Novel 2,5-Diazabicyclo[4.2.0]octanes as GLP-1 Receptor Modulators for Treating Type 2 Diabetes

Abstract

Provided herein are 2,5-diazabicyclo[4.2.0]octanes as GLP-1 receptor modulators, pharmaceutical compositions, use of such compounds in treating type 2 diabetes, and processes for preparing such compounds.

Important Compound Classes

Title

Certain 2,5-Diazabicyclo[4.2.0]octanes as GLP-1 Receptor Modulators

Patent Publication Number

WO 2023/057427 A1

URL: https://patents.google.com/patent/WO2023057427A1/en

Publication Date

April 13, 2023

Priority Application

US 63/262,105 and US 63/264,441

Priority Date

October 5, 2021 and November 23, 2021

Inventors

Polla, M.; Bergman, J.; Sundell, J.; Brånalt, J.; Ratkova, E.; Kajanus, J.; Johansson, M.

Assignee Company

AstraZeneca AB, Sweden

Disease Area

Type 2 diabetes

Biological Target

Glucagon-like peptide-1 receptor (GLP-1R)

Summary

Obesity and type 2 diabetes (T2D) are major and growing health problems worldwide. The two diseases are strongly associated with each other, with obesity proceeding development of insulin resistance and T2D. Incretin hormones including glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are gut peptides that are secreted after nutrient intake and stimulate insulin secretion.

GLP-1 is secreted from L-cells in the lower gut in response to food intake. GLP-1 stimulates insulin secretion from the pancreatic cells in a glucose-dependent manner. GLP-1 also inhibits glucagon secretion, reduces appetite and shows down gastric emptying. The GLP-1 receptor (GLP-1R) is also present in the heart, kidneys and immune system, and its activation has been shown to reduce blood pressure, increase nutrients and decrease inflammation. Pharmacological stimulation of GLP-1 receptors has been shown to significantly reduce HbA1c levels, provide long-term weight loss and reduce blood pressure.

The present application describes a series of novel 2,5-diazabicyclo[4.2.0]octanes as GLP-1 receptor modulators for the treatment of cardiovascular and metabolic diseases, in particular, type 2 diabetes. Further, the application discloses compounds, their preparation, use, and pharmaceutical composition, and treatment.

Definitions

X₁ = N or C;

X₂ = N or C, provided that no more than two atoms in the aromatic ring A are N;

Z₁ = N or CR₃;

Z₂ and Z₃ = N or CR₄, provided that when Z₁ or Z₃ is N, Z₂ is CR₄;

R₁ = 0, 1, 2, or 3 substituents selected from F, Cl, Br, CN, OCH₃, OCFH₂, OCF₂H, OCF₃, CH₃, CFH₂, CF₂H and CF₃;

R₂ = F, Cl or CN;

R₅ = H, CH₃, CFH₂, CF₂H and CF₃;

R₆ = selected from (4- to 6-membered)heterocycloalkyl, (5- to 6-membered)heteroaryl, CN, C_1–4alkyl, O(C_1–4alkyl), S(C_1–4alkyl), cyclopropyl, cyclobutyl, O(cyclopropyl), S(cyclopropyl), wherein (4- to 6-membered)heterocycloalkyl and (5- to 6-membered)heteroaryl is substituted by 0 or 1 substituent selected from C_1–4alkyl and wherein said C_1–4alkyl is substituted by 0 or 1 substituent selected from CN or OCH₃ and 0, 1, 2, or 3 F;

R₇ = F, C_1–2alkyl and OC_1–2alkyl, wherein said C_1–2alkyl is substituted by 0, 1, 2, or 3 F;

m = 1, 2 or 3; n = 0 or 1; p = 1, 2 or 3; and q = 0, 1 or 2.

Key Structures

Biological Assay

The CHOK1 GLP-1R cAMP assay was performed. The compounds described in this application were tested for their ability to inhibit GLP-1R. The GLP-1R EC₅₀ values (nM) are shown in the table below.

Biological Data

The following table shows representative compounds that were tested for GLP-1R inhibition and the biological data obtained from testing representative examples.

Claims

Total claims: 14

Compound claims: 10

Pharmaceutical composition claims: 1

Method of treatment claims: 2

Use of compound claims: 1

Recent Review Articles

See refs (1−6).

The author declares no competing financial interest.