Abstract
Provided herein are novel isoxazolidines derivatives as RIPK1 inhibitors, pharmaceutical compositions, use of such compounds in treating neurodegenerative diseases, and processes for preparing such compounds.
Important Compound Classes
Title
Isoxazolidines as RIPK1 Inhibitors and Uses Thereof
Patent Publication Number
WO 2024/233544 A1
URL
Publication Date
November 14, 2024
Priority Application
EP 23172644.9
Priority Date
May 10, 2023
Inventors
Defossa, E.; Rackelmann, N.; Heinelt, U.; Matter, H.; Mendez Perez, M.; Ritter, K.; Szillat, H.; Zech, G.
Assignee Company
Genzyme Corporation, USA
Disease Area
Neurodegenerative diseases
Biological Target
RIPK1
Summary
Receptor interacting protein kinase 1 (RIPK1) is a key regulator of inflammation, apoptosis, and necroptosis. RIPK1 has an important role in modulating inflammatory responses mediated by the nuclear-factor kappa-light chain enhancer of activated B cells. Further, RIPK1 is part of a pro-apoptotic complex indicating its activity in regulating apoptosis.
The receptor interacting protein kinase 1 (RIPK1) is subject to complex and intricate regulatory mechanisms, including ubiquitylation, deubiquitylation, and phosphorylation. These regulatory events collectively determine whether a cell will survive and activate an inflammatory response or die through apoptosis or necroptosis. Dysregulation of RIPK1 signaling can lead to excessive inflammation or cell death and conversely, research has shown that inhibition of RIPK1 can be effective therapies for diseases involving inflammation or cell death.
The present application describes a series of novel isoxazolidines derivatives as RIPK1 inhibitors for the treatment of neurodegenerative diseases. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.
Definitions
X1, X2 and X3 = CR6 or N;
R1 = 5- or 6-membered heteroaryl group, wherein said heteroaryl is optionally substituted by 1 or 2 groups selected from halogen, (C1–C6)alkyl group and CN group;
R2 = 4-, 5- or 6-membered heteroaryl in which 1 to 3 ring atoms are selected from N, O, or S and wherein heteroaryl is optionally substituted by 1 or 2 R7;
R3 = H or (C1–C4)alkyl group; R4 = H or (C1–C4)alkyl group; and
R5 and R6 = H, (C1–C6)alkyl group or halogen.
Key Structures
Biological Assay: 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 IC50 (nM) values are shown in the following Table.
Biological Data
The Table below shows representative
compounds that were tested for RIPK1 inhibition. The biological data
obtained from testing representative examples are listed in the following
Table.
Claims
Total claims: 13
Compound claims: 12
Pharmaceutical composition claims: 1
Recent Review Articles
The author declares no competing financial interest.
References
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