Solid form of CDK2 inhibitors

Abstract

This invention relates to the solid form of propionic acid (1R,3S)-3-[3-({[3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl]carbonyl}amino)-1H-pyrazol-5-yl]cyclopentyl ester, pharmaceutical compositions comprising such solid forms, and the use of such solid forms and pharmaceutical compositions for the treatment of cancer.

Description

Technical Field

[0001] This invention relates to a solid form of propionic acid (1R,3S)-3-[3-({[3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl]carbonyl}amino)-1H-pyrazol-5-yl]cyclopentyl ester (also referred to herein as PF-07104091), pharmaceutical compositions comprising said solid form, and methods of treating cancer using said solid form and pharmaceutical compositions. Background Technology

[0002] The compound propionic acid (1R,3S)-3-[3-({[3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl]carbonyl}amino)-1H-pyrazol-5-yl]cyclopentyl ester (PF-07104091) is a strong inhibitor of cyclin-dependent kinase 2 (CDK2) and has the following structure:

[0003]

[0004] The preparation of PF-07104091 isolated as a crystalline monohydrate (Form 1) is disclosed in International Patent Publication WO2020 / 157652 and U.S. Patent 11,014,911, the contents of which are incorporated herein by reference in their entirety.

[0005] This invention provides a crystal form of PF-07104091 having desired properties, such as high crystallinity, high purity, low hygroscopicity, favorable solubility or mechanical properties, improved prepareability or filterability, and / or favorable stability. This invention also provides an amorphous form of PF-07104091. Summary of the Invention

[0006] The present invention provides propyl-2-ylcarbamate (1R,3S)-3-[3-({[3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl]carbonyl}amino)-1H-pyrazol-5-yl]cyclopentyl ester (PF-07104091) in solid form.

[0007] In some aspects and embodiments, the present invention provides a crystal form of PF-07104091. In some aspects and embodiments, the crystal form is anhydrous crystalline PF-07104091 (form 2). In preferred aspects and embodiments, the crystal form is crystalline PF-07104091 monohydrate (form 3). In other aspects and embodiments, the crystal form is anhydrous crystalline PF-07104091 (form 5).

[0008] In other aspects and embodiments, the present invention provides an amorphous form of PF-07104091. In some aspects and embodiments, the amorphous form is amorphous PF-07104091 (Form 4).

[0009] In one aspect, the present invention provides anhydrous crystallizer PF-07104091 (form 2), which has:

[0010] (1) Powder X-ray diffraction (PXRD) pattern (2θ) containing: (a) one, two, three, four, five or more peaks selected from the peaks in Table 1 represented as °2θ ± 0.2°2θ; or (b) a peak at the 2θ value substantially the same as... Figure 2 same;

[0011] (2) Raman spectrum, which includes: (a) one, two, three, four, five or more wavenumbers (cm). -1 The wave values ​​are selected from those in Table 2, expressed in cm. -1 ±2cm -1 The value represented; or (b) substantially the same as Figure 7 Same wave number (cm) -1 ) value; or

[0012] (3) 13 C solid-state NMR spectrum (ppm), comprising: (a) one, two, three, four, five or more than five resonance (ppm) values, said resonance values ​​being selected from those expressed in ppm ± 0.2ppm in Table 3; or (b) substantially the same as... Figure 11 The same resonance (ppm) value;

[0013] Or any combination of two or more of (1)(a)-(b), (2)(a)-(b) and (3)(a)-(b), subject to the condition that they are not inconsistent with each other.

[0014] In another aspect, the present invention provides anhydrous crystallizer PF-07104091 (form 2), which has:

[0015] (a) Powder X-ray diffraction (PXRD) pattern containing peaks with 2θ values ​​of 9.8, 13.3 and 17.4°2θ ± 0.2°2θ;

[0016] (b) Raman spectra, which include the following wavenumbers (cm) -1 Values: 1691, 1582, and 996 cm -1 ±2cm -1 ;or

[0017] (c) 13The solid-state NMR spectrum of 1200 ppm contains the following resonance (ppm) values: 24.1, 39.8, and 41.6 ppm ± 0.2 ppm;

[0018] Or any combination of two or more of (a), (b) and (c).

[0019] In some embodiments, the crystal form is substantially pure anhydrous crystalline PF-07104091 (form 2).

[0020] In another aspect, the present invention provides a pharmaceutical composition comprising anhydrous crystalline PF-07104091 (form 2) according to the aspects or embodiments described herein and a pharmaceutically acceptable carrier or excipient.

[0021] In one aspect, the present invention provides crystalline PF-07104091 monohydrate (form 3), which has:

[0022] (1) Powder X-ray diffraction (PXRD) pattern (2θ) containing: (a) one, two, three, four, five or more peaks selected from the peaks in Table 4 expressed as °2θ ± 0.2°2θ; or (b) 2θ values ​​substantially equal to Figure 3 Same peak;

[0023] (2) Raman spectroscopy, which includes: (a) one, two, three, four, five or more wavenumbers (cm). -1 The wave values ​​are selected from those in Table 5, expressed in cm. -1 ±2cm -1 The value represented; or (b) substantially the same as Figure 8 Same wave number (cm) -1 ) value; or

[0024] (3) 13 C solid-state NMR spectra (ppm) comprising: (a) one, two, three, four, five or more than five resonance (ppm) values ​​selected from those expressed in ppm ± 0.2ppm in Table 6; or (b) substantially the same as... Figure 12 The same resonance (ppm) value; or

[0025] Or any combination of two or more of (1)(a)-(b), (2)(a)-(b) and (3)(a)-(b), subject to the condition that they are not inconsistent with each other.

[0026] In another aspect, the present invention provides crystalline PF-07104091 monohydrate (form 3), which has:

[0027] (a) Powder X-ray diffraction (PXRD) pattern containing peaks with 2θ values ​​of 8.4, 10.1 and 21.5°2θ ± 0.2°2θ;

[0028] (b) Raman spectra, which include the following wavenumbers (cm) -1 Values: 1657, 1595, and 1408 cm -1 ±2cm -1 ;or

[0029] (c) 13 The solid-state NMR spectrum of C1000 contains the following resonance (ppm) values: 25.2, 37.5, and 159.3 ppm ± 0.2 ppm;

[0030] Or any combination of two or more of (a), (b) and (c).

[0031] In some embodiments, the crystal form is substantially pure crystalline PF-07104091 monohydrate (form 3).

[0032] In another aspect, the present invention provides a pharmaceutical composition comprising crystalline PF-07104091 monohydrate (form 3) according to the aspects or embodiments described herein and a pharmaceutically acceptable carrier or excipient. Attached Figure Description

[0033] Figure 1 PXRD pattern of PF-07104091 monohydrate (form 1).

[0034] Figure 2 PXRD pattern of PF-07104091 (Form 2).

[0035] Figure 3 PXRD pattern of PF-07104091 monohydrate (form 3).

[0036] Figure 4 PXRD pattern of PF-07104091 (Form 4).

[0037] Figure 5 PXRD pattern of PF-07104091 (Form 5).

[0038] Figure 6 FT-Raman spectrum of PF-07104091 monohydrate (form 1).

[0039] Figure 7 FT-Raman spectrum of PF-07104091 (Form 2).

[0040] Figure 8FT-Raman spectrum of PF-07104091 monohydrate (form 3).

[0041] Figure 9 FT-Raman spectrum of PF-07104091 (Form 5).

[0042] Figure 10 Carbon CPMAS spectrum of PF-07104091 monohydrate (form 1) (# indicates rotating sideband).

[0043] Figure 11 Carbon CPMAS spectrum of PF-07104091 (Form 2) (# indicates rotating sideband).

[0044] Figure 12 Carbon CPMAS spectrum of PF-07104091 monohydrate (form 3) (# indicates rotating sideband).

[0045] Figure 13 Carbon CPMAS spectrum of PF-07104091 (Form 5) (# indicates rotating sideband).

[0046] Figure 14 .PF-07104091 (Form 4) Differential scanning calorimetry thermal analysis chromatogram at a heating rate of 10℃ / min.

[0047] Figure 15 Pyrolysis gravimetric analysis of PF-07104091 (Form 5).

[0048] Figure 16 Single crystal structure of PF-07104091 monohydrate (form 3). Detailed Implementation

[0049] The invention can be more readily understood by referring to the following detailed description of embodiments of the invention and the examples included herein. It should be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. It should be further understood that, unless specifically defined herein, the terms used herein have their conventional meanings known in the related art.

[0050] Unless otherwise specified, as used herein, the singular forms “a / an” and “the” include plural references. For example, a “one” substituent includes one or more substituents.

[0051] When considered by those skilled in the art, the term “about” means having a value that falls within an acceptable error standard of the average.

[0052] As used in this paper, the term "amorphous" refers to a solid substance that (1) has no order in three dimensions, or (2) exhibits order in less than three dimensions, only at short distances (e.g., less than 1000 meters). There is an order, or both. Diffuse PXRD patterns produced by amorphous solids typically contain one or two broad peaks.

[0053] As used in this article, the term "anhydrous" refers to a crystal form that contains only the active pharmaceutical ingredient (API) as part of its crystal lattice.

[0054] As used in this article, the term "crystallization" refers to the regular, repeating arrangement of molecules or outer surface planes. Crystal forms can differ in thermodynamic stability, physical parameters, X-ray structure, and preparation methods.

[0055] The term "polymorph" or "polymorph" refers to the crystal form of a compound that has a different spatial lattice arrangement compared to other crystal forms of the same compound.

[0056] The term "solvent" describes a molecular complex that comprises a compound (e.g., the active pharmaceutical ingredient (API) of a drug) and one or more solvent molecules (e.g., water or ethanol) in stoichiometric or non-stoichiometric amounts. When the solvent is tightly bound to the compound, the resulting complex will have a well-defined stoichiometry independent of humidity. However, when the solvent is weakly bound, as in channel solvates and hygroscopic compounds, the solvent content will depend on humidity and drying conditions. In such cases, the complex will typically be non-stoichiometric.

[0057] The term "hydrate" describes a solvate containing a compound and a stoichiometric or non-stoichiometric amount of water. A "monohydrate" is a hydrate in which each compound molecule contains one water molecule (i.e., a 1:1 stoichiometric ratio of water to compound).

[0058] The expression "substantially pure" means that the crystalline or amorphous form is substantially pure and contains less than 5% by weight, preferably less than 3% by weight and more preferably less than 1% by weight of impurities, including any other physical form of the compound (i.e., a chemical purity of more than 95%, preferably more than 97% and more preferably more than 99%).

[0059] As used herein, the term "substantially identical" means taking into account the typical variability of a particular method. For example, when referring to X-ray diffraction peak positions, the term "substantially identical" means taking into account the typical variability of peak position and intensity. Those skilled in the art will understand that peak position (2θ) will exhibit some variability, typically up to ±0.2°. Furthermore, those skilled in the art will understand that relative peak intensities will exhibit inter-device variability, as well as variability due to crystallinity, preferred orientation, the surface of the prepared sample, and other factors known to those skilled in the art, and should be considered only as qualitative measurements. Similarly, Raman spectral wavenumbers (cm²)-1 The value indicates variability, typically up to ±2 cm. -1 ,and 13 Solid-state NMR spectra (ppm) show variability, typically up to ±0.2 ppm.

[0060] The invention described herein may be practiced in the absence of any element not specifically disclosed herein. Thus, by way of example, in various contexts herein, any of the terms “comprising,” “substantially consisting of,” and “consisting of” may be replaced by any of the other two terms.

[0061] The solid form of PF-07104091 described herein can be characterized by any of the following methods: (1) powder X-ray diffraction (PXRD) (2θ); (2) Raman spectroscopy (cm). -1 (3) 13 C solid-state NMR spectroscopy (ppm); or (4) differential scanning calorimetry (DSC) (Tg °C); or any combination of two or more of methods (1), (2), (3) and (4).

[0062] In each of the aspects characterized by PXRD and the implementation thereof herein, the PXRD peaks were measured using CuKα radiation at 1.5418λ.

[0063] Such solid forms can be further characterized by other techniques, such as Fourier transform infrared spectroscopy (FTIR), pyrolysis gravimetric analysis (TGA), or differential thermal analysis (DTA).

[0064] A comparison of PXRD, Raman, and PXRD results of crystalline PF-07104091 monohydrate (form 1) described in International Patent Publication WO2020 / 157652 and US Patent 11,014,911. 13 C ssNMR data are provided respectively Figure 1 , Figure 6 and Figure 10 middle.

[0065] In one aspect, the present invention provides anhydrous crystallizer PF-07104091 (Form 2).

[0066] In some embodiments, PF-07104091 (Form 2) is characterized by its powder X-ray diffraction (PXRD) pattern. In other embodiments, PF-07104091 (Form 2) is characterized by its Raman spectroscopy. In other embodiments, PF-07104091 (Form 2) is characterized by its... 13 Solid-state NMR spectral characterization.

[0067] In other embodiments, anhydrous crystalline PF-07104091 (Form 2) is characterized by any combination of two or more of these methods. Exemplary combinations including two or more of the following are provided herein: powder X-ray diffraction (PXRD) patterns (2θ), Raman spectral values ​​(cm²). -1 ),or 13 C solid-state NMR spectrum (ppm).

[0068] In some embodiments, PF-07104091 (Form 2) is characterized by PXRD and Raman spectroscopy. In other embodiments, PF-07104091 (Form 2) is characterized by PXRD and Raman spectroscopy. 13 Solid-state NMR characterization. In other embodiments, PF-07104091 (Form 2) was characterized by Raman and... 13 Solid-state NMR characterization. In other embodiments, PF-07104091 (Form 2) was characterized by PXRD, Raman spectroscopy, and... 13 Solid-state NMR characterization.

[0069] In one aspect, the present invention provides anhydrous crystalline PF-07104091 (form 2) characterized by powder X-ray diffraction (PXRD) patterns.

[0070] In one embodiment, the present invention provides PF-07104091 (Form 2), whose powder X-ray diffraction (PXRD) pattern contains peaks with 2θ values ​​of 9.8, 13.3, and 17.4°2θ ± 0.2°2θ.

[0071] In one embodiment, the present invention provides PF-07104091 (Form 2), whose powder X-ray diffraction (PXRD) pattern contains peaks with 2θ values ​​of 4.2, 9.8, 13.3, and 17.4°2θ ± 0.2°2θ.

[0072] In one embodiment, the present invention provides PF-07104091 (Form 2), whose powder X-ray diffraction (PXRD) pattern contains peaks with 2θ values ​​of 7.5, 9.8, 13.3, and 17.4°2θ ± 0.2°2θ.

[0073] In another embodiment, the present invention provides PF-07104091 (Form 2), whose powder X-ray diffraction (PXRD) pattern contains peaks with 2θ values ​​of 4.2, 7.5, 9.8, 13.3 and 17.4°2θ ± 0.2°2θ.

[0074] In one embodiment, the present invention provides PF-07104091 (Form 2), whose powder X-ray diffraction (PXRD) pattern contains peaks with 2θ values ​​of 9.8, 13.3, and 17.4°2θ ± 0.2°2θ; and optionally contains one or two peaks selected from 4.2 and 7.5°2θ ± 0.2°2θ.

[0075] In another embodiment, the present invention provides PF-07104091 (Form 2), whose PXRD spectrum contains three or more peaks with 2θ values ​​selected from 4.2, 7.5, 9.8, 13.3 and 17.4°2θ ± 0.2°2θ.

[0076] In another embodiment, the present invention provides PF-07104091 (Form 2), whose PXRD spectrum comprises: (a) one, two, three, four, five or more peaks selected from those in Table 1 expressed as °2θ ± 0.2°2θ; or (b) 2θ values ​​substantially equal to... Figure 2 The same peak.

[0077] In another aspect, the present invention provides anhydrous crystalline PF-07104091 (form 2) characterized by Raman spectroscopy.

[0078] In one embodiment, the present invention provides PF-07104091 (Form 2), whose Raman spectrum contains the following wavenumbers (cm²). -1 Values: 1691, 1582, and 996 cm -1 ±2cm -1 .

[0079] In another embodiment, the present invention provides PF-07104091 (Form 2), whose Raman spectrum contains the following wavenumbers (cm²). -1 Values: 1691, 1582, 1036, and 996 cm -1 ±2cm -1 .

[0080] In another embodiment, the present invention provides PF-07104091 (Form 2), whose Raman spectrum contains the following wavenumbers (cm²). -1 Values: 1691, 1582, 1365, and 996 cm -1 ±2cm -1 .

[0081] In another embodiment, the present invention provides PF-07104091 (Form 2), whose Raman spectrum contains the following wavenumbers (cm²). -1 Values: 1691, 1582, 1365, 1036, and 996 cm -1 ±2cm -1 .

[0082] In one embodiment, the present invention provides PF-07104091 (Form 2), whose Raman spectrum contains the following wavenumbers (cm²). -1 Values: 1691, 1582, and 996 cm -1 ±2cm -1 ; and selected from 1365 and 1036cm -1 ±2cm -1 One or two peaks in the middle.

[0083] In one embodiment, the present invention provides PF-07104091 (Form 2), whose Raman spectrum includes: (a) one, two, three, four, five or more wavenumbers (cm²). -1 The wave values ​​are selected from those in Table 2 in cm. -1 ±2cm -1 The value represented; or (b) substantially the same as Figure 7 Same wave number (cm) -1 )value.

[0084] In another aspect, the present invention provides a method by means of 13 Anhydrous crystalline PF-07104091 (Form 2) characterized by C solid-state NMR spectroscopy.

[0085] In one embodiment, the present invention provides PF-07104091 (Form 2), which 13 The solid-state NMR spectra of 10⁻⁶ C₀C ...

[0086] In one embodiment, the present invention provides PF-07104091 (Form 2), which 13 The solid-state NMR spectra of 10⁻⁶ C₀C ...

[0087] In one embodiment, the present invention provides PF-07104091 (Form 2), which 13 The solid-state NMR spectra of 1380 ppm contain the following resonance (ppm) values: 24.1, 39.8, 41.6 ppm and 138.2 ppm ± 0.2 ppm.

[0088] In another embodiment, the present invention provides PF-07104091 (Form 2), which 13 The solid-state NMR spectra of 1380 ppm contain the following resonance (ppm) values: 21.8, 24.1, 39.8, 41.6 ppm and 138.2 ppm ± 0.2 ppm.

[0089] In one embodiment, the present invention provides PF-07104091 (Form 2), which 13 The C solid-state NMR spectrum includes the following resonance (ppm) values: 24.1, 39.8, and 41.6 ppm ± 0.2 ppm; and one or two resonance (ppm) values ​​selected from 21.8 and 138.2 ppm ± 0.2 ppm.

[0090] In one embodiment, the present invention provides PF-07104091 (Form 2), which 13 The C solid-state NMR spectrum contains the following resonance (ppm) values: 24.1, 39.8, and 41.6 ppm ± 0.2 ppm; and optionally includes one or two peaks selected from 21.8 and 138.2 ppm ± 0.2 ppm.

[0091] In another embodiment, the present invention provides PF-07104091 (Form 2), which 13 The solid-state NMR spectrum of 1380 ppm contains three or more resonance (ppm) values ​​selected from 21.8, 24.1, 39.8, 41.6 ppm and 138.2 ppm ± 0.2 ppm.

[0092] In another embodiment, the present invention provides PF-07104091 (Form 2), which 13 The solid-state NMR spectrum (ppm) includes: (a) one, two, three, four, five or more resonance (ppm) values, which are selected from the values ​​in Table 3 expressed in ppm ± 0.2 ppm; or (b) substantially the same as... Figure 11 The same resonance (ppm) value.

[0093] In another aspect, the present invention provides anhydrous crystallizer PF-07104091 (form 2), which has:

[0094] (a) Powder X-ray diffraction (PXRD) pattern containing peaks with 2θ values ​​of 9.8, 13.3 and 17.4°2θ ± 0.2°2θ;

[0095] (b) Raman spectra, which include the following wavenumbers (cm) -1 Values: 1691, 1582, and 996 cm -1 ±2cm -1 ;or

[0096] (c) 13 Solid-state NMR spectra with the following resonance (ppm) values: 24.1, 39.8, and 41.6 ppm ± 0.2 ppm; or

[0097] Or any combination of two or more of (a), (b) and (c).

[0098] In another aspect, the present invention provides anhydrous crystallizer PF-07104091 (form 2), which has:

[0099] (a) Powder X-ray diffraction (PXRD) pattern containing peaks with 2θ values ​​of 9.8 and 13.3°2θ ± 0.2°2θ; and optionally further containing a peak with a 2θ value of 17.4°2θ ± 0.2°2θ;

[0100] (b) Raman spectrum, which includes 1691 cm⁻¹ -1 ±2cm -1 wavenumber (cm) -1 ) value; and optionally further include 1582 and 996 cm -1 ±2cm -1 wavenumber (cm) -1 ) value; or

[0101] (c) 13 The solid-state NMR spectrum of 1200 ppm contains the following resonance (ppm) values: 24.1, 39.8, and 41.6 ppm ± 0.2 ppm;

[0102] Or any combination of two or more of (a), (b) and (c).

[0103] In another aspect, the present invention provides anhydrous crystallizer PF-07104091 (form 2), which has:

[0104] (1) Powder X-ray diffraction (PXRD) pattern, which contains peaks with the following 2θ values:

[0105] (a) 9.8, 13.3 and 17.4°2θ±0.2°2θ;

[0106] (b) 4.2, 9.8, 13.3 and 17.4°2θ±0.2°2θ;

[0107] (c) 7.5, 9.8, 13.3, and 17.4°2θ ± 0.2°2θ; or

[0108] (d) 4.2, 7.5, 9.8, 13.3 and 17.4°2θ±0.2°2θ;

[0109] (2) Raman spectroscopy, which includes the following wavenumbers (cm) -1 )value:

[0110] (a) 1691, 1582 and 996 cm -1 ±2cm -1 ;

[0111] (b) 1691, 1582, 1036 and 996 cm-1 ±2cm -1 ;

[0112] (c) 1691, 1582, 1365 and 996 cm -1 ±2cm -1 ;or

[0113] (d) 1691, 1582, 1365, 1036 and 996 cm -1 ±2cm -1 ;or

[0114] (3) 13 C solid-state NMR spectra, which include the following resonance (ppm) values:

[0115] (a) 24.1, 39.8 and 41.6ppm±0.2ppm;

[0116] (b) 21.8, 24.1, 39.8 and 41.6 ppm ± 0.2 ppm;

[0117] (c) 24.1, 39.8, 41.6 and 138.2 ppm ± 0.2 ppm; or

[0118] (d) 21.8, 24.1, 39.8, 41.6 and 138.2 ppm ± 0.2 ppm.

[0119] Or any combination of two or more of (1)(a)-(d), (2)(a)-(d) and (3)(a)-(d).

[0120] In some embodiments of PF-07104091 (Form 2) and each of the embodiments herein, the crystal form is substantially pure anhydrous crystalline PF-07104091 (Form 2).

[0121] In another aspect, the present invention provides a pharmaceutical composition comprising anhydrous crystalline PF-07104091 (form 2) according to the aspects or embodiments described herein and a pharmaceutically acceptable carrier or excipient.

[0122] In another aspect, the present invention provides a method for treating cancer in an individual in need, comprising administering to the individual a therapeutically effective amount of anhydrous crystalline PF-07104091 (Form 2) according to the aspects or embodiments described herein, or a pharmaceutical composition comprising anhydrous crystalline PF-07104091 (Form 2).

[0123] In another aspect, the present invention provides a method for treating cancer in an individual in need, comprising administering to the individual an amount of anhydrous crystalline PF-07104091 (Form 2) or a pharmaceutical composition comprising anhydrous crystalline PF-07104091 (Form 2) according to the aspects or embodiments described herein, and an amount of other anticancer agents, wherein the amount of PF-07104091 (Form 2) together with the other anticancer agents effectively treats cancer.

[0124] In another aspect, the present invention provides anhydrous crystalline PF-07104091 (Form 2) or a pharmaceutical composition comprising anhydrous crystalline PF-07104091 (Form 2) according to the aspects or embodiments described herein, for the treatment of cancer.

[0125] In another aspect, the present invention provides anhydrous crystalline PF-07104091 (Form 2) according to the aspects or embodiments described herein, for use in the preparation of a medicament for the treatment of cancer.

[0126] In another aspect, the present invention provides the use of anhydrous crystalline PF-07104091 (Form 2) or a pharmaceutical composition comprising anhydrous crystalline PF-07104091 (Form 2) according to the aspects or embodiments described herein for the treatment of cancer.

[0127] In another aspect, the present invention provides the use of anhydrous crystalline PF-07104091 (Form 2) according to the aspects or embodiments described herein in the preparation of a medicament for treating cancer.

[0128] In each aspect of and embodiment of the anhydrous crystalline PF-07104091 (Form 2) described herein, the crystal form may be substantially pure anhydrous crystalline PF-07104091 (Form 2).

[0129] Each of the embodiments described herein with respect to anhydrous crystallization PF-07104091 (Form 2) may be combined with other such embodiments, provided that the embodiments are not inconsistent with each other.

[0130] In a preferred aspect, the present invention provides crystalline PF-07104091 monohydrate (form 3). In some embodiments, crystalline PF-07104091 monohydrate (form 3) is characterized by its powder X-ray diffraction (PXRD) pattern. In other embodiments, crystalline PF-07104091 monohydrate (form 3) is characterized by its Raman spectroscopy. In other embodiments, crystalline PF-07104091 monohydrate (form 3) is characterized by its... 13 Solid-state NMR spectral characterization.

[0131] In another embodiment, the crystalline PF-07104091 monohydrate (form 3) is characterized by any combination of two or more of these methods. Exemplary combinations including two or more of the following are provided herein: powder X-ray diffraction (PXRD) patterns (2θ), Raman spectral values ​​(cm²). -1 ),or 13 Solid-state NMR spectroscopy (ppm). In some embodiments, crystalline PF-07104091 monohydrate (form 3) was characterized by PXRD and Raman spectroscopy. In other embodiments, crystalline PF-07104091 monohydrate (form 3) was characterized by PXRD and Raman spectroscopy. 13 Solid-state NMR characterization. In other embodiments, the crystalline PF-07104091 monohydrate (form 3) was characterized by Raman spectroscopy and solid-state NMR. 13 Solid-state NMR characterization. In other embodiments, the crystalline PF-07104091 monohydrate (form 3) was characterized by PXRD, Raman spectroscopy, and... 13 Solid-state NMR characterization.

[0132] In one aspect, the present invention provides crystalline PF-07104091 monohydrate (form 3) characterized by powder X-ray diffraction (PXRD) patterns.

[0133] In one embodiment, the present invention provides crystalline PF-07104091 monohydrate (form 3) whose powder X-ray diffraction (PXRD) pattern contains peaks with 2θ values ​​of 8.4, 10.1, and 21.5°2θ ± 0.2°2θ.

[0134] In one embodiment, the present invention provides crystalline PF-07104091 monohydrate (form 3) whose powder X-ray diffraction (PXRD) pattern contains peaks with 2θ values ​​of 8.4, 10.1, 16.9 and 21.5°2θ ± 0.2°2θ.

[0135] In one embodiment, the present invention provides crystalline PF-07104091 monohydrate (form 3) whose powder X-ray diffraction (PXRD) pattern contains peaks with 2θ values ​​of 8.4, 10.1, 21.5 and 27.0°2θ ± 0.2°2θ.

[0136] In another embodiment, the present invention provides crystalline PF-07104091 monohydrate (form 3) whose powder X-ray diffraction (PXRD) pattern contains peaks with 2θ values ​​of 8.4, 10.1, 16.9, 21.5 and 27.0°2θ ± 0.2°2θ.

[0137] In another embodiment, the present invention provides crystalline PF-07104091 monohydrate (form 3) whose powder X-ray diffraction (PXRD) pattern contains peaks with 2θ values ​​as follows:

[0138] (a) 8.4, 10.1 and 21.5°2θ±0.2°2θ;

[0139] (b) 8.4, 10.1, 16.9 and 21.5°2θ ± 0.2°2θ;

[0140] (c) 8.4, 10.1, 21.5, and 27.0°2θ ± 0.2°2θ; or

[0141] (d)8.4, 10.1, 16.9, 21.5 and 27.0°2θ±0.2°2θ.

[0142] In one embodiment, the present invention provides crystalline PF-07104091 monohydrate (form 3) whose powder X-ray diffraction (PXRD) pattern contains peaks with 2θ values ​​of 8.4, 10.1, and 21.5°2θ ± 0.2°2θ; and optionally contains one or two peaks selected from 16.9 and 27.0°2θ ± 0.2°2θ.

[0143] In another embodiment, the present invention provides crystalline PF-07104091 monohydrate (form 3) whose PXRD spectrum contains three or more peaks with 2θ values ​​selected from 8.4, 10.1, 16.9, 21.5 and 27.0°2θ ± 0.2°2θ.

[0144] In another embodiment, the present invention provides crystalline PF-07104091 monohydrate (form 3) whose PXRD spectrum contains: (a) one, two, three, four, five or more peaks selected from those in Table 4 expressed as °2θ ± 0.2°2θ; or (b) 2θ values ​​substantially equal to... Figure 3 The same peak.

[0145] In another aspect, the present invention provides crystalline PF-07104091 monohydrate (form 3) characterized by Raman spectroscopy.

[0146] In one embodiment, the present invention provides crystalline PF-07104091 monohydrate (form 3) whose Raman spectrum contains the following wavenumbers (cm²). -1 Values: 1657, 1595, and 1408 cm -1 ±2cm -1 .

[0147] In another embodiment, the present invention provides crystalline PF-07104091 monohydrate (form 3) whose Raman spectrum contains the following wavenumbers (cm²).-1 Values: 1657, 1595, 1408, and 923 cm -1 ±2cm -1 .

[0148] In another embodiment, the present invention provides crystalline PF-07104091 monohydrate (form 3) whose Raman spectrum contains the following wavenumbers (cm²). -1 Values: 1657, 1595, 1408, and 1272 cm -1 ±2cm -1 .

[0149] In another embodiment, the present invention provides crystalline PF-07104091 monohydrate (form 3) whose Raman spectrum contains the following wavenumbers (cm²). -1 Values: 1657, 1595, 1408, 1272, and 923 cm -1 ±2cm -1 .

[0150] In another embodiment, the present invention provides crystalline PF-07104091 monohydrate (form 3) whose Raman spectrum contains the following wavenumbers (cm²). -1 )value:

[0151] (a) 1657, 1595 and 1408 cm -1 ±2cm -1 ;

[0152] (b) 1657, 1595, 1408 and 923 cm -1 ±2cm -1 ;

[0153] (c) 1657, 1595, 1408 and 1272 cm -1 ±2cm -1 ;or

[0154] (d) 1657, 1595, 1408, 1272 and 923 cm -1 ±2cm -1 .

[0155] In one embodiment, the present invention provides crystalline PF-07104091 monohydrate (form 3) whose Raman spectrum contains the following wavenumbers (cm²). -1 Values: 1657, 1595, and 1408 cm -1 ±2cm -1 ; and selected from 1272 and 923cm -1 ±2cm -1 One or two peaks in the middle.

[0156] In one embodiment, the present invention provides crystalline PF-07104091 monohydrate (form 3) whose Raman spectrum includes: (a) one, two, three, four, five or more wavenumbers (cm²). -1 The wave values ​​are selected from those in Table 5, expressed in cm. -1 ±2cm -1 The value represented; or (b) substantially the same as Figure 8 Same wave number (cm) -1 )value.

[0157] In another aspect, the present invention provides a method by means of 13 Crystalline PF-07104091 monohydrate (form 3) characterized by C2 solid-state NMR spectroscopy.

[0158] In one embodiment, the present invention provides crystalline PF-07104091 monohydrate (form 3), which 13 The solid-state NMR spectrum of C contains the following resonance (ppm) values: 25.2 and 37.5 ppm ± 0.2 ppm.

[0159] In one embodiment, the present invention provides crystalline PF-07104091 monohydrate (form 3), which 13 The solid-state NMR spectrum of C10 contains the following resonance (ppm) values: 25.2, 37.5, and 159.3 ppm ± 0.2 ppm.

[0160] In one embodiment, the present invention provides crystalline PF-07104091 monohydrate (form 3), which 13 The solid-state NMR spectra of 1200 ppm contain the following resonance (ppm) values: 25.2, 37.5, 151.9 and 159.3 ppm ± 0.2 ppm.

[0161] In one embodiment, the present invention provides crystalline PF-07104091 monohydrate (form 3), which 13 The solid-state NMR spectra of 1200 ppm contain the following resonance (ppm) values: 25.2, 37.5, 152.5 and 159.3 ppm ± 0.2 ppm.

[0162] In another embodiment, the present invention provides crystalline PF-07104091 monohydrate (form 3), which 13 The solid-state NMR spectra of 1200 ppm contain the following resonance (ppm) values: 25.2, 37.5, 151.9, 152.5 and 159.3 ppm ± 0.2 ppm.

[0163] In one embodiment, the present invention provides crystalline PF-07104091 monohydrate (form 3), which 13The C solid-state NMR spectrum includes the following resonance (ppm) values: 25.2, 37.5 and 159.3 ppm ± 0.2 ppm; and one or two resonance (ppm) values ​​selected from 151.9 and 152.5 ppm ± 0.2 ppm.

[0164] In another embodiment, the present invention provides crystalline PF-07104091 monohydrate (form 3), which 13 The C solid-state NMR spectrum contains the following resonance (ppm) values:

[0165] (a) 25.2 and 37.5 ppm ± 0.2 ppm;

[0166] (b) 25.2, 37.5 and 159.3 ppm ± 0.2 ppm;

[0167] (c) 25.2, 37.5, 151.9 and 159.3 ppm ± 0.2 ppm;

[0168] (d) 25.2, 37.5, 152.5 and 159.3 ppm ± 0.2 ppm; or

[0169] (e)25.2, 37.5, 151.9, 152.5 and 159.3 ppm ± 0.2 ppm.

[0170] In one embodiment, the present invention provides crystalline PF-07104091 monohydrate (form 3), which 13 The solid-state NMR spectrum contains the following resonance (ppm) values: 25.2, 37.5, and 159.3 ppm ± 0.2 ppm; and optionally includes one or two peaks selected from 151.9 and 152.5 ppm ± 0.2 ppm.

[0171] In another embodiment, the present invention provides crystalline PF-07104091 monohydrate (form 3), which 13 The solid-state NMR spectrum of 1200 ppm contains three or more resonance (ppm) values ​​selected from 25.2, 37.5, 151.9, 152.5 and 159.3 ppm ± 0.2 ppm.

[0172] In another embodiment, the present invention provides crystalline PF-07104091 monohydrate (form 3), which 13 The solid-state NMR spectrum (ppm) includes: (a) one, two, three, four, five or more resonance (ppm) values, which are selected from the values ​​in Table 6 expressed as ppm ± 0.2ppm; or (b) substantially the same as... Figure 12 The same resonance (ppm) value.

[0173] In another aspect, the present invention provides crystalline PF-07104091 monohydrate (form 3), which has:

[0174] (a) Powder X-ray diffraction (PXRD) pattern containing peaks with 2θ values ​​of 8.4, 10.1 and 21.5°2θ ± 0.2°2θ;

[0175] (b) Raman spectra, which include the following wavenumbers (cm) -1 Values: 1657, 1595, and 1408 cm -1 ±2cm -1 ;or

[0176] (c) 13 C solid-state NMR spectra containing the following resonance (ppm) values: 25.2, 37.5, and 159.3 ppm ± 0.2 ppm; or

[0177] Or any combination of two or more of (a), (b) and (c).

[0178] In another aspect, the present invention provides crystalline PF-07104091 monohydrate (form 3), which has:

[0179] (a) Powder X-ray diffraction (PXRD) pattern containing peaks with 2θ values ​​of 8.4 and 10.1°2θ ± 0.2°2θ; and optionally further containing a peak with a 2θ value of 21.5°2θ ± 0.2°2θ;

[0180] (b) Raman spectrum, which includes 1657 cm⁻¹ -1 ±2cm -1 wavenumber (cm) -1 ) values; and optionally further include 1595 and 1408 cm -1 ±2cm -1 wavenumber (cm) -1 ) value; or

[0181] (c) 13 The solid-state NMR spectrum includes resonance (ppm) values ​​of 25.2 and 37.5 ppm ± 0.2 ppm; and optionally further includes resonance (ppm) values ​​of 159.3 ppm ± 0.2 ppm.

[0182] Or any combination of two or more of (a), (b) and (c).

[0183] In another aspect, the present invention provides crystalline PF-07104091 monohydrate (form 3), which has:

[0184] (1) Powder X-ray diffraction (PXRD) pattern, which contains peaks with the following 2θ values:

[0185] (a) 8.4, 10.1 and 21.5°2θ±0.2°2θ;

[0186] (b) 8.4, 10.1, 16.9 and 21.5°2θ ± 0.2°2θ;

[0187] (c) 8.4, 10.1, 21.5, and 27.0°2θ ± 0.2°2θ; or

[0188] (d) 8.4, 10.1, 16.9, 21.5 and 27.0°2θ±0.2°2θ;

[0189] (2) Raman spectroscopy, which includes the following wavenumbers (cm) -1 )value:

[0190] (a) 1657, 1595 and 1408 cm -1 ±2cm -1 ;

[0191] (b) 1657, 1595, 1408 and 923 cm -1 ±2cm -1 ;

[0192] (c) 1657, 1595, 1408 and 1272 cm -1 ±2cm -1 ;or

[0193] (d) 1657, 1595, 1408, 1272 and 923 cm -1 ±2cm -1 ;or

[0194] (3) 13 C solid-state NMR spectra, which include the following resonance (ppm) values:

[0195] (a) 25.2 and 37.5 ppm ± 0.2 ppm;

[0196] (b) 25.2, 37.5 and 159.3 ppm ± 0.2 ppm;

[0197] (c) 25.2, 37.5, 151.9 and 159.3 ppm ± 0.2 ppm;

[0198] (d) 25.2, 37.5, 152.5 and 159.3 ppm ± 0.2 ppm; or

[0199] (e) 25.2, 37.5, 151.9, 152.5 and 159.3 ppm ± 0.2 ppm;

[0200] Or any combination of two or more of (1)(a)-(d), (2)(a)-(d) and (3)(a)-(e).

[0201] In another aspect, the present invention provides a pharmaceutical composition comprising crystalline PF-07104091 monohydrate (form 3) according to the aspects or embodiments described herein and a pharmaceutically acceptable carrier or excipient.

[0202] In another aspect, the present invention provides a method for treating cancer in an individual in need, comprising administering to the individual a therapeutically effective amount of crystalline PF-07104091 monohydrate (form 3) or a pharmaceutical composition comprising crystalline PF-07104091 monohydrate (form 3) according to the aspects or embodiments described herein.

[0203] In another aspect, the present invention provides a method for treating cancer in an individual in need, comprising administering to the individual a certain amount of crystalline PF-07104091 monohydrate (form 3) according to the aspects or embodiments described herein, or a pharmaceutical composition comprising crystalline PF-07104091 monohydrate (form 3), and a certain amount of other anticancer agents, wherein the certain amount of PF-07104091 monohydrate (form 3), together with the other anticancer agents, effectively treats cancer.

[0204] In another aspect, the present invention provides crystalline PF-07104091 monohydrate (form 3) or a pharmaceutical composition comprising crystalline PF-07104091 monohydrate (form 3) according to the aspects or embodiments described herein, for the treatment of cancer.

[0205] In another aspect, the present invention provides a crystalline PF-07104091 monohydrate (form 3) according to the aspects or embodiments described herein, for use in the preparation of a medicament for the treatment of cancer.

[0206] In another aspect, the present invention provides the use of crystalline PF-07104091 monohydrate (form 3) or a pharmaceutical composition comprising crystalline PF-07104091 monohydrate (form 3) according to the aspects or embodiments described herein for the treatment of cancer.

[0207] In another aspect, the present invention provides the use of crystalline PF-07104091 monohydrate (form 3) according to the aspects or embodiments described herein in the preparation of a medicament for treating cancer.

[0208] In each of the aspects and embodiments of the crystalline PF-07104091 monohydrate (form 3) described herein, the crystal form may be substantially pure crystalline PF-07104091 monohydrate (form 3).

[0209] Each of the embodiments described herein with respect to crystalline PF-07104091 monohydrate (Form 3) may be combined with other such embodiments, provided that the embodiments are not inconsistent with each other.

[0210] In another aspect, the present invention provides an amorphous PF-07104091 (Form 4).

[0211] In some embodiments, the present invention provides amorphous PF-07104091 (Form 4) whose powder X-ray diffraction (PXRD) pattern contains broad peaks with diffraction angles (2θ) of about 5 to about 35°2θ ± 0.2°2θ.

[0212] In some embodiments, the present invention provides amorphous PF-07104091 (form 4), whose powder X-ray diffraction (PXRD) pattern is substantially similar to... Figure 4 same.

[0213] In some embodiments, the present invention provides amorphous PF-07104091 (form 4) with a glass transition temperature (T0). g The temperature was 59.8 ± 5℃. Figure 14 ).

[0214] In another embodiment, the present invention provides amorphous PF-07104091 (form 4), which has:

[0215] (1) Powder X-ray diffraction (PXRD) pattern (2θ), which includes:

[0216] (a) The diffraction angle (2θ) is a broad peak ranging from approximately 5 to approximately 35°2θ ± 0.2°2θ; or

[0217] (b) 2θ value and Figure 4 The peaks are basically the same; or

[0218] (2) DSC thermal analysis chart, which includes:

[0219] (a) Glass transition temperature (T) of approximately 59.8 ± 5 °C g (e.g., measured by DSC at a heating rate of 10 °C / min); or

[0220] (b) and Figure 14 Essentially the same DSC thermal analysis chart;

[0221] Or any combination of two or more of (1)(a)-(b) and (2)(a)-(b).

[0222] In another aspect, the present invention provides a pharmaceutical composition comprising amorphous PF-07104091 (form 4) according to the aspects or embodiments described herein and a pharmaceutically acceptable carrier or excipient.

[0223] In another aspect, the present invention provides a method for treating cancer in an individual in need, comprising administering to the individual a therapeutically effective amount of amorphous PF-07104091 (Form 4) or a pharmaceutical composition comprising amorphous PF-07104091 (Form 4) according to the aspects or embodiments described herein.

[0224] In another aspect, the present invention provides a method for treating cancer in an individual in need, comprising administering to the individual a certain amount of amorphous PF-07104091 (form 4) or a pharmaceutical composition comprising amorphous PF-07104091 (form 4) according to the aspects or embodiments described herein, and a certain amount of other anticancer agents, wherein the certain amount of amorphous PF-07104091 (form 4) together with the other anticancer agents effectively treats cancer.

[0225] In another aspect, the present invention provides amorphous PF-07104091 (Form 4) or a pharmaceutical composition comprising amorphous PF-07104091 (Form 4) according to the aspects or embodiments described herein, for the treatment of cancer.

[0226] In another aspect, the present invention provides an amorphous PF-07104091 (Form 4) according to the aspects or embodiments described herein, for the preparation of a medicament for the treatment of cancer.

[0227] In another aspect, the present invention provides the use of amorphous PF-07104091 (Form 4) or a pharmaceutical composition comprising amorphous PF-07104091 (Form 4) according to the aspects or embodiments described herein for the treatment of cancer.

[0228] In another aspect, the present invention provides the use of amorphous PF-07104091 (Form 4) according to the aspects or embodiments described herein in the preparation of a medicament for treating cancer.

[0229] In each of the aspects of the amorphous PF-07104091 (Form 4) described herein and in each of the embodiments, the amorphous may be substantially pure amorphous PF-07104091 (Form 4).

[0230] Each of the implementation schemes described herein with respect to amorphous PF-07104091 (Form 4) may be combined with other such implementation schemes, subject to the condition that the implementation schemes are not inconsistent with each other.

[0231] In another aspect, the present invention provides anhydrous crystalline PF-07104091 (form 5). Form 5 is prepared by dehydrating PF-07104091 monohydrate (form 3). In some embodiments, PF-07104091 (form 5) is characterized by its powder X-ray diffraction (PXRD) pattern. In other embodiments, PF-07104091 (form 5) is characterized by its Raman spectroscopy. In other embodiments, PF-07104091 (form 5) is characterized by its... 13 Solid-state NMR spectral characterization.

[0232] In other embodiments, PF-07104091 (Form 5) is characterized by any combination of two or more of these methods. Exemplary combinations thereof are provided herein, including two or more of the following: powder X-ray diffraction (PXRD) patterns (2θ), Raman spectral wave values ​​(cm²). -1 ),or 13 Solid-state NMR spectroscopy (ppm). In some embodiments, PF-07104091 (Form 5) is characterized by PXRD and Raman spectroscopy. In other embodiments, PF-07104091 (Form 5) is characterized by PXRD and Raman spectroscopy. 13 Solid-state NMR characterization. In other embodiments, PF-07104091 (Form 5) was characterized by Raman and... 13 Solid-state NMR characterization. In other embodiments, crystalline PF-07104091 (form 5) was characterized by PXRD, Raman spectroscopy, and... 13 Solid-state NMR characterization.

[0233] In one aspect, the present invention provides anhydrous crystalline PF-07104091 (form 5) characterized by powder X-ray diffraction (PXRD) patterns.

[0234] In another embodiment, the present invention provides anhydrous crystalline PF-07104091 (form 5), whose PXRD spectrum contains three or more peaks with 2θ values ​​selected from 10.2, 12.4, 15.4, 17.2, 17.9, 19.8, 21.6, 22.5, 23.7 and 26.2°2θ ± 0.2°2θ.

[0235] In another embodiment, the present invention provides anhydrous crystalline PF-07104091 (Form 5), whose PXRD pattern comprises: (a) one, two, three, four, five or more peaks selected from those expressed in °2θ ± 0.2°2θ in Table 8; or (b) 2θ values ​​substantially equal to... Figure 5 The same peak.

[0236] In another aspect, the present invention provides anhydrous crystalline PF-07104091 (form 5) characterized by Raman spectroscopy.

[0237] In one embodiment, the present invention provides anhydrous crystalline PF-07104091 (Form 5) whose Raman spectrum includes: (a) one, two, three, four, five or more wavenumbers (cm²). -1 The wave values ​​are selected from those in Table 9, expressed in cm. -1 ±2cm -1 The value represented; or (b) substantially the same as Figure 9 Same wave number (cm) -1 )value.

[0238] In another aspect, the present invention provides a method by means of 13 Anhydrous crystalline PF-07104091 (form 5) characterized by C solid-state NMR spectroscopy.

[0239] In some of these embodiments, the present invention provides anhydrous crystallizer PF-07104091 (Form 5), which 13 The C solid-state NMR spectrum (ppm) includes: (a) one, two, three, four, five, or more than five resonance (ppm) values, said resonance values ​​being selected from those expressed in ppm ± 0.2ppm in Table 10; or (b) substantially the same as... Figure 13 The same resonance (ppm) value.

[0240] In another aspect, the present invention provides anhydrous crystallizer PF-07104091 (form 5), which has:

[0241] (a) 2θ value and Figure 5 Basically the same peak;

[0242] (b) Wavenumber (cm) -1 )and Figure 9 Basically the same; or

[0243] (c) Resonance (ppm) value and Figure 13 Basically the same; or

[0244] Or any combination of two or more of (a), (b) and (c).

[0245] In another aspect, the present invention provides a pharmaceutical composition comprising anhydrous crystalline PF-07104091 (form 5) according to the aspects or embodiments described herein and a pharmaceutically acceptable carrier or excipient.

[0246] In another aspect, the present invention provides a method for treating cancer in an individual in need, comprising administering to the individual a therapeutically effective amount of anhydrous crystalline PF-07104091 (Form 5) according to the aspects or embodiments described herein, or a pharmaceutical composition comprising anhydrous crystalline PF-07104091 (Form 5).

[0247] In another aspect, the present invention provides a method for treating cancer in an individual in need, comprising administering to the individual an amount of anhydrous crystalline PF-07104091 (Form 5) or a pharmaceutical composition comprising anhydrous crystalline PF-07104091 (Form 5) according to the aspects or embodiments described herein, and an amount of other anticancer agents, wherein the amount of PF-07104091 (Form 5) together with the other anticancer agents effectively treats cancer.

[0248] In another aspect, the present invention provides anhydrous crystalline PF-07104091 (Form 5) or a pharmaceutical composition comprising anhydrous crystalline PF-07104091 (Form 5) according to the aspects or embodiments described herein, for the treatment of cancer.

[0249] In another aspect, the present invention provides anhydrous crystalline PF-07104091 (Form 5) according to the aspects or embodiments described herein, for use in the preparation of a medicament for the treatment of cancer.

[0250] In another aspect, the present invention provides the use of anhydrous crystalline PF-07104091 (Form 5) or a pharmaceutical composition comprising anhydrous crystalline PF-07104091 (Form 5) according to the aspects or embodiments described herein for the treatment of cancer.

[0251] In another aspect, the present invention provides the use of anhydrous crystalline PF-07104091 (Form 5) according to the aspects or embodiments described herein in the preparation of a medicament for treating cancer.

[0252] In each of the aspects and embodiments of the anhydrous crystalline PF-07104091 (Form 5) described herein, the crystal form may be substantially pure PF-07104091 crystal form (Form 5).

[0253] Each of the embodiments described herein with respect to anhydrous crystallization PF-07104091 (Form 5) may be combined with other such embodiments, provided that the embodiments are not inconsistent with each other.

[0254] In some embodiments of the methods and uses described herein, the cancer is selected from the group consisting of: breast cancer, prostate cancer, lung cancer (including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC)), liver cancer (including hepatocellular carcinoma (HCC)), kidney cancer (including renal cell carcinoma (RCC)), bladder cancer (including urethral epithelial carcinoma, such as upper urinary tract urethral epithelial carcinoma (UUTUC)), ovarian cancer (including epithelial ovarian cancer (EOC)), peritoneal cancer (including primary peritoneal cancer). Pancreatic cancer (PPC), fallopian tube cancer, cervical cancer, uterine cancer (including endometrial cancer), pancreatic cancer, gastric cancer, colorectal cancer, esophageal cancer, head and neck cancer (including squamous cell carcinoma of the head and neck (SCCHN), thyroid cancer, and salivary gland cancer), testicular cancer, adrenal cancer, skin cancer (including basal cell carcinoma and melanoma), brain cancer (including astrocytoma, meningioma, and glioblastoma), sarcoma (including osteosarcoma and liposarcoma), and lymphoma (including mantle cell lymphoma (MCL)).

[0255] In some embodiments of the methods and uses described herein, the cancer is SCLC. In some of these embodiments, the SCLC is Rb-negative or Rb-deficient.

[0256] In some embodiments of the methods and uses described herein, the cancer is NSCLC. In some such embodiments, NSCLC is characterized by the amplification or overexpression of cyclin E1 (CCNE1) and / or cyclin E2 (CCNE2).

[0257] In some embodiments of the methods and uses described herein, the cancer is ovarian cancer (including epithelial ovarian cancer (EOC)), peritoneal cancer (including primary peritoneal cancer (PPC)), or fallopian tube cancer. In some such embodiments, the cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0258] In some embodiments of the methods and uses described herein, the cancer is TNBC. In some such embodiments, TNBC is difficult to treat with CDK4 / 6 inhibitors (such as palbociclib).

[0259] In some embodiments of the methods and uses described herein, the cancer is HR-positive, HER2-negative breast cancer, including advanced or metastatic breast cancer. In some such embodiments, the breast cancer is difficult to treat with CDK4 / 6 inhibitors (such as palbociclib).

[0260] In some embodiments of the methods and uses described herein, the cancer is advanced or metastatic. In some embodiments of the methods and uses described herein, the cancer is early or non-metastatic.

[0261] In other embodiments, the cancer is breast cancer, including, for example, ER-positive / HR-positive, HER2-negative breast cancer; ER-positive / HR-positive, HER2-positive breast cancer; triple-negative breast cancer (TNBC); or inflammatory breast cancer. In some embodiments, the breast cancer exhibits initial or acquired resistance to endocrine therapy, anti-HER2 targeted agents, CDK4 / CDK6 inhibitors, or chemotherapy (e.g., taxanes or platinum).

[0262] In some embodiments, the breast cancer is advanced or metastatic breast cancer. In some embodiments of each of the foregoing, the breast cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0263] In some embodiments of the methods provided herein, abnormal cell growth is characterized by cancer featuring amplification or overexpression of CCNE1 and / or CCNE2. In some embodiments of the methods provided herein, the individual is identified as having cancer characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0264] In some embodiments, the cancer is breast cancer or ovarian cancer. In some such embodiments, the cancer is breast cancer or ovarian cancer characterized by amplification or overexpression of CCNE1 and / or CCNE2. In some such embodiments, the cancer is (a) breast cancer or ovarian cancer; (b) characterized by amplification or overexpression of CCNE1 or CCNE2; or (c) both (a) and (b).

[0265] In some embodiments, the compounds of the present invention are administered as a first-line therapy. In other embodiments, the compounds of the present invention are administered as a second (or subsequent)-line therapy.

[0266] In some embodiments, the compounds of the present invention are administered as a second (or subsequent) line of therapy after treatment with endocrine therapy and / or CDK4 / 6 inhibitors. In some embodiments, the compounds of the present invention are administered as a second (or subsequent) line of therapy after treatment with endocrine therapy (e.g., aromatase inhibitors, SERMs, or SERDs). In some embodiments, the compounds of the present invention are administered as a second (or subsequent) line of therapy after treatment with CDK4 / 6 inhibitors (e.g., palbociclib, ribociclib, or abemaciclib, or pharmaceutically acceptable salts thereof). In some embodiments, the compounds of the present invention are administered as a second (or subsequent) line of therapy after treatment with one or more chemotherapy regimens (e.g., including taxanes or platinum agents). In some implementations, the compounds of the present invention are administered as a second (or subsequent) line of therapy after treatment with anti-HER2 targeted agents such as trastuzumab, pertuzumab, lapatinib, or trastuzumab-mettansin conjugate (T-DM1).

[0267] As used herein, an “effective dose,” “effective amount,” or “therapeutic effective amount” of a compound or pharmaceutical composition is an amount sufficient, when used as directed (either alone or in combination with other agents) to affect one or more beneficial or desired outcomes, including prevention, improvement, or treatment of the biochemical, histological, or behavioral symptoms of a disease, its complications, and intermediate pathological phenotypes manifested during the development of the disease. For prophylactic use, beneficial or desired outcomes may include: eliminating or reducing the risk of disease, reducing the severity of disease, or delaying the onset of disease. For therapeutic use, beneficial or desired outcomes may include: reducing the incidence of disease or improving one or more symptoms of disease; reducing the dosage of another drug used to treat the disease; enhancing the efficacy or safety of another drug used to treat the disease; or delaying the onset of disease.

[0268] When referring to cancer treatment, the effective dose of treatment refers to a dose that has the following effects: (1) reducing tumor size; (2) inhibiting (i.e., slowing down to some extent, preferably stopping) tumor metastasis; (3) inhibiting (i.e., slowing down to some extent, preferably stopping) tumor growth or tumor invasion to some extent; (4) alleviating (or preferably eliminating) one or more symptoms or signs associated with cancer to some extent; (5) reducing the dosage of other medicines required to treat the disease and / or (6) enhancing the effect of another medicine and / or (7) delaying the progression of the patient's disease.

[0269] Effective doses can be administered via one or more administration methods. For the purposes of this invention, an effective dose of a drug, compound, or pharmaceutical composition is an amount sufficient to directly or indirectly achieve preventative or therapeutic treatment. As understood in clinical contexts, an effective dose of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition.

[0270] A “non-standard dosing regimen” refers to a regimen for administering a substance, agent, compound, or pharmaceutical composition in a manner that differs from the amount, dose, or duration typically used in a clinical or therapeutic setting. “Non-standard dosing regimens” include “non-standard doses” or “non-standard dosing durations.”

[0271] A “low-dose regimen” refers to a dosing regimen in which one or more substances, agents, compounds or pharmaceutical compositions are administered in amounts or doses lower than those normally used in a clinical or therapeutic setting, such as when the agent is administered as a single-agent therapy.

[0272] The retinoblastoma susceptibility gene (RB1) is the first tumor suppressor gene defined molecularly. The retinoblastoma gene product RB is frequently mutated or deleted in retinoblastoma and osteosarcoma, and is mutated or deleted at variable frequencies in other tumor types, such as prostate cancer (including neuroendocrine prostate cancer), breast cancer (including triple-negative breast cancer (TNBC), lung cancer (including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), liver cancer, bladder cancer, ovarian cancer, uterine cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, glioblastoma, and lymphoma). In human cancers, RB function can be disrupted by the neutralization of binding proteins (e.g., the human papillomavirus-E7 protein in cervical cancer; Ishiji, T, 2000

[0021] , J Dermatol., 27:73-86) or by dysregulation of the pathway ultimately responsible for its phosphorylation.

[0273] The “RB pathway” refers to the entire molecular signaling pathway, including retinoblastoma protein (RB) and other proteins / protein families in the pathway, including (but not limited to) CDK, E2f, atypical protein kinase C, and Skp2. Inactivation of the RB pathway is usually caused by perturbations of p16INK4a, cyclin D1, and CDK4.

[0274] The terms “RB+”, “RB plus”, “RB gene normal”, or “RB positive” are used to describe cells that express detectable amounts of functional RB proteins. RB positivity includes wild-type and non-mutant RB proteins. Wild-type RB (RB-WT) is generally understood to mean the form of the RB protein that is normally present in the corresponding population and has the function currently assigned to this protein. RB positive cells can be cells containing functional RB genes. RB positive cells can also be cells that encode the function of detectable RB proteins.

[0275] The terms “RB-”, “RB-reduced”, “RB-deficient”, or “RB-negative” describe several types of cells with impaired RB function, including cells that produce undetectable amounts of functional RB proteins. RB-negative cells may be cells that do not contain functional RB genes. RB-negative cells may also be cells that encode RB proteins, but in which the protein cannot function properly.

[0276] In some embodiments of each of the methods and uses described herein, the cancer is characterized as retinoblastoma wild-type (RB-WT). In some embodiments of each of the methods and uses described herein, the cancer is characterized as RB-positive or RB gene-normal. Such RB-positive or RB gene-normal cancers contain at least some functional retinoblastoma genes. In some embodiments, such RB-WT, RB-positive, or RB gene-normal cancers are characterized as RB1-WT, RB1-positive, or RB1 gene-normal cancers.

[0277] In some embodiments of each of the methods and uses described herein, the cancer is characterized as RB-negative or RB-deleted. Such RB-negative or RB-deleted cancers may be characterized by loss-of-function mutations that encode missense mutations (i.e., encoding incorrect amino acids) or nonsense mutations (i.e., encoding stop codons). Alternatively, such RB-negative cancers may be characterized by the complete or partial deletion of the retinoblastoma gene. In some embodiments, such RB-negative or RB-deleted cancers are characterized as RB1-negative or RB1-deleted.

[0278] When applied to an individual diagnosed with or suspected of having cancer, "tumor" refers to any malignant or potentially malignant growth or mass of tissue of any size, including primary tumors and secondary growths. Solid tumors are abnormal growths or masses of tissue that do not typically contain cysts or fluid-filled areas. Examples of solid tumors include sarcomas, carcinomas, and lymphomas. Leukemia (blood cancers) generally does not form solid tumors (National Cancer Institute, Dictionary of Cancer Terms).

[0279] "Tumor burden" or "tumor load" refers to the total amount of tumor material distributed throughout the body. Tumor burden refers to the total number of cancer cells or the total size of the tumor throughout the body (including lymph nodes and bone marrow). Tumor burden can be measured using various methods known in this technique, such as using a diaphragm, or, when in vivo, using imaging techniques such as ultrasound, bone scans, computed tomography (CT), or magnetic resonance imaging (MRI).

[0280] The term "tumor size" refers to the total size of a tumor, which can be measured by its length and width. Tumor size can be determined by various methods known in this technique, such as measuring the size of the tumor after removal from an individual using a caliper, or when in vivo using imaging techniques such as bone scans, ultrasound, CR, or MRI scans.

[0281] The terms "patient" or "individual" refer to any single individual requiring treatment or participating in a clinical trial, epidemiological study, or used as a control, including human and veterinary mammal patients such as cattle, horses, dogs, and cats. In some implementations, the individual is a human.

[0282] In some embodiments of each of the methods and uses described herein, the patient or individual is an adult. In some embodiments, the individual is a woman or man in any menopausal state. In some embodiments, the individual is a postmenopausal woman or man. In some embodiments, the individual is a postmenopausal woman. In some embodiments, the individual is a premenopausal or perimenopausal woman. In some embodiments, the individual is a premenopausal or perimenopausal woman treated with a luteinizing hormone-releasing hormone (LHRH) agonist. In some embodiments, the individual is a man. In some embodiments, the individual is a man treated with an LHRH or gonadotropin-releasing hormone (GnRH) agonist.

[0283] As used herein, the term "treat" or "treating" in cancer means administering the compounds of this invention to an individual who has cancer or has been diagnosed with cancer to achieve at least one positive therapeutic effect, such as reducing the number of cancer cells, reducing tumor size, slowing the rate of cancer cell invasion into peripheral organs, or slowing tumor metastasis or tumor growth rate; reversing, alleviating, or inhibiting the worsening of the condition or disease to which such terms apply, or preventing the occurrence of one or more symptoms of the condition or disease to which such terms apply. Unless otherwise specified, the term "treatment" as used herein refers to a therapeutic act, as defined above. The term "treatment" also includes adjuvant and neoadjuvant therapy for an individual.

[0284] For the purposes of this invention, beneficial or desired clinical outcomes include (but are not limited to) one or more of the following: reduction (or destruction) of the proliferation of neoplastic or cancerous cells; inhibition of cancer cell metastasis or neoplastic cells; reduction or decrease in tumor size; cancer relief; reduction of cancer-related symptoms; improvement of the quality of life of cancer patients; reduction of the dosage of other drugs required to treat cancer; delay of cancer progression; cure of cancer; overcoming one or more cancer resistance mechanisms; and / or prolongation of cancer patient survival. The positive therapeutic effect on cancer can be measured by several methods (see, for example, W.A. Weber, Assessing tumor response to therapy, J. Nucl. Med. 50 Supplement 1: 1S-10S (2009)). For example, regarding tumor growth inhibition (T / C), according to the National Cancer Institute (NCI) criteria, a T / C of less than or equal to 42% is considered the minimum level of antitumor activity. A T / C < 10% is considered a high level of antitumor activity, where T / C (%) = median tumor volume in treatment / median tumor volume in the control group × 100.

[0285] In some embodiments, the treatment achieved by the compounds of the present invention is defined with reference to any of the following: partial response (PR), complete response (CR), overall response (OR), objective response rate (ORR), progression-free survival (PFS), radiation-induced PFS, metastasis-free survival (MFS), disease-free survival (DFS), and overall survival (OS).

[0286] As used in this article, the terms "complete response" or "CR" mean that, in response to treatment, all cancer symptoms have disappeared (e.g., all target lesions have disappeared). This does not always mean that the cancer has been cured.

[0287] As used in this article, the term “disease-free survival” (DFS) refers to the length of time a patient survives without developing any signs or symptoms of cancer after initial treatment for cancer.

[0288] As used in this article, the term “duration of response” (DoR) refers to the length of time a tumor remains responsive to treatment without cancer growth or spread. Treatments demonstrating improved DoR can produce a durable and meaningful delay in disease progression.

[0289] As used herein, the terms “objective response” and “overall response” refer to a measurable response, including complete response (CR) or partial response (PR). The term “overall response rate” (ORR) refers to the sum of the complete response (CR) rate and the partial response (PR) rate.

[0290] As used in this article, the term "overall survival" (OS) refers to the length of time a patient diagnosed with a disease (such as cancer) survives from the date of diagnosis or the start of treatment. OS is typically measured as the extended life expectancy of patients receiving a particular therapy compared to patients in a control group (i.e., those taking another drug or a placebo).

[0291] As used herein, the term "partial response" or "PR" refers to a reduction in the size of one or more tumors or lesions or a reduction in the degree of cancer in the body as a response to treatment. For example, in some implementations, PR is defined as a reduction of at least 30% in the sum of the longest diameters (SLD) of the target lesion, using a baseline SLD as a reference.

[0292] As used in this article, the term “progression-free survival” or “PFS” refers to the length of time during and after treatment during which the treated disease (e.g., cancer) does not worsen. PFS, also known as “time of tumor progression,” can include the amount of time a patient has experienced complete remission (CR) or partial remission (PR) and the amount of time a patient has experienced severe stagnation (SD).

[0293] As used herein, the term "progressive disease" or "PD" refers to cancer that grows, spreads, or worsens. In some implementations, PR is an indicator of a target lesion with a SLD increase of at least 20%, using the minimum SLD recorded since the start of treatment as a reference, or the presence of one or more new lesions.

[0294] As used in this article, the term “stable disease” (SD) refers to cancer whose degree or severity neither decreases nor increases.

[0295] As used herein, the term "sustained response" refers to a sustained effect that reduces tumor growth after treatment has been discontinued. For example, the tumor size may be the same as or smaller than the size at the start of the drug administration phase. In some embodiments, the duration of the sustained response is at least the same as, at least 1.5 times, 2 times, 2.5 times, or 3 times longer than the duration of treatment.

[0296] The anticancer effects of the cancer treatment methods used in this article, including "objective response", "complete response", "partial response", "progressive disease", "stable disease", "adverse disease-free survival" and "duration of response", can be defined and evaluated by researchers using RECIST v1.1 (Eisenhauer et al., New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1), Eur J of Cancer, 2009; 45(2):228-47).

[0297] In some embodiments of each of the methods and uses described herein, the invention relates to neoadjuvant therapy, adjuvant therapy, first-line therapy, second-line therapy, second- or subsequent-line therapy, or third- or subsequent-line therapy. In the cases further described herein, the cancer may be local, advanced, or metastatic, and the intervention may occur at points along the disease continuum (i.e., at any stage of the cancer).

[0298] Treatment regimens of the compounds of the present invention for the effective treatment of cancer patients may vary depending on factors such as disease condition, patient age and weight, and the ability of the therapy to elicit an anticancer response in an individual. While embodiments of any aspect of the invention may not effectively achieve a positive therapeutic effect in every individual, they should be performed on a statistically significant number of individuals as determined by any statistical test known in this art, such as Student's t-test, chi2 test, U-test according to Mann and Whitney, Kruskal-Wallis test (H-test), Jonckheere-Terpstrat test, and Wilcon on-test.

[0299] The terms “treatment protocol,” “dosing protocol,” and “dosing protocol” are used interchangeably to refer to the dosage and timing of administration of any crystalline or amorphous form of PF-07104091, as described in this invention, alone or in combination with other anticancer agents.

[0300] "Improvement" means that, compared to not receiving the compound, treatment with a compound or drug (such as any crystalline or amorphous form of PF-07104091 described in this invention) results in a reduction or improvement of one or more symptoms to a certain extent. "Improvement" also includes shortening or reducing the duration of symptoms. That is, reducing symptoms to a certain extent, preferably eliminating symptoms.

[0301] Unless otherwise specified, "abnormal cell growth" as used herein refers to cell growth that does not depend on normal regulatory mechanisms (e.g., loss of contact inhibition). Abnormal cell growth can be benign (non-cancerous) or malignant (cancerous). In a common embodiment of the methods provided herein, the abnormal cell growth is cancerous.

[0302] Abnormal cell growth includes the following abnormal growths: (1) tumors characterized by CDK2 amplification or overexpression; (2) tumors characterized by CCNE1 and / or CCNE2 amplification or overexpression; (3) tumors characterized by deletion or Rb; and (4) tumors resistant to endocrine therapy, anti-HER2 targeting agents, CDK4 / 6 inhibition or chemotherapy (e.g., taxane or platinum).

[0303] In some embodiments, the methods and uses of the present invention may further include one or more other anticancer agents. In some embodiments, the other anticancer agents are selected from the group consisting of: antitumor agents, antiangiogenic agents, signal transduction inhibitors, and antiproliferative agents. In some embodiments, the other anticancer agents are selected from the group consisting of: mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxic agents, and endocrine therapeutic agents, such as antiandrogens, androgen depletion therapy (ADT), and antiestrogens. Other anticancer agents may include small molecule therapeutic agents and their pharmaceutically acceptable salts or solvates, therapeutic antibodies, antibody-drug conjugates (ADCs), target protein degradation chimeras (PROTACs), or antisense molecules.

[0304] In some embodiments, the other anticancer agent is an anti-estrogen, wherein the anti-estrogen is an aromatase inhibitor, SERD, or SERM. In some embodiments, the anti-estrogen is an aromatase inhibitor. In some such embodiments, the aromatase inhibitor is selected from the group consisting of letrozole, anastrozole, and exemestane. In some such embodiments, the aromatase inhibitor is letrozole. In some embodiments, the anti-estrogen is a SERD. In some such embodiments, the SERD is selected from the group consisting of: fulvestrant, elacestrant (RAD-1901, Radius Health), SAR439859 (Sanofi), RG6171 (Roche), AZD9833 (AstraZeneca), AZD9496 (AstraZeneca), rintodestrant (G1 Therapeutics), ZN-c5 (Zentalis), LSZ102 (Novartis), D-0502 (Inventisbio), LY3484356 (Lilly), and SHR9549 (Jiansu Hengrui Medicine). In some such embodiments, the SERD is fulvestrant. In some embodiments, the anti-estrogen is SERM. In some such embodiments, the SERM is selected from the group consisting of tamoxifen, raloxifene, toremifene, lasofoxifene, bazedoxifene, and afimoxifene. In some such embodiments, the SERM is either tamoxifen or raloxifene.

[0305] In some embodiments, other anticancer agents are antiandrogens, such as abiraterone, apalutamide, bicalutamide, cyproterone, enzalutamide, flutamide, or nilutamide. In some embodiments, the method or use further includes androgen depletion therapy (ADT), such as luteinizing hormone-releasing hormone (LHRH) agonists, LHRH antagonists, gonadotropin-releasing hormone (GnRH) agonists, or GnRH antagonists.

[0306] In some embodiments, the methods and uses of the present invention further comprise one or more other anticancer agents selected from the following:

[0307] Anti-angiogenic agents, such as VEGF inhibitors, VEGFR inhibitors, TIE-2 inhibitors, PDGFR inhibitors, angiopoietin inhibitors, PKCβ inhibitors, COX-2 (cyclooxygenase II) inhibitors, integrins (α-v / β-3), MMP-2 (matrix metalloproteinase 2) inhibitors, and MMP-9 (matrix metalloproteinase 9) inhibitors.

[0308] Signal transduction inhibitors include, for example, kinase inhibitors (such as inhibitors of tyrosine kinases, serine / threonine kinases, or cyclin-dependent kinases), proteasome inhibitors, PI3K / AKT / mTOR pathway inhibitors, phosphoinositol 3-kinase (PI3K) inhibitors, isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) inhibitors, B-cell lymphoma 2 (BCL2) inhibitors, neurotrophic protein receptor kinase (NTRK) inhibitors, transfection rearrangement (RET) inhibitors, Notch inhibitors, PARP inhibitors, Hedgehog pathway inhibitors, and nuclear export selective inhibitors (SINE).

[0309] Examples of signal transduction inhibitors include, but are not limited to: acalabrutinib, afatinib, alectinib, alpelisib, axitinib, binimetinib, bortezomib, bosutinib, brigatinib, cabozantinib, carfilzomib, ceritinib, cobimetinib, and cobancosib. opanlisib, crizotinib, dabrafenib, dacomitinib, dasatinib, duvelisib, enasidenib, encorafenib, entrectinib, erlotinib, gefitinib, gilteritinib, gladegib, ibrutinib, idelalis ib), imatinib, ipatasertib, ivosidenib, ixazomib, lapatinib, larotrectinib, lenvatinib, lorlatinib, midostaurin, neratinib, nilotinib, niraparib, olaparib, osimertinib, pazopanib Zopanib, ponatinib, regorafenib, rucaparib, ruxolitinib, sonidegib, sorafenib, sunitinib, talazoparib, trametinib, vandetanib, vemurafenib, venetoclax, and vismodegib, or pharmaceutically acceptable salts and solvates thereof.

[0310] Antitumor agents, such as alkylating agents, platinum coordination complexes, cytotoxic antibiotics, antimetabolites, biological response modifiers, histone deacetylation (HDAC) inhibitors, hormonal agents, monoclonal antibodies, growth factor inhibitors, taxanes, topoisomerase inhibitors, vinca alkaloids, and other agents.

[0311] Alkylating agents include: altretamine, bendamustine, busulfan, carmustine, chlorambucil, cyclophosphamide, dacarbazine, ifosfamide, lomustine, mechlorethamine, melphalan, procarbazine, streptozocin, temozolomide, thiotepa, and trabectedin.

[0312] Platinum coordination complexes (also referred to as “platinum agents” in this document) include carboplatin, cisplatin, and oxaliplatin.

[0313] Cytotoxic antibiotics include: bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitomycin, mitoxantrone, plicamycin, and valrubicin.

[0314] Antimetabolites include: antifolate agents such as methotrexate, pemetrexed, pralatrexate, and trimetrexate; purine analogs such as azathioprine, cladribine, fludarabine, mecaptopurine, and thioguanine; and pyrimidine analogs such as azacitidine, capecitabine, cytarabine, decitabine, fluxuridine, fluorouracil, gemcitabine, and trifluridine / tipracil.

[0315] Biological response modifiers include: aldesleukin (IL-2), denileukin diftitox, and interferon-γ.

[0316] Histone deacetylase inhibitors include belinostat, panobinostat, romidepsin, and vorinostat.

[0317] Hormonal agents include antiandrogens, antiestrogens, gonadotropin-releasing hormone (GnRH) analogs, and peptide hormones. Examples of antiestrogens include: aromatase inhibitors, such as letrozole, anastrozole, and exemestane; SERDs, such as fulvestrant, erastrant (RAD-1901, Radius Health), SAR439859 (Sanofi), RG6171 (Roche), AZD9833 (AstraZeneca), AZD9496 (AstraZeneca), lintodextrin (G1 Therapeutics), ZN-c5 (Zentalis), LSZ102 (Novartis), D-0502 (Inventisbio), LY3484356 (Lilly), and SHR9549 (Jiansu Hengrui Medicine); and serMs, such as tamoxifen, ranoxifene, toremifene, lasoxifene, bardoxifene, and aflixifen. Examples of GnRH analogues include degarelix, goserelin, histrelin, leuprolide, and triptorelin. Examples of peptide hormones include lanreotide, octreotide, and pasireotide. Examples of antiandrogens include abiraterone, aproutamide, bicalutamide, cyproterone acetate, enzalutamide, flutamide, and nilumidide, as well as their pharmaceutically acceptable salts and solvates.

[0318] Monoclonal antibodies include: alemtuzumab, atezolizumab, avelumab, bevacizumab, blinatumomab, brentuximab, cemiplimab, cetuximab, daratumumab, dinutuximab, durvalumab, elotuzumab, gemtuzumab, and inotuzumab. ozogamicin), ipilimumab, mogamulizumab, moxetumomabpasudotox, necitumumab, nivolumab, ofatumumab, olaratumab, panitumumab, pembrolizumab, pertuzumab, ramucirumab, rituximab, tositumomab, and trastuzumab.

[0319] Taxanes include: cabazitaxel, docetaxel, paclitaxel, and paclitaxel albumin-stabilized nanoparticle formulations (nanoparticle albumin-bound paclitaxel).

[0320] Topoisomerase inhibitors include etoposide, irinotecan, teniposide, and topotecan.

[0321] Vinca alkaloids include vinblastine, vincristine, and vinorelbine, and their pharmaceutically acceptable salts.

[0322] Other antitumor agents include: asparaginase (pegaspargase), bexarotene, eribulin, everolimus, hydroxyurea, ixabepilone, lenalidomide, mitotane, omacetaxine, pomalidomide, tagraxofusp, telotristat, temsirolimus, thalidomide, and venetoclax.

[0323] In some implementations, other anticancer agents are selected from the group consisting of: abiraterone acetate; acalatinib; trastuzumab emtansine; afatinib dimaleate; aflixifen; interleukin; alectinib; alemtuzumab; apelixix; amifostine; anastrozole; aproutamide; aprepitant; arsenic trioxide; Erwinia chrysanthemi recombinant asparaginase; atezolizumab; avapritinib; averulimab; and axicabtagene. ciloleucel); axitinib; azacitidine; AZD9833 (AstraZeneca); AZD9496 (AstraZeneca); badoxifene; belistat; bendamustine hydrochloride; bevacizumab; bexarotin; bicalutamide; bemetinib; bleomycin sulfate; bonatetumab; bortezomib; bosutinib; vendocillin; brigatinib; cabazitaxel; cabozantinib-S-malate; pegylated asparaginase-mknl; capecitabine; capsulbizumab-yhdp(c aplacizumab-yhdp); capotinib hydrochloride; carboplatin; carfilzomib; carmustine; cimipril-rwlc; selitinib; cetuximab; chlorambucil; cisplatin; cladribine; clofarapine; cobimetinib; cobancoxib hydrochloride; crizotinib; cyclophosphamide; cytarabine; D-0502 (Inventisbio); dabrafenib mesylate; dacarbazine; dacomitinib; actinomycin; daratumumab; daratumumab and hyaluronidase-fihj; dapoxetine α (darbepoetin) alfa); darolutamide; dasatinib; danomycin hydrochloride; decitabine; defibrinolytic sodium; degarelix; denosumab; dexamethasone; dexrazoxane hydrochloride; denutoximab; docetaxel; cranberry hydrochloride; devarulmab; deviliximab; ellastrantrol; eltrombopag olamine; emapalumab-lzsg; enanthrab mesylate; enrafenib; enfortumab-vedotin-ejfv; entrectinib; enzalutamide; epirubicin hydrochloride; epioetin alfa); erdafitinib; erribur mesylate; erlotinib hydrochloride; etoposide; etoposide phosphate;Everolimus; Exemestane; FAM-trastuzumab deruxtecan-NXK; Fedratinib hydrochloride; Filgrastim; Fludarabine phosphate; Fluuracil; Flutamide; Fotatinib disodium; Fulvestrant; Gefitinib; Gemcitabine hydrochloride; Gemtuzumab ozogamicin; Giglitinib fumarate; Grazibucisate; Glucarpidase; Goserelin acetate; Granisetron; Granisetron hydrochloride; Hydroxyurea; Ibritumomab Tiuxetan); Ibrutinib, Edamycin Hydrochloride, Adalaris; Ifosfamide; Imatinib Mesylate; Imiquimod; Intozumab Ozomicin; Recombinant Interferon α-2b; Iodobenzylguanidine I-131; Patashote; Ipilimumab; Irinotecan Hydrochloride; Ixatuximab-IRFC; Evonib; Ixapiron; Ezazomic Citrate; Lanreitide Acetate; Lapatinib Xylenesulfonate; Larotrectinib Sulfate; Lasoxifene; Lenalidomide; Lenvatinib Mesylate; Letrozole; Leucovorin; Leuprorelin Acetate; Lomustine; Lorlatinib; LSZ102 (Novartis); Lubicartin (lur binectedin); LY3484356 (Lilly); medroxyprogesterone acetate; melphalan; melphalan hydrochloride; mercaptopurine; methotrexate; midottotolin; mitomycin; mitoxantrone hydrochloride; mogliflozin-kpkc; parcetomumab-tdfk; lexicon; nerabine; neratinib cistanoate; nilotinib; nilumet; niraparib tosylate monohydrate; nivolumab; atrocillin (obinutuzumab); olfamumab; olaparib; omacetaxel (omacetaxel) Mepesuccinate); Ondansetron hydrochloride; Osimertinib mesylate; Oxaliplatin; Paclitaxel; Paclitaxel albumin-stabilized nanoparticle formulation; Palifermin; Palonosetron hydrochloride; Pamidronate disodium; Panitumumab; Pabistat; Pazopanib hydrochloride; Pegaspargase; Pegfilgrastim; Pegylated interferon alpha-2b; Pembrolizumab; Pemetrexed disodium salt;Pemigatinib; Pertuzumab; Pexidartinib hydrochloride; Plerixafor; Polatuzumab vedotin-piiq; Polidomide; Ponatinib hydrochloride; Pralatrexate; Prednisone; Procarbazine hydrochloride; Propranolol hydrochloride; Radium-223 dichloride; Rhanoxifol hydrochloride; Ramucirumab; Rasburicase; Lavalilumab-CWVZ; Recombinant interferon alpha-2b; Regorafenib; RG6171 (Roche); Rintodestrant; Ripretinib; Rituximab; Rolapitant hydrochloride hydrochloride; Romidexin; Romistachytin; Lucapanib camphor sulfonate; Ruxotetinib phosphate; Sacituzumab govitecan-hziy; SAR439859 (Sanofi); Selinexor; Selpercatinib; Selumetinib sulfate; SHR9549 (Jiansu Hengrui Medicine); Siltuximab; Sipuleucel-t; Sonexavir; Sorafenib tosylate; Tagraxofusp-erzs; Lazopanib tosylate; Talimogenelaherparepvec; Tamoxifen citrate; Tazemetostat hydrobromide hydrobromide; temozolomide; tamsulosin; thalidomide; thioguanine; thiotepa; tisagenlecleucel; tocilizumab; toponotecan hydrochloride; toremifene; trabectedin; trametinib; trastuzumab; trastuzumab and hyaluronidase-oysk; trafluuridine and tipyrimidine hydrochloride; tucatinib; uridine triacetate; vararubicin Star; vandetanib; vemurafenib; venetoc; vinblastine sulfate; vincristine sulfate; vinorelbine; tartrate; vemodega; vorinostat; zanubrutinib; aflibercept; ZN-C5; and zoledronic acid; or the free base, pharmaceutically acceptable salt (including alternative salts of the salts named above), or solvate form of the foregoing; or combinations thereof.

[0324] The term “cancer” or “cancerous” refers to or describes a malignant and / or aggressive growth or tumor caused by abnormal cell growth. As used herein, “cancer” refers to a solid tumor named for the type of cells that form it, as well as cancers of the blood, bone marrow, or lymphatic system. Examples of solid tumors include (but are not limited to) sarcomas and carcinomas. Examples of blood cancers include, but are not limited to, leukemia, lymphoma, and myeloma. The term “cancer” includes, but is not limited to, primary cancer originating at a specific site in the body, metastatic cancer that has spread from its origin to other parts of the body, recurrence of an initial primary cancer after remission, and a second primary cancer that is a new primary cancer in an individual whose prior cancer history differs from the type of the subsequent cancer.

[0325] The efficacy of the methods and uses described herein in certain tumors can be enhanced by combination with other approved or experimental cancer therapies, such as radiation, surgery, chemotherapy agents, targeted therapies, agents that inhibit other abnormally regulated signaling pathways in tumors, and other immune enhancers, such as PD-1 or PD-L1 antagonists and their analogues. The methods and uses of the present invention may further include one or more other anticancer agents.

[0326] The crystalline or amorphous administration of the present invention can be influenced by any method capable of delivering the compound to the site of action. Such methods include oral, duodenal, non-gastrointestinal injection (including intravenous, subcutaneous, intramuscular, intravascular, or infusion), topical, and rectal administration.

[0327] Dosing regimens can be adjusted to provide the optimal desired response. For example, the crystalline or amorphous forms of the present invention can be administered as a single bolus injection, administered in several fractions over time, or the dose can be reduced or increased proportionally as indicated by the urgency of the treatment situation. Preparing therapeutic agents in unit dosage forms is particularly advantageous for ease of administration and uniformity of dosage. As used herein, a unit dosage form refers to a solid, discontinuous unit suitable as a unit dose for a mammalian individual to be treated; each unit contains a predetermined amount of active compound calculated to combine with the desired pharmaceutical carrier to produce the desired therapeutic effect. The specifications of the unit dosage forms of the present invention can be determined by and directly depend on: (a) the unique characteristics of the solid form and the specific therapeutic or preventative effect to be achieved, and (b) the inherent limitations of such active compound mixing techniques for treating individual sensitivities.

[0328] Therefore, those skilled in the art will understand that, based on the disclosure provided herein, dosages and dosing regimens can be adjusted according to methods well known in therapeutic techniques. That is, the maximum tolerable dose can be easily determined, as can the effective amount to provide a detectable therapeutic benefit to an individual, and the timing requirements for administering each agent to provide a detectable therapeutic benefit to an individual. Therefore, although certain dosages and dosing regimens are illustrated herein, these examples are not in any way limited to the dosages and dosing regimens that can be provided to an individual when practicing the present invention.

[0329] It should be noted that dosage values ​​may vary depending on the type and severity of the condition to be alleviated, and may include single or multiple doses. It should be further understood that for any given individual, a particular dosing regimen should be adjusted over time based on individual needs and the professional judgment of the person administering or supervising the administration of the compound or pharmaceutical composition, taking into account factors such as the severity of the illness or condition, the rate of administration, compound handling, and the prescribing physician's judgment. The dosage ranges described herein are illustrative only and are not intended to limit the scope or practice of the claimed solid forms or pharmaceutical compositions. For example, dosages may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and / or experimental values. Therefore, this invention covers intra-patient dose escalation as determined by those skilled in the art. Determining appropriate dosages and regimens for administered chemotherapeutic agents is well known in the relevant art, and such dosages and regimens will be understood by those skilled in the art upon the provision of the teachings disclosed herein.

[0330] The crystalline or amorphous dosage of the present invention is generally in the range of about 0.001 to about 100 mg / kg body weight per day, preferably about 1 to about 35 mg / kg / day, and is administered as a single or divided dose. For a 70 kg human, this totals about 0.01 to about 7 g per day, preferably about 0.02 to about 2.5 g per day. In some cases, dosage levels below the lower limit of the foregoing range may be perfectly adequate, while in other cases, larger doses may be used without causing any harmful side effects, provided that such larger doses are first divided into several smaller doses for administration throughout the day. The dose may be administered as a single dose (QD) or, as appropriate, further divided into smaller doses suitable for BID (twice daily), TID (three times daily), or QID (four times daily). The dosing regimen can be adjusted to provide the best therapeutic response. For example, the dose may be reduced or increased proportionally as indicated by the urgency of the treatment situation, including temporary or permanent dose reductions when it is necessary to improve or prevent side effects.

[0331] Dosing or dosing regimens may be repeated or adjusted as needed to achieve the desired therapeutic effect. As used herein, "continuous dosing duration" refers to dosing or dosing regimens without interruption of the dose, such as without treatment interruption days. An example of a continuous dosing duration is repeating 21 or 28-day treatment cycles without interruption of the dose between treatment cycles.

[0332] In some embodiments, the crystalline or amorphous form of PF-07104091 is administered at a daily dose of about 1 mg to about 1000 mg. In some embodiments, the crystalline or amorphous form of the present invention is administered at a daily dose of about 10 mg to about 500 mg, and in some embodiments, it is administered at a dose of about 25 mg to about 300 mg per day. In some embodiments, it is administered at doses of about 1, 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 18 Dosages of 0, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 260, 270, 275, 280, 290, 300, 325, 350, 375, 400, 425, 450, 475, or 500 mg may be administered via QD, BID, TID, or QID schedules.

[0333] Dosing or dosing regimens may be repeated or adjusted as needed to achieve the desired therapeutic effect. "Intermittent dosing schedule" refers to a dosing or dosing regimen that includes dose interruption periods, such as treatment interruption days. Repeating 14 or 21-day treatment cycles with a 7-day break between cycles is an example of an intermittent dosing schedule. Such schedules, involving 2 or 3 weeks of treatment followed by a 1-week break, are sometimes referred to as 2 / 1-week or 3 / 1-week treatment cycles, respectively. Alternatively, intermittent dosing may consist of a 7-day treatment cycle, with 5 days of treatment and 2 days of interruption.

[0334] As used herein, "continuous dosing duration" refers to a dosing or dosing regimen without interruption of the dose, such as without treatment interruption days. An example of a continuous dosing duration is repeating a 21- or 28-day treatment cycle without interruption of the dose between treatment cycles.

[0335] In some embodiments, any crystalline or amorphous form of PF-07104091 described herein is administered over an intermittent dosing schedule. In other embodiments, any crystalline or amorphous form of PF-07104091 described herein is administered over a continuous dosing schedule.

[0336] "Pharmaceutical composition" means a mixture of one or more therapeutic agents or pharmaceutically acceptable salts, solvates, hydrates or prodrugs described herein as active ingredients, and at least one pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition comprises two or more pharmaceutically acceptable carriers and / or excipients.

[0337] As used in this article, "pharmaceutically acceptable carrier" refers to a carrier or diluent that does not significantly irritate the organism and does not eliminate the biological activity and properties of the active compound or therapeutic agent.

[0338] Pharmaceutically acceptable carriers may contain any conventional drug carrier or excipient. The selection of the carrier and / or excipient will depend to a great extent on factors such as the specific administration route, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0339] In one embodiment, the present invention relates to a pharmaceutical composition comprising anhydrous crystalline PF-07104091 (form 2) and a pharmaceutically acceptable carrier or excipient.

[0340] In one embodiment, the present invention relates to a pharmaceutical composition comprising crystalline PF-07104091 monohydrate (form 3) and a pharmaceutically acceptable carrier or excipient.

[0341] In one embodiment, the present invention relates to a pharmaceutical composition comprising amorphous PF-07104091 (form 4) and a pharmaceutically acceptable carrier or excipient.

[0342] In one embodiment, the present invention relates to a pharmaceutical composition comprising anhydrous crystalline PF-07104091 (form 5) and a pharmaceutically acceptable carrier or excipient.

[0343] Suitable drug carriers include inert diluents or fillers, water, and various organic solvents (such as hydrates and solvates). Where necessary, the pharmaceutical composition may contain other ingredients, such as flavoring agents, binders, excipients, and the like. Therefore, for oral administration, tablets containing various excipients (such as citric acid) can be used with various disintegrants (such as starch, alginate, and certain complex silicates) and binders (such as sucrose, gelatin, and gum arabic). Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol. Additionally, lubricants (such as magnesium stearate, sodium lauryl sulfate, and talc) are generally suitable for tablet formulations. Similar types of solid pharmaceutical compositions can also be used in the form of soft and hard solid gelatin capsules. Therefore, non-limiting examples of materials include lactose or milk candy and high molecular weight polyethylene glycol. When oral administration of aqueous suspensions or elixirs is required, the active compounds therein may be combined with various sweeteners or flavorings, colorants or dyes, and, if necessary, emulsifiers or suspending agents, as well as diluents such as water, ethanol, propylene glycol, glycerol, or combinations thereof.

[0344] The pharmaceutical compositions of the present invention may be in, for example, forms suitable for oral administration, such as tablets, capsules, pills, powders, sustained-release formulations, solutions, and suspensions; forms suitable for non-gastrointestinal injection, such as sterile solutions, suspensions, or emulsions; forms suitable for topical administration, such as ointments or creams; or forms suitable for rectal administration, such as suppositories. The pharmaceutical compositions may be in unit dosage forms suitable for a precise single-dose administration. The pharmaceutical compositions will include conventional drug carriers or excipients and the compound of the present invention as the active ingredient. Furthermore, they may include other drugs or pharmaceutical preparations, carriers, adjuvants, etc.

[0345] Exemplary non-gastrointestinal administration forms include solutions or suspensions of the active compound in sterile aqueous solutions (e.g., propylene glycol or dextrose solution). Such dosage forms may be appropriately buffered if necessary.

[0346] Methods for preparing various pharmaceutical compositions having specific amounts of active compounds are known or will be apparent to those skilled in the art. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easter, Pa., 19th edition (1995).

[0347] Either the crystalline or amorphous form of the invention described herein can be administered orally. Oral administration may include swallowing to allow the therapeutic agent to enter the gastrointestinal tract, or it may be administered via buccal or sublingual administration, thereby allowing the therapeutic agent to enter the bloodstream directly from the oral cavity.

[0348] Formulas suitable for oral administration include solid formulations such as tablets, capsules containing granules, liquids or powders, lozenges (including lozenges filled with liquid), chewable tablets, multi-particle and nanoparticle formulations, gels, solid solutions, liposomes, films (including mucoadhesive films), ovules, sprays and liquid formulations.

[0349] Liquid formulations include suspensions, solutions, syrups, and elixirs. These formulations can be used as fillers in soft or hard capsules and typically include a carrier such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifiers and / or suspending agents. Liquid formulations can also be prepared by reconstituted solids (e.g., solids derived from capsules).

[0350] The crystalline or amorphous forms of the present invention described herein may also be used in rapidly dissolving, rapidly disintegrating dosage forms, such as those described by Liang and Chen (2001) in Expert Opinion in Therapeutic Patents, 11(6), 981-986, the disclosure of which is incorporated herein by reference in its entirety.

[0351] For tablet formulations, the crystalline or amorphous form of PF-07104091 may constitute from 1% to 80% by weight of the dosage form, more typically from 5% to 60% by weight. In addition to the active agent, tablets generally also contain a disintegrant. Examples of disintegrants include sodium glycolate starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, low-carbon alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate. Generally, the disintegrant may constitute from 1% to 25% by weight, preferably from 5% to 20% by weight, of the dosage form.

[0352] Binders are generally used to impart viscous qualities to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous form, and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and dicalcium phosphate dihydrate.

[0353] The tablets may optionally include surfactants, such as sodium lauryl sulfate and polysorbate 80, and lubricants, such as silica and talc. When present, the amount of surfactant is typically from 0.2% to 5% by weight of the tablet, and the amount of lubricant is typically from 0.2% to 1% by weight of the tablet.

[0354] Tablets generally also contain lubricants, such as magnesium stearate, calcium stearate, zinc stearate, sodium stearoyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate. The lubricant is typically present in tablets at 0.25% to 10% by weight, preferably 0.5% to 3% by weight.

[0355] Other common ingredients include antioxidants, colorants, flavorings, preservatives, and taste masking agents.

[0356] An exemplary tablet may contain about 1% to about 80% by weight of an active agent, about 10% to about 90% by weight of a binder, about 0% to about 85% by weight of a diluent, about 2% to about 10% by weight of a disintegrant, and about 0.25% to about 10% by weight of a lubricant.

[0357] Tablet blends can be formed into tablets directly or by roller compression. Tablet blends or partial blends may alternatively be wet-processed, dry-processed, melt-granulated, melt-coated, or extruded prior to tableting. The final formulation may include one or more layers and may be coated or uncoated; or encapsulated.

[0358] The formulation of tablets is discussed in detail in "Pharmaceutical Dosage Forms: Tablets, Volume 1" by H. Lieberman and L. Lachman, Marcel Dekker, NY, NY, 1980 (ISBN 0-8247-6918-X), the contents of which are incorporated herein by reference in their entirety.

[0359] Capsules (e.g., made from gelatin or HPMC), blister packs, and cartridges for inhalers or blowpipes can be formulated into powder mixtures containing a therapeutic agent, a suitable powder matrix (such as lactose or starch), and a performance modifier (such as L-leucine, mannitol, or magnesium stearate). Lactose can be anhydrous or in monohydrate form, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

[0360] Solid formulations intended for oral administration can be formulated as immediate-release and / or modified-release formulations. Modified-release formulations include delayed-release, sustained-release, pulsatile-release, controlled-release, targeted-release, and programmed-release formulations.

[0361] Suitable modified release formulations are described in U.S. Patent No. 6,106,864. Details of other suitable release techniques, such as high-energy dispersions and permeation and coating particles, can be found in Verma et al., Current Status of Drug Delivery Technologies and Future Directions, Pharmaceutical Technology On-line, (2001) 25:1-14. Controlled release using chewable tablets is described in WO 00 / 35298. The disclosures of these references are incorporated herein by reference in their entirety.

[0362] Any crystalline or amorphous form of PF-07104091 described herein can be administered directly into the bloodstream, muscles, or internal organs. Suitable routes of administration outside the digestive tract include intravenous, intra-arterial, intraperitoneal, intrathecal, intracardiac, intraurethral, ​​intrasternal, intracranial, intramuscular, and subcutaneous. Devices suitable for administration outside the digestive tract include needle (including microneedle) injectors, needle-free injectors, and infusion techniques.

[0363] Non-digestive tract preparations are typically aqueous solutions that may contain excipients such as salts, carbohydrates, and buffers (preferably buffered to a pH of 3 to 9). However, in some applications, non-digestive tract preparations may be better formulated as sterile, non-aqueous solutions or in a dried form to be used in combination with a suitable medium (such as sterile, pyrogen-free water).

[0364] Under aseptic conditions, the preparation of non-digestive formulations, for example by lyophilization, can be readily achieved using standard pharmaceutical techniques known to those skilled in the art.

[0365] The solubility of therapeutic agents used to prepare non-digestive tract solutions can potentially be increased by using suitable formulation techniques, such as the addition of solubility enhancers.

[0366] The crystalline and amorphous forms of PF-07104091 described herein are available in kit form suitable for administering pharmaceutical compositions. Such kits may contain an active agent in the form of a pharmaceutical composition comprising the active agent or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier. The kit may contain components for separately storing the pharmaceutical composition, such as containers, separator bottles, or separator foil seals. Examples of such kits are familiar blister packs for packaging tablets, capsules, and the like. To aid compliance, the kit typically includes instructions for use and may provide memory aids. The kit may further contain other materials suitable for administering the drug, such as diluents, filters, IV bags and tubing, needles and syringes, and the like.

[0367] In some preferred embodiments, the present invention provides one or more of embodiments E1 to E41:

[0368] E1. A crystalline form (form 3) of a monohydrate of propionic-2-ylcarbamate (1R,3S)-3-[3-({[3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl]carbonyl}amino)-1H-pyrazol-5-yl]cyclopentyl ester (PF-07104091), the powder X-ray diffraction (PXRD) pattern of which contains peaks with 2θ values ​​of 8.4, 10.1 and 21.5°2θ ± 0.2°2θ as measured using CuKα radiation.

[0369] E2, as in embodiment E1, has a PXRD pattern that further includes a peak with a 2θ value of 16.9°2θ ± 0.2°2θ, measured using CuKα radiation.

[0370] E3, as in embodiment E1 or E2, has a PXRD pattern that further includes a peak with a 2θ value of 27.0°2θ ± 0.2°2θ, measured using CuKα radiation.

[0371] E4. The crystal form of any of the embodiments E1 to E3 has a Raman spectrum containing 1657 cm⁻¹. -1 ±2cm -1 wavenumber (cm) -1 )value.

[0372] E5, as in embodiment E4, the Raman spectrum further includes 1595 cm⁻¹. -1 ±2cm -1 wavenumber (cm) -1 )value.

[0373] E6. As in embodiments E4 to E5, the Raman spectrum further includes 1408 cm⁻¹. -1 ±2cm -1 wavenumber (cm) -1 )value.

[0374] E7. Crystal form of any of the implementation schemes E1 to E6, 13 The solid-state NMR spectrum contains one, two, or three resonance (ppm) values ​​selected from the following group: 25.2, 37.5, and 159.3 ppm ± 0.2 ppm.

[0375] E8, as in implementation scheme E7, its crystal form 13 The C solid-state NMR spectrum further includes the following resonance (ppm) values: 151.9 and 152.5 ppm ± 0.2 ppm.

[0376] E9. A monohydrate of crystal form PF-07104091 (form 3), whose Raman spectrum contains the following wavenumbers (cm). -1Values: 1657, 1595, and 1408 cm -1 ±2cm -1 .

[0377] E10, a crystal form (form 3) of PF-07104091 monohydrate, which 13 The C solid-state NMR spectrum includes the following resonance (ppm) values: 25.2 and 37.5 ppm ± 0.2 ppm; and optionally further includes a resonance (ppm) value of 159.3 ppm ± 0.2 ppm.

[0378] E11, the crystal form of embodiment E10, has a PXRD pattern containing peaks with 2θ values ​​of 8.4 and 10.1°2θ ± 0.2°2θ, as measured using CuKα radiation.

[0379] E12, the crystal forms of embodiments E10 to E11, have a Raman spectrum containing 1657 cm⁻¹. -1 ±2cm -1 wavenumber (cm) -1 )value.

[0380] E13. A crystal form (form 3) of PF-07104091 monohydrate, which has:

[0381] (a) PXRD pattern containing peaks with 2θ values ​​of 8.4, 10.1 and 21.5°2θ ± 0.2°2θ, measured using CuKα radiation;

[0382] (b) Raman spectra, which include the following wavenumbers (cm) -1 Values: 1657, 1595, and 1408 cm -1 ±2cm -1 ;or

[0383] (c) 13 The solid-state NMR spectrum of C1000 contains the following resonance (ppm) values: 25.2, 37.5, and 159.3 ppm ± 0.2 ppm;

[0384] Or any combination of two or more of (a), (b) and (c).

[0385] E14. A crystal form (form 3) of PF-07104091 monohydrate, which has:

[0386] (a) PXRD pattern containing peaks with 2θ values ​​of 8.4 and 10.1°2θ ± 0.2°2θ as measured using CuKα radiation; and optionally further containing a peak with 2θ values ​​of 21.5°2θ ± 0.2°2θ as measured using CuKα radiation;

[0387] (b) Raman spectrum, which includes 1657 cm⁻¹ -1 ±2cm -1 wavenumber (cm) -1 ) values; and optionally further include 1595 and 1408 cm -1 ±2cm -1 wavenumber (cm) -1 ) value; or

[0388] (c) 13 C solid-state NMR spectra, including resonance (ppm) values ​​of 25.2 and 37.5 ppm ± 0.2 ppm; and optionally further including resonance (ppm) values ​​of 159.3 ppm ± 0.2 ppm;

[0389] Or any combination of two or more of (a), (b) and (c).

[0390] E15. The crystal form of any of embodiments E1 to E14, wherein the crystal form is substantially pure PF-07104091 monohydrate (form 3).

[0391] E16, a crystal-free type (form 2) of PF-07104091, whose PXRD spectrum contains peaks with 2θ values ​​of 9.8, 13.3, and 17.4°2θ ± 0.2°2θ, as measured using CuKα radiation.

[0392] E17, the crystal form of embodiment E16, further includes a peak with a 2θ value of 4.2°2θ ± 0.2°2θ as measured using CuKα radiation.

[0393] E18, as in embodiment E16 or E17, has a PXRD pattern that further includes a peak with a 2θ value of 7.5°2θ ± 0.2°2θ, as measured using CuKα radiation.

[0394] E19. The crystal form of any of embodiments E16 to E18, whose Raman spectrum contains 1691 cm⁻¹ -1 ±2cm -1 wavenumber (cm) -1 )value.

[0395] E20, as in embodiment E19, has a Raman spectrum further comprising 1582 cm⁻¹. -1 ±2cm -1 wavenumber (cm) -1 )value.

[0396] E21, as in embodiment E19 or E20, the Raman spectrum further includes 996 cm⁻¹. -1 ±2cm -1 wavenumber (cm)-1 )value.

[0397] E22. The crystal form of any of the embodiments E16 to E21, 13 The solid-state NMR spectrum contains one, two, or three resonance (ppm) values ​​selected from the following group: 24.1, 39.8, and 41.6 ppm ± 0.2 ppm.

[0398] E23, as in implementation scheme E22, its crystal form 13 The C solid-state NMR spectrum further includes the following resonance (ppm) values: 21.8 and 138.2 ppm ± 0.2 ppm.

[0399] E24, a crystal-free form (form 2) of PF-07104091, whose Raman spectrum contains the following wavenumbers (cm²). -1 Values: 1691, 1582, and 996 cm -1 ±2cm -1 .

[0400] E25, a crystal-free type (Form 2) of PF-07104091, which 13 The solid-state NMR spectra of 10⁻⁶ C₀C ...

[0401] E26, the crystal form of embodiment E25, has a PXRD pattern containing peaks with 2θ values ​​of 9.8 and 13.3°2θ ± 0.2°2θ, as measured using CuKα radiation.

[0402] E27, as in embodiment E25 or E26, has a Raman spectrum containing 1691 cm⁻¹. -1 ±2cm -1 wavenumber (cm) -1 )value.

[0403] E28. A crystal-free type (Form 2) of PF-07104091, which has:

[0404] (a) PXRD pattern containing peaks with 2θ values ​​of 9.8, 13.3 and 17.4°2θ ± 0.2°2θ, measured using CuKα radiation;

[0405] (b) Raman spectra, which include the following wavenumbers (cm) -1 Values: 1691, 1582, and 996 cm -1 ±2cm -1 ;or

[0406] (c) 13The solid-state NMR spectrum of 1200 ppm contains the following resonance (ppm) values: 24.1, 39.8, and 41.6 ppm ± 0.2 ppm;

[0407] Or any combination of two or more of (a), (b) and (c).

[0408] E29. A crystal-free type (form 2) of PF-07104091, which has:

[0409] (a) PXRD pattern containing peaks with 2θ values ​​of 9.8 and 13.3°2θ ± 0.2°2θ as measured using CuKα radiation; and optionally further containing a peak with a 2θ value of 17.4°2θ ± 0.2°2θ as measured using CuKα radiation;

[0410] (b) Raman spectrum, which includes 1691 cm⁻¹ -1 ±2cm -1 wavenumber (cm) -1 ) value; and optionally further include 1582 and 996 cm -1 ±2cm -1 wavenumber (cm) -1 ) value; or

[0411] (c) 13 The solid-state NMR spectrum of 1200 ppm contains the following resonance (ppm) values: 24.1, 39.8, and 41.6 ppm ± 0.2 ppm;

[0412] Or any combination of two or more of (a), (b) and (c).

[0413] E30, the crystal form of any of embodiments E16 to E29, wherein the crystal form is substantially pure PF-07104091 (form 2).

[0414] E31, a crystal-free type (form 5) of PF-07104091, whose PXRD spectrum contains three or more peaks with 2θ values ​​selected from 10.2, 12.4, 15.4, 17.2, 17.9, 19.8, 21.6, 22.5, 23.7 and 26.2°2θ ± 0.2°2θ, measured using CuKα radiation.

[0415] E32. A pharmaceutical composition comprising a crystal form as described in any of embodiments E1 to E31 and a pharmaceutically acceptable carrier or excipient.

[0416] E33. A method of treating cancer in an individual in need, comprising administering to said individual a therapeutically effective amount of a crystal form as described in any of embodiments E1 to E31.

[0417] E34. The method of implementation scheme E33, wherein the cancer is selected from the group consisting of: breast cancer, prostate cancer, lung cancer, liver cancer, kidney cancer, bladder cancer, ovarian cancer, peritoneal cancer, fallopian tube cancer, cervical cancer, uterine cancer, pancreatic cancer, stomach cancer, colorectal cancer, esophageal cancer, head and neck cancer, testicular cancer, adrenal cancer, skin cancer, brain cancer, sarcoma, and lymphoma.

[0418] E35, an amorphous form (form 4) of PF-07104091.

[0419] E36, the amorphous form of embodiment E35, has a PXRD pattern containing broad peaks with diffraction angles (2θ) of about 5 to about 35°2θ ± 0.2°2θ as measured using CuKα radiation.

[0420] E37, as in the implementation of the amorphous form of E35 or E36, its PXRD pattern is essentially the same as... Figure 4 same.

[0421] E38. An amorphous form as described in any of embodiments E35 to E37, having a glass transition temperature (Tg) of 59.8 ± 5 °C. g ).

[0422] E39. A pharmaceutical composition comprising an amorphous and pharmaceutically acceptable carrier or excipient as described in any of embodiments E35 to E38.

[0423] E40. A method of treating cancer in an individual in need, comprising administering to said individual a therapeutically effective amount of an amorphous substance as described in any of embodiments E35 to E38.

[0424] E41. The method of implementation E40, wherein the cancer is selected from the group consisting of: breast cancer, prostate cancer, lung cancer, liver cancer, kidney cancer, bladder cancer, ovarian cancer, peritoneal cancer, fallopian tube cancer, cervical cancer, uterine cancer, pancreatic cancer, stomach cancer, colorectal cancer, esophageal cancer, head and neck cancer, testicular cancer, adrenal cancer, skin cancer, brain cancer, sarcoma, and lymphoma.

[0425] Example

[0426] The examples and formulations provided below further illustrate and demonstrate aspects and embodiments of the invention. It should be understood that the scope of the invention is not limited to the scope of the examples provided below.

[0427] Example 1

[0428] Instrumental Methods

[0429] General Method A. Powder X-ray Diffraction (PXRD)

[0430] Instrumentation and Methods:

[0431] Powder X-ray diffraction analysis was performed using a Bruker AXS D8 Endeavor diffractometer equipped with a Cu radiation source. Diffracted radiation was detected using a LYNXEYE XET detector with a motorized slit. The X-ray tube voltage and ampere were set to 40 kV and 40 mA, respectively. A scan rate of 1.0 second per step was used, with increments of 0.01 degrees, at the Cu Kα wavelength. Data were collected in an θ-θ goniometer using a locked-coupled scan of 3.0 to 40.0 degrees 2θ. An antiscattering sieve was set to a fixed distance of 1.5 mm. Samples were prepared by placing them in a silicon low-background sample holder. The samples were rotated at 15 rpm during collection. Data were collected using Bruker DIFFRAC Plus software.

[0432] Peak picking method:

[0433] Data analysis was performed using Bruker DIFFRAC Plus software (version 5.0.0). The PXRD data file was not processed prior to peak search. The peak search algorithm in EVA software was applied, with an initial peak allocation using a threshold of 1. To ensure effectiveness, manual adjustments were made; the automatically allocated output was visually inspected, and peak positions were adjusted to their maximum values. Peaks with a relative intensity ≥3% were typically selected. Peaks that were not resolved or were consistent with noise were selected. Typical errors related to PXRD peak positions as described in the USP are + / - 0.2°2-θ (USP-941).

[0434] General Method B. Raman Spectroscopy

[0435] Instrumentation and Methods:

[0436] Raman spectra were collected using a Thermo Scientific iS50 FT-Raman attachment attached to the FT-IR stage. A CaF2 beam splitter was used in the FT-Raman configuration. The spectrometer was equipped with a 1064 nm diode laser and a room-temperature InGaAs detector. Instrument performance and calibration were validated using polystyrene prior to data acquisition. Samples were analyzed in tablet form in glass NMR tubes or held statically in a suitable sample holder during data acquisition. Spectra were acquired using laser power between 0.1 and 0.5 W and 512 co-scans. The acquisition range was 3700–100 cm⁻¹. -1 Use 2cm -1 API spectra were recorded at high resolution, and the Happ-Genzel apodization method was used for all spectra. Multiple spectra were recorded, and the reported spectra represent two spots.

[0437] Peak picking method:

[0438] Before peak picking, the intensity scale was normalized relative to 1. Peaks were manually identified using Thermo Nicolet Omnic 9.7.46 software. Peak positions were picked at the peak maxima, and peaks were identified only if slopes existed on each side; peak shoulders were excluded. For pure form 3 APIs, an absolute threshold of 0.012 and a sensitivity of 75 were used during peak picking. For pure form 2 APIs, an absolute threshold of 0.04 and a sensitivity of 75 were used during peak picking. Peaks with normalized intensities between (1–0.75), (0.74–0.30), and (0.29–0) were labeled as strong, moderate, and weak, respectively. Relative peak intensity values ​​are also plotted in this report.

[0439] General Method C. 13 Solid-state NMR (ssNMR) spectroscopy:

[0440] Instrumentation and Methods:

[0441] Solid-state NMR (ssNMR) analysis was performed on a Bruker-BioSpin Avance III 500MHz transistor. 1 The study was performed on a CPMAS probe in an H-frequency NMR spectrometer. The material was packed into a 4 mm rotor. A magic angle rotation rate of 15.0 kHz was used.

[0442] The proton decoupled cross-polarized magic angle rotation (CPMAS) experiment was used to collect data. 13 Css NMR spectroscopy was performed. A phase-modulated proton decoupling field of 80–90 kHz was applied during spectral acquisition. The cross-polarization contact time was set to 2 ms. Recirculation delays of 4.5 s, 3.9 s, 4.5 s, and 2.4 s were used for forms 1, 2, 3, and 5, respectively. The number of scans was adjusted to obtain an appropriate signal-to-noise ratio, with 768 or 1024 scans collected for each API. Crystalline adamantane was used as the external target. 13 The C CPMAS experiment was used as a reference, with the high-field resonance set at 29.5 ppm (as measured by pure TMS). 13 C chemical shift scale.

[0443] Peak picking method:

[0444] Automated peak picking was performed using Bruker-BioSpin TopSpin version 3.6 software. Generally, a 5% relative intensity threshold was used for initial peak selection. The output of the automated peak picking was visually inspected to ensure effectiveness, and manual adjustments were made as necessary. Although specific solid-state NMR peaks are reported in this paper, these peaks do indeed exhibit a certain range due to variations in instrumentation, sample, and sample preparation. This is a common practice in solid-state NMR techniques due to the inherent variability in peak positions. (The last sentence appears to be incomplete and possibly refers to a different topic.)13 The typical variability of the C chemical shift X-axis value is approximately 0.2 ppm. The solid-state NMR peak heights reported in this paper are relative intensities. Solid-state NMR intensities can vary depending on the actual settings of the CPMAS experimental parameters and the thermal history of the sample.

[0445] Example 2

[0446] Preparation of anhydrous crystalline PF-07104091 (Form 2)

[0447]

[0448] Anhydrous crystalline PF-07104091 (Form 2) was prepared as follows: PF-07104091 monohydrate (Form 1) (prepared as described in U.S. Patent No. 11,014,911) was dissolved at approximately 80 °C in a 50:50% v / v methyl isobutyl ketone:heptane solution, followed by self-heating to remove the solution and cooling to room temperature. The resulting solid was collected by filtration, washed with heptane, and dried under vacuum to obtain crystalline PF-07104091 (Form 2), which was confirmed by elemental analysis to be in anhydrous free form.

[0449] PF-07104091 (Form 2) was also obtained by crystallization from other solvents (e.g., ethyl acetate, cyclohexane, or mixtures thereof), as shown by PXRD analysis. In some cases, trace amounts of residual solvent can be detected by ssNMR, possibly because the solvent is trapped within lattice defects during crystallization in the anhydrous form.

[0450] Differential scanning calorimetry (DSC) showed an endothermic melting peak with an initial temperature of approximately 113°C (confirmed by a melting point apparatus).

[0451] Moisture adsorption (DVS) studies revealed that PF-07104091 (Form 2) is slightly hygroscopic: its mass increases by approximately 0.7% at 60% RH; approximately 1% at 75% RH; and approximately 1.6% at 90% RH. PXRD analysis after moisture absorption showed no change in the solid form of the material.

[0452] Thermogravimetric analysis (TGA) of a reliable sample of acetone:cyclohexane (1:2.1) crystallization form 2 showed a total weight loss of approximately 1%, which was confirmed by solution NMR to be residual solvent (cyclohexane).

[0453] Table 1: PXRD Peak Value List for PF-07104091 (Form 2)

[0454]

[0455]

[0456] Table 2: Raman peak list for PF-07104091 (Form 2)

[0457]

[0458]

[0459] Table 3: PF-07104091 (Form 2) 13 C ssNMR peak list

[0460]

[0461]

[0462] Peaks attributable to trapped solvent molecules

[0463] Example 3

[0464] Preparation of crystalline PF-07104091 monohydrate (form 3)

[0465]

[0466] Using magnetic stirring and high stirring, N-(5-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-3-yl)-3-(methoxymethyl)-1-methyl-1H-pyrazol-5-carboxamide (compound A) (187 g, 0.586 mol) (prepared by acidic removal of protecting group from intermediate 13B as described in Example 13 of U.S. Patent No. 11,014,911) was dissolved in tetrahydrofuran (THF) (1.78 L). The solution was heated to 25 °C, and then 1,1'-carbonyldiimidazole (CDI) (142 g, 0.876 mol) was added. The mixture was stirred at 25 °C for 5 min, and then heated to 50 °C at 1 °C / min and held for 30 min. The mixture was cooled to 30 °C, and then 2-propylamine (iPrNH2) (70 g, 1.184 mol) was added. The reactants were heated to 50°C at a rate of 1°C / min and then maintained at 50°C until the reaction was complete. If necessary, additional iPrNH2 (18 g, 0.304 mol) was added to achieve completion. Water (1.22 L) was added, and the mixture was heated to 50°C. A solution of potassium hydroxide (20 g, 0.356 mol) in water (0.561 L) was added, and the mixture was maintained at 50°C for 5 hours. The reactants were cooled to 25°C, and the reaction mixture was distilled under vacuum until the solution volume based on compound A was 6 mL / g, the internal temperature was between 45°C and 50°C, and the THF was less than 0.1% according to GCHS. The mixture was cooled to 25°C, and H2O was added until the reactant volume based on compound A was 16 mL / g. Acetonitrile (0.75 L) was added via a dropping funnel, and the mixture was maintained for 10 minutes, followed by the addition of 37% hydrochloric acid aqueous solution (29 g) over 30 minutes to adjust the pH to between 7 and 8. Add additional HCl or KOH to adjust the pH of the mixture to 7 to 8. Heat the mixture to 40°C and maintain for 3 hours. Cool the mixture to 15°C at 0.1°C / min and stir at 15°C for 1 hour. Filter the mixture, and wash the solid with 9:1 H₂O / acetonitrile (0.500 L). Dry the solid in a humidified vacuum oven at 50°C until the Karl Fischer (KF) titration is between 4.2% and 4.5%, to give PF-07104091 monohydrate (form 3).

[0467] Table 4: PXRD Peak List of PF-07104091 Monohydrate (Form 3)

[0468]

[0469]

[0470] Table 5: List of Raman peaks for PF-07104091 monohydrate (form 3)

[0471]

[0472]

[0473] Table 6: PF-07104091 monohydrate (form 3) 13 C ssNMR peak list

[0474] <![CDATA[ 13 C chemical shift ppm ± 0.2 ppm Relative strength (%) <![CDATA[ 13 C chemical shift ppm ± 0.2 ppm Relative strength (%) 23.6 56 76.6 32 25.2 62 80.0 31 34.2 32 92.9 43 35.5 100 110.9 26 37.5 55 111.6 26 39.3 27 135.8 36 40.8 27 149.2 54 43.9 55 151.9 27 58.2 40 152.5 26 58.6 41 156.7 36 67.8 52 159.3 30

[0475] Example 4

[0476] Preparation of anhydrous crystalline PF-07104091 (Form 5)

[0477]

[0478] Anhydrous crystalline PF-07104091 (form 5) is prepared as follows: PF-07104091 monohydrate (form 3) is placed in an open dish in an oven at about 50°C and then rinsed with dry nitrogen gas for about 3 hours.

[0479] Alternatively, anhydrous crystalline PF-07104091 (form 5) is prepared by storing PF-07104091 monohydrate (form 3) at ambient temperature on DRIERITE desiccant (approximately 0% RH) for 17 days.

[0480] The elemental analysis of PF-07104091 (Form 5) is consistent with that of the anhydrous form, as shown in Table 7.

[0481] Table 7: Elemental Analysis of PF-07104091 (Form 5)

[0482]

[0483]

[0484] like Figure 15 As shown, pyrolysis gravimetric analysis of PF-07104091 (Form 5) showed a weight loss of less than 1% at 200°C, confirming that this form is anhydrous.

[0485] Table 8: PXRD Peak Value List for PF-07104091 (Form 5)

[0486] Angle (2-θ°)±0.2°2θ Relative strength (%) Angle (2θ°) ± 0.2°2θ Relative strength (%) 10.2 29.2 19.8 100.0 12.4 6.1 21.6 13.0 15.4 4.7 22.5 8.6 17.2 5.1 23.7 3.5 17.9 15.8 26.2 10.5

[0487] Table 9: Raman peak list for PF-07104091 (Form 5)

[0488]

[0489]

[0490] Table 10: PF-07104091 (Form 5) 13 C ssNMR peak list

[0491] <![CDATA[ 13 C chemical shift ppm ± 0.2 ppm Relative strength (%) <![CDATA[ 13 C chemical shift ppm ± 0.2 ppm Relative strength (%) 21.6 35 78.7 62 22.7 53 94.4 53 23.1 58 109.9 41 27.0 28 135.3 42 33.4 64 144.6 23 34.6 62 146.9 27 35.6 100 149.5 47 40.8 99 152.3 37 43.5 80 153.6 32 57.0 66 157.2 61 67.7 30 158.1 62 69.0 40

[0492] Example 5

[0493] Preparation of amorphous PF-07104091 (Form 4)

[0494]

[0495] Amorphous PF-07104091 (form 4) was prepared in situ by melt quenching of PF-07104091 monohydrate (form 1) (prepared as described in U.S. Patent No. 11,014,911) within a differential scanning calorimeter (DSC). Attempts were made to prepare amorphous 4 on a large scale using both melt quenching and freeze-drying.

[0496] The general DSC program for providing amorphous PF-07104091 (Form 4) is provided as follows:

[0497] 1. Weigh 3-5 mg of API and place it in an aluminum tray, then seal it with a non-airtight aluminum lid.

[0498] 2. Load the disk into the DSC under nitrogen purging at 50 L / min.

[0499] 3. Cool down to -30℃ at a rate of 20℃ / min.

[0500] 4. Maintain isothermal temperature for 1 minute

[0501] 5. Increase the temperature to 160℃ at a rate of 10℃ / min.

[0502] 6. Maintain isothermal temperature for 1 minute

[0503] 7. Cool down to -30℃ at a rate of 20℃ / min.

[0504] 8. Keep at the same temperature for 1 minute.

[0505] 9. Increase the temperature to 160℃ at a rate of 10℃ / min.

[0506] A representative DSC thermal analysis plot of the second heating cycle (i.e., step 9 above) is provided. Figure 14 In the figure, it shows a glass transition temperature (T0) of approximately 59.8 ± 5 °C. g (e.g., measured by DSC at a heating rate of 10 °C / min).

[0507] The PXRD pattern (2θ) of amorphous PF-07104091 (form 4) contains broad peaks with diffraction angles (2θ) from approximately 5 to approximately 35°2θ ± 0.2°2θ, without any steep peaks characteristic of any crystalline form. Figure 4 As shown in the image.

[0508] Comparative Example 6

[0509] Crystalline PF-07104091 monohydrate (form 1)

[0510]

[0511] PF-07104091 monohydrate (Form 1) was prepared as described in Example 13 of U.S. Patent No. 11,014,911. PXRD, Raman spectroscopy, and... 13 C ssNMR feature data are provided in Tables 11, 12 and 13, respectively.

[0512] Table 11: PXRD peak list of PF-07104091 monohydrate (form 1)

[0513] Angle (2-θ°)±0.2°2θ Relative strength (%) Angle (2θ°) ± 0.2°2θ Relative strength (%) 3.9 19.5 25.0 25.9 9.1 18.3 25.7 8.3 10.4 96.5 26.0 10.1 11.7 64.3 26.3 15.1 12.9 41.4 26.6 8.4 16.0 15.5 27.0 5.0 18.2 100.0 27.6 21.3 18.6 14.4 28.2 31.7 19.4 38.1 28.9 5.2 19.6 20.3 30.4 6.8 20.0 10.5 31.1 7.8 20.3 20.6 31.5 9.9 20.6 43.0 33.9 11.6 20.8 26.1 35.1 3.3 21.0 23.7 35.8 3.0 22.2 20.6 36.6 7.1 22.7 3.4 37.6 3.9 23.5 22.9 38.3 5.2 24.2 64.0

[0514] Table 12: List of Raman peaks for PF-07104091 monohydrate (form 1)

[0515]

[0516]

[0517] Table 13: PF-07104091 monohydrate (form 1) 13 C ssNMR peak list

[0518]

[0519]

[0520] Example 7

[0521] Stability Study

[0522] The slurry experiments were conducted as follows. PF-07104091 in the specified starting form was transferred to a 2 mL vial. The specified solvent or solvent mixture was added at the specified temperature to obtain the slurry (Table 14). Additional solids were added as needed to ensure a sufficiently thick slurry. A magnetic stir bar was added and the vial was tightly capped to prevent solvent loss. The resulting slurry was stirred at the specified temperature. Aliquots were extracted from the slurry periodically or after a certain period. The solids were separated from the liquid by centrifugation and characterized by powder X-ray diffraction. PF-07104091 monohydrate (form 3) was thermodynamically most stable at 4 °C, approximately 25 °C (ambient), and 40 °C.

[0523] Table 14. Stability Tests

[0524]

[0525] The single-crystal X-ray structure of PF-07104091 monohydrate (form 3) was determined and illustrated. Figure 16 Computational analysis shows that PF-07104091 monohydrate (form 3) possesses excellent intermolecular geometry and hydrogen bond network topology, and lacks interstitial space compared to PF-07104091 monohydrate (form 1), thus it is expected to be more stable. The single-crystal X-ray structure of PF-07104091 monohydrate (form 1) is provided in US Patent No. 11,014,911. Figure 1 middle.

Claims

1. A propyl-2-ylcarbamic acid (1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl-1 H -pyrazole-5-yl]carbonyl}amino)-1 H Crystal form 3 of pyrazole-5-yl]cyclopentyl ester monohydrate, its powder X-ray diffraction pattern contains peaks with 2θ values ​​of 8.4, 10.1, 16.9, 21.5 and 27.0 °2θ ± 0.2 °2θ, measured using CuKα radiation.

2. The crystal form 3 according to claim 1, wherein its Raman spectrum comprises one, two, or three wavenumbers selected from the group consisting of 1657, 1595, and 1408 cm⁻¹. -1 ± 2 cm -1 .

3. The crystal form 3 according to claim 1, wherein... 13 The solid-state NMR spectrum contains one, two, or three resonance values ​​selected from the group consisting of 25.2, 37.5, and 159.3 ppm ± 0.2 ppm.

4. The crystal form 3 according to claim 3, wherein 13 The C solid-state NMR spectrum further includes the following resonance values: 151.9 and 152.5 ppm ± 0.2 ppm.

5. A pharmaceutical composition comprising crystal form 3 according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier or excipient.

6. Use of crystal form 3 according to any one of claims 1 to 4 in the preparation of a medicament for treating cancer in an individual in need.

7. The use according to claim 6, wherein the cancer is selected from the group consisting of: breast cancer, prostate cancer, lung cancer, liver cancer, kidney cancer, bladder cancer, ovarian cancer, peritoneal cancer, fallopian tube cancer, cervical cancer, uterine cancer, pancreatic cancer, stomach cancer, colorectal cancer, esophageal cancer, head and neck cancer, testicular cancer, adrenal cancer, skin cancer, brain cancer, sarcoma, and lymphoma.

8. The use according to claim 6, wherein the drug comprises other anticancer agents.

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