Solid state forms of substituted pyrazolopyrimidines and uses thereof
Inventors
Liu, Hanlan • Wilt, Jeremy Clinton • BLATTER, Friedrich • LAPADULA, Giuseppe
Assignees
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Publication Number
US-11718624-B2
Publication Date
2023-08-08
Expiration Date
Abstract
The present disclosure relates to: a) solid state forms of a compound of Formula (I), a compound of Formula (II), and a compound of Formula (III); b) pharmaceutical compositions comprising one or more solid state forms of a compound of Formula (I), a compound of Formula (II), and a compound of Formula (III), and optionally, a pharmaceutically acceptable carrier or diluent; c) methods of treating tumors or cancers by administering one or more solid state forms of a compound of Formula (I), a compound of Formula (II), and a compound of Formula (III) to a subject in need thereof; and d) methods for the preparation of solid state forms of a compound of Formula (I), a compound of Formula (II), and a compound of Formula (III).
Core Innovation
The invention relates to solid state forms of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine of Formula (II), and to pharmaceutically acceptable salts thereof. The solid state forms include crystalline forms and mixtures of solid state forms, as well as non-crystalline forms, hydrates, anhydrates, and solvates, including a dichloromethane solvate, with solid-state characterization using XRPD and thermal analysis including DSC and TGA.
Specific crystalline forms are defined for the Formula (II) compound, including crystalline Forms A, C, D, E, F, 1, 2, 7, 8, and 9, as well as corresponding hydrochloric acid salt crystalline Form 1 and co-crystal forms derived from benzoic acid, salicylic acid, and gentisic acid. Related solid state forms of Formula (III) are also described, including crystalline Forms A1 and B1, each associated with XRPD peak patterns and DSC features.
The disclosure further includes pharmaceutical compositions formulated as solid dosage forms with carriers and diluents, and includes anticancer or cancer treatment use for the Formula (II) compound and described salts and co-crystals. Cancer treatment methods involving USP1 inhibition are also described, including USP1 inhibitor-sensitive cancer, biomarker-stratified approaches using RAD18 levels, and combinations with PARP inhibitors, including targeting PARP inhibitor resistant cancer.
Claims Coverage
The claim coverage centers on solid state forms of the Formula (II) compound or a pharmaceutically acceptable salt, with dependent claims refining the solid state into specific crystalline forms, salt and co-crystal forms, and forms defined by analytical signatures. The coverage also extends to a pharmaceutical composition in the form of an oral solid dosage form. Multiple inventive features are present across the provided claims.
Solid state form of Formula (II) compound or pharmaceutically acceptable salt
A solid state form of 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1H-pyrazolo[3,4-d]pyrimidine of Formula (II), or a pharmaceutically acceptable salt thereof.
Crystalline forms defined by XRPD peak-position constraints
A solid state form selected as crystalline Forms A, C, D, E, or F, or combinations thereof, each defined by characteristic XRPD peak positions at specified two-theta values.
Crystalline forms defined by XRPD and thermal analysis signatures
A crystalline form, including crystalline Form A, characterized by an XRPD pattern together with DSC and TGA features, including an endothermic peak and mass-loss behavior.
Hydrochloric acid salt crystalline Form 1 defined by XRPD peaks
A solid-state form where the pharmaceutically acceptable salt is a hydrochloric acid salt that is crystalline Form 1, defined by an XRPD pattern having peaks at specified two-theta values.
Benzoic acid co-crystal crystalline Form 8 defined by XRPD peaks
A solid-state form where the solid is a benzoic acid co-crystal, and the resulting co-crystal is crystalline Form 8 defined by an XRPD pattern with specified peaks at specified degrees two theta.
Oral solid dosage form pharmaceutical composition
A pharmaceutical composition in the form of an oral solid dosage form.
Overall, the claims coverage centers on the Formula (II) compound solid-state forms and pharmaceutically acceptable salts, with specific embodiments defined by XRPD peak-position constraints and, in some cases, by additional DSC and TGA signatures. The claims also cover pharmaceutical compositions formulated as oral solid dosage forms.
Stated Advantages
Polymorphic purity or polymorphic-free embodiments are addressed for crystalline Form D.
The use of defined crystalline forms with characteristic XRPD peak sets and thermal signatures provides defined solid-form identification for polymorph, co-crystal, and solvate forms.
Documented Applications
Cancer treatment use for the Formula (II) compound and described salts and co-crystals.
Cancer treatment methods using USP1 inhibition in USP1 inhibitor-sensitive cancer, including biomarker-stratified approaches using RAD18 levels.
Combination approaches with PARP inhibitors, including targeting PARP inhibitor resistant cancer.
An oral solid dosage form pharmaceutical composition.
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