.5 mg / kg QW, about 0.06 to about 1 mg / kg QW, about 0.06 to about 0.5 mg / kg QW, about 0.062 to 2.001 mg / kg QW, about 0.07 to about 2.5 mg / kg QW, about 0.07 to about 2 mg / kg QW, about 0.07 to about 1.5 mg / kg QW, about 0.07 to about 1 mg / kg QW, about 0.07 to about 0.5 mg / kg QW, about 0.073 to 0.998 mg / kg QW, about 0.08 to about 2.5 mg / kg QW, about 0.08 to about 2 mg / kg QW, about 0.08 to about 1.5 mg / kg QW, about 0.08 to about 1 mg / kg QW, about 0.08 to about 0.5 mg / kg QW, about 0.09 to about 2.5 mg / kg QW, about 0.09 to about 2 mg / kg QW, about 0.09 to about 1.5 mg / kg QW, about 0.0.9 to about 1 mg / kg QW, about 0.09 to about 0.5 mg / kg QW, about 0.1 to about 2.5 mg / kg QW, about 0.1 to about 2 mg / kg QW, about 0.1 to about 1.5 mg / kg QW, about 0.1 to about 1 mg / kg QW, about 0.1 to about 0.5 mg / kg QW, about 0.15 to about 2.5 mg / kg QW, about 0.15 to about 2 mg / kg QW, about 0.15 to about 1.5 mg / kg QW, about 0.15 to about 1 mg / kg QW, about 0.15 to about 0.5 mg / kg QW, about 0.2 to about 2.5 mg / kg QW, about 0.2 to about 2 mg / kg QW, about 0.2 to about 1.5 mg / kg QW, about 0.2 to about 1 mg / kg QW, about 0.2 to about 0.5 mg / kg QW, about 0.25 to about 2.5 mg / kg QW, about 0.25 to about 2 mg / kg QW, about 0.25 to about 1.5 mg / kg QW, about 0.25 to about 1 mg / kg QW, about 0.25 to about 0.5 mg / kg QW, about 0.3 to about 2.5 mg / kg QW, about 0.3 to about 2 mg / kg QW, about 0.3 to about 1.5 mg / kg QW, about 0.3 to about 1 mg / kg QW, about 0.3 to about 0.5 mg / kg QW, about 0.301 to 2.001 mg / kg QW, about 0.35 to about 2.5 mg / kg QW, about 0.35 to about 2 mg / kg QW, about 0.35 to about 1.5 mg / kg QW, about 0.35 to about 1 mg / kg QW, about 0.35 to about 0.5 mg / kg QW, about 0.4 to about 2.5 mg / kg QW, about 0.4 to about 2 mg / kg QW, about 0.4 to about 1.5 mg / kg QW, about 0.4 to about 1 mg / kg QW, about 0.4 to about 0.5 mg / kg QW, about 0.5 to about 2 mg / kg QW, about 0.5 to about 1.5 mg / kg QW, about 0.5 to about 1 mg / kg QW, about 2.5 mg / kg QW, about 2.0 mg / kg QW, about 1.95 mg / kg QW, about 1.9 mg / kg QW, about 1.85 mg / kg QW, about 1.8 mg / kg QW, about 1.75 mg / kg QW, about 1.7 mg / kg QW, about 1.65 mg / kg QW, about 1.6 mg / kg QW, about 1.55 mg / kg QW, about 1.5 mg / kg QW, about 1.45 mg / kg QW, about 1.4 mg / kg QW, about 1.35 mg / kg QW, about 1.3 mg / kg QW, about 1.25 mg / kg QW, about 1.2 mg / kg QW, about 1.15 mg / kg QW, about 1.1 mg / kg QW, about 1.0.5 mg / kg QW, about 1.0 mg / kg QW, about 0.95 mg / kg QW, about 0.9 mg / kg QW, about 0.85 mg / kg QW, about 0.8 mg / kg QW, about 0.75 mg / kg QW, about 0.7 mg / kg QW, about 0.65 mg / kg QW, about 0.6 mg / kg QW, about 0.55 mg / kg QW, about 0.5 mg / kg QW, about 0.45 mg / kg QW, about 0.4 mg / kg QW, about 0.35 mg / kg QW, about 0.3 mg / kg QW, about 0.25 mg / kg QW, or about 0.2 mg / kg QW.

[0576] 111. A method according to any one of embodiments 82-106, wherein the compound or a pharmaceutically acceptable salt thereof is continuously administered to cats or dogs at a frequency of once a week, and the dosing cycle is determined according to the needs of the subject, and the dosing cycle can be 4-8 weeks, or 8-20 weeks, for example 4, 5, 6, 7 or 8 weeks.

[0577] 112. The method according to any one of embodiments 82-106, wherein the compound of the present invention or a pharmaceutically acceptable salt thereof is administered to dogs once a week for 6 weeks, with each administration being the same or different doses.

[0578] 113. The method of any one of embodiments 82-106, wherein the compound of the present invention or a pharmaceutically acceptable salt thereof is administered to the cat once a week for 5 weeks, with each administration being the same or different.

[0579] 114. The method of embodiment 112 or 113, wherein the compound or a pharmaceutically acceptable salt thereof is administered to the cat or dog in increasing doses.

[0580] 115. The method of any one of embodiments 82-106, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a cat at the following dosage:

[0581] The doses of the first and second administrations are the same, both being a first dose of about 0.02 to about 0.35 mg / kg QW.

[0582] The third dose is a second dose of about 0.49 to about 1 mg / kg QW, and the second dose is about 1.2 to 50 times the first dose, preferably about 10 to about 15 times, for example about 12 times,

[0583] The fourth and fifth administrations have the same dose, which is the third dose of about 0.49 to about 2.5 mg / kg QW. The third dose is about 1.75 to about 3.5 times the second dose, preferably about 1.95 to 2.05 times, more preferably about 2 times.

[0584] 116. The method of any one of embodiments 82-106, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a cat at a dose of:

[0585] The first dose is about 0.019 mg / kg QW,

[0586] The second dose is about 0.25 mg / kg QW,

[0587] The third dose is about 0.50 mg / kg QW.

[0588] 117. The method of any one of embodiments 82-106, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a cat at a dose of:

[0589] The first dose is about 0.075 mg / kg QW,

[0590] The second dose is about 0.50 mg / kg QW,

[0591] The third dose is about 1.00 mg / kg QW.

[0592] 118. The method of any one of embodiments 82-106, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a cat at a dose of:

[0593] The first dose is about 0.30 mg / kg QW,

[0594] The second dose is about 1.00 mg / kg QW,

[0595] The third dose is about 2.00 mg / kg QW.

[0596] 119. The method of any one of embodiments 82-106, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a cat at a dose of:

[0597] The dosage is about 0.25-2.5 mg / kg; alternatively, the dosage is about 0.25-2.5 mg per injection;

[0598] Dosing frequency is QW;

[0599] The dosing cycle is 5 weeks.

[0600] 120. The method of any one of embodiments 82-106, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a dog at the following dosage:

[0601] The doses of the first and second administrations are the same, both being a first dose of about 0.015 to about 0.07 mg / kg QW.

[0602] The third dose is a second dose of about 0.02 to about 0.14 mg / kg QW, preferably about 0.03 to about 0.1 mg / kg QW, and the second dose is about 1.4 to 2 times the first dose, preferably about 1.45 to about 1.6 times, more preferably about 1.5 times,

[0603] The doses for the fourth to sixth administrations are the same, which are all the third dose of about 0.49 to about 2.5 mg / kg QW, preferably about 0.495 to about 2.1 mg / kg QW, and the third dose is about 13 to about 25 times the second dose, more preferably about 16 to about 21 times.

[0604] 121. The method of embodiment 120, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a dog at the following dosage:

[0605] The first dose is about 0.02 mg / kg QW,

[0606] The second dose is about 0.03 mg / kg QW,

[0607] The third dose is about 0.50 mg / kg QW.

[0608] 122. The method of embodiment 120, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a dog at the following dosage:

[0609] The first dose is about 0.06 mg / kg QW,

[0610] The second dose is about 0.10 mg / kg QW,

[0611] The third dose is about 2.00 mg / kg QW.

[0612] 123. The method of embodiment 120, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a dog according to the following dosing regimen:

[0613] The dosage is about 0.1-2.5 mg / kg; or, the dosage is about 0.1-2.5 mg / injection per injection;

[0614] The dosing cycle is QW;

[0615] Dosing frequency is 6 weeks.

[0616] 124. The method according to any one of embodiments 82-123, wherein the compound is selected from SEQ ID NO: 14, SEQ ID NO: 16 and SEQ ID NO: 20, preferably SEQ ID NO: 16. Description of the drawings:

[0617] Figures 1A-1B show blood glucose changes in db / db mice after drug administration. Figure 1A shows blood glucose changes in db / db mice after a single subcutaneous administration of 10 nmol / kg to P007, P008, P014, P019, Tirzepatide, and P001; Figure 1B shows blood glucose changes in db / db mice after a single subcutaneous administration of 10 nmol / kg to P013, P015, P016, P017, P018, P020, and Tirzepatide.

[0618] Figures 2A-2C show the blood glucose AUC after dosing in db / db mice. Figure 2A shows the AUC of P007, P008, P014, P019, Tirzepatide, and P001 after a single 10 nmol / kg subcutaneous dose over the 0-48 hour period; Figure 2B shows the AUC of P007, P008, P014, P019, and Tirzepatide after a single 10 nmol / kg subcutaneous dose over the 0-72 hour period; and Figure 2C shows the AUC of P013, P015, P016, P017, P018, P020, and Tirzepatide after a single 10 nmol / kg subcutaneous dose over the 0-56 hour period. In Figure 2A, T-test, *p<0.05, **p<0.01, ***p<0.001 compared with Vehicle; §p<0.05, §§p<0.01, §§§p<0.001 compared with P001. In Figure 2B, T-test, *p<0.05, **p<0.01, ***p<0.001 compared with Vehicle; #p<0.05, ##p<0.01 compared with Tirzepatide. In Figure 2C, T-test, *p<0.05, **p<0.01, ***p<0.001 compared with Vehicle; #p<0.05 compared with Tirzepatide.

[0619] Figures 3A-3D show changes in blood glucose levels in db / db mice after multiple dosing. Figure 3A compares blood glucose levels in db / db mice after multiple subcutaneous administration of P014 and Tirzepatide; Figure 3B compares blood glucose levels in db / db mice after multiple subcutaneous administration of P016 and Tirzepatide; Figure 3C compares blood glucose levels in db / db mice after multiple subcutaneous administration of P017 and Tirzepatide; and Figure 3D compares blood glucose levels in db / db mice after multiple subcutaneous administration of P020 and Tirzepatide.

[0620] FIG4 shows the body weight change trend of DIO mice after multiple subcutaneous administration of P016 (0.3, 1, 3, 30 nmol / kg) and Tirzepatide (1, 30 nmol / kg) at a frequency of once every 3 days.

[0621] Figure 5 shows the percentage change in body weight on day 28 (D28) of DIO mice after multiple subcutaneous administration of P016 (0.3, 1, 3, 30 nmol / kg) and Tirzepatide (1, 30 nmol / kg) at a dosing frequency of once every 3 days. *p≤0.05, ****p≤0.0001 compared with the Vehicle group, ####p≤0.0001 compared with the positive control Tirzepatide group at the same dose.

[0622] Figure 6 shows the weekly body weight change trend of obese dogs after 6 consecutive subcutaneous administrations of P016 at a dosing frequency of once a week (4, 4, 6, 96, 96, 96 nmol / kg; or 12, 12, 19, 385, 385, 385 nmol / kg) and 42 consecutive administrations of the positive control Dirlotapide at a dosing frequency of once a day.

[0623] Figure 7 shows the weekly percentage change in body weight in obese dogs after 6 consecutive subcutaneous administrations of P016 at a dosing frequency of once a week (4, 4, 6, 96, 96, 96 nmol / kg; or 12, 12, 19, 385, 385, 385 nmol / kg) and 42 consecutive administrations of the positive control Dirlotapide at a dosing frequency of once a day, compared with Vehicle, *p<0.05, **p<0.01.

[0624] Figure 8 shows the weekly weight change trend of obese cats after 5 consecutive subcutaneous administration of P016 at a dosing frequency of once a week (4, 4, 48, 96, 96 nmol / kg; or 14, 14, 96, 192, 192 nmol / kg; or 58, 58, 192, 385, 385 nmol / kg).

[0625] Figure 9 shows the weekly percentage change in body weight of obese cats after 5 consecutive subcutaneous administrations of P016 at a dosing frequency of once a week (4, 4, 48, 96, 96 nmol / kg; or 14, 14, 96, 192, 192 nmol / kg; or 58, 58, 192, 385, 385 nmol / kg), compared with Vehicle, *p<0.05, **p<0.01, ****p<0.0001.

[0626] The present invention also includes novel intermediates and methods that can be used to synthesize the compounds of the present invention or their pharmaceutically acceptable salts. The intermediates and compounds of the present invention can be prepared by a variety of methods known in the art. In particular, methods using chemical synthesis are illustrated in the following examples. The specific synthetic steps of each described approach can be combined in different ways to prepare the compounds of the present invention or their salts. Reagents and raw materials are readily available to those of ordinary skill in the art. It should be understood that these examples are not intended to limit the scope of the present invention in any way. Mass spectrometry was performed using an Agilent 1260 / 6110 liquid chromatograph-mass spectrometer with a scan range of 100-1500.

[0627] Example 1:

[0628] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0629] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 24 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)3-CO-(CH2) 16 The K side chain was chemically modified by conjugating -CO2H to the ε-amino group; and the C-terminal amino acid was amidated to a C-terminal primary amide (SEQ ID NO: 15).

[0630] The above structure contains the standard single-letter amino acid code except for residues Aib2, αMePhe6, Aib11, Aib13 and K24, for which the structure has been unfolded.

[0631] The preparation method adopts the Fmoc solid phase peptide synthesis strategy, and the method includes:

[0632] (1) Synthesis of peptide resin intermediate 1

[0633] Take Fmoc-Rink Linker-Nle-MBHA resin (S = 0.49 mmol / g), swell it with an appropriate amount of DCM, and wash it with DCM 2-3 times. Deprotect it with 20% PIP / DMF solution for 30 minutes, filter and wash it to obtain the Fmoc-free NH2-Rink linker-Nle-MBHA resin, and drain the solvent for later use.

[0634] Take 4 equivalents of Fmoc-Lys(Boc)-OH and HOBt respectively, dissolve them in appropriate amount of DMF / DCM; take another 4 equivalents of DIC, dilute it half with DCM, slowly add it to the DMF / DCM solution with stirring, and react with stirring at -5~0℃ for not less than 60 minutes. After activation, set aside.

[0635] Add the activated Fmoc-Lys(Boc)-OH solution to the NH2-Rink linker–Nle-MBHA resin, control the reaction temperature at 10-30°C, and conduct the coupling reaction for 240–480 min. Filter and wash to obtain the Fmoc-Lys(Boc)-Rink linker–Nle-MBHA resin. Deprotect the resin with a 20% PIP / DMF solution for 30 min, filter and wash to obtain the de-Fmoc Lys(Boc)-Rink linker–Nle-MBHA resin.

[0636] Under the same reaction conditions, start from the second amino acid at the C-terminus and couple to the N-terminus one by one. If the coupling is incomplete (color reaction), use HBTU / DIEA for a second condensation to ensure that each amino acid is completely condensed. The coupling sequence is Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc-Ala-OH.H2O, Fmoc-Gly-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Gly- Gly-OH, Fmoc-Lys(Boc)-OH, Fmoc-Leu-OH, Fmoc-Leu-OH, Fmoc-Trp(Boc)-OH, Fmoc-Lys(Mtt)-OH, Fmoc-Val-OH, Fmoc-Phe-OH, Fmoc-Glu(OtBu)-OH.H2O, Fmoc-Ala-OH.H2O , Fmoc-Gln(Trt)-OH, Fmoc-Ala-OH.H2O, Fmoc-Gln(Trt)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Leu-OH, Fmoc-Aib-OH, Fmoc-Ile-OH, Fmoc-Aib-OH, Fmoc-Tyr( tBu)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-α-Me-Phe-OH, Fmoc-Thr(tBu)-OH, Fmoc-Glu(OtBu)-Gly-OH, Fmoc-Aib-OH, Boc-Tyr(tBu)-OH.

[0637] get:

[0638] Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln (Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Mtt)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Rink Linker-Nle-MBHA Resin

[0639] After the above condensation is complete, the Mtt protection is removed with 50% HFIP / DCM solution for 30 minutes, followed by washing and filtration to obtain the peptide resin intermediate 1:

[0640] Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala- Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Rink Linker-Nle-MBHA Resin.

[0641] (2) Modification chain modification step

[0642] Dissolve 4 equivalents of Fmoc-AEEA-OH and HOBt in an appropriate amount of DMF / DCM. Dissolve another 4 equivalents of DIC in DCM by half, then slowly add it to the DMF / DCM solution with stirring. Stir and react at -5 to 0°C for at least 60 minutes. Activate and set aside.

[0643] The activated Fmoc-AEEA-OH solution was added to the previously swollen and washed peptide resin intermediate 1. The reaction temperature was controlled at 10-30°C. The coupling reaction was carried out for 240-480 minutes. The mixture was filtered and washed. The Fmoc protection was removed with a 20% PIP / DMF solution for 30 minutes. The mixture was filtered and washed. According to the above reaction conditions, the activated Fmoc-AEEA-OH, Fmoc-AEEA-OH, Fmoc-Glu(α-OtBu)-OH, Fmoc-Glu(α-OtBu)-OH, Fmoc-Glu(α-OtBu)-OH and octadecanediol mono-tert-butyl ester were coupled on the resin, Fmoc was removed, and the mixture was washed with DCM and dried to obtain P015 peptide resin:

[0644] Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-A ib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(tBuO -Ste-γ-Glu(α-OtBu)-γ-Glu(α-OtBu)-γ-Glu(α-OtBu)-AEEA-AEEA)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gl y-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Rink-Linker-Nle-MBHA Resin.

[0645] Take P015 peptide resin, add 12-15mL / g peptide resin cleavage agent (TFA:EDT:TIS:H2O, volume ratio 94:2:2:2), stir and react at 25±5℃ for 4 hours, filter the reaction mixture using a sand core funnel, collect the filtrate, wash the resin with a small amount of TFA three times, combine the filtrates and concentrate under reduced pressure, add methyl tert-butyl ether (MBTE) to precipitate, and then wash with MBTE 3-4 times. After evaporating MTBE, the crude product is dried under reduced pressure at room temperature to constant weight to obtain crude P015. After subsequent purification and drying, a P015 sample (mass spectrum MS: 5255.2) is obtained.

[0646] Example 2:

[0647] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0648] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)3-(γ-Glu)1-CO-(CH2) 16 The K side chain was chemically modified by conjugating -CO2H to the ε-amino group; and the C-terminal amino acid was amidated to a C-terminal primary amide (SEQ ID NO: 19).

[0649] The above structure contains the standard single-letter amino acid code except for residues Aib2, αMePhe6, Aib11, Aib13 and K28, for which the structure has been unfolded.

[0650] The preparation method adopts the Fmoc solid phase peptide synthesis strategy, and the method includes:

[0651] (1) Synthesis of peptide resin intermediate 2

[0652] Take Fmoc-Rink Linker-Nle-MBHA resin (S = 0.49 mmol / g), swell it with an appropriate amount of DCM, and wash it with DCM 2-3 times. Deprotect it with 20% PIP / DMF solution for 30 minutes, wash and filter to obtain the Fmoc-free NH2-Rink linker-Nle-MBHA resin, and drain the solvent for use.

[0653] Take 4 equivalents of Fmoc-Lys(Boc)-OH and HOBt respectively, dissolve them in appropriate amount of DMF / DCM; take another 4 equivalents of DIC, dilute it half with DCM, slowly add it to the DMF / DCM solution with stirring, and react with stirring at -5~0℃ for not less than 60 minutes. After activation, set aside.

[0654] Add the activated Fmoc-Lys(Boc)-OH solution to the NH2-Rink linker–Nle-MBHA resin, control the reaction temperature at 10-30°C, and conduct the coupling reaction for 240–480 min. Filter and wash to obtain the Fmoc-Lys(Boc)-Rink linker–Nle-MBHA resin. Deprotect the resin with a 20% PIP / DMF solution for 30 min, filter and wash to obtain the de-Fmoc Lys(Boc)-Rink linker–Nle-MBHA resin.

[0655] Under the same reaction conditions, start from the second amino acid at the C-terminus and couple to the N-terminus one by one. If the coupling is incomplete (color reaction), use HBTU / DIEA for a second condensation to ensure that each amino acid is completely condensed. The coupling sequence is Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc-Ala-OH.H2O, Fmoc-Gly-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Gly- Gly-OH, Fmoc-Lys(Mtt)-OH, Fmoc-Leu-OH, Fmoc-Leu-OH, Fmoc-Trp(Boc)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Val-OH, Fmoc-Phe-OH, Fmoc-Glu(OtBu)-OH.H2O, Fmoc-Ala-OH.H2O , Fmoc-Gln(Trt)-OH, Fmoc-Ala-OH.H2O, Fmoc-Gln(Trt)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Leu-OH, Fmoc-Aib-OH, Fmoc-Ile-OH, Fmoc-Aib-OH, Fmoc-Tyr( tBu)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-α-Me-Phe-OH, Fmoc-Thr(tBu)-OH, Fmoc-Glu(OtBu)-Gly-OH, Fmoc-Aib-OH, Boc-Tyr(tBu)-OH.

[0656] get:

[0657] Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln (Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Mtt)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Rink Linker-Nle-MBHA Resin

[0658] After the above condensation is complete, the Mtt protection is removed with 50% HFIP / DCM solution for 30 minutes, followed by washing and filtration to obtain peptide resin intermediate 2:

[0659] Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala- Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Rink Linker-Nle-MBHA Resin.

[0660] (2) Modification chain modification step

[0661] Dissolve 4 equivalents of Fmoc-AEEA-OH and HOBt in an appropriate amount of DMF / DCM. Dissolve another 4 equivalents of DIC in DCM by half, then slowly add it to the DMF / DCM solution with stirring. Stir and react at -5 to 0°C for at least 60 minutes. Activate and set aside.

[0662] The activated Fmoc-AEEA-OH solution was added to the previously swollen and washed peptide resin intermediate 2. The reaction temperature was controlled at 10-30°C. The coupling reaction was carried out for 240-480 minutes. The mixture was filtered and washed. The Fmoc protection was removed with a 20% PIP / DMF solution for 30 minutes. The mixture was filtered and washed. According to the above reaction conditions, the activated Fmoc-AEEA-OH, Fmoc-AEEA-OH, Fmoc-AEEA-OH, Fmoc-Glu(α-OtBu)-OH and octadecanediol mono-tert-butyl ester were coupled on the resin in sequence. The Fmoc protection was removed and the mixture was washed with DCM and dried to obtain the P019 peptide resin:

[0663] Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(t Bu)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln(Trt)-Ala-Glu(OtBu)-Phe-V al-Lys(tBuO-Ste-γ-Glu(α-OtBu)-AEEA-AEEA-AEEA)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Rink-Linker-Nle-MBHA Resin.

[0664] Take P019 peptide resin, add 12-15mL / g peptide resin cleavage agent (TFA:EDT:TIS:H2O, volume ratio 94:2:2:2), stir and react at 25±5℃ for 4 hours, filter the reaction mixture using a sand core funnel, collect the filtrate, wash the resin with a small amount of TFA three times, combine the filtrates and concentrate under reduced pressure, add methyl tert-butyl ether (MBTE) to precipitate, and then wash with MBTE 3-4 times. After evaporating MTBE, the crude product is dried under reduced pressure at room temperature to constant weight to obtain crude P019. After subsequent purification and drying, a P019 sample (mass spectrum MS: 5142.0) is obtained.

[0665] Example 3

[0666] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0667] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 24 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)1-CO-(CH2) 16 The K side chain was chemically modified by conjugating -CO2H to the ε-amino group; and the C-terminal amino acid was amidated to a C-terminal primary amide (SEQ ID NO: 7).

[0668] The above structure contains the standard single-letter amino acid code except for residues Aib2, αMePhe6, Aib11, Aib13 and K24, for which the structure has been unfolded.

[0669] The peptide of SEQ ID NO: 7 of the present invention (mass spectrum MS: 4997.2) was synthesized using peptide resin intermediate 1 in a similar manner as described in Example 1 above. The difference was that the modification process for the modified chain involved sequentially coupling Fmoc-AEEA-OH, Fmoc-AEEA-OH, Fmoc-Glu(α-OtBu)-OH, and octadecandioic acid mono-tert-butyl ester on the resin, followed by Fmoc deprotection, washing with DCM, and drying to obtain the P007 peptide resin. The other steps were similar.

[0670] Example 4:

[0671] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0672] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 24 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)1-CO-(CH2) 18 The K side chain was chemically modified by conjugating -CO2H to the ε-amino group; and the C-terminal amino acid was amidated to a C-terminal primary amide (SEQ ID NO: 13).

[0673] The above structure contains the standard single-letter amino acid code except for residues Aib2, αMePhe6, Aib11, Aib13 and K24, for which the structure has been unfolded.

[0674] Similar to Example 1 above, peptide resin intermediate 1 was used to carry out the preparation steps to synthesize the peptide of SEQ ID NO: 13 of the present invention (mass spectrum MS: 5025.2). The difference was that the modification process of the modified chain was to sequentially couple Fmoc-AEEA-OH, Fmoc-AEEA-OH, Fmoc-Glu(α-OtBu)-OH, and mono-tert-butyl eicosadioate on the resin, followed by Fmoc deprotection, washing with DCM, and drying to obtain the P013 peptide resin. The other steps were similar.

[0675] Example 5:

[0676] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0677] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 24 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)1-CO-(CH2) 20 The K side chain was chemically modified by conjugating -CO2H to the ε-amino group; and the C-terminal amino acid was amidated to a C-terminal primary amide (SEQ ID NO: 14).

[0678] The above structure contains the standard single-letter amino acid code except for residues Aib2, αMePhe6, Aib11, Aib13 and K24, for which the structure has been unfolded.

[0679] Similar to Example 1 above, peptide resin intermediate 1 was used to carry out the preparation steps to synthesize the peptide of SEQ ID NO: 14 of the present invention (mass spectrum MS: 5052.4). The difference was that the modification process of the modified chain was to sequentially couple Fmoc-AEEA-OH, Fmoc-AEEA-OH, Fmoc-Glu(α-OtBu)-OH, and mono-tert-butyl docosanediolate on the resin, followed by Fmoc deprotection, washing with DCM, and drying to obtain the P014 peptide resin. The other steps were similar.

[0680] Example 6:

[0681] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0682] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 24 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)3-(γ-Glu)1-CO-(CH2) 20 The K side chain was chemically modified by conjugating -CO2H to the ε-amino group; and the C-terminal amino acid was amidated to a C-terminal primary amide (SEQ ID NO: 16).

[0683] The above structure contains the standard single-letter amino acid code except for residues Aib2, αMePhe6, Aib11, Aib13 and K24, for which the structure has been unfolded.

[0684] Similar to Example 1 above, peptide resin intermediate 1 was used to carry out the preparation steps to synthesize the peptide of SEQ ID NO: 16 of the present invention (mass spectrum MS: 5198.0). The difference was that the modification process of the modified chain was to sequentially couple Fmoc-AEEA-OH, Fmoc-AEEA-OH, Fmoc-AEEA-OH, Fmoc-Glu(α-OtBu)-OH, and mono-tert-butyl docosanediolate on the resin, followed by Fmoc deprotection, washing with DCM, and drying to obtain the P016 peptide resin. The other steps were similar.

[0685] Example 7:

[0686] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0687] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)1-CO-(CH2) 16 The K side chain was chemically modified by conjugating -CO2H to the ε-amino group; and the C-terminal amino acid was amidated to a C-terminal primary amide (SEQ ID NO: 8).

[0688] The above structure contains the standard single-letter amino acid code except for residues Aib2, αMePhe6, Aib11, Aib13 and K28, for which the structure has been unfolded.

[0689] Similar to Example 2 above, peptide resin intermediate 2 was used to carry out the preparation steps to synthesize the peptide of SEQ ID NO: 8 of the present invention (mass spectrum MS: 4996.8). The difference was that the modification process of the modified chain was to sequentially couple Fmoc-AEEA-OH, Fmoc-AEEA-OH, Fmoc-Glu(α-OtBu)-OH, and octadecandioic acid mono-tert-butyl ester on the resin, followed by Fmoc deprotection, washing with DCM, and drying to obtain P008 peptide resin. The other steps were similar.

[0690] Example 8:

[0691] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0692] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)1-CO-(CH2) 20 The K side chain was chemically modified by conjugating -CO2H to the ε-amino group; and the C-terminal amino acid was amidated to a C-terminal primary amide (SEQ ID NO: 17).

[0693] The above structure contains the standard single-letter amino acid code except for residues Aib2, αMePhe6, Aib11, Aib13 and K28, for which the structure has been unfolded.

[0694] Similar to Example 2 above, peptide resin intermediate 2 was used to carry out the preparation steps to synthesize the peptide of SEQ ID NO: 17 of the present invention (mass spectrum MS: 5052.8). The difference was that the modification process of the modified chain was to sequentially couple Fmoc-AEEA-OH, Fmoc-AEEA-OH, Fmoc-Glu(α-OtBu)-OH, and mono-tert-butyl docosanediolate on the resin, followed by Fmoc deprotection, washing with DCM, and drying to obtain the P017 peptide resin. The other steps were similar.

[0695] Example 9:

[0696] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0697] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)3-CO-(CH2) 16 The K side chain was chemically modified by conjugating -CO2H to the ε-amino group; and the C-terminal amino acid was amidated to a C-terminal primary amide (SEQ ID NO: 18).

[0698] The above structure contains the standard single-letter amino acid code except for residues Aib2, αMePhe6, Aib11, Aib13 and K28, for which the structure has been unfolded.

[0699] The peptide of SEQ ID NO: 18 of the present invention (mass spectrum MS: 5255.2) was synthesized using peptide resin intermediate 2 in a similar manner as described in Example 2 above. The difference was that the modification process for the modified chain involved sequentially coupling Fmoc-AEEA-OH, Fmoc-AEEA-OH, Fmoc-Glu(α-OtBu)-OH, Fmoc-Glu(α-OtBu)-OH, Fmoc-Glu(α-OtBu)-OH, and octadecandioic acid mono-tert-butyl ester on the resin, followed by Fmoc deprotection, washing with DCM, and drying to obtain the P018 peptide resin. The other steps were similar.

[0700] Example 10:

[0701] Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK;

[0702] wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)3-(γ-Glu)1-CO-(CH2) 20 The K side chain was chemically modified by conjugating -CO2H to the ε-amino group; and the C-terminal amino acid was amidated to a C-terminal primary amide (SEQ ID NO: 20).

[0703] The above structure contains the standard single-letter amino acid code except for residues Aib2, αMePhe6, Aib11, Aib13 and K28, for which the structure has been unfolded.

[0704] Similar to Example 2 above, peptide resin intermediate 2 was used to carry out the preparation steps to synthesize the peptide of SEQ ID NO: 20 of the present invention (mass spectrum MS: 5198.4). The difference was that the modification process of the modified chain was to sequentially couple Fmoc-AEEA-OH, Fmoc-AEEA-OH, Fmoc-AEEA-OH, Fmoc-Glu(α-OtBu)-OH and mono-tert-butyl docosane dioate on the resin, followed by Fmoc deprotection, washing with DCM, and drying to obtain P020 peptide resin. The other steps were similar.

[0705] In some embodiments of the present invention, peptide resin intermediate 3 (a peptide resin intermediate with a modified chain at position 16 Lys) is obtained by following the preparation method of peptide resin intermediate 1 in Reference Example 1:

[0706] Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys-Gln(Trt)-Ala-Gln(T rt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Boc)-Rink Linker-Nle-MBHA Resin

[0707] Peptide resin intermediate 4 (peptide resin intermediate with a modified chain at position 40 Lys) was obtained by following the preparation method of peptide resin intermediate 1 in Reference Example 1:

[0708] Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-αMePhe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Aib-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala- Gln(Trt)-Ala-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys-Rink Linker-Nle-MBHA Resin

[0709] Other dual agonist compounds in the present invention can be prepared by referring to the above method.

[0710] Related assays

[0711] The conditions and data used in the examples for several assays are provided below.

[0712] 1. In vitro function

[0713] (I) In vitro binding activity to human GLP-1 and GIP receptors

[0714] The in vitro binding potency of the compounds of the present invention to human GIP and GLP-1 receptors was evaluated by measuring the binding affinity Ki using crude cell membranes obtained from clonal cell lines overexpressing human GLP-1R cDNA or human GIP-R cDNA.

[0715] 1) In vitro binding activity to human GLP-1 receptor

[0716] hGLP-1 and the compounds of the present invention were dissolved in DMSO and stored at -80°C. 89 μL of membrane (5 μg / well) dissolved in binding buffer (50 mM Hepes, pH 7.4, 5 mM MgCl2, 5 mM EDTA, 0.005% TWEEN, 0.005% HSA) was transferred to a 96-well assay plate. The compounds were serially diluted in DMSO, and then 1 μL of the diluted compound or 100% DMSO was added to the assay plate containing the membrane solution. 10 μL of [ 125 I] GLP-1 (final reaction concentration 0.15 nM). The assay plates were incubated at room temperature for 90 minutes. Membrane complexes were harvested using a Cell Harvester onto 0.5% PEI-coated GF / B plates and rinsed three times with 500 μL of 4°C pre-cooled elution buffer (50 mM Hepes, pH 7.4, 500 mM NaCl). After drying at 37°C for 2 hours, 50 μL of scintillation fluid was added to each well, sealed, and incubated for at least 1 hour. The membrane-bound radioligand levels were then determined using a Microbet2 reader.

[0717] pass[ 125 I] Nonlinear regression of the percentage of GLP-1 binding and the concentration of added compound was used to obtain the absolute IC 50 Concentration. Use the Cheng-Prusoff formula to calculate IC 50 The concentration was converted to Ki (Ki is the inhibition constant).

[0718] 2) In vitro binding activity to human GIP receptor

[0719] hGIP and the compounds of the present invention were dissolved in DMSO and stored at -80°C. 98 μL of membrane (15 μg / well) dissolved in binding buffer (50 mM HEPES pH 7.4, 5 mM MgCl2, 1 mM CaCl2, 0.1% BSA, 0.005% Tween-20) was transferred to a 96-well assay plate. The compounds were serially diluted in DMSO, and then 2 μL of the diluted compound or 100% DMSO was added to the assay plate containing the membrane solution. 100 μL of [ 125 I] GIP (final reaction concentration 0.0315 nM). The assay plate was incubated at room temperature for 90 minutes. Membrane complexes were harvested using a Cell Harvester onto 0.5% PEI-coated GF / B plates and rinsed three times with 500 μL of 4°C pre-cooled elution buffer (50 mM Tris-HCl pH 7.4, 125 mM NaCl). After drying at 37°C for 2 hours, 50 μL of scintillation fluid was added to each well, sealed, and incubated for at least 1 hour. The membrane-bound radioligand levels were then determined using a Microbeta2 reader.

[0720] pass[ 125 The absolute IC was obtained by nonlinear regression of the percentage of GIP binding and the concentration of the added compound. 50 Concentration. Use the Cheng-Prusoff formula to calculate IC 50 The concentration was converted to Ki (Ki is the inhibition constant).

[0721] Table 1. Receptor binding affinities, Ki ratios NA: Not determined Ki ratio: the ratio of the Ki value of the endogenous ligand to the Ki value of the test compound

[0722] The binding affinity of all compounds to receptors is expressed as Ki ratio, with a larger Ki ratio indicating a stronger binding affinity of the compound. Compared with P001, the binding affinity of the compounds of the present invention to human GLP-1R and GIPR is decreased to a certain extent (see Table 1).

[0723] Compared with Tirzepatide, except for P015, the binding affinity of the other nine compounds of the present invention to human GLP-1R is slightly stronger than that of Tirzepatide, and among them, the binding affinity of five compounds, P008, P013, P014, P016 and P019, to GIPR is also slightly stronger than that of Tirzepatide (see Table 1).

[0724] In summary, the compounds of the present invention with different forms of modified chains have a binding affinity to human GLP-1R and GIPR that is somewhat lower than that of P001, but is slightly stronger than or equivalent to that of Tirzepatide.

[0725] (II) Agonistic activity on hGLP-1R and hGIPR

[0726] For human GLP-1 and GIP receptors, the in vitro functional activity of the compounds of the invention at these receptors was determined in HEK-293 clonal cell lines expressing these receptors.

[0727] 1) Agonist activity on human GLP-1 receptor (cAMP reporter gene method)

[0728] The cAMP reporter gene assay was used to determine the agonist activity of the compounds of the present invention on human GLP-1R, with P001, Tirzepatide and endogenous ligand GLP-1 as references.

[0729] HEK293 / CRE / GLP-1R cells were seeded at 50,000 cells / well (80 μL / well) in a 96-well plate and cultured overnight in a 37°C, 5% CO2 incubator. 20 μL / well of assay medium (DMEM containing 0.1% casein) containing a compound (a compound of the present invention, P001, Tirzepatide, or GLP-1) was added to the 96-well plate and incubated in a 37°C, CO2 incubator for another 6 hours. After equilibration to room temperature, the supernatant was removed, and 50 μL / well of Bright-Glo reagent was added. The cells were shaken and lysed at room temperature for 10 minutes. Luminescence was read using an Envision microplate reader to measure luciferase activity.

[0730] The response value of 100 nM GLP-1 was set as 100% response value, and nonlinear regression was performed using GraphPad based on the response percentage and the added compound concentration to obtain the EC of each compound. 50 value.

[0731] 2) Agonist activity on human GIP receptor (LANCE Ultra cAMP assay)

[0732] The LANCE Ultra cAMP Kit was used to determine the agonist activity of the compounds of the present invention on human GIPR, with P001, Tirzepatide and endogenous ligand GIP as references.

[0733] The in vitro agonist activity of the compounds of the present invention against GIPR was determined in HEK293 cells stably expressing human GIPR (HEK293 / GIPR cells). HEK293 / GIPR cells were prepared in HBSS buffer (0.1% Casein, 500 μM IBMX, 5 mM HEPES) and seeded at 1000 cells / well (5 μL / well) in 384-well cell culture plates. 5 μL of HBSS buffer containing 2× compound was added to the 384-well cell culture plates. The plates were sealed and incubated in a 37°C, 5% CO2 incubator for approximately 30 minutes. After incubation, 5 μL of cAMP-Eu working solution and 5 μL of cAMP-Ulight working solution were added, followed by shaking to mix. The plates were incubated at 25°C for 1 hour. The signals at 665 nm and 615 nm were read on an Envision microplate reader. The 665 nm / 615 nm ratio was calculated and converted to cAMP concentration using a cAMP standard curve. The response value of 1 μM GIP was set as 100% response value, and nonlinear regression was performed using GraphPad based on the response percentage and the concentration of the added compound to obtain the EC value of each compound. 50 value.

[0734] Table 2. Agonist activity at human GLP-1 and GIP receptors, EC 50 value NA: EC not detected 50 Value: Endogenous ligand EC 50 EC values ​​of the tested compounds 50 Value ratio

[0735] The agonist activities of all compounds on human GLP-1 and GIP receptors were expressed as EC 50 The value indicates that EC 50 The larger the value, the stronger the activity of the compound. Compared with P001, the agonist activity of the compound of the present invention on human GLP-1R and GIPR is decreased to a certain extent (see Table 2).

[0736] Compared with Tirzepatide, all compounds of the present invention have stronger agonist activity on human GLP-1R than Tirzepatide, and among them, six compounds P007, P008, P013, P016, P018 and P019 also have slightly stronger agonist activity on human GIPR than Tirzepatide (see Table 2).

[0737] In summary, the compounds of the present invention with different forms of modified chains have different degrees of reduced agonist activity on human GLP-1R and GIPR compared with P001, but 6 compounds are more potent than Tirzepatide.

[0738] In vitro functional assays showed that the activities of the 10 compounds of the present invention were similar, so a single-dose hypoglycemic experiment in db / db mice was used to further screen the compounds.

[0739] (III) Agonist activity on GLP-1R and GIPR in different species

[0740] The in vitro functional activities of the compounds of the invention at human, cat, dog, mouse, rat, rabbit, and monkey GLP-1 and GIP receptors were determined in cells stably expressing these receptors and in CHO-K1 cells transiently transfected with these receptors.

[0741] 1) Agonist activity on GLP-1 receptors in humans, dogs, mice, rats, rabbits, and monkeys (LANCE Ultra cAMP assay)

[0742] The LANCE Ultra cAMP Kit was used to determine the agonist activity of the compounds of the present invention on human, dog, mouse, rat, rabbit and monkey GLP-1R, with endogenous ligand GLP-1 as a reference.

[0743] The in vitro agonist activity of the compounds of the present invention on GLP-1R was determined in cells stably expressing human, dog, mouse, rat, rabbit, and monkey GLP-1R (human GLP-1R-HEK, dog GLP-1R-HEK, mouse GLP-1R-HEK, rat GLP-1R-HEK, rabbit GLP-1R-CHO, and monkey GLP-1R-HEK cells). Human GLP-1R-HEK, canine GLP-1R-HEK, mouse GLP-1R-HEK, rat GLP-1R-HEK, rabbit GLP-1R-CHO, and monkey GLP-1R-HEK cells were prepared with 1× Casein Stimulation Buffer (HBSS, 5mM HEPES, 0.5mM IBMX, 0.1% casein, pH 7.4) and seeded into 384-well cell culture plates at 9μL / well (cell numbers were 1000, 1000, 1000, 1500, 1000, and 1000 cells / well, respectively). 1μL of 1× Casein Stimulation Buffer containing 10× compound was added to the above 384-well cell culture plates. The plates were incubated at 37°C for 30 minutes. After incubation, 5μL of Eu-cAMP working solution and 5μL of Ulight were added in sequence. TM-cAMP working solution was centrifuged and incubated at room temperature for 1 hour. The readings at 665 nm and 620 nm were measured on a microplate reader under 330 nm excitation light. The 665 nm / 620 nm reading ratio was calculated, and the response value of the highest concentration of GLP-1 was set as 100% response value. Nonlinear regression was performed using GraphPad based on the response percentage and the added compound concentration to obtain the EC value of each compound. 50 value.

[0744] 2) Agonist activity on GIP receptors in humans, dogs, mice, rats, rabbits, and monkeys (LANCE Ultra cAMP assay)

[0745] The LANCE Ultra cAMP Kit was used to determine the GIPR agonist activity of the compounds of the present invention on humans, dogs, mice, rats, rabbits, and monkeys, with the endogenous ligand GIP as a reference.

[0746] CHO-K1 cells were cultured at 0.6×10 6 Cells / well were seeded in a 6-well plate and cultured overnight in a 37°C 5% CO2 incubator. The next day, the CHO-K1 cells were treated with a culture medium change. Two tubes, A and B, were prepared for each plasmid. 100 μL Opti-MEM was added to tube A, followed by 4 μL Lipofectamine. TM First, add 100 μL of Opti-MEM to tube B, then add 2 μg of one of the plasmids (human GIPR-pcDNA5(+) plasmid, dog GIPR-pcDNA5(+) plasmid, mouse GIPR-pcDNA5(+) plasmid, rat GIPR-pcDNA5(+) plasmid, rabbit GIPR-pcDNA5(+) plasmid, monkey GIPR-pcDNA5(+) plasmid), mix well, and then add 4 μL of P3000 to tube B. TM Mix thoroughly (the ratio of plasmid to transfection reagent is 1 μg:2 μL). Add the diluted solution in tube A to the diluted solution in tube B, mix thoroughly, and incubate at room temperature for 15 minutes. Finally, gently add the mixture to the cells, which have been replaced with fresh medium, shake gently to mix, and then incubate overnight in a 37°C, 5% CO2 incubator. 18-20 hours after transfection, cells are used to assay compound functional activity.

[0747] 18-20 hours after transfection, human GIPR-CHO, canine GIPR-CHO, mouse GIPR-CHO, rat GIPR-CHO, rabbit GIPR-CHO, and monkey GIPR-CHO cells were prepared with 1× Casein Stimulation Buffer (HBSS, 5mM HEPES, 0.5mM IBMX, 0.1% casein, pH 7.4) and seeded into 384-well cell culture plates at 9μL / well (cell numbers were 1000, 2000, 2000, 2000, 2000, and 2000 cells / well, respectively). 1μL of 1× Casein Stimulation Buffer containing 10× compound was added to the above 384-well cell culture plates. The plates were incubated at 37°C for 30 minutes. After incubation, 5μL of Eu-cAMP working solution and 5μL of Ulight were added in sequence. TM -cAMP working solution, centrifuged and incubated at room temperature for 1 hour. Readings at 665 nm and 620 nm were measured on a microplate reader under 330 nm excitation light. The 665 nm / 620 nm reading ratio was calculated, and the response value of the highest concentration of GIP was set as 100%. Nonlinear regression was performed using GraphPad based on the response percentage and the added compound concentration to obtain the EC of each compound. 50 value.

[0748] For human, feline GLP-1 and GIP receptors, the in vitro functional activities of the compounds of the invention at these receptors were determined in CHO cells transiently transfected with these receptors.

[0749] 3) Agonist activity at human and feline GLP-1 and GIP receptors (LANCE Ultra cAMP assay)

[0750] The LANCE Ultra cAMP Kit was used to determine the agonist activity of the compounds of the present invention on human and cat GLP-1R and GIP, with endogenous ligands GLP-1R or GIP as references.

[0751] CHO-K1 cells were cultured at 0.6×10 6 Cells / well were seeded in a 6-well plate and cultured overnight in a 37°C 5% CO2 incubator. The next day, the CHO-K1 cells were treated with a culture medium change. Two tubes, A and B, were prepared for each plasmid. 100 μL Opti-MEM was added to tube A, followed by 4 μL Lipofectamine. TMFirst, add 100 μL of Opti-MEM to tube B, then add 2 μg of one of the plasmids (human GLP-1R-pcDNA5(+) plasmid, cat GLP-1R-pcDNA5(+) plasmid, human GIPR-pcDNA5(+) plasmid, cat GIPR-pcDNA5(+) plasmid), mix well, and then add 4 μL of P3000 to tube B. TM Mix thoroughly (the ratio of plasmid to transfection reagent is 1 μg:2 μL). Add the diluted solution in tube A to the diluted solution in tube B, mix thoroughly, and incubate at room temperature for 15 minutes. Finally, gently add the mixture to the cells, which have been replaced with fresh medium, shake gently to mix, and then incubate overnight in a 37°C, 5% CO2 incubator. 18-20 hours after transfection, cells are used to assay compound functional activity.

[0752] 18-20 hours after transfection, human GLP-1R-CHO, cat GLP-1R-CHO, human GIPR-CHO, and cat GIPR-CHO cells were prepared with 1×Casein Stimulation Buffer (HBSS, 5mM HEPES, 0.5mM IBMX, 0.1% casein, pH 7.4) and inoculated into 384-well cell culture plates at 9μL / well (cell numbers were 2000, 2000, 1000, and 2000 cells / well, respectively). 1μL of 1×Casein Stimulation Buffer containing 10× compound was added to the above 384-well cell culture plates. The plates were incubated at 37°C for 30 minutes. After incubation, 5μL of Eu-cAMP working solution and 5μL of Ulight were added in sequence. TM -cAMP working solution, centrifuged and incubated at room temperature for 1 hour. Readings at 665 nm and 620 nm were measured on a microplate reader under 330 nm excitation light. The 665 nm / 620 nm reading ratio was calculated, and the response value of the highest concentration of GLP-1R or GIP was set as 100% response value. Nonlinear regression was performed using GraphPad based on the response percentage and the added compound concentration to obtain the EC value of each compound. 50 value.

[0753] Table 3. Agonist activity at GLP-1 and GIP receptors in different species, EC 50 Compare

[0754] EC 50 Comparison: Other species EC 50 Value and People EC 50 Value ratio

[0755] The agonist activities of all compounds on GLP-1 receptor and GIP receptor were expressed as EC50 Ratio means EC 50 The smaller the ratio, the more active the compound.

[0756] Compared with the agonist activity on human receptors, the agonist activity of the compound P016 of the present invention on mouse, rat, rabbit, cat and monkey GLP-1R is equivalent to that on human GLP-1R, and the agonist activity on canine GLP-1R is slightly weaker (4.52 times weaker); the agonist activity of P016 on rat and dog GIPR is equivalent to that on human GIPR, and the agonist activity on cat, rabbit, monkey and mouse GIPR is slightly weaker (3.59, 5.34, 5.77 and 12.49 times weaker, respectively). The agonist activity of Tirzepaitde on mice, rats, rabbits and monkeys is comparable to its agonist activity on human GLP-1R, but its agonist activity on cat and dog GLP-1R is >30-fold or >80-fold weaker than its agonist activity on human GLP-1R (the agonist activity is less than 1 / 30 or less than 1 / 80); the agonist activity of Tirzepaitde on dog, monkey, cat, rat and rabbit GIPR is slightly weaker than that on human GIPR (6.13, 7.38, 8.05, 9.53 and 16.04 times weaker, respectively), and its agonist activity on mouse GIPR is >220-fold weaker than its agonist activity on human GIPR (the agonist activity is less than 1 / 220) (see Table 3).

[0757] In summary, the compounds of the present invention exhibit strong agonist activity against the GLP-1R and GIPR in cats, dogs, mice, rats, rabbits, and monkeys, with agonist activity comparable to that against human GLP-1R and GIPR (1.05-12.5 times weaker). This indicates that cats, dogs, mice, rats, rabbits, and monkeys are all non-human-relevant species for the compounds of the present invention. Tirzepatide, on the other hand, exhibited significant variability in its agonist activity across the species tested, with its agonist activity against cat and dog GLP-1R being significantly weaker than that against human GLP-1R.

[0758] 4) Sequence comparison of GLP-1R and GIPR in different species

[0759] Comparison of the GLP-1R / GIPR sequences of cats, dogs, mice, rats, rabbits, monkeys, pigs, alpacas, horses, sheep, and cattle with those of humans using NCBI (National Center for Biotechnology Information) BLAST revealed that the GLP-1R / GIPRs of these species share >80% homology with the human GLP-1R / GIPR. Combined with the results in Table 3, it is expected that the compounds of the present invention exhibit comparable or slightly weaker agonistic effects on the GLP-1R / GIPR of pigs, alpacas, horses, sheep, and cattle than on the human GLP-1R / GIPR. It is speculated that the compounds of the present invention may have therapeutic effects on type 2 diabetes, obesity, and other related diseases in these animal species.

[0760] Table 4. Comparison of homology between GLP-1R / GIPR of different species and human GLP-1R / GIPR Note: There are 2, 3, and 4 transcripts of ovine GLP-1R, porcine GIPR, and bovine GIPR, respectively.

[0761] 2. Pharmacokinetics

[0762] (I) Single-dose pharmacokinetics in SD rats

[0763] Plasma was collected from SD rats after subcutaneous or intravenous administration and its plasma drug concentration was measured to illustrate the pharmacokinetic properties of the compounds of the present invention in vivo. The compound was dissolved in phosphate buffer and filtered through a PTFE membrane (0.45 μm) to obtain a 25 nmol / mL compound solution. Male SD rats (230-268 g, n=3) were given a dose of 50.0 nmol / kg subcutaneously (sc) or 25.0 nmol / kg intravenously (iv). Approximately 150 μL of whole blood was collected from the internal jugular vein in EDTA-K2 anticoagulant tubes at predose, 0.0833 (iv), 0.25, 0.5, 1, 2, 4, 6, 8, 24, 48, 72, 96, and 120 h. Blood samples were centrifuged at 1500 g for 10 min at 4 ° C to obtain plasma, which was stored frozen at -90 ° C to -60 ° C for analysis.

[0764] Sample processing

[0765] (1) Sample processing methods for Tirzepatide, P007, P008, P013, and P014

[0766] Take 30.0 μL of thawed plasma sample and add 150 μL of acetonitrile solution (containing 5 ng·mL -1 Verapamil, 50 ng mL -1 Glyburide, 200 ng·mL -1Tolbutamide and 200 ng·mL -1 Protein was precipitated with diclofenac (diclofenac), the mixture was vortexed for 5 minutes, and centrifuged at 3700 rpm for 8 minutes. 70.0 μL of the supernatant was added to 70.0 μL of 0.5% formic acid solution, and the mixture was vortexed for 5 minutes. 15 μL of the mixture was sampled and injected into LC-MS / MS to measure the plasma drug concentration.

[0767] (2) Sample processing method for P015, P016, P017, and P018:

[0768] Take 20.0 μL of thawed plasma sample and add 60.0 μL of acetonitrile solution (containing 5 ng·mL -1 Verapamil, 50 ng mL -1 Glyburide, 200 ng·mL -1 Tolbutamide and 200 ng·mL -1 Protein was precipitated with diclofenac (diclofenac), the mixture was vortexed for 1 minute, and centrifuged at 13,000 rpm for 8 minutes. 60.0 μL of the supernatant was added to 60.0 μL of 0.5% formic acid solution, and the mixture was vortexed for 10 minutes. 10.0 μL of the mixture was sampled and injected into LC-MS / MS for plasma drug concentration determination.

[0769] (3) Sample processing method for P019 and P020:

[0770] Take 30.0 μL of thawed plasma sample and add 150 μL of acetonitrile solution (containing 5 ng·mL -1 Verapamil, 50 ng mL -1 Glyburide, 200 ng·mL -1 Tolbutamide and 200 ng·mL -1 Protein was precipitated with diclofenac (diclofenac), the mixture was vortexed for 5 minutes, and centrifuged at 3700 rpm for 8 minutes. 70.0 μL of the supernatant was added to 70.0 μL of 0.5% formic acid solution, and the mixture was vortexed for 5 minutes. 10.0 μL of the mixture was sampled and injected into LC-MS / MS to measure the plasma drug concentration.

[0771] Based on the blood concentrations of the compounds in SD rats, the pharmacokinetic parameters were calculated using the Winnolin 8.2 software with a non-compartmental model. The results are shown in Tables 5 and 6 below.

[0772] Table 5 Pharmacokinetic parameters of different polypeptide compounds after subcutaneous injection in rats

[0773] Table 6 Pharmacokinetic parameters of different polypeptide compounds after subcutaneous injection in rats

[0774] PK studies of subcutaneous injections of the compounds of this invention in rats demonstrated that the half-lives of P007, P008, P013, P014, P015, P016, P017, P018, and P020 were greater than that of Tirzepatide (increases of approximately 23.7% to 64.0%). The modified chains of the compounds of this invention achieved longer plasma half-lives than Tirzepatide, the marketed dual-target product. Furthermore, compared to P001, the half-lives of the compounds of this invention were significantly prolonged, increasing by more than 15-fold, 20-fold, and even 30-fold.

[0775] (II) Pharmacokinetics in C57 mice

[0776] After subcutaneous or intravenous administration to C57 mice, plasma was collected and its blood drug concentration was measured to illustrate the pharmacokinetic properties of the compounds of the present invention in vivo. The compound was dissolved in phosphate buffer containing 0.1% Tween 20 and filtered through a filter membrane (PTFE, 0.45μm) to obtain a 15nmol / mL compound solution. C57 mice (18-22g) were given a dose of 30nmol / kg subcutaneously (sc) or 15.0nmol / kg intravenously (iv). Approximately 100μL of whole blood was collected from the orbital venous plexus in EDTA-K2 anticoagulant tubes at predose, 0.5, 1, 2, 4, 8, 24, 48 and 72h. The blood samples were centrifuged at 1500g for 10min at 4°C to obtain plasma, which was frozen at -90°C to -60°C for analysis and testing.

[0777] Sample processing

[0778] (1) Sample processing methods for Tirzepatide, P014, P016, and P020

[0779] Take 20.0 μL of thawed plasma samples and add 20 μL of 50% methanol aqueous solution (containing 100 ng·mL -1 Tolbutamide) and 60 μL of acetonitrile were added to precipitate protein. The mixture was vortexed for 5 minutes and centrifuged at 4815 g for 8 minutes. 50.0 μL of the supernatant was added to 50.0 μL of 0.5% formic acid solution and vortexed for 5 minutes. 50 μL of the mixture was sampled and injected into LC-MS / MS for plasma drug concentration analysis.

[0780] Based on the blood concentrations of the compound in C57 mice, the pharmacokinetic parameters were calculated using the Winnolin 8.3 software with a non-compartmental model. The results are shown in Tables 7 and 8 below.

[0781] Table 7 Average pharmacokinetic parameters after single subcutaneous administration in mice

[0782] Table 8 Average pharmacokinetic parameters after single intravenous administration in mice

[0783] PK studies of the compounds of this invention in mice following subcutaneous injection showed that the half-lives of P014, P016, and P020 were significantly greater than that of Tirzepatide (increases of approximately 116.0% to 150.3%). The compounds of this invention modified with modified chains can achieve a longer plasma half-life than Tirzepatide, a marketed dual-target product.

[0784] (III) Pharmacokinetics in cynomolgus monkeys

[0785] Plasma concentrations were collected from cynomolgus monkeys after subcutaneous or intravenous administration to elucidate the pharmacokinetic properties of the compounds of this invention. The compounds were dissolved in 1.4% PG in 8mM Na2HPO4 buffer (pH 7.39) and filtered through a 0.45μm PTFE membrane to obtain 25 and 12.5 nmol / mL solutions, respectively. Cynomolgus monkeys (4-8 kg) were administered 25 nmol / kg subcutaneously (sc) or 12.5 nmol / kg intravenously (iv). Blood was collected via the cephalic vein or other appropriate vein at predose, 2 h, 12 h, 24 h, 32 h, 48 h, 3 d (72 h), 4 d (96 h), 6 d (144 h), 9 d (216 h), 12 d (288 h), 15 d (360 h), and 18 d (432 h). Approximately 500 μL of whole blood was collected in EDTA-K2 anticoagulant tubes. Blood samples were centrifuged at 2200 g for 10 min to obtain plasma, which was frozen at -90°C to -60°C for analysis.

[0786] Sample processing

[0787] (1) Sample processing methods for Tirzepatide, P014, P016, P017, and P020

[0788] 70 μL of thawed plasma sample was collected and protein was precipitated with 70 μL of acetonitrile (containing 1 ng / mL internal standard). The mixture was vortexed for 1 minute and centrifuged at 14,000 rpm for 10 minutes. 60 μL of the supernatant was added to 60 μL of 0.5% formic acid solution and vortexed for 5 minutes. 10 μL of the mixture was sampled and injected into LC-MS / MS for plasma drug concentration analysis.

[0789] Based on the plasma concentrations of the compound in cynomolgus monkeys, the pharmacokinetic parameters were calculated using the Winnolin 8.2 software with a non-compartmental model. The results are shown in Tables 9 and 10 below.

[0790] Table 9 Mean pharmacokinetic parameters after single subcutaneous administration in cynomolgus monkeys

[0791] Table 10 Average pharmacokinetic parameters after single intravenous administration in cynomolgus monkeys

[0792] The PK test of the compounds of the present invention injected subcutaneously in cynomolgus monkeys showed that the half-life of P014, P016 and P020 was comparable to that of Tirzepatide, and the half-life of P016 and P017 was comparable to that of Tirzepatide. max The compounds of the present invention modified with modified chains can achieve a plasma half-life comparable to that of Tirzepatide, a dual-target product on the market, and P016 and P017 T max It is about twice that of Tirzepatide, and the time to peak drug concentration is significantly delayed compared to Tirzepatide. It may have milder / fewer gastrointestinal reactions or a shorter titration time.

[0793] (IV) Pharmacokinetics in Beagles

[0794] Plasma was collected from beagle dogs after subcutaneous administration and its blood drug concentration was measured to illustrate the pharmacokinetic properties of the compounds of this invention in vivo. Beagle dogs (7-9 kg) were administered a 0.05 mg / kg subcutaneous (sc) dose. Blood was drawn from the saphenous vein at predose, 0.5, 1, 2, 6, 10, 24, 48, 72, and 96 h. Approximately 500 μL of whole blood was collected in EDTA-K2 anticoagulant tubes. The blood samples were centrifuged at 3000 g for 10 min at 2-8°C to obtain plasma, which was then frozen at -90°C to -60°C for analysis.

[0795] Sample processing

[0796] (1) Sample processing method of P016

[0797] 20.0 μL of thawed plasma sample was added to 20 μL of 100 ng / mL P016 and mixed for 2 minutes. Protein was then precipitated by adding 120 μL of 0.1% formic acid in methanol. The mixture was vortexed for 5 minutes and centrifuged at 4815 g for 10 minutes. 100 μL of the supernatant was added to 100 μL of 0.5% formic acid in water and vortexed for 5 minutes. 10 μL of the mixture was then injected into the sample for LC-MS / MS analysis of plasma drug concentrations.

[0798] Based on the blood concentration of the compound in beagle dogs, the pharmacokinetic parameters were calculated using the Winnolin 8.3 software with a non-compartmental model. The results are shown in Table 11 below.

[0799] Table 11 Mean pharmacokinetic parameters after single subcutaneous administration in beagle dogs

[0800] A PK study of subcutaneous injection of the compound P016 of the present invention in beagle dogs showed that P016 had a half-life of 69.32 hours, a peak time of 19.33 hours, a peak concentration of 407.33 ng / mL, and an AUC0-t of 29925 hr*ng / mL. Subcutaneous administration demonstrated a certain exposure, supporting subcutaneous administration and a once-a-week dosing frequency.

[0801] (V) Single-dose pharmacokinetics in cats

[0802] Plasma was collected from cats after subcutaneous administration and assayed for drug concentration to elucidate the in vivo pharmacokinetic properties of the compounds of this invention. The compound was dissolved in citrate buffer to yield a 0.125 mg / mL solution. Female and male cats (2.5-4.5 kg, n=3 / sex) were administered a 0.025 mg / kg subcutaneous (sc) dose. Approximately 0.5 mL of whole blood was collected via the jugular vein in an anticoagulant tube containing ETDA-K2 at predose, 0.5, 2, 4, 8, 24, 48, 72, 96, 120, 168, and 240 h. The blood was stored on wet ice and centrifuged within 0.5 h (1500-1600 g, 2-8°C, 10 min). Plasma was collected from each sample, requiring at least 100 μL. Plasma was frozen at -90°C to -60°C for analysis.

[0803] Sample processing

[0804] (1) Sample processing method of P016:

[0805] 30.0 μL of thawed plasma sample was taken and 300 μL of acetonitrile solution containing internal standard was added to precipitate the protein. The mixture was vortexed for 1 minute and centrifuged at 13,000 rpm for 5 minutes. 165 μL of the supernatant was transferred to a 96-well plate and injected into the plate for LC-MS / MS analysis of drug concentration in plasma.

[0806] Based on the blood concentration of the compound in cats, the pharmacokinetic parameters were calculated using the non-compartmental model using Winnolin 8.3 software. The results are shown in Table 12 below.

[0807] Table 12 Average pharmacokinetic parameters after single subcutaneous administration in cats

[0808] The PK test of cats injected subcutaneously with the compound P016 of the present invention showed that the half-life of P016 was 37.4 hours, the peak time was 24.0 hours, the peak concentration was 123 ng / mL, and the AUC 0-tThe exposure is 9260hr*ng / mL, which has a certain exposure after subcutaneous administration and can support subcutaneous administration and a dosing frequency of once a week.

[0809] Pharmacodynamics

[0810] (I) Pharmacodynamics in db / db mice: To study the effects of the compounds of the present invention on blood glucose in diabetic model mice (db / db mice)

[0811] This study used a single subcutaneous administration of a compound to db / db mice. Changes in blood glucose, food intake, and body weight were measured to elucidate the hypoglycemic effects and duration of efficacy of the compound described herein, and compared with positive controls Tirzepatide and P001. Male db / db mice, 8-9 weeks of age, were used in this study. The mice were housed in individually ventilated cages in an IVC facility with controlled temperature (20-26°C) and humidity (40-70%), under a 12h:12h light / dark cycle, with free access to food and water. Blood was collected via tail tip, and random basal blood glucose was measured using a Roche blood glucose meter. The mice were randomly divided into groups (n=6 / group) based on their initial fasting blood glucose and initial body weight. All groups had similar body weights and blood glucose levels.

[0812] The compound of the present invention (10 nmol / kg) or the positive control Tirzepatide (10 nmol / kg) or P001 (10 nmol / kg) were dissolved in a vehicle (PBS containing 0.1% Tween 20, pH 7.2-7.4). After a single subcutaneous administration, random basal blood glucose was recorded at set time points (0-120 h, recording of random basal blood glucose for the compound was stopped when the random basal blood glucose for the compound was no different from that of the vehicle group), as well as daily body weight and food intake. The data were statistically analyzed using GraphPad Prism 8. Statistical differences between groups were analyzed using T-TEST, and differences were considered significant when p < 0.05.

[0813] Duration of hypoglycemic effect: the longest time during which the random basal blood glucose of the compound is significantly different from that of the Vehicle group (p<0.05).

[0814] Table 13. Duration of hypoglycemic effect of compounds

[0815] Compared with P001, the glucose-lowering effect of the compounds of the present invention lasts 24 hours or longer (P007, P008, P014, P019), even longer than 40 hours (P008, P014), and longer than 72 hours (P014) (see Table 13, Figure 1A, Figure 1B).

[0816] Compared with Tirzepatide, the duration of blood sugar lowering effect of the compounds of the present invention is comparable to or longer (P007, P008, P013, P014, P016, P017, P018, P019, P020), even 16 hours or more (P008, P013, P014, P016, P017, P020), 24 hours or more (P013, P014, P016, P017, P020), 48 hours or more (P014, P016, P020), and 56 hours or more (P016, P020) (see Table 13).

[0817] Compared with P001: Based on the test described above, during the experimental period, P008 (p < 0.01), P014 (p < 0.001), and P019 (p < 0.05) showed significantly better glucose-lowering efficacy than P001 (blood glucose AUC, p < 0.05, as shown in Figure 2A). The glucose AUC inhibition rates were 2.3, 2.6, and 2.2 times that of P001, respectively. The duration of glucose-lowering effects was 40 hours, 72 hours, and 24 hours longer than that of P001, respectively (Table 13). P007 had a glucose-lowering effect comparable to that of P001, but the duration of glucose-lowering effects was 24 hours longer than that of P001 (as shown in Figure 2A and Table 13).

[0818] Compared with Tirzepatide: P014 (p < 0.05, Figure 2B), P016 (p < 0.05, Figure 2C), and P020 (p < 0.05, Figure 2C) showed stronger glucose-lowering effects (blood glucose AUC, p < 0.05) than Tirzepatide, with glucose AUC inhibition rates of 1.7, 2.2, and 2.0 times that of Tirzepatide, respectively. Furthermore, they exhibited significantly longer durations of action (48, 56, and 56 hours longer than Tirzepatide, respectively; Table 13). P013 and P017 had comparable glucose-lowering effects to Tirzepatide (Figure 2C), but their duration of action was 24 hours longer than that of Tirzepatide (Table 13).

[0819] Surprisingly, compared to P001, the GLP-1R / GIPR dual-target agonist of this invention significantly enhances its glucose-lowering efficacy while achieving a long-lasting effect. Compounds of this invention with various modified chains can achieve stronger and more sustained glucose-lowering effects than P001, and some compounds of this invention exhibit stronger and more sustained glucose-lowering effects than Tirzepatide.

[0820] In addition, based on the performance of the compounds of the present invention on target binding and agonist activity of human GLP-1R and GIPR, it was unexpectedly found that the target binding and agonist activity of the compounds of the present invention on human GLP-1R were significantly reduced compared with P001, and the target binding and agonist activity of human GIPR were also significantly reduced, but the hypoglycemic effect of the compounds of the present invention was significantly better than that of P001.

[0821] (II) Multiple-dose experiment in db / db mice

[0822] In this study, the compounds of the present invention were administered subcutaneously multiple times to db / db mice, and changes in the blood glucose of the mice were detected to further illustrate the hypoglycemic effect of the compounds of the present invention and to compare with the positive control Tirzepatide. In this study, male db / db mice aged 7-8 weeks were used. The db / db mice were housed in an IVC facility with controlled temperature (20-26°C) and humidity (40-70%), a 12h:12h light / dark cycle, and free access to food and water. Blood was collected from the tip of the tail, and basal blood glucose was measured with a Roche blood glucose meter. The mice were randomly divided into groups (n=6 / group) based on initial blood glucose and initial body weight, and each group had similar body weight and blood glucose.

[0823] The compound of the present invention (3, 10, 30 nmol / kg) or the positive control Tirzepatide (3, 10, 30 nmol / kg) was dissolved in a solvent (PBS containing 0.1% Tween20, pH 7.2-7.4). The drug was administered by subcutaneous injection once every 3 days for four weeks. Subcutaneous injection was performed on days 1, 4, 7, 10, 13, 16, 19, 22 and 25. Random blood glucose was recorded every 3 days throughout the study. Fasting blood glucose was tested on day 28, and then blood was collected by orbital bleeding. After orbital bleeding, the animals were sacrificed and the liver was removed and weighed. The collected blood was centrifuged at 3000 rpm for 10 minutes after 1 to 2 hours to separate the serum. Biochemical indicators such as triglycerides (TG), alanine aminotransferase (ALT), and total bilirubin (TBIL) were measured using a biochemical analyzer. The data results were statistically analyzed using GraphPad Prism8, and the statistical differences between the groups were analyzed using T-TEST. A value of p < 0.05 was considered significant.

[0824] In experiments conducted as described above, compounds of the present invention, such as P014, P016, P017, and P020, all demonstrated superior blood glucose suppression compared to Tirzepatide at a 3 nmol / kg dose; at a 30 nmol / kg dose, P016 was more effective than Tirzepatide (see Figures 3A-3D and Table 14). P016, P017, and P020 significantly reduced liver weight in db / db mice at multiple doses, whereas Tirzepatide did not reduce liver weight at any of the three experimental doses. Compounds of the present invention, such as P014, P016, P017, P020, and Tirzepatide, all effectively reduced serum triglycerides in db / db mice (except in the 3 nmol / kg P017 and Tirzepatide groups), with P016 and P020 exhibiting superior efficacy to Tirzepatide in some dose groups (see Table 15). In addition, P014 and P016 could also reduce serum TBIL and / or ALT (see Table 16).

[0825] Table 14. Fasting blood glucose (FBG) and blood glucose AUC of db / db mice T-test, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 compared with the vehicle group; #p<0.05, ##p<0.01, ###p<0.001 compared with the Tirzepatide (TZP) group at the same dose. Results are expressed as Mean ± SEM of 6 mice.

[0826] Table 15. Liver weight and serum TG of db / db mice T-test, *p<0.05, **p<0.01, ***p<0.001 compared with the vehicle group; #p<0.05, ##p<0.01 compared with the Tirzepatide (TPZ) group at the same dose. The results are expressed as Mean ± SEM of 6 mice.

[0827] Table 16. Serum ALT and TBIL of db / db mice T-test, *p<0.05 compared with the vehicle group; #p<0.05, ##p<0.01 compared with the Tirzepatide (TPZ) group at the same dose. The results are expressed as Mean ± SEM of 6 mice.

[0828] In summary, in this experimental system, the compounds of this invention effectively lowered blood glucose in db / db mice after subcutaneous administration for four weeks. The effective dose (≤3 nmol / kg) was one-third that of Tirzepatide (10 nmol / kg). Furthermore, some compounds of this invention, such as P016, exhibited a greater maximum efficacy (30 nmol / kg) than Tirzepatide. Furthermore, some compounds of this invention demonstrated liver weight reduction and liver protection in db / db mice, whereas Tirzepatide did not exhibit similar effects.

[0829] (III) Weight loss effect in the DIO mouse obesity model

[0830] In this study, compounds of the present invention were administered subcutaneously multiple times to DIO mice. Changes in body weight and blood glucose were measured to demonstrate the weight-reducing effects of the compounds of the present invention and to compare them with the positive control, tirzepatide. 26-week-old male DIO mice were used in this study. DIO mice were housed in appropriately sized cages in an SPF-grade animal facility with a controlled environment of 20-26°C, 40%-70% relative humidity, and a 12-hour light-dark cycle. Food and water were available ad libitum. DIO mice with similar randomized blood glucose (RBG) (D1) and body weight (D1) were randomly divided into groups (n=10 / group). Compound P016 of the present invention (0.3, 1, 3, or 30 nmol / kg) or the positive control, tirzepatide (1 or 30 nmol / kg), were dissolved in a vehicle (PBS containing 0.1% Tween 20, pH 7.2-7.4). Subcutaneous injections were administered every three days for four consecutive weeks. The drug was administered by subcutaneous injection on days 1, 4, 7, 10, 13, 16, 19, 22, 25, and 28.

[0831] The animals were weighed before administration on the first day of administration (D1) and at fixed times every 3 days thereafter. Food intake was measured once a day after administration. Random blood glucose (RBG) was measured before grouping and 48 hours after each administration. On D30, after a 5-hour fast (water was not allowed), FBG and glycosylated hemoglobin (HbA1c) were measured. Blood was collected venously to separate serum. Serum insulin content was measured using a mouse insulin ELISA kit, and serum total cholesterol (TC), TG, low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), free fatty acids (FFA), ALT, and aspartate aminotransferase (AST) levels were measured using a biochemical analyzer. The liver was removed, and the perirenal and peritesticular adipose tissues were separated and weighed to calculate the organ-to-body ratio. The liver was stained with HE and Oil Red O for pathological scoring. Data were analyzed using one-way analysis of variance (ANOVA). If the ANOVA was statistically significant (P ≤ 0.05) and the variances were homogeneous, intergroup comparisons were performed using the Tukey test. If the variances were unequal, intergroup comparisons were performed using the Dunnet's T3 test. Results are expressed as mean ± SEM. The p-value was 0.05, and both statistical and biological significance were considered in the analysis.

[0832] In experiments conducted as described above, the compounds of the present invention significantly reduced the cumulative food intake and body weight of obese mice in a dose-dependent manner. The onset of action was at a dose of 1 nmol / kg, which was significantly more effective than the positive control, Tirzepatide, at the same dose. At a dose of 30 nmol / kg, the compounds of the present invention achieved greater weight reduction than Tirzepatide (percentage weight reduction, 39.97% vs. 34.47%) (see Figures 4 and 5, Table 17). The compounds of the present invention significantly reduced total abdominal fat (the sum of perirenal and peritesticular fat) and serum TC in DIO mice (Tables 17 and 19), demonstrating a significant lipid-lowering effect. Compounds of the present invention at 1, 3, and 30 nmol / kg significantly reduced fasting blood glucose and insulin levels on Day 30, ameliorating insulin resistance (Table 18). The compounds of the present invention significantly reduced liver weight and serum ALT levels, improving liver function (Table 19).

[0833] Table 17. Cumulative food intake, body weight, fat and liver weight of DIO mice Note: **p≤0.01, ***p≤0.001, ****p≤0.0001 compared with the Vehicle group; ##p≤0.01, ####p≤0.0001 compared with the positive control Tirzepatide group at the same dose. Results are expressed as Mean ± SEM of 10 mice.

[0834] Table 18. Fasting blood glucose, insulin and insulin resistance index of DIO mice Note: *p≤0.05, **p≤0.01, ***p≤0.001, ****p≤0.0001 compared with the Vehicle group; #p≤0.05 compared with the positive control Tirzepatide group at the same dose. Results are expressed as Mean ± SEM of 10 mice.

[0835] Table 19. Serum TC and ALT of DIO mice Note: *p≤0.05, ***p≤0.001, ****p≤0.0001 compared with the Vehicle group. Results are expressed as Mean ± SEM of 10 mice.

[0836] In summary, in this experimental system, the compound of the present invention effectively reduced the body weight of DIO mice after subcutaneous administration for four weeks, with an onset dose of 1 nmol / kg. This dose significantly outperformed the positive control, Tirzepatide, at the same dose. Furthermore, the compound of the present invention achieved a greater maximum weight loss (30 nmol / kg) than Tirzepatide at the same dose (percentage weight loss, 39.97% vs. 34.47%). Furthermore, the compound of the present invention exhibited effects on lowering blood sugar, improving insulin resistance, and improving liver function.

[0837] (IV) Weight loss efficacy in obese dogs

[0838] In this study, the compound of the present invention was administered subcutaneously to obese dogs multiple times, and the changes in the dogs' body weight were detected to illustrate the weight-loss effect of the compound of the present invention. In this study, obese dogs aged 8 months and above with a body condition score (BCS) ≥ 6 were used. The obese dogs were kept in dog cages of appropriate specifications; the environmental conditions were controlled at room temperature of 20-26°C and relative humidity of 40%-70%; and food and water were freely available. The experiment selected experimental dogs with similar body weight and BCS (weight: 15-24 kg, BCS: 6-9) and randomly divided them into groups (n=6 / group): G1 group, G2 group, G3 group and G4 group. Group G1 was the vehicle control group. As shown in Table 20 below, for obese dogs in groups G2 and G3, the compound P016 of the present invention was administered subcutaneously once a week (QW) with increasing doses for a total of 6 consecutive administrations. For obese dogs in group G2, the first dose (4 nmol / kg) was administered on day 1 (D1) and day 8 (D8), adjusted to the second dose (6 nmol / kg) on ​​day 15 (D15), and adjusted to the third dose (96 nmol / kg) on ​​day 22 (D22). On day 29 (D29) and day 36 (D36), the third dose (96 nmol / kg) was maintained. For obese dogs in group G3, the first dose (12 nmol / kg) was administered on day 1 (D1) and day 8 (D8), adjusted to the second dose (19 nmol / kg) on ​​day 15 (D15), and adjusted to the third dose (385 nmol / kg) on ​​day 22 (D22). On day 29 (D29) and day 36 (D36), the third dose (385 nmol / kg) was maintained. For the obese dogs in group G4, the positive control Dirlotapide was administered at a dose of 0.5 mg / kg by gavage once a day for 42 consecutive days.

[0839] After dosing, animals in the dirlotapide-treated G4 group were weighed daily at a fixed time, while animals in the other groups (G1, G2, and G3) were weighed at a fixed time every 7 days. Food intake was measured daily after dosing. Blood routine and biochemical tests were performed before grouping and on Day 43. Abdominal fat volume was assessed by imaging before grouping and on Days 43 to 45. Total adipose tissue volume (TFV) and visceral adipose tissue volume (VFV) were measured, and abdominal subcutaneous fat volume (SFV) was calculated. Body condition score (BCS), body mass index (BMI), and abdominal circumference (AC) were measured weekly. Data were analyzed using ANOVA. If the ANOVA was statistically significant (p < 0.05) and the variances were homogeneous, intergroup comparisons were performed using the Tukey test. If the variances were not homogeneous, intergroup comparisons were performed using the Dunnet's T3 test. Results are expressed as mean ± SEM. The test level was 0.05, and both statistical and biological significance were considered when analyzing the results.

[0840] In experiments conducted as described above, the compound P016 of the present invention, administered subcutaneously in increasing doses QW for six consecutive times, significantly reduced body weight, BMI, SFV, and TFV in obese dogs (Table 20), as well as food intake. The effective dose of P016 for weight loss was 96 nmol / kg (equivalent to 0.5 mg / kg), with a maximum weight loss of 9.51%. This weight loss efficacy was superior to that of the marketed drug Dirlotapide (weight loss: 4.72%), as shown in Figures 6 and 7.

[0841] Table 20. Dosage regimen of compound P016 administered to obese dogs in groups G2 and G3

[0842] Table 21. Comparison of the change rate of abdominal fat index in each group of dogs (D43) (Mean ± SEM) Note: The dose of G2 and G3 groups was adjusted from the first dose (4 and 12 nmol / kg) to the second dose (6 and 19 nmol / kg) on ​​D15, and then to the third dose (96 and 385 nmol / kg) on ​​D22, D29 and D36; *p<0.05, **p<0.05 compared with Vehicle

[0843] (5) Weight loss efficacy in obese cats

[0844] In this study, the compound of the present invention was administered subcutaneously to obese cats multiple times, and the changes in the cats' weight were detected to illustrate the weight-loss effect of the compound of the present invention. In this study, cats aged 8 months and above with a body condition score (BCS) ≥ 6 were used. Obese cats were kept in cat cages of appropriate specifications; environmental conditions were controlled at room temperature of 20-26°C and relative humidity of 40%-70%; food and water were freely available. The experiment selected experimental cats with similar weight and BCS (weight: 3.3-7.5 kg, BCS: 6-9) and randomly divided them into groups (n=6 / group): G11 group, G12 group, G13 group and G14 group. Group G11 was the vehicle control group. As shown in Table 22 below, the compound P016 of the present invention was administered subcutaneously to groups G12, G13 and G14, once a week (QW), with increasing doses, for a total of 5 consecutive administrations. For obese cats in group G12, the first dose (4 nmol / kg) was administered on day 1 (D1) and day 8 (D8), adjusted to the second dose (48 nmol / kg) on ​​day 15 (D15), adjusted to the third dose (96 nmol / kg) on ​​day 22 (D22), and maintained at the third dose (96 nmol / kg) on ​​day 29 (D29). For obese cats in group G13, the first dose (14 nmol / kg) was administered on day 1 (D1) and day 8 (D8), adjusted to the second dose (96 nmol / kg) on ​​day 15 (D15), adjusted to the third dose (192 nmol / kg) on ​​day 22 (D22), and maintained at the third dose (192 nmol / kg) on ​​day 29 (D29). For obese cats in group G14, the first dose (58 nmol / kg) was given on day 1 (D1) and day 8 (D8), adjusted to the second dose (192 nmol / kg) on ​​day 15 (D15), and adjusted to the third dose (385 nmol / kg) on ​​day 22 (D22), and maintained at the third dose (385 nmol / kg) on ​​day 29 (D29).

[0845] The animals were weighed at a fixed time every 7 days after administration. Food intake was measured once a day after administration. Routine blood tests and blood biochemistry were performed before grouping and on D36. Cat body condition score (BCS), cat body mass index (FBMI) and abdominal circumference (AC) were tested once a week. The data results were statistically analyzed using ANOVA. If the ANOVA was statistically significant (p<0.05) and the variance was homogeneous, the Tukey test was used for inter-group comparison analysis. If the variance was not homogeneous, the Dunnet't T3 test was used for inter-group comparison analysis. The results were expressed as mean and standard deviation (Mean±SEM). The test level was 0.05, and both statistical significance and biological significance were considered when analyzing the results.

[0846] In experiments conducted as described above, the compound P016, administered subcutaneously five times daily (QW) in increasing doses, significantly reduced body weight, cumulative food intake, AC, and BCS in obese cats. The effective dose of P016 for weight loss was 96 nmol / kg (equivalent to 0.5 mg / kg), with a maximum weight loss of 19.45%, as shown in Figures 8 and 9.

[0847] Table 22 Dosage regimen of compound P016 administered to obese cats in groups G12, G13, and G14

[0848] (VI) Repeated administration of drugs to male rats for 2 weeks

[0849] 1. Experimental Design

[0850] Seventy-seven male Sprague-Dawley (SPF) rats were randomly divided into 10 groups according to body weight. Group 1 was a vehicle control group consisting of 5 animals. Groups 2-4 were commercially available drug control groups (Tirzepatide), each consisting of 8 animals (5 animals in the main test and 3 animals in the toxicity group), with doses of 1, 3, and 10 mg / kg, respectively. Groups 5-7 were test group 1, and groups 8-10 were test group 2. Each group consisted of 8 animals (5 animals in the main test and 3 animals in the toxicity group), with doses of 1, 3, and 10 mg / kg, respectively. All groups were dosed twice weekly for 2 consecutive weeks (dosing days: Days 1, 5, 8, 12, and 15).

[0851] During the experiment, all groups of animals were subjected to cage observation, detailed clinical observation, food consumption measurement, body weight measurement, blood biochemistry and hematological index measurement, gross anatomical observation, organ weighing, and toxicokinetic study.

[0852] 2. Data Statistics

[0853] The following table details the combinations used for statistical comparison.

[0854] Statistical Methods Table

[0855] Raw data for each time period will be tabulated, and the mean and standard deviation / or category change will be calculated for each endpoint by group and sex. For each endpoint, the treated group will be compared to the control group as described below. Endpoint data will be log-transformed before the start of specific analyses, as required.

[0856] Statistical analysis table

[0857] 3. Experimental Results

[0858] Body Weight / Weight Gain: After the first dose, weight loss was observed in all treatment groups at the following doses: Tirzepatide ≥ 3 mg / kg; P014 and P016 ≥ 1 mg / kg. With continued dosing, body weight recovered, and by the end of dosing, all groups maintained weight gain, but weight gain was lower than that of the control group, demonstrating a clear dose-related relationship.

[0859] Food intake: A dose-related decrease in food intake was observed in all the treatment groups (Tirzepatide, P014 and P016) throughout the entire experiment. Blood biochemistry: Amylase and triglyceride levels decreased. Hematology: Reticulocyte levels were slightly decreased. Gross autopsy: No abnormalities were found in any of the treatment groups (Tirzepatide, P014 and P016). Organ weight: The weight of the heart, liver, spleen, etc. in each treatment group (Tirzepatide, P014 and P016) was reduced, with little difference compared with the vehicle control group, which may be related to weight loss and is considered to be related to pharmacological effects. Toxicity: C in the Tirzepatide, P014 and P016 groups was significantly decreased. max Both the AUC and the TZP level increased in a dose-proportional manner. No significant accumulation was observed in the TZP, P014, and P016 dose groups after administration twice a week for 2 consecutive weeks.

[0860] Each treatment group (Tirzepatide, P014 and P016) was given twice a week, and the MTD of the two-week treatment was ≥10 mg / kg, corresponding to the C max and AUC last And the test safety window results are as follows:

[0861] Table 23. Safety window of each dosing group

[0862] In summary, the toxicity properties of P016 and P014 are similar to those of Tirzepatide, but they have a higher safety window (calculated by exposure, the safety window of P014 is more than 4 times that of Tirzepatide, while the safety window of P016 is more than 7 times that of Tirzepatide).

[0863] In addition, relative to the safety window of P001, the safety window of the compounds of the present invention is 10 times larger, or 20 times larger, or 30 times larger, or 40 times larger, or 50 times larger, or 60 times larger, or 70 times larger, or 80 times larger, or 90 times larger than that of P001, especially P014 and P016.

[0864] At the same time, at the same exposure dose, the effect of the compound of the present invention on HR is lower than that of Tirepatide, the heart rate increase of P016 is lower than that of Tirepatide, and there is no sustained heart rate acceleration of more than 30%. At the same exposure dose, the heart rate recovery of P016 is faster than that of TZP (the recovery time of P016 is between 72 and 120 hours, and the recovery time of TZP is greater than 120 hours).

[0865] The peptide compounds and applications provided by the present invention are introduced in detail above.

[0866] Specific examples are used herein to illustrate the principles and implementation methods of the present invention. The above examples are merely intended to facilitate understanding of the methods and central concepts of the present invention. It should be noted that those skilled in the art may make various improvements and modifications to the present invention without departing from the principles of the present invention, and such improvements and modifications are also protected by the claims of the present invention.

[0867] Amino acid sequence:

Claims

1. Use of a compound of the following formula (AI) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal: Y-X1-EGT-X2-TSDY-A11-A12-A13-LDK-A17-AQ-A20-EFVKWLLK-A29-GPSSGAPPPSK Formula (AI); wherein X1 is Aib; X2 is αMePhe; A11 is Aib or Ala; A12 is Ala, Ile, Lys, Phe or Pya (4); A13 is Aib, Cha, Leu, αMePhe or αMeTyr; A17 is Gln or Ile; A20 is Ala or Ser; A29 is Gln or Gly, 1 K, 2 K, 3 K or 4 K positions are selected from the 16th, 24th, 28th and 40th positions by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -Z is chemically modified by conjugating to the ε-amino group of the K side chain, wherein each a is independently an integer from 0 to 5, each b is independently an integer from 0 to 5, and each c is independently an integer from 10 to 24, wherein Z is independently selected from -CH3, carboxylic acid or carboxylic acid bioisostere, phosphonate / ester or sulfonate / ester.

2. The use according to claim 1, wherein A11 is Aib; or / and A12 is Ile; or / and A13 is Aib; or / and A17 is Gln; or / and A20 is Ala; or / and A29 is Gly; or / and a is independently selected from an integer of 1, 2, 3, 4 or 5, b is independently selected from an integer of 1, 2, 3, 4 or 5, c is independently selected from an integer of 12 to 22; further, c is independently selected from 14, 16, 18 or 20.

3. Use of a compound of the following formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a disease in a non-primate or non-rodent animal: Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK formula (I); wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; 1, 2, 3 or 4 K positions are selected from positions 16, 24, 28 and 40, by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -Z is chemically modified by conjugating to the ε-amino group of the K side chain, wherein each a is independently an integer from 0 to 5, each b is independently an integer from 0 to 5, each c is independently an integer from 10 to 24, wherein Z is independently selected from -CH3, carboxylic acid or carboxylic acid bioisostere, phosphonate / ester or sulfonate / ester; and the C-terminal amino acid is amidated to form a C-terminal primary amide.

4. The use according to claim 3, wherein the compound is: Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK formula (I), or a pharmaceutically acceptable salt thereof, wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; one or two K positions are selected from the 16th, 24th, 28th, and 40th positions by using ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -Z is chemically modified by conjugating to the ε-amino group of the K side chain, wherein Z is independently selected from -CH3, carboxylic acid or carboxylic acid bioisostere, phosphonate / ester or sulfonate / ester, preferably -CO2H, each a is independently an integer from 0 to 5, each b is independently an integer from 0 to 5, and each c is independently an integer from 10 to 22; and the C-terminal amino acid is amidated to form a C-terminal primary amide.

5. The use according to claim 4, wherein At position 16, K is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain for chemical modification; or At position 24, K is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain for chemical modification; or At position 28, K is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain for chemical modification; or At position 40, K is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H was conjugated to the ε-amino group of the K side chain for chemical modification.

6. The use according to claim 4, wherein K at positions 24 and 28 is synthesized by replacing ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain to chemically modify the two modified chains; or K at positions 16 and 24 is synthesized by replacing ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain to chemically modify the two modified chains; or K at positions 16 and 28 was synthesized by replacing ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain to chemically modify the two modified chains; or K at positions 16 and 40 was synthesized by replacing ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain to chemically modify the two modified chains; or K at positions 24 and 40 is synthesized by replacing ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain to chemically modify the two modified chains; or K at positions 28 and 40 is synthesized by replacing ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H was conjugated to the ε-amino group of the K side chain to perform chemical modification of the two modified chains.

7. The use according to any one of claims 3 to 6, wherein a is independently selected from an integer of 1, 2, 3, 4 or 5, b is independently selected from an integer of 1, 2, 3, 4 or 5, c is independently selected from an integer of 12 to 22; further, c is independently selected from 14, 16, 18 or 20; and / or Z is -CO2H.

8. The use according to claim 4, wherein the compound is Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK formula (I); wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 24 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain and chemically modified, wherein a is independently selected from an integer from 0 to 5, b is independently selected from an integer from 0 to 5, and c is independently selected from an integer from 10 to 24; and the C-terminal amino acid is amidated to a C-terminal primary amide.

9. The use according to claim 4, wherein the compound is Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK formula (I); wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl) a -(γ-Glu) b -CO-(CH2) c -CO2H is conjugated to the ε-amino group of the K side chain and chemically modified, wherein a is independently selected from an integer from 0 to 5, b is independently selected from an integer from 0 to 5, and c is independently selected from an integer from 10 to 24; and the C-terminal amino acid is amidated to a C-terminal primary amide.

10. The use according to any one of claims 8-9, wherein a is independently selected from an integer of 1, 2, 3, 4 or 5, b is independently selected from an integer of 1, 2, 3, 4 or 5, c is independently selected from an integer of 12 to 22; further, c is independently selected from 14, 16, 18 or 20.

11. The use according to claim 4, wherein the compound is Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK; wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 24 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)1-CO-(CH2) 16 -CO2H is conjugated to the ε-amino group of the K side chain and chemically modified; and the C-terminal amino acid is amidated to a C-terminal primary amide (SEQ ID NO: 7); or Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK; wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 24 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)1-CO-(CH2) 18 -CO2H is conjugated to the ε-amino group of the K side chain and chemically modified; and the C-terminal amino acid is amidated to a C-terminal primary amide (SEQ ID NO: 13); or Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK; wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 24 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)1-CO-(CH2) 20 -CO2H is conjugated to the ε-amino group of the K side chain and chemically modified; and the C-terminal amino acid is amidated to a C-terminal primary amide (SEQ ID NO: 14); or Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK; wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 24 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)3-CO-(CH2) 16 -CO2H is conjugated to the ε-amino group of the K side chain and chemically modified; and the C-terminal amino acid is amidated to a C-terminal primary amide (SEQ ID NO: 15); or Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK; wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 24 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)3-(γ-Glu)1-CO-(CH2) 20 -CO2H is conjugated to the ε-amino group of the K side chain and chemically modified; and the C-terminal amino acid is amidated to a C-terminal primary amide (SEQ ID NO: 16); or Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK; wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)1-CO-(CH2) 16 -CO2H is conjugated to the ε-amino group of the K side chain and chemically modified; and the C-terminal amino acid is amidated to a C-terminal primary amide (SEQ ID NO: 8); or Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK; wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)1-CO-(CH2) 20 -CO2H is conjugated to the ε-amino group of the K side chain and chemically modified; and the C-terminal amino acid is amidated to a C-terminal primary amide (SEQ ID NO: 17); or Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK; wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)3-CO-(CH2) 16 -CO2H is conjugated to the ε-amino group of the K side chain and chemically modified; and the C-terminal amino acid is amidated to a C-terminal primary amide (SEQ ID NO: 18); or Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK; wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)3-(γ-Glu)1-CO-(CH2) 16 -CO2H is conjugated to the ε-amino group of the K side chain and chemically modified; and the C-terminal amino acid is amidated to a C-terminal primary amide (SEQ ID NO: 19); or Y-X1-EGT-X2-TSDY-X3-I-X4-LDKQAQAEFVKWLLKGGPSSG-APPPSK; wherein X1 is Aib; X2 is αMePhe; X3 is Aib; X4 is Aib; K at position 28 is replaced by ([2-(2-amino-ethoxy)-ethoxy]-acetyl)3-(γ-Glu)1-CO-(CH2) 20 -CO2H was conjugated to the ε-amino group of the K side chain and chemically modified; and the C-terminal amino acid was amidated to a C-terminal primary amide (SEQ ID NO: 20).

12. The use according to claim 4, wherein the compound is or a pharmaceutically acceptable salt thereof.

13. The method of claim 1 , wherein the disease comprises hyperglycemia, impaired glucose tolerance, diabetes (including type I diabetes, type II diabetes), obesity, hypertension, dyslipidemia, cognitive impairment, atherosclerosis, myocardial infarction, coronary heart disease and other cardiovascular diseases, stroke, inflammatory bowel syndrome, dyspepsia and gastric ulcer.

14. The use according to any one of claims 1 to 12, wherein the drug is a drug for preventing, delaying or treating type II diabetes.

15. The use according to any one of claims 1 to 12, wherein the compound or a pharmaceutically acceptable salt thereof is used to prepare a medicament for reducing animal food intake, reducing β-cell apoptosis, increasing β-cell function and β-cell mass and / or restoring β-cell glucose sensitivity.

16. The use according to any one of claims 1 to 12, wherein the disease comprises metabolic disorders, dyslipidemia associated with insulin resistance and diabetes, obesity and / or hepatic steatosis.

17. The use according to any one of claims 1 to 12, wherein the disease comprises osteopenia, bone / joint diseases, such as knee osteoarthritis, hip osteoarthritis, and / or deforming spondylitis.

18. The use according to any one of claims 1 to 12, wherein the compound or a pharmaceutically acceptable salt thereof is used in overweight or obese animals as an adjunct to a reduced calorie diet and increased physical activity for long-term weight management.

19. The use according to any one of claims 1 to 12, wherein the disease comprises: Symptomatic obesity, obesity based on simple obesity, disease states or diseases related to obesity, eating disorders, diabetes (e.g., type I diabetes, type II diabetes, gestational diabetes, obese diabetes), hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, high LDL-cholesterolemia, low HDL-cholesterolemia, postprandial hyperlipidemia), hypertension, heart failure, complications of diabetes (e.g., neuropathy, nephropathy, retinopathy, diabetic cardiomyopathy, cataracts, macroangiopathy, osteopenia, hyperosmolar diabetic coma), infectious diseases (e.g., respiratory tract infections, urinary tract infections, gastrointestinal infections, superficial soft tissue infections, lower limb infections), diabetic gangrene, dry mouth, hearing loss, cerebrovascular disorders, peripheral blood circulation disorders, metabolic syndrome (a disease state having three or more selected from hypertriglyceridemia, low HDL cholesterolemia, hypertension, abdominal obesity and impaired glucose tolerance), and / or sarcopenia.

20. The use according to any one of claims 1 to 19, wherein the animal is a pet.

21. The use according to claim 20, wherein the pet is selected from the group consisting of dogs, cats, rabbits, pigs, alpacas, horses, sheep and cattle.

22. The use according to any one of claims 1 to 21, wherein the animal is a dog or a cat.

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