Abstract
Provided herein are novel fused bicyclic heteroaryl compounds as NLRP3 inhibitors, pharmaceutical compositions, use of such compounds in treating asthma or COPD and processes for preparing such compounds.
Important Compound Classes
Title
Fused Bicyclic Heteroaryl Compounds Useful as NLRP3 Inhibitors
Patent Publication Number
WO 2023/066825 A1
Publication Date
April 27, 2023
Priority Application
EP 21203314.6 and EP 22174872.6
Priority Date
October 19, 2021 and May 23, 2022
Inventors
Aitken, L. S.; Bouche, L. A.; Guba, W.; Jaeschke, G.; Johnston, H. J.; Mesch, S. K.; Patiny-Adam, A.; Shannon, J. M.; Schnider, C.; Steiner, S.; Tosstorff, A. M.
Assignee Company
F. Hoffmann-La Roche AG, Switzerland, and Hoffmann-La Roche Inc., USA
Disease Area
Asthma or COPD
Biological Target
NOD-like receptor protein 3
Summary
A member of the NOD-like receptor (NLR) family, NOD-like receptor protein 3 (NLRP3) inflammasome is a component of the inflammatory process, and its aberrant activity is pathogenic in inherited disorders such as cryopyrin-associated periodic syndromes (CAPS) and complex diseases such as multiple sclerosis, Alzheimer’s disease, and atherosclerosis. NLRP3 is an intracellular signaling molecule that senses many pathogen-derived, environmental, and host-derived factors. Upon activation, NLRP3 binds to apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC). ASC then polymerizes to form a large aggregate known as an ASC speck. Polymerized ASC in turn interacts with the cysteine protease caspase-1 to form a complex termed as an inflammasome.
Active cytokines derived from NLRP3 inflammasome activation are important drivers of inflammation and interact with other cytokine pathways to shape the immune response to infection and injury. A role for NLRP3 in diseases of the central nervous system and lung diseases is emerging. Furthermore, NLRP3 has a role in the development of liver diseases, kidney diseases, and aging.
The present application describes a series of novel fused bicyclic heteroaryl compounds as NLRP3 inhibitors for the treatment of asthma or chronic obstructive pulmonary disease (COPD). Further, the application discloses compounds, their preparation, use, and pharmaceutical composition, and treatment.
Definitions
A1 = -N- or -CR10;
A2 = -O-, -NH-, -NCH3- or -S-;
R1 = H, halo, alkyl, haloalkyl, haloalkoxy, cyano, alkoxy, cycloalkyl or alkylsulfonyl;
R9 = H, alkyl, halo or cyano; or R1 and R9 form a 4- to 6-membered cycloalkyl or heterocycle comprising a single O heteroatom;
R2 = H, halo, alkyl, cyano, haloalkoxy, haloalkyl, alkoxy, alkoxyalkyl, or hydroxyalkyl;
R3 = H, halo or alkyl, wherein at least one of R2 and R3 is not H;
R8 = H or halo; Rx = H, alkyl, alkoxyalkyl or hydroxyalkyl;
W = 4- to 10-membered heterocycle comprising up to 3 heteroatoms selected from N and O, 4- to 10-membered heterocycle-CH2- comprising up to 2 heteroatoms selected from N and O, 3- to 6-membered cycloalkyl optionally substituted with 1 to 2 substituents selected from OH, alkylamino and dialkylamino, 4-membered cycloalkyl-CH2- optionally substituted with 1 to 2 substituents selected from OH, and alkyl, and 5-membered heteroaryl-CH2- comprising 2 N heteroatoms; and n = 0 or 1.
Key Structures
Biological Assay
The NLRP3 THP-1 pyroptosis assay was performed. The compounds described in this application were tested for their ability to inhibit NLRP3. The NLRP3 IC50 values (nM) are shown in the table below.
Biological Data
The following table shows representative
compounds tested for NLRP3 inhibition and the biological data obtained
from testing representative examples.
Claims
Total claims: 41
Compound claims: 33
Pharmaceutical composition claims: 1
Method of treatment claims: 1
Method of inhibition claims: 1
Method of preparation claims: 1
Use of compound claims: 3
Invention claims: 1
Recent Review Articles
The author declares no competing financial interest.
References
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