Abstract
Provided herein are novel TYK2 inhibitors, pharmaceutical compositions, use of such compounds in treating autoimmune and inflammatory diseases, and processes for preparing such compounds.
Important Compound Classes
Title
TYK2 Inhibitors
Patent Publication Number
WO 2023/220046 A1
Publication Date
November 16, 2023
Priority Applications
US 63/340,142 and US 63/424,583
Priority Dates
May 10, 2022, and November 11, 2022
Inventors
Chen, T.; Lin, E. Y. S.; Xin, Z.; Levin, T. H.; Genung, N.; Vessels, J.; Zhang, L.; Van Vloten, K. D.; Guckian, K. M.; Sciabola, S.; Vandeveer, H. G.; Maitra, S.; Nevalainen, M.; Schulz, J.; Lopez De Turiso, F. G.; Helal, C.
Assignee Company
Biogen Ma Inc., USA
Disease Area
Autoimmune and inflammatory diseases
Biological Target
TYK2
Summary
Cytokines are small, secreted proteins released by cells and have a specific effect on the interaction and communication between cells. Cytokine pathways mediate a broad range of biological functions, including many aspects of inflammation and immunity, through mostly extracellular signaling. Tyrosine kinase 2 (TYK2) is a member of Janus kinases (JAKs) that are cytoplasmic protein kinases associated with cytokine receptors and play a central role in mediating cytokine signaling. The JAK family also includes JAK1, JAK2, and KAK3.
TYK2 is important in the signaling of the type I interferons, IL-6, IL-10, IL-12, and IL-23. TYK2 has been shown to be important in the differentiation and function of multiple cell types important in inflammatory diseases and autoimmune diseases, including natural killer cells, B cells, and T helper cell types. Aberrant TYK2 expression is associated with multiple autoimmune or inflammatory conditions.
The present application describes a series of novel TYK2 inhibitors for treating autoimmune and inflammatory diseases. Further, the application discloses compounds, their preparation, use, and pharmaceutical composition, and treatment.
Definitions
Ring A = aromatic or heteroaromatic ring fused with ring B that is a 5-membered heteroaromatic ring;
X1 = N or CH; X2 = N or CR2; X3 = N or CR3; X4 = N or CR4;
Ring C = phenyl or 5- or 6-membered monocyclic heterocyclyl, or 5- or 6-membered heteroaryl, each of which is optionally substituted by one or more Rc;
R1 = H, C1–6 alkyl, OR1A, NRN1RN2, C3–6 cycloalkyl, phenyl, 5- or 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, or 4- to 7-membered monocyclic heterocyclyl; and
R1A = H or C1–6 alkyl.
Key Structures
Biological Assay
The TYK2-JH2 biochemical assay was performed. The compounds described in this application were tested for their ability to inhibit TYK2. The TYK2 IC50 values (nM) are shown in the following table.
Biological Data
The table below shows representative
compounds that were tested for TYK2 inhibition and the biological
data obtained from testing representative examples.
For IC50: ++++ means ≤ 10 nM.
Claims
Total claims: 120
Compound claims: 116
Pharmaceutical composition claims: 1
Method of treatment claims: 2
Method of inhibition claims: 1
Recent Review Articles
The author declares no competing financial interest.
References
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