Novel Heterocyclic PAD4 Inhibitors for Treating Diseases

Abstract

Provided herein are novel heterocyclic PAD4 inhibitors, pharmaceutical compositions, use of such compounds in treating multiple diseases, and processes for preparing such compounds.

Important Compound Classes

Title

Heterocyclic PAD4 Inhibitors

Patent Publication Number

WO 2023/230612 A1

URL:https://patents.google.com/patent/WO2023230612A1/en

Publication Date

November 30, 2023

Priority Application

US 63/365,370

Priority Date

May 26, 2022

Inventors

Antropow, A. H.; Seletsky, B. M.; Ross, A. G.; Zhu, X.; Gormisky, P. E.; Miao, G.

Assignee Company

Celgene Corporation, USA

Disease Area

Multiple diseases

Biological Target

PAD4

Summary

PAD4 is a member of the peptidylarginine deiminase (PAD) family of enzymes capable of catalyzing the citrullination of arginine into citrulline within peptide sequences. PAD4 is responsible for the deimination or citrullination of a variety of proteins in vitro and in vivo, with consequences of diverse functional responses in a variety of diseases, including rheumatoid arthritis and diseases with neutrophilic contributions to pathogenesis and oncology.

Inhibitors of PAD4 have utility against rheumatoid arthritis. PAD4 inhibitors have applicability for diseases where neutrophil extracellular trap (NET) formation in the tissue contributes to local injury and disease pathology. Such diseases include small vessel vasculitis, systemic lupus erythematosus, ulcerative colitis, cystic fibrosis, asthma, deep vein thrombosis, periodontitis, appendicitis, and stroke. PAD4 inhibitors are also useful in the treatment of cancers.

The present application describes a series of novel heterocyclic PAD4 inhibitors for the treatment of multiple diseases. Further, the application discloses compounds, their preparation, use, and pharmaceutical composition, and treatment.

Definitions

X = C-R₆ and N; X′ = C-R_6′ and N, wherein X and X′ are not simultaneously N;

R₁ = C_1–4 aliphatic;

R₂ = C_1–6 aliphatic substituted by 0–4 instances of R₇;

R₃ = C_1–6 aliphatic substituted by 0–3 instances of R₈;

R₄ = halogen; R₅ = halogen; and m and n = 0 or 1.

Key Structures

Biological Assay

The RFMS1 assay was performed. The compounds described in this application were tested for their ability to inhibit PAD4. The PAD4 IC₅₀ values (nM) are shown in the following table.

Biological Data

The table below shows representative compounds that were tested for PAD4 inhibition and the biological data obtained from testing representative examples.For IC₅₀, A means ≤10 nM.

Recent Review Articles

See refs (1−6).

Claims

Total claims: 20

Compound claims: 16

Pharmaceutical composition claims: 1

Method of treatment claims: 2

Method of inhibition claims: 1

The author declares no competing financial interest.