Abstract
Provided herein are novel pyrrolidinone derivatives as NIK inhibitors, pharmaceutical compositions, use of such compounds in treating autoimmune and inflammatory diseases, and processes for preparing such compounds.
Important Compound Classes
Title
Pyrrolidinone Derivatives as Inhibitors of NF-κB Inducing Kinase
Patent Publication Number
WO 2023/217851 A1
Publication Date
November 16, 2023
Priority Application
US 63/364,549
Priority Date
May 11, 2022
Inventors
Rovira, A. R.; Murphy, S. K.; Lebsack, A. D.; Chai, W.; Enny, D.; Maertens, A.; Ameriks, M.
Assignee Company
Janssen Pharmaceutica NV, Belgium
Disease Area
Autoimmune and inflammatory diseases
Biological Target
NIK
Summary
NF-κB inducing kinase (NIK) is a serine/threonine kinase transcription factor regulating the expression of various genes involved in immune response disorders. Because of this immune system regulatory role, inhibition of NIK blocks several downstream pathways that produce inflammatory molecules. Clinical validation with biologics has confirmed a key role for several NIK-dependent pathways in autoimmune diseases. One way to mitigate or eliminate the adverse effects associated with NIK activity is to increase INK inhibition.
The present application describes a series of novel pyrrolidinone derivatives as NIK inhibitors for the treatment of autoimmune and inflammatory diseases. Further, the application discloses compounds, their preparation, use, and pharmaceutical composition, and treatment.
Definitions
A = 5-membered heteroaryl that is optionally substituted with one or more C1–4alkyl groups;
W = CH2, CHF, CF2, or CHRw;
X = N, CH or CRx; Y = N, CH or CRy;
R1 = H, C1–4alkyl or C1–4haloalkyl; R2 = H or C1–4alkyl;
L = absent, C1–4alkylene, or C3–6cycloalkylene;
R3 = C1–10alkyl, C3–10cycloalkyl, 3- to 10-membered heterocyclyl, 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms, C6–10aryl, 5- to 10-membered heteroaryl, or C(O)N(RN3)(RN4);
R4 = H, halo, or C1–4alkyl; and R5 = H, halo, or C1–4alkyl.
Key Structures
Biological Assay
The human NF-KappaB-inducing kinase (NIK/MAP3K14) activity (AlphaScreen) assay was performed. The compounds described in this application were tested for their ability to inhibit NIK. The NIK IC50 values (nM) are shown in the following table.
Biological Data
The table below shows representative
compounds that were tested for NIK inhibition and the biological data
obtained from testing representative examples. For IC50: A means <50 nM.
Claims
Total claims: 117
Compound claims: 111
Pharmaceutical composition claims: 1
Method of treatment claims: 5
Recent Review Articles
The author declares no competing financial interest.
References
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