Novel CD73 Inhibitors for Treating Cancer

Abstract

Provided herein are novel CD73 inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.

Important Compound Classes

Title

CD73 Compounds

Patent Publication Number

WO 2024/006929 A1

URL: https://patents.google.com/patent/WO2024006929A1/en

Publication Date

January 4, 2024

Priority Application

US 63/357,948

Priority Date

July 1, 2022

Inventors

Bartlett, M. J.; Chin, G. F.; Cosman Ellis, J. L.; Mackman, R. L.; Mish, M. R.

Assignee Company

Gilead Sciences Inc., USA

Disease Area

Cancer

Biological Target

CD73

Summary

The glycosyl-phosphatidylinositol (GPI)-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. CD73 is a 70-kDa GPI-anchored protein normally expressed on endothelial cells and subsets of hematopoietic cells. CD73, together with CD39, regulates adenosine triphosphate (ATP) metabolism. CD39 converts ATP into AMP, with only trace amounts of ADP being released, while CD73 catalyzes the conversion of AMP to adenosine (Ado).

Extracellular Ado accumulates in cancerous tissues and constitutes an important mechanism of tumor immune escape. CD73 can be found constitutively expressed at high levels on various types of cancer cells. CD73-generated adenosine is assumed to suppress adaptive antitumor immune responses, thereby promoting tumor growth and metastasis. The studies in animal models have shown that blockade of CD73 activity suppresses tumor growth and prolongs survival by promoting antitumor adaptive immunity.

The present application describes a series of novel CD73 inhibitors for the treatment of cancer. Further, the application discloses compounds, their preparation, use, and pharmaceutical composition, and treatment.

Definitions

Y = C_1–6 alkyl, C_3–7 cycloalkyl, O-C_1–6 alkyl-O, 4–8 membered heterocyclyl or O-4–8 membered heterocyclyl;

R₁ = H, C_1–6 alkyl, O-C_1–6 alkyl, O-C_1–6 alkyl-O, C_3–7 cycloalkyl, O-(4–12 membered heteroaryl), C_6–10 aryl, 4–12 membered heteroaryl, C_1–6 alkyl-C_6–10 aryl, C_1–6 alkyl-4–12 membered heteroaryl, C(O)N(R₄)(R₄), C(O)N(H)C_6–12 aryl; and

R₅ = H, C_1–6 alkyl, CN, C_3–7 cycloalkyl, O-C_1–6 alkyl, C_1–6 alkyl-O-C_1–6 alkyl.

Key Structures

Biological Assay

The CD73 biochemical assay was performed. The compounds described in this application were tested for their ability to inhibit CD73. The CD73 IC₅₀ values (nM) are shown in the following table.

Biological Data

The table below shows representative compounds that were tested for CD73 inhibition and the biological data obtained from testing representative examples.

Claims

Total claims: 15

Compound claims: 13

Pharmaceutical composition claims: 1

Method of treatment claims: 1

Recent Review Articles

See refs (1−6).

The author declares no competing financial interest.