Novel Imidazopyridine and Imidazopyridazine Derivatives as DGAT2 Inhibitors for Treating Multiple Diseases

Abstract

Provided herein are novel imidazopyridine and imidazopyridazine derivatives as DGAT2 inhibitors, pharmaceutical compositions, use of such compounds in treating multiple diseases, and processes for preparing such compounds.

Important Compound Classes

Title

Preparation of Imidazopyridine and Imidazopyridazine Derivatives as Novel Diacylglyceride O-acyltransferase 2 Inhibitors

Patent Publication Number

WO 2024/097573 A1

URL: https://patents.google.com/patent/WO2024097573A1/en

Publication Date

May 10, 2024

Priority Application

US 63/421,362

Priority Date

November 1, 2022

Inventors

Lim, Y.-H.; Hugelshofer, C. L.; Metwally, E.; Roane, J. P.; Shockley, S. E.

Assignee Company

Merck Sharp & Dohme LLC, USA

Disease Area

Hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type-2 diabetes mellitus, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, chronic kidney diseases and heart failure

Biological Target

Diacylglyceride O-acyltransferase 2

Summary

Triacylglycerols (TGs) serve several functions in living organisms. One such function of TGs is in the storage of energy. TGs also play a role in the synthesis of membrane lipids. TG synthesis in cells may protect them from the potentially toxic effects of excess fatty acid (FA). The glycerol phosphate and the monoacylglycerol pathways are the major pathways for the biosynthesis of TG, However, the last step in the synthesis of TG involves the reaction of a fatty acyl-CoA and diacylglycerol (DAG) to form TG. The reaction is catalyzed by acyl-CoA: diacylglyceride acyltransferase (DGAT) enzymes. These have been identified two DGAT enzymes: DGAT1 and DGAT2. Inactivation of DGAT2 impaired cytosolic lipid droplet growth, whereas inactivation of DGAT1 exerts the opposite effect.

DGAT2 appears to be the dominant DGAT enzyme controlling TG homeostasis in vivo. The metabolic role of DGAT2 has been mostly understood from effort exploiting antisense oligonucleotides (ASO) in rodents. In this setting, DGAT2 knockdown in ob/ob mice with a DGAT2 gene-specific ASO resulted in a dose-dependent decrease in very low density lipoprotein (VLDL) and a reduction in plasma TG, total cholesterol and ApoB. Another study showed that diet-induced hepatic steatosis and insulin resistance was improved by knocking down DGAT2 in rats.

The present application describes a series of novel imidazopyridine and imidazopyridazine derivatives as DGAT2 inhibitors for the treatment of multiple diseases. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.

Definitions

X, Y and Z = N and C(R₄);

R₁ = 6-membered aryl unsubstituted or substituted with 1, 2, or 3 R₅, 6-membered heteroaryl containing 1 or 2 N atoms, -(C_1–6)alkyl-aryl, -(C_1–6)alkyl-heteroaryl, -(C_1–3)haloalkyl, or -(C_1–6)alkyl-O-(C_1–6)alkyl;

R₂ = 4- to 7-membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O and S, phenyl, 5- or 6-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O and S, -(C_1–6)alkyl-hetercyclyl, -(C_1–6)alkyl-aryl, -(C_3–6)cycloalkyl, -(C_3–6)cyclic amine, -(C_3–6)cycloalkyl-(C_1–6)alkyl-SO₂-(C_1–6)alkyl or 8–10-membered fused bicyclic heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O and S; and

R₃ = hydrogen, halogen, hydroxy, (C_1–6)alkyl, (C_1–6)haloalkyl, (C_1–6)alkylhydroxy, (C_1–6)alkoxy, C(=O)NH₂, C(=O)OH or O-(C_1–6)alkyl.

Key Structures

Biological Assay

The DGAT2 enzymatic activity assay was performed. The compounds described in this application were tested for their ability to inhibit DGAT2. The DGAT2 IC₅₀ values (nM) are shown in the following table.

Biological Data

The table below shows representative compounds that were tested for DGAT2 inhibition and the biological data obtained from testing representative examples.

Claims

Total claims: 47

Compound claims: 43

Composition claims: 2

Method of treatment claims: 1

Use of compound claims: 1

Recent Review Articles

See refs (1−5).

The author declares no competing financial interest.