Inhibitors of adenosine 5′-nucleotidase

Inventors

DEBIEN, Laurent Pierre Paul • Kalisiak, Jaroslaw • LAWSON, Kenneth V. • Leleti, Manmohan Reddy • LINDSEY, Erick Allen • MILES, Dillon Harding • NEWCOMB, Eric • Powers, Jay Patrick • Rosen, Brandon Reid • Sharif, Ehesan Ul

Assignees

Arcus Biosciences Inc

Abstract

Compounds that modulate the conversion of AMP to adenosine by 5′-nucleotidase, ecto, and compositions containing the compounds and methods for synthesizing the compounds, are described herein. The use of such compounds and compositions for the treatment and/or prevention of a diverse array of diseases, disorders and conditions, including cancer- and immune-related disorders, that are mediated by 5′-nucleotidase, ecto is also provided.

Core Innovation

The patent concerns CD73 inhibitor compounds and preparation processes involving phosphonate-containing CD73-inhibitor scaffolds. The described scaffold includes a purine core with a chloro substituent and an oxolane ring, together with phosphonate moieties and prodrug or ester protecting groups.

The process is directed to preparing a CD73 inhibitor by contacting a compound of formula (i) with a protected analog of ribofuranose to form a protected analog of compound of formula (iii), and then contacting the protected analog of compound of formula (iii) with cyclopentyl amine to form a protected analog of compound of formula (iv). The protected intermediates are defined using specific formula representations, and the protecting groups are described as acyl and acetonide in an alcohol solvent such as methanol.

The patent also defines conversion of a compound of formula (i) to a compound of formula (iv) or a protected analog thereof, including embodiments in which the protected form of compound of formula (iv) is formula (iv-a) or formula (iv-b). The examples additionally document labeled compounds featuring alternative amino or heteroaryl substitutions and characterization data such as 1H NMR and ESI MS.

Claims Coverage

The independent claims cover three related aspects: a two-stage process to prepare a CD73 inhibitor through protected ribofuranose and cyclopentyl amine contacting, a broader conversion process from formula (i) to formula (iv) or a protected analog, and a compound defined by a specified structure or protected form. The inventive features center on protected intermediates, cyclopentyl amine conversion, and defined protected-form embodiments.

Overall, the claims are centered on preparing CD73 inhibitors by forming ribofuranose-derived protected intermediates from a compound of formula (i), converting these intermediates using cyclopentyl amine to reach a protected analog of compound of formula (iv), and alternatively covering direct CD73 inhibitor compound structures or their protected forms with specific protected-form variants.

Stated Advantages

Documented Applications