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EP-4735456-A1 - HETEROCYCLIC GLP-1 AGONISTS

EP4735456A1EP 4735456 A1EP4735456 A1EP 4735456A1EP-4735456-A1

Abstract

The present invention relates to a compound of formula I, which is a GLP-1 agonist, and pharmaceutical compositions comprising the same, as well as methods for treating a GLP-1 associated disease, disorder, or condition.

Inventors

  • JIANG, XINGLONG
  • LEI, HUI
  • LIU, CUIPING
  • LU, CHUNLIANG
  • ZHANG, Jinqiang

Assignees

  • Gasherbrum Bio, Inc.

Dates

Publication Date
20260506
Application Date
20240628

Claims (20)

  1. CLAIMS: or a stereoisomer or mixture of stereoisomers thereof, or pharmaceutically acceptable salt thereof; wherein: R 1 and R 2 are each independently C 1-3 alkyl or cyclopropyl.
  2. 2. The compound of claim 1, or a stereoisomer or mixture of stereoisomers thereof, or pharmaceutically acceptable salt thereof, wherein R 1 is methyl.
  3. 3. The compound of claim 1, or a stereoisomer or mixture of stereoisomers thereof, or pharmaceutically acceptable salt thereof, wherein R 1 is ethyl.
  4. 4. The compound of claim 1, or a stereoisomer or mixture of stereoisomers thereof, or pharmaceutically acceptable salt thereof, wherein R 1 is zz-propyl.
  5. 5. The compound of claim 1, or a stereoisomer or mixture of stereoisomers thereof, or pharmaceutically acceptable salt thereof, wherein R 1 is z-propyl.
  6. 6. The compound of claim 1, or a stereoisomer or mixture of stereoisomers thereof, or pharmaceutically acceptable salt thereof, wherein R 1 is cyclopropyl.
  7. 7. The compound of any one of claims 1-6, or a stereoisomer or mixture of stereoisomers thereof, or pharmaceutically acceptable salt thereof, wherein R 2 is methyl.
  8. 8. The compound of any one of claims 1-6, or a stereoisomer or mixture of stereoisomers thereof, or pharmaceutically acceptable salt thereof, wherein R 2 is ethyl.
  9. 9. The compound of any one of claims 1-6, or a stereoisomer or mixture of stereoisomers thereof, or pharmaceutically acceptable salt thereof, wherein R 2 is n-propyl.
  10. 10. The compound of any one of claims 1-6, or a stereoisomer or mixture of stereoisomers thereof, or pharmaceutically acceptable salt thereof, wherein R 2 is z-propyl.
  11. 11. The compound of any one of claims 1-6, or a stereoisomer or mixture of stereoisomers thereof, or pharmaceutically acceptable salt thereof, wherein R 2 is cyclopropyl.
  12. 12. The compound of claim 1, wherein the compound is Compound IA: or a stereoisomer or mixture of stereoisomers thereof, or pharmaceutically acceptable salt thereof.
  13. 13. The compound of claim 1, wherein the compound is Compound IB: or a stereoisomer or mixture of stereoisomers thereof, or pharmaceutically acceptable salt thereof.
  14. 14. A compound selected from: or a pharmaceutically acceptable salt thereof.
  15. 15. The compound of any one of claims 1-14, or a stereoisomer or mixture of stereoisomers thereof, or pharmaceutically acceptable salt thereof, wherein the compound, or stereoisomer or mixture of stereoisomers thereof, or pharmaceutically acceptable salt thereof, is substantially isolated.
  16. 16. The compound of any one of claims 1-15, or a stereoisomer or mixture of stereoisomers thereof, or pharmaceutically acceptable salt thereof, wherein the compound, or stereoisomer or mixture of stereoisomers thereof, or pharmaceutically acceptable salt thereof, is substantially solid.
  17. 17. A composition comprising a compound, or a stereoisomer or mixture of stereoisomers thereof, or pharmaceutically acceptable salt thereof, of any one of claims 1-16, which has greater than about 75%, or about 80%, or about 85%, or about 90%, or about 95% purity.
  18. 18. A composition comprising the compound, or a stereoisomer or mixture of stereoisomers thereof, or pharmaceutically acceptable salt thereof, of any one of claims 1-16, wherein the compound, or a stereoisomer or mixture of stereoisomers thereof, or pharmaceutically acceptable salt thereof, is present in the composition in an amount greater than about 25%, or 50%, or 75%, by weight.
  19. 19. A pharmaceutical composition comprising the compound of any one of claims 1-16, or a stereoisomer or mixture of stereoisomers thereof, or pharmaceutically acceptable salt thereof, or the composition of claim 17 or 18, and a pharmaceutically acceptable excipient.
  20. 20. The pharmaceutical composition of claim 19, wherein the compound, or a stereoisomer or mixture of stereoisomers thereof, or pharmaceutically acceptable salt thereof, is present in the composition in an amount greater than about 0.1 % by weight.

Description

HETEROCYCLIC GLP-1 AGONISTS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of International Patent Application Number PCT/CN2023/105088, filed June 30, 2023, which is hereby incorporated by reference in its entirety. FIELD [0002] This disclosure relates to GLP-1 agonists, pharmaceutical compositions, and methods of use thereof. BACKGROUND [0003] Incretin metabolic hormones, including glucagon-like peptide- 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), arc important in the regulation of glucose homeostasis. Medicaments targeting this family of intestinal peptides, such as GLP-1 agonists, have been shown to suppress glucagon production, decrease gastric motility, and increase satiety. [0004] 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 more than 90% of diabetes cases. Typical onset occurs in obese or otherwise sedentary adults and begins with insulin resistance. Though lifestyle changes can be useful in management of this disorder, patients with T2DM may be required to take antidiabetic medications, including dipeptidyl peptidase-4 inhibitors, SGLT2 inhibitors, and sulfonylureas, among others. [0005] In healthy individuals, the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) provide tandem modulation of insulin secretory response to glucose ingestion. While this incretin effect is significantly diminished (if at all present) in cases of T2DM, GLP- 1 retains insulinotropic properties, even as endocrine pancreatic response to GIP is effectively halted. As such, incretin mimetics and other GLP-l-based therapies can help stimulate insulin production in T2DM patients. SUMMARY [0006] The present application describes heterocyclic GLP-1 agonists, as well as pharmaceutical compositions comprising the compounds disclosed herein. Also provided are methods for treating GLP- 1-associated diseases, disorders, and conditions. [0007] This disclosure also provides pharmaceutical compositions comprising one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [0008] Also provided herein are pharmaceutical compositions comprising one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [0009] Also provided herein are methods for treating type 2 diabetes mellitus in a patient in need thereof, the methods comprising administering to the patient a therapeutically effective amount of one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. [0010] Also provided herein are methods for treating type 2 diabetes mellitus in a patient, the methods comprising administering to a patient identified or diagnosed as having type 2 diabetes mellitus a therapeutically effective amount of one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. [0011] Also provided herein are methods for treating diabetes mellitus in a patient, the methods comprising determining that the patient has type 2 diabetes mellitus; and administering to the patient a therapeutically effective amount of one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the step of determining that the patient has type 2 diabetes mellitus includes performing an assay to determine the level of an analyte in a sample from the patient, wherein the analyte is selected from the group consisting of hemoglobin Ale (HbAlc), fasting plasma glucose, non-fasting plasma glucose, or any combination thereof. In some embodiments, the level of HbAlc is greater than or about 6.5%. In some embodiments, the level of fasting plasma glucose is greater than or about 126 mg/dL. In some embodiments, the level of non-fasting plasma glucose is greater than or about 200 mg/dL. [0012] In some embodiments, the methods further comprise obtaining a sample from the patient. In some embodiments, the sample is a body fluid sample. In some embodiments, the patient is about 40 to about 70 years old and is overweight or obese. In some embodiments, the patient has a body mass index (BMI) greater than or about 22 kg/m2. In some embodiments, the patient has a BMI greater than or about 30 kg/m2. [0013] In some embodiments, the methods for the treatment of type 2 diabetes mellitus comprise a reduction in fas