Abstract
Provided herein are novel heteroaryl compounds as CD73 inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.
Important Compound Classes
Title
Heteroaryl Compounds for the Treatment of Cancer
Patent Publication Number
WO 2024/033454 A1
Publication Date
February 15, 2024
Priority Application
CN PCT/CN2022/112150 and CN PCT/CN2022/135460
Priority Date
August 12, 2022, and November 30, 2022
Inventors
Ding, D.; Li, L.; Liu, Y.; Lyu, M.; Xu, H.; Zhao, D.; Zou, G.
Assignee Company
F. Hoffmann-La Roche AG, Switzerland, and Hoffmann La Roche Inc., USA
Disease Area
Cancer
Biological Target
CD73
Summary
The glycosyl-phosphatidylinositol-anchored CD73 antigen (also known as Cluster of Differentiation 73, ecto-5′-nucleotidase, ecto-5′-NT, 5′-NT, and NT5E) is considered the rate-limiting enzyme in the generation of extracellular adenosine. Hyper activation of the adenosine pathway contributes to immunosuppressive tumor microenvironment (TME) that impairs antitumor immunity and limits efficacy of immune checkpoint inhibitors. In the last step of the adenosine pathway, the enzyme ecto-5′-nucleotidase (CD73) catalyzes the conversion of AMP to adenosine, which is recognized by the adenosine receptors present in multiple immune cell-types, leading to suppression of the effector T cells and natural killer (NK) cells, activation of the regulatory T (Treg) and myeloid-derived suppressor cells (MDSCs), as well as other changes in the immune system that collectively culminate in an immunosuppressed environment. Preclinical work in various in vivo tumor models demonstrated restoration of immune cell function and tumor growth inhibition upon genetic ablation or pharmacological inhibition of CD73.
The present application describes a series of novel heteroaryl compounds as CD73 inhibitors for the treatment of cancer. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.
Definitions
W = CH or N;
A1 and A2 = CH or N; A3 and A7 = C or N; and
A4, A5 and A6 = O, S, N, CR1 or NR2.
Key Structures
Biological Assay
The CD73 cellular assay was performed. The compounds described in this application were tested for their ability to inhibit CD73. The CD73 IC50 (nM) are shown in the following Table.
Biological Data
The Table below
shows representative
compounds that were tested for CD73 inhibition. The biological data
obtained from testing representative examples are listed in the following
Table.
Claims
Total claims: 29
Compound claims: 21
Pharmaceutical composition claims: 1
Method of preparation claims: 1
Use of compound claims: 5
Invention claims: 1
Recent Review Articles
The author declares no competing financial interest.
References
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