Novel RIPK1 Inhibitors for Treating Neurodegenerative, Autoimmune, and Inflammatory Diseases

Important Compound Classes

Title

RIPK1 Inhibitors and Methods of Use

Patent Publication Number

WO 2021/252307 A1

URL: https://patents.google.com/patent/WO2021252307A1/en

Publication Date

December 16, 2021

Priority Application

US 63/038,467

Priority Date

June 12, 2020

Inventors

Rico Duque, J. L.; Brill, Z. G.; Fradera, X.; Siliphaivanh, P.; Su, J.

Assignee Company

Merck Sharp & Dohme Corp., USA

Disease Area

Neurodegenerative, autoimmune, and inflammatory diseases

Biological Target

RIPK1

Summary

Receptor interacting protein kinase 1 (RIPK1) belongs to the family serine/threonine protein kinase involved in innate immune signaling. RIPK1 has emerged as a promising therapeutic target for the treatment of a wide range of human neurodegenerative, autoimmune, and inflammatory diseases. RIPK1 is a key mediator of apoptotic and necrotic cell death as well as inflammatory pathways. For example, RIPK1 inhibition has been found to be useful for the treatment of acute kidney injury (AKI). It has been found that RIPK1-mediated necroptosis plays an important role in AKI and a RIPK1 inhibitor may serve as a promising clinical candidate for AKI treatment.

Additionally, human genetic evidence has linked the dysregulation of RIPK1 to the pathogenesis of amyotrophic lateral sclerosis (ALS), Alzheimer’s disease and multiple sclerosis. RIPK1 inhibition may play a promising role for the treatment of stroke.

The present application describes a series of novel compounds as RIPK1 inhibitors for the treatment of neurodegenerative, autoimmune, and inflammatory diseases. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.

Definitions

R₁ = aryl, C₃–C₁₀cycloalkyl or heteroaryl, wherein the aryl, C₃–C₁₀cycloalkyl or heteroaryl is unsubstituted or substituted with one to three substituents selected from the group consisting of halogen, C₁–C₆alkyl, CN, OH, alkoxy, −N(R₃)₂, −SC₁–C₆alkyl and C₃–C₆cycloalkyl;

R₂ = hydrogen, OH, C₁–C₆alkylOH, CN, C₁–C₆alkylCN, C₁–C₆alkyl, haloC₁–C₆alkyl, halogen, alkoxy, C₁–C₆alkylOC₁–C₆alkyl, aryl, heteroaryl, cycloheteroalkyl, C₃–C₁₀cycloalkyl, −O-aryl, −O-heteroaryl, −O-cycloheteroalkyl, −OC₃–C₁₀cycloalkyl, C₁–C₆alkylaryl, C₁–C₆alkylheteroaryl, C₁–C₆alkyl-cycloheteroaryl, C₁–C₆alkylC₃–C₁₀cycloalkyl, haloC₁–C₆alkylaryl, haloC₁–C₆alkylheteroaryl, haloC₁–C₆alkylcycloheteroalkyl, haloC₁–C₆alkylC₃–C₁₀cycloalkyl, −CO-aryl, −OC₁–C₆alkylaryl, −OC₁–C₆alkylheteroaryl, −OC₁–C₆alkylcycloheteroalkyl, −OC₁–C₆alkylC₃–C₁₀cycloalkyl, −SO₂C₁–C₆alkyl, −SO₂aryl, −S-aryl, −SC₁–C₆alkyl, −N(R₃)₂, and C₁–C₆alkylN(R₃)₂; and

n = 1, 2, 3, 4, 5 or 6.

Key Structures

Biological Assay

The RIPK1-ADP-Glo enzymatic assay was performed. The compounds described in this application were tested for their ability to inhibit RIPK1. The RIPK1 EC₅₀ (nM) are shown in the following table.

Biological Data

The table below shows representative compounds were tested for RIPK1 inhibition. The biological data obtained from testing representative examples are listed in the following table.

Claims

Total claims: 24

Compound claims: 19

Pharmaceutical composition claims: 2

Method of treatment claims: 2

Use of compound claims: 1

Recent Review Articles

• 1.Li S.; Qu L.; Wang X.; Kong L.. Pharmacol. Ther. 2022, 231, 107979.
• 2.Liu X.; Xie X.; Ren Y.; Shao Z.; Zhang N.; Li L.; Ding X.; Zhang L.. MedComm 2021, 2, 730.
• 3.Wang Q.; Fan D.; Xia Y.; Ye Q.; Xi X.; Zhang G.; Xiao C.. Biomed. Pharmacother. 2021, 142, 112082.
• 4.Liu L.; Lalaoui N.. Semin. Cell Dev. Biol. 2021, 109, 86.
• 5.Martens S.; Hofmans S.; Declercq W.; Augustyns K.; Vandenabeele P.. Trends Pharmacol. Sci. 2020, 41, 209.
• 6.Jin L.; Liu P.; Yin M.; Zhang M.; Kuang Y.; Zhu W.. J. Dermatol. Sci. 2020, 99, 146.

The author declares no competing financial interest.