KR-20260064683-A - Heterocyclic GLP-1 agonists

Abstract

The present invention relates to a compound of formula I which is a GLP-1 agonist and a pharmaceutical composition containing the same, as well as a method for treating GLP-1-related diseases, disorders, or conditions.

Inventors

• 지앙, 싱롱
• 레이, 후이
• 리우, 쿠이핑
• 루, 춘리앙
• 장, 진치앙

Assignees

• 가셔브룸 바이오, 인크.

Dates

Publication Date

20260507

Application Date

20240628

Priority Date

20230630

Claims (20)

1. Compound of Formula I or its stereoisomers or mixtures of stereoisomers or its pharmaceutically permissible salts: Here R1 and R2 are each independently C1-3 alkyl or cyclopropyl.
2. In claim 1, a compound in which R1 is methyl, or its stereoisomer or a mixture of stereoisomers, or a pharmaceutically permissible salt thereof.
3. In paragraph 1, a compound in which R1 is ethyl, or its stereoisomer or a mixture of stereoisomers or its pharmaceutically permissible salt.
4. In claim 1, a compound in which R1 is n-propyl, or its stereoisomer or a mixture of stereoisomers or a pharmaceutically permissible salt thereof.
5. In claim 1, a compound in which R1 is i-propyl or its stereoisomer or a mixture of stereoisomers or a pharmaceutically permissible salt thereof.
6. In claim 1, a compound in which R1 is cyclopropyl or its stereoisomer or a mixture of stereoisomers or its pharmaceutically permissible salt.
7. In any one of claims 1 to 6, a compound in which R2 is methyl, or its stereoisomer or a mixture of stereoisomers, or a pharmaceutically permissible salt thereof.
8. In any one of claims 1 to 6, a compound in which R₂ is ethyl, or its stereoisomer or a mixture of stereoisomers, or a pharmaceutically permissible salt thereof.
9. In any one of claims 1 to 6, a compound in which R2 is n-propyl, or its stereoisomer or a mixture of stereoisomers, or a pharmaceutically permissible salt thereof.
10. In any one of claims 1 to 6, a compound in which R2 is i-propyl, or its stereoisomer or a mixture of stereoisomers, or a pharmaceutically permissible salt thereof.
11. In any one of claims 1 to 6, a compound in which R2 is cyclopropyl, or its stereoisomer or a mixture of stereoisomers, or a pharmaceutically permissible salt thereof.
12. In paragraph 1, the compound that is compound IA, or its stereoisomer or a mixture of stereoisomers or its pharmaceutically permissible salt: .
13. In paragraph 1, the compound that is compound IB, or its stereoisomer or a mixture of stereoisomers or a pharmaceutically permissible salt thereof: .
14. Compounds selected from the following: Or a salt permitted by his constraints.
15. In any one of claims 1 to 14, a substantially isolated compound or its stereoisomer or a mixture of stereoisomers or a salt thereof that is pharmaceutically permissible.
16. In any one of claims 1 to 15, a substantially solid compound or its stereoisomer or a mixture of stereoisomers or a salt thereof that is pharmaceutically permissible.
17. A composition comprising a compound of any one of claims 1 to 16, or a stereoisomer thereof, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, having a purity of about 75%, or about 80%, or about 85%, or about 90%, or more than about 95%.
18. A composition comprising a compound of any one of claims 1 to 16, a stereoisomer thereof, a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, wherein the compound or the stereoisomer thereof, a mixture of stereoisomers thereof, or the pharmaceutically acceptable salt thereof is present in an amount greater than about 25%, 50%, or 75% by weight in the composition.
19. A pharmaceutical composition comprising a compound of any one of claims 1 to 16, or its stereoisomer or a mixture of stereoisomers or a pharmaceutically acceptable salt thereof, or the composition of claim 17 or 18, and a pharmaceutically acceptable excipient.
20. A pharmaceutical composition according to claim 19, wherein a compound or its stereoisomer or a mixture of stereoisomers or a pharmaceutically permissible salt thereof is present in the composition in an amount greater than about 0.1% by weight.

Description

Heterocyclic GLP-1 agonists Cross-reference regarding related applications This application claims priority to international patent application number PCT/CN2023/105088 filed on June 30, 2023, the full text of which is incorporated herein by reference. field The present disclosure relates to a GLP-1 agonist, a pharmaceutical composition, and a method of using the same. Incretin metabolic hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulin secretion-stimulating polypeptide (GIP), are important for regulating glucose homeostasis. Drugs targeting this family of intestinal peptides, such as GLP-1 agonists, have been shown to inhibit glucagon production, reduce gastric motility, and increase satiety. Diabetes mellitus refers to a group of metabolic disorders characterized by persistent hyperglycemia. The most common form, Type 2 diabetes mellitus (T2DM), is an acquired condition that accounts for over 90% of diabetes cases. Typical onset occurs in obese or otherwise sedentary adults and begins with insulin resistance. While lifestyle changes can be useful in managing this disorder, patients with T2DM may be required to take antidiabetic medications, particularly dipeptidyl peptidase-4 inhibitors, SGLT2 inhibitors, and sulfonylureas. In healthy individuals, the incretin hormones glucose-dependent insulin secretion-stimulating polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) provide tandem modulation of the insulin secretion response to glucose uptake. Although these incretin effects are significantly reduced in the case of T2DM (even if present), GLP-1 retains its insulin secretion-stimulating properties even when the endocrine pancreatic response to GIP is effectively stopped. Therefore, incretin mimics and other GLP-1-based therapies can help stimulate insulin production in patients with T2DM. This application describes heterocyclic GLP-1 agonists as well as pharmaceutical compositions comprising compounds disclosed herein. Methods for treating GLP-1-related diseases, disorders, and conditions are also provided. The present disclosure also provides a pharmaceutical composition comprising one or more compounds as disclosed herein, or stereoisomers thereof or mixtures of stereoisomers thereof, or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients. In addition, a pharmaceutical composition comprising one or more compounds as disclosed herein, or stereoisomers thereof or a mixture of stereoisomers thereof, or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients is provided herein. Additionally, the present invention provides a method for treating type 2 diabetes in a patient requiring treatment for type 2 diabetes, comprising administering to the patient a therapeutically effective amount of one or more compounds as disclosed herein, or stereoisomers thereof, or mixtures of stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof. Additionally, a method for treating type 2 diabetes in a patient is provided herein, comprising administering a therapeutically effective amount of one or more compounds as disclosed herein, or stereoisomers thereof, or mixtures of stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof to a patient confirmed or diagnosed to have type 2 diabetes. Additionally, the present invention provides a method for treating diabetes in a patient comprising: determining whether the patient has type 2 diabetes; and administering to the patient a therapeutically effective amount of one or more compounds as disclosed herein, or stereoisomers thereof, or mixtures of stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof. In some embodiments, the step of determining whether the patient has type 2 diabetes comprises performing a test to determine the level of an analyte in a sample from the patient, wherein the analyte is selected from the group consisting of hemoglobin A1c (HbA1c), fasting plasma glucose, non-fasting plasma glucose, or any combination thereof. In some embodiments, the level of HbA1c is about 6.5% or higher. In some embodiments, the level of fasting plasma glucose is about 126 mg/dL or higher. In some embodiments, the level of non-fasting plasma glucose is about 200 mg/dL or higher. In some embodiments, the method further comprises obtaining a sample from a patient. In some embodiments, the sample is a body fluid sample. In some embodiments, the patient is about 40 to about 70 years of age and is overweight or obese. In some embodiments, the patient has a body mass index (BMI) of about 22 kg/ m² or higher. In some embodiments, the patient has a BMI of about 30 kg/ m² or higher. In some embodiments, the treatment method for type 2 diabetes includes reducing fasting plasma glucose levels. In some embodiments, fasting plasma glucose levels a