Abstract
Provided herein are novel pyrrolidinone derivatives as NIK inhibitors, pharmaceutical compositions, use of such compounds in treating inflammatory and autoimmune diseases, and processes for preparing such compounds.
Important Compound Classes
Title
Pyrrolidinone Derivatives as Inhibitors of NF Kappa B Inducing Kinase
Patent Publication Number
WO 2023/217906 A1
Publication Date
November 16, 2023
Priority Application
US 63/364,552
Priority Date
May 11, 2022
Inventors
Chai, W.; Wolin, R. L.; Murphy, S. K.; Rovira, A. R.; Lebsack, A. D.; Adler, M.; Eccles, W.; Greenman, K.; Hack, M. D.; Jones, W. M.; Krawczuk, P. J.
Assignee Company
Janssen Pharmaceutica NV, Belgium
Disease Area
Inflammatory and autoimmune 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 NIK inhibition.
The present application describes a series of novel pyrrolidinone derivatives as NIK inhibitors for the treatment of inflammatory and autoimmune 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 to three groups selected from C1–4alkyl and C1–4haloalkyl;
B = furanyl, piperidinyl,
or 
;
W = CH2, CHF, or CF2;
V = N, CH, or CRv; X = N, CH, or CRx;
Y = N, CH, or CRy; Z = N, CH, or CRz;
R1 = H, C1–4alkyl, or C1–4haloalkyl; and
R2 = NH (5- to 10-membered heteroaryl), C6–10aryl, 5- to 12-membered bicyclic or tricyclic ring system containing one or more heteroatoms or 5- to 10-membered heteroaryl.
Key Structures
Biological Assay
The human NF-kappa B-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 <100 nM.
Claims
Total claims: 69
Compound claims: 63
Pharmaceutical composition claims: 1
Method of treatment claims: 5
Recent Review Articles
The author declares no competing financial interest.
References
- Freigeh G. E.; Michniacki T. F. NF-κB and Related Autoimmune and Autoinflammatory Diseases. Rheum. Dis. Clin. North Am. 2023, 49, 805–823. 10.1016/j.rdc.2023.06.008. [DOI] [PubMed] [Google Scholar]
- Morrison H. A.; Trusiano B.; Rowe A. J.; Allen I. C. Negative regulatory NLRs mitigate inflammation via NF-κB pathway signaling in inflammatory bowel disease. Biomed. J. 2023, 46, 100616 10.1016/j.bj.2023.100616. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Xu G.; Dong F.; Su L.; Tan Z.-X.; Lei M.; Li L.; Wen D.; Zhang F. The role and therapeutic potential of nuclear factor κB (NF-κB) in ischemic stroke. Biomed. Pharmacother. 2024, 171, 116140 10.1016/j.biopha.2024.116140. [DOI] [PubMed] [Google Scholar]
- Casper E. The crosstalk between Nrf2 and NF-κB pathways in coronary artery disease: Can it be regulated by SIRT6?. Life Sci. 2023, 330, 122007 10.1016/j.lfs.2023.122007. [DOI] [PubMed] [Google Scholar]