Crystalline forms of a CD73 inhibitor and uses thereof
Inventors
Pennell, Andrew M. K. • Connor, Eric F • GOTTSCHLING, Stephen Edmund • COLOMVAKOS, Jim Dimetrios • KHAN, Mohammed Asadullah
Assignees
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Publication Number
US-12281136-B2
Publication Date
2025-04-22
Expiration Date
Abstract
Crystalline forms of the compound of Formula (I), which modulates the conversion of AMP to adenosine by 5′-nucleotidase, ecto, and compositions containing the compound and methods for preparing the crystalline forms, are described herein. The use of such crystalline form of Formula (I) 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 invention relates to a CD73 inhibitor compound of Formula (I) and to crystalline forms of that compound, including Crystalline Form III and Crystalline Form VI. These crystalline forms are defined by X-ray powder diffraction (XRPD) patterns, with Crystalline Form III characterized by peaks at 6.6, 10.9, 14.2, 16.1, 18.4, and 19.3 degrees 2θ (±0.2 degrees 2θ), and Crystalline Form VI characterized by peaks at 19.4, 21.3, 22.4, and 24.4 degrees 2θ (±0.2 degrees 2θ).
Crystalline Form VI further comprises additional peaks at 5.8, 10.4, 27.5, and 31.1 degrees 2θ (±0.2 degrees 2θ). The crystalline forms are further characterized by phase composition and thermal characterization features, including being substantially free of other crystalline or amorphous forms of the compound of Formula (I), and by differential scanning calorimetry (DSC) thermograms with endothermic peak temperatures and DSC-determined melting point onset values.
Crystalline Form III includes a DSC thermogram with an endothermic peak at about 161.8°C, and Crystalline Form VI includes a DSC thermogram with an endothermic peak at about 142.9°C and a DSC-determined melting point onset at about 116.6°C. The disclosure also links the crystalline forms and compositions derived from the crystalline forms to therapeutic use by CD73 inhibition, including treatment of diseases mediated by CD73 inhibition, cancer, immune/inflammatory disorders, and viral infections, as well as combination therapy with additional therapeutic agents.
Claims Coverage
The independent claims define two crystalline forms of a compound of Formula (I), with 2 inventive features centered on XRPD-based phase identification. Dependent claim coverage adds phase-purity and DSC thermal characterization, and further dependent claims cover CD73-mediated treatment methods and cancer combination therapy.
Crystalline form III defined by xrpd peaks
Crystalline Form III of a compound of Formula (I) characterized by an XRPD pattern comprising peaks at 6.6, 10.9, 14.2, 16.1, 18.4, and 19.3 degrees 2θ (±0.2 degrees 2θ).
Crystalline form VI defined by xrpd peaks
Crystalline Form VI of a compound of Formula (I) characterized by an XRPD pattern comprising peaks at 19.4, 21.3, 22.4, and 24.4 degrees 2θ (±0.2 degrees 2θ) and further comprising additional peaks at 5.8, 10.4, 27.5, and 31.1 degrees 2θ (±0.2 degrees 2θ).
Overall, the claims focus on XRPD-defined crystalline phases of Formula (I), with dependent refinements that require being substantially free of other crystalline or amorphous forms and add DSC thermogram characteristics. The claim scope also includes CD73-mediated treatment methods, including treatment of cancer with at least one additional therapeutic agent.
Stated Advantages
Enables identification of crystalline forms of the compound of Formula (I) by XRPD peak pattern characterization.
Provides phase-purity limitation by requiring being substantially free of other crystalline or amorphous forms.
Adds additional characterization via DSC thermogram features, including endothermic peak temperatures and melting point onset values.
Documented Applications
Treatment of a disease, disorder, or condition mediated at least in part by CD73 by administering an effective amount of a crystalline form of the compound.
Treatment of cancer by administering an effective amount of a crystalline form of the compound together with at least one additional therapeutic agent.
Treatment of immune/inflammatory disorders and viral infections by CD73 inhibition.
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