Solid forms, pharmaceutical compositions and preparation of heteroaromatic macrocyclic ether compounds
Inventors
Chen, Sibao • COOPER, Christopher G. F. • Gerard, Baudouin • Horan, Joshua Courtney • KROPP, Jason T. • LANE, Benjamin Stephen • Pearson, David James
Assignees
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Publication Number
US-12630560-B2
Publication Date
2026-05-19
Expiration Date
Abstract
Provided herein are solid forms comprising a compound of formula (I), or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof. Also provided herein are methods of synthesizing a compound of formula (I), pharmaceutical compositions comprising the same, and methods of treating, preventing, and managing various disorders using the compositions provided herein.
Core Innovation
The invention relates to solid forms comprising a compound of Formula (I) and its salts, including a free base solid form, besylate and phosphate salts, and non-Form solid forms that can convert to Forms 2-7. The solid form is characterized by XRPD patterns measured using Cu Kα radiation, and multiple crystalline solid forms are identified by solid-state measurement.
The disclosure provides processes for crystallization and recrystallization using solvent systems and anti-solvent based crystallization, including solvent/anti-solvent exposure and subsequent crystallization to yield targeted solid forms. It also includes temperature cycling and solvent exposure concepts for converting amorphous material and non-Form solid forms into specific polymorphs, with conversion described in terms of targeted solid-form identity.
The disclosure additionally provides salt formation and characterization for besylate and phosphate salts of the compound of Formula (I), including forms described as unsolvated/anhydrous and solvated/hydrate types. It reports XRPD pattern peak sets for Form A besylate and Form A phosphate measured using Cu Kα radiation, and it provides thermal and sorption characterization including TGA, DSC, and DVS metrics for decomposition/melting behavior and hygroscopic uptake.
The document provides pharmaceutical compositions and solid-form formulations comprising Compound 1 in free base and/or salt forms, including tablet and granular formulations, along with excipients and quality metrics such as chemical and physical purity and degradation product-related limits. Therapeutic-method context is provided for treating ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) positive cancer by administering a therapeutically effective amount of a defined solid form of a compound of Formula (I) or a pharmaceutically acceptable salt.
Claims Coverage
The independent claim is a single method claim for treating cancer using a therapeutically effective amount of a defined solid form of a compound of Formula (I) or a pharmaceutically acceptable salt. It includes multiple alternative XRPD-defined solid-form variants, each tied to Cu Kα XRPD peak sets with ±0.2° 2θ tolerance.
Treating ros1-positive cancer with a defined xrpd solid form
A method of treating cancer by administering a therapeutically effective amount of a solid form comprising a compound of Formula (I), or a pharmaceutically acceptable salt, to a subject having the cancer that is ROS1 positive, where the solid form is characterized by a Cu Kα XRPD pattern comprising specific peaks for one of multiple free-base and/or salt-defined peak sets.
Free-base solid form characterized by cu kα xrpd peak sets
The solid form comprises a free base of a compound of Formula (I) and is characterized by an XRPD pattern measured using Cu Kα radiation comprising peaks at selected 2θ values within ±0.2° 2θ, including 10.7, 15.0, and 21.2; 8.6, 14.0, and 20.8; 13.4, 19.5, and 20.9; 12.1, 12.7, and 18.4; 10.5, 10.8, and 21.9; 8.6, 18.7, and 20.5; or 12.5, 13.4, and 14.6.
Besylate salt solid form characterized by cu kα xrpd peak set
The solid form comprises a besylate salt of a compound of Formula (I) and is characterized by an XRPD pattern measured using Cu Kα radiation comprising peaks at 15.0, 17.9, and 23.0 within ±0.2° 2θ.
Phosphate salt solid form characterized by cu kα xrpd peak set
The solid form comprises a phosphate salt of a compound of Formula (I) and is characterized by an XRPD pattern measured using Cu Kα radiation comprising peaks at 10.8, 18.5, and 24.8 within ±0.2° 2θ.
Claim coverage is focused on a ROS1-positive cancer treatment method where the administered compound is a solid form of Formula (I) or a pharmaceutically acceptable salt, and the solid form is required to match specific Cu Kα XRPD peak sets for either a free base or selected salts (besylate and phosphate).
Stated Advantages
Obtaining solids with purity and low levels of impurities, including chemical purity and enantiomeric purity concepts.
CNS-penetration and minimizing CNS-related adverse events concepts are referenced in connection with TRK-related CNS adverse events.
Documented Applications
Treating cancer in a subject where the cancer is ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) positive, using a therapeutically effective amount of a solid form comprising a compound of Formula (I) or a pharmaceutically acceptable salt defined by Cu Kα XRPD peak patterns.
Pharmaceutical compositions and solid-form formulations comprising Compound 1 in free base and/or salt forms, including tablet and granular formulations.
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