Novel MRGX2 Antagonists for Treating Diseases

Important Compound Classes

Title

MrgX2 Antagonists

Patent Publication Number

WO 2022/073904 A1

URL: https://patents.google.com/patent/WO2022073904A1/en

Publication Date

April 14, 2022

Priority Application

US 63/087,997

Priority Date

October 6, 2020

Inventors

Brnardic, E.; Bury, M.; Cadilla, R.; Collins, J.; Guo, Y.; Handlon, A.; Li, H.; Li, Y.; Paone, D.; Schulte, C.; Shearer, B.; Ye, G.; Ying, M.; Zhang, H.

Assignee Company

GlaxoSmithKline Intellectual Property Development Limited, Great Britain

Disease Area

Skin disorders, inflammatory bowel disease (IBD), arthritis, asthma, and migraine

Biological Target

MRGX2

Summary

Mature mammalian mast cells ordinarily reside near blood vessels or nerves, beneath or within epithelia, within airways, gastrointestinal tracts, and near smooth muscle and mucus-producing glands. Recent work has emphasized the role of the Mas-related G protein-coupled receptor (MRGPR) family, specifically, Mrgprb2, in mast cell activation. Mrgprb2 is the mouse receptor for several cationic molecules, collectively called basic secretagogues, and the ortholog of the human receptor MRGPRX2. Various observations using knock-out (KO) mice are consistent with the Mrgprb2/MRGPRX2 receptors playing a role in mast-cell-mediated neurogenic inflammation.

A substance P/Mrgprb2 sensory cluster was demonstrated to be critical in driving the clinical score of a severe preclinical model of atopic dermatitis. In addition to the various reports using Mrgprb2-deficient mice, further evidence suggests a role for various ligands of MRGPRX2 in human disease; for example, the number of MRGPRX2-expressing mast cells is significantly increased in severe chronic urticaria. In additional to skin disorders, mast cell involvement has been highlighted for inflammatory bowel disease (IBD), arthritis, asthma, and migraine.

The present application describes a series of novel compounds as MrgX2 (Mas-related Gene X2) antagonists for the treatment of skin disorders, IBD, arthritis, asthma, and migraine. Further, the application discloses compounds, their preparation, use, and pharmaceutical composition, and treatment.

Definitions

W = N or CH; X₁ = N or CR₁₀; X₂ = N or CR₁₁;

Y₁ = N or CR₁₂; Y₂ = N or CR₁₂;

Z =

R₁ = H, halogen, (C₁–C₆)alkyl, -(C₁–C₆)alkyl-NH₂, -(C₁–C₆)alkyl-NH(C₁–C₆)alkyl, -(C₁–C₆)alkyl-N(C₁–C₆)alkyl(-(C₁–C₆)alkyl), -(C₁–C₆)alkyl-(C₃–C₈)cycloalkyl, -(C₁–C₆)alkyl-aryl, 5- or 6-membered heteroaryl-(C₁–C₄)alkyl, -(C₃–C₈)cycloalkyl, -(C₂–C₆)alkenyl, -(C₂–C₆)alkenyl-(C₃–C₈)cycloalkyl, OH;

R₂ = H, halogen, (C₁–C₆)alkyl or OH, wherein (C₁–C₆)alkyl is substituted with 1, 2, or 3 halogens;

R₃ = H, halogen, (C₁–C₆)alkyl or OH, wherein (C₁–C₆)alkyl is substituted with 1, 2, or 3 halogens;

R₄ = H, halogen, (C₁–C₆)alkyl; R₅ = H, halogen, (C₁–C₆)alkyl;

R₆ = H, halogen, (C₁–C₆)alkyl, (C₃–C₈)cycloalkyl, -(C₁–C₄)alkoxy, (C₁–C₆)alkyl–OH, (C₁–C₆)alkyl-O-(C₁–C₆)alkyl, (C₁–C₆)alkyl-NH₂, -(C₁–C₆)alkyl-NH(C₁–C₆)alkyl, -(C₁–C₆)alkyl-N(C₁–C₆)alkyl(-(C₁–C₆)alkyl);

R₇ = H, (C₁–C₆)alkyl or OH;

R₈ = H, (C₁–C₆)alkyl or (C₁–C₆)alkoxy;

R₉ = H, (C₁–C₆)alkyl or (C₁–C₆)alkoxy; and n = 0 or 1.

Key Structures

Biological Assay

The MRGX2 FLIPR^TETRA assay was performed. The compounds described in this application were tested for their ability to inhibit MRGX2. The MRGX2 pIC₅₀ (nM) are shown in the table below.

Biological Data

The following table shows representative compounds tested for MRGX2 inhibition and the biological data obtained from testing the representative examples.^1,2,3,4

Claims

Total claims: 30

Compound claims: 25

Pharmaceutical composition claims: 1

Method of treatment claims: 2

Use of compound claims: 2

The author declares no competing financial interest.