Solid form of CDK2 inhibitors

Abstract

This provides a crystalline form of PF-07104091 that has desirable properties such as high crystallinity, high purity, low hygroscopicity, favorable solubility or mechanical properties, improved manufacturability or filterability, and / or favorable stability. [Solution] A crystal (Form 3) of (1R,3S)-3-[3-({[3-(methoxymethyl)-1-methyl-1H-pyrazole-5-yl]carbonyl}amino)-1H-pyrazole-5-yl]cyclopentylpropan-2-ylcarbamate (PF-07104091) monohydrate is provided, having a powder X-ray diffraction (PXRD) pattern including peaks at 2θ values ​​measured using CuKα radiation at 8.4, 10.1 and 21.5°2θ±0.2°2θ.

Description

[Technical Field]

[0001] The present invention relates to a solid form of (1R,3S)-3-[3-({[3-(methoxymethyl)-1-methyl-1H-pyrazole-5-yl]carbonyl}amino)-1H-pyrazole-5-yl]cyclopentylpropan-2-ylcarbamate (also referred to herein as PF-07104091), a pharmaceutical composition comprising such a solid form, and a method of using such a solid form and pharmaceutical composition for the treatment of cancer. [Background technology]

[0002] The compound (1R,3S)-3-[3-({[3-(methoxymethyl)-1-methyl-1H-pyrazole-5-yl]carbonyl}amino)-1H-pyrazole-5-yl]cyclopentylpropane-2-ylcarbamate (PF-07104091) has the following structure:

[0003] [ka] It is a potent inhibitor of cyclin-dependent kinase 2 (CDK2).

[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 No. 11,014,911, the contents of which are incorporated herein by reference in their entirety. [Overview of the Initiative] [Problems that the invention aims to solve]

[0005] The present invention provides a crystalline form of PF-07104091 having desirable properties such as high crystallinity, high purity, low hygroscopicity, favorable solubility or mechanical properties, improved manufacturability or filterability, and / or favorable stability. The present invention also provides amorphous PF-07104091. [Means for solving the problem]

[0006] The present invention provides a solid form of (1R,3S)-3-[3-({[3-(methoxymethyl)-1-methyl-1H-pyrazole-5-yl]carbonyl}amino)-1H-pyrazole-5-yl]cyclopentylpropan-2-ylcarbamate (PF-07104091).

[0007] In some embodiments and settings, the present invention provides a crystalline form of PF-07104091. In some embodiments and settings, the crystalline form is anhydrous crystalline PF-07104091 (Form 2). In preferred embodiments and settings, the crystalline form is crystalline PF-07104091 monohydrate (Form 3). In other embodiments and settings, the crystalline 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 is (1)(a)One, two, three, four, five, or more than five peaks selected from the group consisting of peaks at °2θ ± 0.2°2θ in Table 1, or (b)A powder X-ray diffraction (PXRD) pattern (2θ) that includes peaks at essentially the same 2θ values ​​as in Figure 2. (2)(a) cm in Table 2 -1 ±2cm -1 One, two, three, four, five, or more than five wavenumbers (cm) are selected from the group consisting of the values ​​in the given range. -1 ) value, or (b) essentially the same wavenumber (cm) as in Figure 7. -1 ) Raman spectrum including value, or (3) (a) One, two, three, four, five, or more than five resonance (ppm) values ​​selected from the group consisting of values ​​at ppm ± 0.2 ppm in Table 3, or (b) Resonance (ppm) values ​​that are essentially the same as those in Figure 11. 1313C solid-state NMR spectrum (ppm), or having any combination of two or more of (1)(a)-(b), (2)(a)-(b) and (3)(a)-(b), provided that they are not mutually contradictory, Provided is anhydrous crystalline PF-07104091 (Form 2).

[0010] In a further aspect, the invention (a) A powder X-ray diffraction (PXRD) pattern comprising peaks at 2θ values of 9.8, 13.3 and 17.4° 2θ ± 0.2° 2θ, (b) A Raman spectrum comprising wavenumber (cm -1 ± 2 cm -1 ) values of 1691, 1582 and 996 cm -1 ), or (c) A 13C solid-state NMR spectrum comprising resonance (ppm) values of 24.1, 39.8 and 41.6 ppm ± 0.2 ppm, 13 or any combination of two or more of (a), (b) and (c) is provided for anhydrous crystalline PF-07104091 (Form 2).

[0011] In some embodiments, the crystalline form is substantially pure anhydrous crystalline PF-07104091 (Form 2).

[0012] In another aspect, the 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 additive.

[0013] In one aspect, the invention (1)(a) One, two, three, four, five or more than five peaks selected from the group consisting of peaks at ° 2θ ± 0.2° 2θ in Table 4, or (b) a powder X-ray diffraction (PXRD) pattern (2θ) comprising peaks at 2θ values essentially the same as in FIG. 3, (2)(a) cm in Table 5 -1 ± 2 cm -1One, two, three, four, five, or more than five wavenumbers (cm) are selected from the group consisting of the values ​​in the given range. -1 ) value, or (b) essentially the same wavenumber (cm) as in Figure 8. -1 ) Raman spectrum including value, or (3) (a) One, two, three, four, five, or more than five resonance (ppm) values ​​selected from the group consisting of values ​​in ppm ± 0.2 ppm in Table 6, or (b) Resonance (ppm) values ​​that are essentially the same as those in Figure 12. 13 ¹¹¹ solid-state NMR spectrum (ppm), Or (1)(a)~(b), (2)(a)~(b), and (3)(a)~(b) have any combination of two or more, provided that they do not contradict each other. Crystalline PF-07104091 monohydrate (Form 3) is provided.

[0014] In a further embodiment, the present invention is (a) Powder X-ray diffraction (PXRD) pattern including peaks at 2θ values ​​of 8.4, 10.1 and 21.5°2θ ± 0.2°2θ, (b) 1657, 1595 and 1408 cm -1 ±2cm -1 wavenumber (cm -1 ) Raman spectrum including the value, or (c) Includes resonance (ppm) values ​​of 25.2, 37.5 and 159.3 ppm ± 0.2 ppm 13 C solid-state NMR spectrum, or any combination of two or more of (a), (b), and (c) The present invention provides a crystalline PF-07104091 monohydrate (Form 3) having the following properties.

[0015] In some embodiments, the crystalline form is substantially pure crystalline PF-07104091 monohydrate (Form 3).

[0016] In another aspect, the present invention provides a pharmaceutical composition comprising a crystalline PF-07104091 monohydrate (Form 3) according to an aspect or embodiment described herein, and a pharmaceutically acceptable carrier or additive. [Brief explanation of the drawing]

[0017] [Figure 1] This figure shows the PXRD pattern of PF-07104091 monohydrate (Form 1). [Figure 2] This is a diagram showing the PXRD pattern of PF-07104091 (Form 2). [Figure 3] This figure shows the PXRD pattern of PF-07104091 monohydrate (Form 3). [Figure 4] This is a diagram showing the PXRD pattern of PF-07104091 (Form 4). [Figure 5] This is a diagram showing the PXRD pattern of PF-07104091 (Form 5). [Figure 6] This figure shows the FT-Raman spectrum of PF-07104091 monohydrate (Form 1). [Figure 7] This figure shows the FT-Raman spectrum of PF-07104091 (Form 2). [Figure 8] This figure shows the FT-Raman spectrum of PF-07104091 monohydrate (form 3). [Figure 9] This figure shows the FT-Raman spectrum of PF-07104091 (Form 5). [Figure 10] This figure shows the carbon CPMAS spectrum of PF-07104091 monohydrate (Form 1) (# indicates the spinning sideband). [Figure 11] This figure shows the carbon CPMAS spectrum of PF-07104091 (Form 2) (# indicates the spinning sideband). [Figure 12] This figure shows the carbon CPMAS spectrum of PF-07104091 monohydrate (Form 3) (# indicates the spinning sideband). [Figure 13]This figure shows the carbon CPMAS spectrum of PF-07104091 (Form 5) (# indicates the spinning sideband). [Figure 14] This figure shows a differential scanning calorimetry thermogram of PF-07104091 (Form 4) at a temperature change rate of 10°C / min. [Figure 15] This is a diagram showing the thermogravimetric analysis of PF-07104091 (Form 5). [Figure 16] This figure shows the single crystal structure of PF-07104091 monohydrate (form 3). [Modes for carrying out the invention]

[0018] The present 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 terms used herein are intended solely to describe specific embodiments and are not intended to be limiting. It should also be understood that, unless specifically defined herein, the terms used herein are given their conventional meanings as they are known in the relevant art.

[0019] As used herein, the singular forms "a," "an," and "the" include multiple references unless otherwise indicated. For example, the "a" substituent includes one or more substituents.

[0020] The term "approximately" means that, as considered by those skilled in the art, it has a value that falls within the allowable standard error.

[0021] The term "amorphous," as used herein, refers to a solid material that (1) lacks order in three dimensions, or (2) exhibits order in less than three dimensions, only short-range (e.g., less than 10 Å) order, or both. Amorphous solids typically give a scattered PXRD pattern containing one or two broad peaks.

[0022] As used herein, the term "anhydrous" refers to a crystalline form that contains only the active pharmaceutical ingredient (API) as part of its crystal lattice.

[0023] As used herein, the term "crystalline" means having a regularly repeating arrangement of molecules or outer planes. Crystalline morphologies may differ with respect to thermodynamic stability, physical parameters, X-ray structure, and preparation processes.

[0024] The term "polymorph" or "polymorph" refers to a crystalline form of a compound that has a distinct spatial lattice arrangement compared to other crystalline forms of the same compound.

[0025] The term "solvate" describes a molecular complex containing a compound (e.g., the active pharmaceutical ingredient (API) of a drug product) 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 clearly defined stoichiometry independent of humidity. However, when the solvent is weakly bound, such as in channel solvates and hygroscopic compounds, the solvent content will depend on humidity and dry conditions. In such cases, the complex is often non-stoichiometric.

[0026] The term "hydrate" describes a solvate of a compound containing a stoichiometric or non-stoichiometric amount of water. A "monohydrate" is a hydrate containing one molecule of water per molecule of compound (i.e., a 1:1 stoichiometric water-pair compound).

[0027] The expression “substantially pure” means that the crystalline or amorphous form described as substantially pure 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 greater than 95%, preferably greater than 97%, and more preferably greater than 99%).

[0028] As used herein, the term “essentially the same” means that typical variability in a particular method is taken into account. For example, with respect to X-ray diffraction peak position, the term “essentially the same” means that typical variability in peak position and intensity is taken into account. Those skilled in the art will see that the peak position (2θ) exhibits some variability, typically around ±0.2°. Furthermore, those skilled in the art will see that the relative peak intensity reflects inter-instrument variability, as well as variability due to crystallinity, selective orientation, surface of the prepared sample, and other factors known to those skilled in the art, and should be interpreted as merely a qualitative measurement. Similarly, the Raman spectral wavenumber (cm) -1 The values ​​are typically ±2 cm. -1 It shows variability to a certain extent, on the other hand, 13 The 13C solid-state NMR spectrum (ppm) typically exhibits a variability of approximately ±0.2 ppm.

[0029] The inventions described herein may be put into practice as appropriate in the absence of any elements not specifically disclosed herein. For example, in each example herein, any of the terms “including,” “essentially consisting of,” and “consisting of” may be replaced with any of the other two terms.

[0030] The solid form of PF-07104091 as described herein is determined by the following methods: (1) powder X-ray diffraction (PXRD) (2θ), (2) Raman spectroscopy (cm²). -1 ), (3) 13 It can be characterized by either (4) 13C solid-state NMR spectroscopy (ppm) or differential scanning calorimetry (DSC) (Tg°C), or by any combination of two or more of methods (1), (2), (3), and (4).

[0031] In each of the embodiments and examples described herein characterized by PXRD, the PXRD peak was measured using CuKα radiation at 1.5418λ.

[0032] Such solid morphologies can be further characterized by additional techniques such as Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), or differential thermal analysis (DTA).

[0033] Comparative PXRD, Raman and 13 The C ssNMR data are provided in Figures 1, 6, and 10, respectively.

[0034] In one embodiment, the present invention provides anhydrous crystalline PF-07104091 (Embodiment 2).

[0035] In some embodiments, PF-07104091 (Embodiment 2) is characterized by its powder X-ray diffraction (PXRD) pattern. In other embodiments, PF-07104091 (Embodiment 2) is characterized by its Raman spectrum. In other embodiments, PF-07104091 (Embodiment 2) is characterized by its 13 Characterized by 13C solid-state NMR spectra.

[0036] In further embodiments, anhydrous crystalline PF-07104091 (Embodiment 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) pattern (2θ), Raman spectral wave value (cm -1 )or 13 13C solid-state NMR spectrum (ppm).

[0037] In some embodiments, PF-07104091 (Embodiment 2) is characterized by PXRD and Raman. In other embodiments, PF-07104091 (Embodiment 2) is characterized by PXRD and 13 It is characterized by 13C solid-state NMR. In other embodiments, PF-07104091 (Embodiment 2) is characterized by Raman and 13It is characterized by 13C solid-state NMR. In other embodiments, PF-07104091 (Embodiment 2) is characterized by PXRD, Raman and 13 Characterized by 14C solid-state NMR.

[0038] In one embodiment, the present invention provides an anhydrous crystalline PF-07104091 (Embodiment 2) characterized by a powder X-ray diffraction (PXRD) pattern.

[0039] In one embodiment, the present invention provides PF-07104091 (Embodiment 2) having a powder X-ray diffraction (PXRD) pattern including peaks at 2θ values ​​of 9.8, 13.3, and 17.4°2θ±0.2°2θ.

[0040] In one embodiment, the present invention provides PF-07104091 (Embodiment 2) having a powder X-ray diffraction (PXRD) pattern including peaks at 2θ values ​​of 4.2, 9.8, 13.3, and 17.4°2θ±0.2°2θ.

[0041] In one embodiment, the present invention provides PF-07104091 (Embodiment 2) having a powder X-ray diffraction (PXRD) pattern including peaks at 2θ values ​​of 7.5, 9.8, 13.3, and 17.4°2θ±0.2°2θ.

[0042] In another embodiment, the present invention provides PF-07104091 (Embodiment 2) having a powder X-ray diffraction (PXRD) pattern including peaks at 2θ values ​​of 4.2, 7.5, 9.8, 13.3, and 17.4°2θ±0.2°2θ.

[0043] In one embodiment, the present invention provides PF-07104091 (Embodiment 2) having a powder X-ray diffraction (PXRD) pattern including peaks at 2θ values ​​of 9.8, 13.3, and 17.4°2θ±0.2°2θ, and optionally one or two peaks selected from the group consisting of 4.2 and 7.5°2θ±0.2°2θ.

[0044] In another embodiment, the present invention provides PF-07104091 (Embodiment 2) having a PXRD pattern including three or more peaks at 2θ values ​​selected from the group consisting of 4.2, 7.5, 9.8, 13.3, and 17.4°2θ±0.2°2θ.

[0045] In another embodiment, the present invention provides PF-07104091 (Embodiment 2) having a PXRD pattern that includes (a) one, two, three, four, five, or more than five peaks selected from the group consisting of peaks at °2θ ± 0.2°2θ in Table 1, or (b) a peak at essentially the same 2θ value as in Figure 2.

[0046] In another embodiment, the present invention provides anhydrous crystalline PF-07104091 (Embodiment 2) characterized by Raman spectroscopy.

[0047] In one embodiment, the present invention relates to 1691, 1582 and 996 cm -1 ±2cm -1 wavenumber (cm -1 PF-07104091 (Form 2) is provided, which has a Raman spectrum including the value.

[0048] In another embodiment, the present invention relates to 1691, 1582, 1036 and 996 cm -1 ±2cm -1 wavenumber (cm -1 PF-07104091 (Form 2) is provided, which has a Raman spectrum including the value.

[0049] In another embodiment, the present invention relates to 1691, 1582, 1365, and 996 cm. -1 ±2cm -1 wavenumber (cm -1 PF-07104091 (Form 2) is provided, which has a Raman spectrum including the value.

[0050] In another embodiment, the present invention relates to 1691, 1582, 1365, 1036, and 996 cm. -1 ±2cm -1 wavenumber (cm -1PF-07104091 (Form 2) is provided, which has a Raman spectrum including the value.

[0051] In one embodiment, the present invention relates to 1691, 1582 and 996 cm -1 ±2cm -1 wavenumber (cm -1 ) values, as well as 1365 and 1036 cm -1 ±2cm -1 The present invention provides PF-07104091 (Form 2) having a Raman spectrum containing one or two peaks selected from the group consisting of the following.

[0052] In one embodiment, the present invention relates to (a) cm in Table 2. -1 ±2cm -1 One, two, three, four, five, or more than five wavenumbers (cm) are selected from the group consisting of the values ​​in the given range. -1 ) value, or (b) essentially the same wavenumber (cm) as in Figure 7. -1 PF-07104091 (Form 2) is provided, which has a Raman spectrum including the value.

[0053] In another embodiment, the present invention is 13 We provide anhydrous crystalline PF-07104091 (Form 2) characterized by its 1C solid-state NMR spectrum.

[0054] In one embodiment, the present invention includes resonance (ppm) values ​​of 24.1, 39.8, and 41.6 ppm ± 0.2 ppm. 13 This invention provides PF-07104091 (Form 2) having a 1C solid-state NMR spectrum.

[0055] In one embodiment, the present invention includes resonance (ppm) values ​​of 21.8, 24.1, 39.8, and 41.6 ppm ± 0.2 ppm. 13 This invention provides PF-07104091 (Form 2) having a 1C solid-state NMR spectrum.

[0056] In one embodiment, the present invention includes resonance (ppm) values ​​of 24.1, 39.8, 41.6, and 138.2 ppm ± 0.2 ppm.13 This invention provides PF-07104091 (Form 2) having a 1C solid-state NMR spectrum.

[0057] In another embodiment, the present invention includes resonance (ppm) values ​​of 21.8, 24.1, 39.8, 41.6 and 138.2 ppm ± 0.2 ppm. 13 This invention provides PF-07104091 (Form 2) having a 1C solid-state NMR spectrum.

[0058] In one embodiment, the present invention includes resonance (ppm) values ​​of 24.1, 39.8, and 41.6 ppm ± 0.2 ppm, and one or two resonance (ppm) values ​​selected from the group consisting of 21.8 and 138.2 ppm ± 0.2 ppm. 13 This invention provides PF-07104091 (Form 2) having a 1C solid-state NMR spectrum.

[0059] In one embodiment, the present invention includes resonance (ppm) values ​​of 24.1, 39.8, and 41.6 ppm ± 0.2 ppm, and optionally one or two peaks selected from the group consisting of 21.8 and 138.2 ppm ± 0.2 ppm. 13 This invention provides PF-07104091 (Form 2) having a 1C solid-state NMR spectrum.

[0060] In another embodiment, the present invention includes three or more resonance (ppm) values ​​selected from the group consisting of 21.8, 24.1, 39.8, 41.6, and 138.2 ppm ± 0.2 ppm. 13 This invention provides PF-07104091 (Form 2) having a 1C solid-state NMR spectrum.

[0061] In another embodiment, the present invention includes (a) one, two, three, four, five, or more than five resonance (ppm) values ​​selected from the group consisting of values ​​in ppm ± 0.2 ppm in Table 3, or (b) resonance (ppm) values ​​that are essentially the same as those in Figure 11. 13 This invention provides PF-07104091 (Form 2) having a 1C solid-state NMR spectrum (ppm).

[0062] In another embodiment, the present invention is (a) Powder X-ray diffraction (PXRD) pattern including peaks at 2θ values ​​of 9.8, 13.3, and 17.4°2θ ± 0.2°2θ, (b) 1691, 1582 and 996 cm -1 ±2cm -1 wavenumber (cm -1 ) Raman spectrum including the value, or (c) Includes resonance (ppm) values ​​of 24.1, 39.8 and 41.6 ppm ± 0.2 ppm. 13 C solid-state NMR spectrum, or any combination of two or more of (a), (b), and (c) We provide anhydrous crystalline PF-07104091 (Form 2) having the following properties.

[0063] In another embodiment, the present invention is (a) Powder X-ray diffraction (PXRD) pattern including peaks at 2θ values ​​of 9.8 and 13.3°2θ±0.2°2θ, and further including a peak at 2θ value of 17.4°2θ±0.2°2θ, (b) 1691cm -1 ±2cm -1 wavenumber (cm -1 ) Includes values ​​of 1582 and 996 cm -1 ±2cm -1 wavenumber (cm -1 A Raman spectrum that may also contain values, or (c) Includes resonance (ppm) values ​​of 24.1, 39.8 and 41.6 ppm ± 0.2 ppm. 13 C solid-state NMR spectrum, or any combination of two or more of (a), (b), and (c) We provide anhydrous crystalline PF-07104091 (Form 2) having the following properties.

[0064] In another embodiment, the present invention is (1) (a) 9.8, 13.3 and 17.4°2θ ± 0.2°2θ, (b) 4.2, 9.8, 13.3 and 17.4°2θ ± 0.2°2θ, (c) 7.5, 9.8, 13.3 and 17.4°2θ ± 0.2°2θ, or (d) 4.2, 7.5, 9.8, 13.3 and 17.4°2θ ± 0.2°2θ Powder X-ray diffraction (PXRD) pattern including peaks at the 2θ value, (2) (a) 1691, 1582 and 996 cm -1 ±2cm -1 , (b) 1691, 1582, 1036 and 996 cm -1 ±2cm -1 , (c) 1691, 1582, 1365 and 996 cm -1 ±2cm -1 ,or (d) 1691, 1582, 1365, 1036 and 996 cm -1 ±2cm -1 wavenumber (cm -1 ) Raman spectrum including value, or (3) (a) 24.1, 39.8 and 41.6 ppm ± 0.2 ppm, (b) 21.8, 24.1, 39.8 and 41.6 ppm ± 0.2 ppm, (c) 24.1, 39.8, 41.6 and 138.2 ppm ± 0.2 ppm, or (d) 21.8, 24.1, 39.8, 41.6 and 138.2 ppm ± 0.2 ppm Includes the resonance (ppm) value. 13 C solid-state NMR spectrum, Or any combination of two or more of (1)(a)~(d), (2)(a)~(d), and (3)(a)~(d). We provide anhydrous crystalline PF-07104091 (Form 2) having the following properties.

[0065] In some embodiments of the aspects and embodiments of PF-07104091 (Form 2) described herein, the crystalline form is substantially pure anhydrous crystalline PF-07104091 (Form 2).

[0066] In another aspect, the present invention provides a pharmaceutical composition comprising anhydrous crystalline PF-07104091 (Form 2) according to the embodiments or models described herein, and a pharmaceutically acceptable carrier or additive.

[0067] In another aspect, the present invention provides a method for treating cancer in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of anhydrous crystalline PF-07104091 (Form 2) according to the embodiments or models described herein, or a pharmaceutical composition comprising anhydrous crystalline PF-07104091 (Form 2).

[0068] In another aspect, the present invention provides a method for treating cancer in a subject in need thereof, comprising the steps of administering to the subject a certain amount of anhydrous crystalline PF-07104091 (Form 2) according to an aspect or embodiment described herein, or a pharmaceutical composition comprising anhydrous crystalline PF-07104091 (Form 2), and a certain amount of an additional anticancer agent, wherein the amounts of PF-07104091 (Form 2) and the additional anticancer agent together are effective in treating cancer.

[0069] 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 embodiments or models described herein, for use in the treatment of cancer.

[0070] In another aspect, the present invention provides anhydrous crystalline PF-07104091 (Form 2) according to the embodiments or models described herein for use in the manufacture of pharmaceuticals for the treatment of cancer.

[0071] 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 embodiments or models described herein, for the treatment of cancer.

[0072] In another aspect, the present invention provides the use of anhydrous crystalline PF-07104091 (Form 2) in the manufacture of a pharmaceutical for the treatment of cancer, according to the forms or embodiments described herein.

[0073] In each of the embodiments and forms of anhydrous crystalline PF-07104091 (Form 2) described herein, the crystalline form may be substantially pure anhydrous crystalline PF-07104091 (Form 2).

[0074] Each of the embodiments described herein with respect to anhydrous crystalline PF-07104091 (Embodiment 2) may be combined with other such embodiments, provided that the embodiments are not inconsistent with each other.

[0075] In a preferred embodiment, the present invention provides a crystalline PF-07104091 monohydrate (Form 3). In some embodiments, the crystalline PF-07104091 monohydrate (Form 3) is characterized by its powder X-ray diffraction (PXRD) pattern. In other embodiments, the crystalline PF-07104091 monohydrate (Form 3) is characterized by its Raman spectrum. In other embodiments, the crystalline PF-07104091 monohydrate (Form 3) is characterized by its 13 Characterized by 13C solid-state NMR spectra.

[0076] In further embodiments, crystalline PF-07104091 monohydrate (Embodiment 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) pattern (2θ), Raman spectral wave value (cm -1 )or 13¹¹C solid-state NMR spectrum (ppm). In some embodiments, crystalline PF-07104091 monohydrate (Form 3) is characterized by PXRD and Raman. In other embodiments, crystalline PF-07104091 monohydrate (Form 3) is characterized by PXRD and 13 Characterized by 13C solid-state NMR. In other embodiments, crystalline PF-07104091 monohydrate (Form 3) is characterized by Raman and 13 It is characterized by 13C solid-state NMR. In other embodiments, crystalline PF-07104091 monohydrate (Form 3) is characterized by PXRD, Raman and 13 Characterized by 14C solid-state NMR.

[0077] In one embodiment, the present invention provides a crystalline PF-07104091 monohydrate (Embodiment 3) characterized by a powder X-ray diffraction (PXRD) pattern.

[0078] In one embodiment, the present invention provides a crystalline PF-07104091 monohydrate (Form 3) having a powder X-ray diffraction (PXRD) pattern including peaks at 2θ values ​​of 8.4, 10.1, and 21.5°2θ±0.2°2θ.

[0079] In one embodiment, the present invention provides a crystalline PF-07104091 monohydrate (Form 3) having a powder X-ray diffraction (PXRD) pattern including peaks at 2θ values ​​of 8.4, 10.1, 16.9, and 21.5°2θ±0.2°2θ.

[0080] In one embodiment, the present invention provides a crystalline PF-07104091 monohydrate (Form 3) having a powder X-ray diffraction (PXRD) pattern including peaks at 2θ values ​​of 8.4, 10.1, 21.5, and 27.0°2θ±0.2°2θ.

[0081] In another embodiment, the present invention provides a crystalline PF-07104091 monohydrate (Form 3) having a powder X-ray diffraction (PXRD) pattern including peaks at 2θ values ​​of 8.4, 10.1, 16.9, 21.5, and 27.0°2θ±0.2°2θ.

[0082] In another embodiment, the present invention is (a) 8.4, 10.1 and 21.5°2θ ± 0.2°2θ, (b) 8.4, 10.1, 16.9 and 21.5°2θ±0.2°2θ, (c) 8.4, 10.1, 21.5 and 27.0°2θ ± 0.2°2θ, or (d) 8.4, 10.1, 16.9, 21.5 and 27.0°2θ ± 0.2°2θ This invention provides a crystalline PF-07104091 monohydrate (Form 3) having a powder X-ray diffraction (PXRD) pattern that includes a peak at the 2θ value.

[0083] In one embodiment, the present invention provides a crystalline PF-07104091 monohydrate (Form 3) having a powder X-ray diffraction (PXRD) pattern including peaks at 2θ values ​​of 8.4, 10.1, and 21.5°2θ±0.2°2θ, and optionally one or two peaks selected from the group consisting of 16.9 and 27.0°2θ±0.2°2θ.

[0084] In another embodiment, the present invention provides a crystalline PF-07104091 monohydrate (Form 3) having a PXRD pattern including three or more peaks at 2θ values ​​selected from the group consisting of 8.4, 10.1, 16.9, 21.5, and 27.0°2θ±0.2°2θ.

[0085] In another embodiment, the present invention provides a crystalline PF-07104091 monohydrate (Form 3) having a PXRD pattern including (a) one, two, three, four, five, or more than five peaks selected from the group consisting of peaks at °2θ ± 0.2°2θ in Table 4, or (b) a peak at essentially the same 2θ value as in Figure 3.

[0086] In another embodiment, the present invention provides a crystalline PF-07104091 monohydrate characterized by Raman spectroscopy (Embodiment 3).

[0087] In one embodiment, the present invention provides crystalline PF-07104091 monohydrate (Form 3) having a Raman spectrum including wavenumber (cm -1 ±2 cm -1 ) values of 1657, 1595, and 1408 cm -1 .

[0088] In another embodiment, the present invention provides crystalline PF-07104091 monohydrate (Form 3) having a Raman spectrum including wavenumber (cm -1 ±2 cm -1 ) values of 1657, 1595, 1408, and 923 cm -1 .<00006​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​-1 The present invention provides a crystalline PF-07104091 monohydrate (Form 3) having a Raman spectrum including the value.

[0092] In one embodiment, the present invention relates to 1657, 1595 and 1408 cm -1 ±2cm -1 wavenumber (cm -1 ) values, as well as 1272 and 923 cm -1 ±2cm -1 The present invention provides a crystalline PF-07104091 monohydrate (Form 3) having a Raman spectrum containing one or two peaks selected from the group consisting of the following.

[0093] In one embodiment, the present invention relates to (a) cm in Table 5. -1 ±2cm -1 One, two, three, four, five, or more than five wavenumbers (cm) are selected from the group consisting of the values ​​in the given range. -1 ) value, or (b) essentially the same wavenumber (cm) as in Figure 8. -1 The present invention provides a crystalline PF-07104091 monohydrate (Form 3) having a Raman spectrum including the value.

[0094] In another embodiment, the present invention is 13 This provides a crystalline PF-07104091 monohydrate (Form 3) characterized by its solid-state NMR spectrum.

[0095] In one embodiment, the present invention includes resonance (ppm) values ​​of 25.2 and 37.5 ppm ± 0.2 ppm. 13 This invention provides a crystalline PF-07104091 monohydrate (Form 3) having a 1C solid-state NMR spectrum.

[0096] In one embodiment, the present invention includes resonance (ppm) values ​​of 25.2, 37.5, and 159.3 ppm ± 0.2 ppm. 13 This invention provides a crystalline PF-07104091 monohydrate (Form 3) having a 1C solid-state NMR spectrum.

[0097] In one embodiment, the present invention includes resonance (ppm) values ​​of 25.2, 37.5, 151.9, and 159.3 ppm ± 0.2 ppm. 13 This invention provides a crystalline PF-07104091 monohydrate (Form 3) having a 1C solid-state NMR spectrum.

[0098] In one embodiment, the present invention includes resonance (ppm) values ​​of 25.2, 37.5, 152.5, and 159.3 ppm ± 0.2 ppm. 13 This invention provides a crystalline PF-07104091 monohydrate (Form 3) having a 1C solid-state NMR spectrum.

[0099] In another embodiment, the present invention includes resonance (ppm) values ​​of 25.2, 37.5, 151.9, 152.5, and 159.3 ppm ± 0.2 ppm. 13 This invention provides a crystalline PF-07104091 monohydrate (Form 3) having a 1C solid-state NMR spectrum.

[0100] In one embodiment, the present invention includes resonance (ppm) values ​​of 25.2, 37.5, and 159.3 ppm ± 0.2 ppm, and one or two resonance (ppm) values ​​selected from the group consisting of 151.9 and 152.5 ppm ± 0.2 ppm. 13 This invention provides a crystalline PF-07104091 monohydrate (Form 3) having a 1C solid-state NMR spectrum.

[0101] In another embodiment, the present invention is (a) 25.2 and 37.5 ppm ± 0.2 ppm, (b) 25.2, 37.5 and 159.3 ppm ± 0.2 ppm, (c) 25.2, 37.5, 151.9 and 159.3 ppm ± 0.2 ppm, (d) 25.2, 37.5, 152.5 and 159.3 ppm ± 0.2 ppm, or (e) 25.2, 37.5, 151.9, 152.5 and 159.3 ppm ± 0.2 ppm Includes the resonance (ppm) value. 13This invention provides a crystalline PF-07104091 monohydrate (Form 3) having a 1C solid-state NMR spectrum.

[0102] In one embodiment, the present invention includes one or two peaks selected from the group consisting of resonance (ppm) values ​​of 25.2, 37.5, and 159.3 ppm ± 0.2 ppm, and optionally 151.9 and 152.5 ppm ± 0.2 ppm. 13 This invention provides a crystalline PF-07104091 monohydrate (Form 3) having a 1C solid-state NMR spectrum.

[0103] In another embodiment, the present invention includes three or more resonance (ppm) values ​​selected from the group consisting of 25.2, 37.5, 151.9, 152.5, and 159.3 ppm ± 0.2 ppm. 13 This invention provides a crystalline PF-07104091 monohydrate (Form 3) having a 1C solid-state NMR spectrum.

[0104] In another embodiment, the present invention includes (a) one, two, three, four, five, or more than five resonance (ppm) values ​​selected from the group consisting of values ​​in ppm ± 0.2 ppm in Table 6, or (b) resonance (ppm) values ​​that are essentially the same as those in Figure 12. 13 This invention provides a crystalline PF-07104091 monohydrate (Form 3) having a 1C solid-state NMR spectrum (ppm).

[0105] In another embodiment, the present invention is (a) Powder X-ray diffraction (PXRD) pattern including peaks at 2θ values ​​of 8.4, 10.1 and 21.5°2θ ± 0.2°2θ, (b) 1657, 1595 and 1408 cm -1 ±2cm -1 wavenumber (cm -1 ) Raman spectrum including the value, or (c) Includes resonance (ppm) values ​​of 25.2, 37.5 and 159.3 ppm ± 0.2 ppm 13 C solid-state NMR spectrum, or any combination of two or more of (a), (b), and (c) The present invention provides a crystalline PF-07104091 monohydrate (Form 3) having the following properties.

[0106] In another embodiment, the present invention is (a) Powder X-ray diffraction (PXRD) pattern including peaks at 2θ values ​​of 8.4 and 10.1°2θ±0.2°2θ, and further including a peak at 2θ value of 21.5°2θ±0.2°2θ, (b) 1657cm -1 ±2cm -1 wavenumber (cm -1 ) Includes values ​​of 1595 and 1408 cm -1 ±2cm -1 wavenumber (cm -1 A Raman spectrum that may also contain values, or (c) Includes resonance (ppm) values ​​of 25.2 and 37.5 ppm ± 0.2 ppm, and may further include resonance (ppm) value of 159.3 ppm ± 0.2 ppm. 13 C solid-state NMR spectrum, or any combination of two or more of (a), (b), and (c) The present invention provides a crystalline PF-07104091 monohydrate (Form 3) having the following properties.

[0107] In another embodiment, the present invention is (1) (a) 8.4, 10.1 and 21.5°2θ ± 0.2°2θ, (b) 8.4, 10.1, 16.9 and 21.5°2θ±0.2°2θ, (c) 8.4, 10.1, 21.5 and 27.0°2θ±0.2°2θ, or (d) 8.4, 10.1, 16.9, 21.5 and 27.0°2θ ± 0.2°2θ Powder X-ray diffraction (PXRD) pattern including peaks at the 2θ value, (2) (a) 1657, 1595 and 1408 cm -1 ±2cm -1 , (b) 1657, 1595, 1408 and 923 cm -1±2cm -1 , (c) 1657, 1595, 1408 and 1272 cm -1 ±2cm -1 ,or (d) 1657, 1595, 1408, 1272 and 923 cm -1 ±2cm -1 wavenumber (cm -1 ) Raman spectrum including value, or (3) (a) 25.2 and 37.5 ppm ± 0.2 ppm, (b) 25.2, 37.5 and 159.3 ppm ± 0.2 ppm, (c) 25.2, 37.5, 151.9 and 159.3 ppm ± 0.2 ppm, (d) 25.2, 37.5, 152.5 and 159.3 ppm ± 0.2 ppm, or (e) 25.2, 37.5, 151.9, 152.5 and 159.3 ppm ± 0.2 ppm Includes the resonance (ppm) value. 13 C solid-state NMR spectrum, Or any combination of two or more of (1)(a)~(d), (2)(a)~(d), and (3)(a)~(e). The present invention provides a crystalline PF-07104091 monohydrate (Form 3) having the following properties.

[0108] In another aspect, the present invention provides a pharmaceutical composition comprising a crystalline PF-07104091 monohydrate (Form 3) according to an aspect or embodiment described herein, and a pharmaceutically acceptable carrier or additive.

[0109] In another aspect, the present invention provides a method for treating cancer in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of crystalline PF-07104091 monohydrate (Form 3) according to the embodiments or models described herein, or a pharmaceutical composition comprising crystalline PF-07104091 monohydrate (Form 3).

[0110] In another aspect, the present invention provides a method for treating cancer in a subject in need thereof, comprising the step of administering to the subject a certain amount of crystalline PF-07104091 monohydrate (Form 3) according to an aspect or embodiment described herein, or a pharmaceutical composition comprising crystalline PF-07104091 monohydrate (Form 3), and a certain amount of an additional anticancer agent, wherein the amounts of PF-07104091 monohydrate (Form 3) and the additional anticancer agent together are effective in treating cancer.

[0111] 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 embodiments or models described herein, for use in the treatment of cancer.

[0112] In another aspect, the present invention provides a crystalline PF-07104091 monohydrate (Form 3) according to the embodiments or models described herein, for use in the manufacture of pharmaceuticals for the treatment of cancer.

[0113] 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 embodiments or models described herein, for the treatment of cancer.

[0114] In another aspect, the present invention provides the use of crystalline PF-07104091 monohydrate (Form 3) in the manufacture of a pharmaceutical for the treatment of cancer, in accordance with the aspects or embodiments described herein.

[0115] In each of the embodiments and forms of crystalline PF-07104091 monohydrate (form 3) described herein, the crystalline form may be substantially pure crystalline PF-07104091 monohydrate (form 3).

[0116] Each of the embodiments described herein for crystalline PF-07104091 monohydrate (Embodiment 3) may be combined with other such embodiments, provided that the embodiments are not inconsistent with each other.

[0117] In another embodiment, the present invention provides amorphous PF-07104091 (Embodiment 4).

[0118] In some embodiments, the present invention provides amorphous PF-07104091 (Embodiment 4) having a powder X-ray diffraction (PXRD) pattern including a broad peak at diffraction angles (2θ) from about 5 to about 35°2θ ± 0.2°2θ.

[0119] In some embodiments, the present invention provides amorphous PF-07104091 (Embodiment 4) having essentially the same powder X-ray diffraction (PXRD) pattern as that shown in Figure 4.

[0120] In some embodiments, the present invention has a glass transition temperature (T) of 59.8±5℃. g The amorphous PF-07104091 (Form 4) having ) is provided (Figure 14).

[0121] In another embodiment, the present invention is (1) (a) Broad peaks at diffraction angles (2θ) from approximately 5 to approximately 35°2θ ± 0.2°2θ, or (b) Peak at essentially the same 2θ value as in Figure 4 Powder X-ray diffraction (PXRD) pattern (2θ) including, or (2) (a) Glass transition temperature of approximately 59.8±5℃ (T g (Measured by DSC at a rate of change of 10°C / min), or (b) DSC thermogram essentially the same as Figure 14 DSC thermogram including Or any combination of two or more of (1)(a)~(b) and (2)(a)~(b) The present invention provides amorphous PF-07104091 (Form 4) having the following characteristics.

[0122] In another aspect, the present invention provides a pharmaceutical composition comprising amorphous PF-07104091 (Form 4) according to an aspect or embodiment described herein, and a pharmaceutically acceptable carrier or additive.

[0123] In another aspect, the present invention provides a method for treating cancer in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of amorphous PF-07104091 (Form 4) or a pharmaceutical composition comprising amorphous PF-07104091 (Form 4) according to the embodiments or forms described herein.

[0124] In another aspect, the present invention provides a method for treating cancer in a subject in need thereof, comprising the steps of administering to the subject a certain amount of amorphous PF-07104091 (Form 4) according to an aspect or embodiment described herein, or a pharmaceutical composition comprising amorphous PF-07104091 (Form 4), and a certain amount of an additional anticancer agent, wherein the amounts of amorphous PF-07104091 (Form 4) and the additional anticancer agent together are effective in treating cancer.

[0125] 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 embodiments or models described herein, for use in the treatment of cancer.

[0126] In another aspect, the present invention provides amorphous PF-07104091 (Form 4) according to the embodiments or models described herein for use in the manufacture of pharmaceuticals for the treatment of cancer.

[0127] 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 embodiments or models described herein, for the treatment of cancer.

[0128] In another aspect, the present invention provides the use of amorphous PF-07104091 (Form 4) in the manufacture of a pharmaceutical for the treatment of cancer, according to the forms or embodiments described herein.

[0129] In each of the embodiments and forms of amorphous PF-07104091 (form 4) described herein, the amorphous form may be substantially pure amorphous PF-07104091 (form 4).

[0130] Each of the embodiments described herein with respect to amorphous PF-07104091 (Embodiment 4) may be combined with other such embodiments, provided that the embodiments are not inconsistent with each other.

[0131] In further embodiments, the present invention provides anhydrous crystalline PF-07104091 (Form 5). Form 5 is prepared by dehydration of 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 spectrum. In other embodiments, PF-07104091 (Form 5) is characterized by its 13 Characterized by 13C solid-state NMR spectra.

[0132] In further embodiments, PF-07104091 (Embodiment 5) 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) pattern (2θ), Raman spectral wave value (cm -1 )or 13 1C solid-state NMR spectrum (ppm). In some embodiments, PF-07104091 (Embodiment 5) is characterized by PXRD and Raman. In other embodiments, PF-07104091 (Embodiment 5) is characterized by PXRD and 13It is characterized by 13C solid-state NMR. In other embodiments, PF-07104091 (Embodiment 5) is characterized by Raman and 13 It is characterized by 13C solid-state NMR. In other embodiments, crystalline PF-07104091 (Embodiment 5) is characterized by PXRD, Raman and 13 Characterized by 14C solid-state NMR.

[0133] In one embodiment, the present invention provides an anhydrous crystalline PF-07104091 (Embodiment 5) characterized by a powder X-ray diffraction (PXRD) pattern.

[0134] In another embodiment, the present invention provides an anhydrous crystalline PF-07104091 (Embodiment 5) having a PXRD pattern including three or more peaks at 2θ values ​​selected from the group consisting of 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.

[0135] In another embodiment, the present invention provides an anhydrous crystalline PF-07104091 (Form 5) having a PXRD pattern including (a) one, two, three, four, five, or more than five peaks selected from the group consisting of peaks at °2θ ± 0.2°2θ in Table 8, or (b) a peak at essentially the same 2θ value as in Figure 5.

[0136] In another embodiment, the present invention provides anhydrous crystalline PF-07104091 (Embodiment 5) characterized by Raman spectroscopy.

[0137] In one embodiment, the present invention relates to (a) cm in Table 9. -1 ±2cm -1 One, two, three, four, five, or more than five wavenumbers (cm) are selected from the group consisting of the values ​​in the given range. -1 ) value, or (b) essentially the same wavenumber (cm) as in Figure 9. -1 The present invention provides anhydrous crystalline PF-07104091 (Form 5) having a Raman spectrum including the value.

[0138] In another embodiment, the present invention is 13 We provide anhydrous crystalline PF-07104091 (Form 5) characterized by 13C solid-state NMR spectroscopy.

[0139] In some such embodiments, the present invention includes (a) one, two, three, four, five, or more than five resonance (ppm) values ​​selected from the group consisting of values ​​at ppm ± 0.2 ppm in Table 10, or (b) resonance (ppm) values ​​that are essentially the same as those in Figure 13. 13 This provides anhydrous crystalline PF-07104091 (Form 5) having a 1C solid-state NMR spectrum (ppm).

[0140] In another embodiment, the present invention is (a) The peak at essentially the same 2θ value as in Figure 5, (b) The same wave number (cm) as in Figure 9 -1 ) value, or (c) Essentially the same resonance (ppm) value as in Figure 13, or any combination of two or more of (a), (b), and (c) An anhydrous crystalline PF-07104091 (Form 5) having the following properties is provided.

[0141] In another aspect, the present invention provides a pharmaceutical composition comprising anhydrous crystalline PF-07104091 (Form 5) according to an aspect or embodiment described herein, and a pharmaceutically acceptable carrier or additive.

[0142] In another aspect, the present invention provides a method for treating cancer in a subject requiring such treatment, comprising the step of administering to the subject a therapeutically effective amount of anhydrous crystalline PF-07104091 (Form 5) according to the embodiments or models described herein, or a pharmaceutical composition comprising anhydrous crystalline PF-07104091 (Form 5).

[0143] In another aspect, the present invention provides a method for treating cancer in a subject in need thereof, comprising the steps of administering to the subject a certain amount of anhydrous crystalline PF-07104091 (Form 5) according to an aspect or embodiment described herein, or a pharmaceutical composition comprising anhydrous crystalline PF-07104091 (Form 5), and a certain amount of an additional anticancer agent, wherein the amounts of PF-07104091 (Form 5) and the additional anticancer agent together are effective in treating cancer.

[0144] 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 embodiments or models described herein, for use in the treatment of cancer.

[0145] In another aspect, the present invention provides anhydrous crystalline PF-07104091 (Form 5) according to the embodiments or models described herein, for use in the manufacture of pharmaceuticals for the treatment of cancer.

[0146] 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 embodiments or models described herein, for the treatment of cancer.

[0147] In another aspect, the present invention provides the use of anhydrous crystalline PF-07104091 (Form 5) in the manufacture of a pharmaceutical for the treatment of cancer, according to the forms or embodiments described herein.

[0148] In each of the embodiments and forms of anhydrous crystalline PF-07104091 (Form 5) described herein, the crystalline form may be the substantially pure crystalline form (Form 5) of PF-07104091.

[0149] Each of the embodiments described herein with respect to anhydrous crystalline PF-07104091 (Embodiment 5) may be combined with other such embodiments, provided that the embodiments are not inconsistent with each other.

[0150] In some embodiments of the methods and uses described herein, cancer refers to 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 urothelial carcinoma of the upper urinary tract, such as UUTUC), ovarian cancer (including epithelial ovarian cancer, EOC), peritoneal cancer (including primary peritoneal cancer, PPC), fallopian tube cancer, and uterine cancer. The group is selected from the following: 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 tumors (including astrocytoma, meningioma, and glioblastoma), sarcomas (including osteosarcoma and liposarcoma), and lymphomas (including mantle cell lymphoma and MCL).

[0151] In some embodiments of the methods and uses described herein, the cancer is SCLC. In some such embodiments, the SCLC is Rb-negative or Rb-deficient.

[0152] In some embodiments of the methods and uses described herein, the cancer is NSCLC. In some such embodiments, NSCLC is characterized by amplification or overexpression of cyclin E1 (CCNE1) and / or cyclin E2 (CCNE2).

[0153] In some embodiments of the methods and uses described herein, cancer is ovarian cancer (including epithelial ovarian cancer, EOC), peritoneal cancer (including primary peritoneal cancer, PPC), or fallopian tube cancer. In some such embodiments, cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0154] In some embodiments of the methods and uses described herein, the cancer is TNBC. In some such embodiments, TNBC is refractory to CDK4 / 6 inhibitors such as palbociclib.

[0155] 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 refractory to CDK4 / 6 inhibitors such as palbociclib.

[0156] In some embodiments of the methods and uses described herein, the cancer is advanced or metastatic cancer. In some embodiments of the methods and uses described herein, the cancer is early-stage or non-metastatic cancer.

[0157] 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 demonstrates primary or acquired resistance to endocrine therapy, anti-HER2 targeted agents, CDK4 / CDK6 inhibitors, or chemotherapy (e.g., taxanes or platins).

[0158] In some embodiments, the breast cancer is advanced or metastatic breast cancer. In each of the aforementioned embodiments, the breast cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0159] In some embodiments of the methods provided herein, the abnormal cell growth is a cancer characterized by amplification or overexpression of CCNE1 and / or CCNE2. In some embodiments of the methods provided herein, the subject is identified as having a cancer characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0160] 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).

[0161] In some embodiments, the compounds of the present invention are administered as first-line therapy. In other embodiments, the compounds of the present invention are administered as second-line (or retrospective) therapy.

[0162] In some embodiments, the compounds of the present invention are administered as a second (or retrospective) choice 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 retrospective) choice 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 retrospective) choice 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 retrospective) choice therapy after treatment with one or more chemotherapy regimens (e.g., taxanes or platinum agents). In some embodiments, the compounds of the present invention are administered as a second (or retrospective) choice therapy after treatment with anti-HER2 targeted agents (e.g., trastuzumab, patuzumab, lapatinib, or adtrastuzumab emtansine (T-DM1)).

[0163] Where used herein, “effective dose,” “effective amount,” or “therapeutic effective amount” of a compound or pharmaceutical composition is an amount sufficient to affect one or more beneficial or desired outcomes, including preventing, improving, or treating the biochemical, histological, or behavioral symptoms of a disease, its complications, and intermediate pathological phenotypes present during the course of the disease, when used as directed (either alone when used as a monotherapy agent, or together with other active agents when used in combination). In protective use, beneficial or desired outcomes may include eliminating or reducing risk, reducing severity, or delaying the onset of the disease. In therapeutic use, beneficial or desired outcomes may include reducing the incidence of the disease or improving one or more of its symptoms, reducing the dose of another agent used to treat the disease, enhancing the efficacy or safety of another agent used to treat the disease, or delaying the time to disease progression.

[0164] In relation to the treatment of cancer, a therapeutically effective dose refers to a dose that has the effect of (1) reducing the size of the tumor, (2) inhibiting tumor metastasis (i.e., slowing it to some extent, preferably stopping it), (3) inhibiting tumor growth or tumor invasiveness to some extent (i.e., slowing it to some extent, preferably stopping it), (4) alleviating (or preferably eliminating) one or more signs or symptoms associated with cancer to some extent, (5) reducing the dose of other drugs required to treat the disease, and / or (6) enhancing the effect of another drug, and / or (7) delaying the progression of the disease in the patient.

[0165] The effective dose may be administered in one or more doses. For the purposes of the present invention, the effective dose of a drug, compound, or pharmaceutical composition is sufficient to perform a protective or therapeutic action, either directly or indirectly. As understood in a clinical context, the effective dose of a drug, compound, or pharmaceutical composition may or may not be achieved in combination with another drug, compound, or pharmaceutical composition.

[0166] "Non-standard dosing regimen" refers to a regimen for administering an amount of a substance, agent, compound or pharmaceutical composition that is different from the amount, dosage or schedule typically used for that substance, agent, compound or pharmaceutical composition in a clinical or therapeutic setting. "Non-standard dosing regimen" includes "non-standard dosage" or "non-standard dosing schedule".

[0167] "Low-dose regimen" refers to a dosing regimen in which one or more of the amounts of a substance, agent, compound or pharmaceutical composition in the regimen are dosed at an amount or dosage lower than that typically used in a clinical or therapeutic setting for that agent, for example, when the agent is dosed as monotherapy.

[0168] The retinoblastoma susceptibility gene (RB1) was the first molecularly defined tumor suppressor gene. The retinoblastoma gene product, RB, is frequently mutated or deleted in retinoblastoma and osteosarcoma, and is variably mutated or deleted 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 cancer, the function of RB can be disrupted through neutralization by binding proteins (e.g., human papillomavirus-E7 protein in cervical cancer; Ishiji, T, 2000

[0021] , J Dermatol., 27:73-86) or deregulation of the pathway that ultimately phosphorylates it.

[0169] The "RB pathway" means the entire molecular signaling pathway that includes the retinoblastoma protein (RB), as well as other proteins / protein families including, but not limited to, CDK, E2f, atypical protein kinase C and Skp2. Inactivation of the RB pathway often results from perturbations of p16INK4a, cyclin D1 and CDK4.

[0170] The terms "RB+", "RB plus", "RB proficient", or "RB positive" can be used to describe cells that express a detectable amount of functional RB protein. RB positive includes wild-type and non-mutated RB proteins. Wild-type RB (RB-WT) is generally understood to mean the form of the RB protein that is typically present in the corresponding parent population and has the functions currently assigned to this protein. RB positive cells may be cells that contain a functional RB gene. RB positive cells may also be cells that can encode a detectable RB protein function.

[0171] The terms "RB-", "RB minus", "RB deficient", or "RB negative" describe several types of cells in which the function of RB is disrupted, including cells that produce undetectable amounts of functional RB protein. RB negative cells may be cells that do not contain a functional RB gene. RB negative cells may also be cells that can encode an RB protein but the protein does not function properly.

[0172] In some embodiments of each of the methods and uses described herein, cancer is characterized as retinoblastoma wild-type (RB-WT). In some embodiments of each of the methods and uses described herein, cancer is characterized as RB positive or RB proficient. Such RB positive or RB proficient cancers contain at least some functional retinoblastoma genes. In some embodiments, such RB-WT, RB positive or RB proficient cancers are characterized as RB1-WT, RB1 positive or RB1 proficient cancers.

[0173] In some embodiments of the methods and uses described herein, cancer is characterized as RB-negative or RB-deficient. Such RB-negative or RB-deficient cancers may be characterized by loss-of-function mutations, which may encode missense mutations (i.e., those encoding the wrong amino acid) or nonsense mutations (i.e., those encoding a stop codon). Alternatively, such RB-negative cancers may be characterized by deletion of all or part of the retinoblastoma gene. In some embodiments, such RB-negative or RB-deficient cancers are characterized as RB1-negative or RB1-deficient.

[0174] When applied to a person diagnosed with or suspected of having cancer, "tumor" refers to a malignant or occult malignant neoplasm or tissue mass of any size, including primary and secondary neoplasms. A solid tumor is an abnormal growth or mass of tissue that does not usually contain cysts or fluid areas. Examples of solid tumors are sarcomas, carcinomas, and lymphomas. Leukemia (a cancer of the blood) generally does not form solid tumors (National Cancer Institute, Dictionary of Cancer Terms).

[0175] "Tumor tissue volume" or "tumor burden" refers to the total amount of neoplastic material distributed throughout the body. Tumor tissue volume 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 tissue volume can be determined by various methods known in the art, such as using calipers or, while in the body, using imaging techniques such as ultrasound, bone scanning, computed tomography (CT), or magnetic resonance imaging (MRI) scanning.

[0176] The term "tumor size" refers to the total size of a tumor, which can be measured as the length and width of the tumor. Tumor size can be determined by various methods known in the art, such as measuring the dimensions of the tumor using imaging techniques, such as bone scanning, ultrasound, CR, or MRI scanning, when the tumor is removed from the body, for example, using calipers, or while it is still in the body.

[0177] The term “patient” or “subject” refers to any single subject to which a therapy is desired or which is participating in or being used as a control in a clinical trial, epidemiological study, including humans and veterinary patients of mammals such as cattle, horses, dogs, and cats. In some embodiments, the subject is human.

[0178] In some embodiments of the methods and uses described herein, the patient or subject is an adult. In some embodiments, the subject is a woman or man in any menopausal state. In some embodiments, the subject is a postmenopausal woman or man. In some embodiments, the subject is a postmenopausal woman. In some embodiments, the subject is a premenopausal or perimenopausal woman. In some embodiments, the subject is a premenopausal or perimenopausal woman treated with a luteinizing hormone-releasing hormone (LHRH) agonist. In some such embodiments, the subject is a man. In some embodiments, the subject is a man treated with LHRH or a gonadotropin-releasing hormone (GnRH) agonist.

[0179] The terms “to treat” or “to treat” cancer, as used herein, mean administering the compounds of the present invention to a subject having or diagnosed with cancer in order to achieve at least one positive therapeutic effect, such as reducing the number of cancer cells, reducing the size of the tumor, reducing the rate of cancer cell invasion into peripheral organs, or reducing the rate of tumor metastasis or tumor growth, or one or more symptoms of any disorder or condition to which such terms apply. The term “treatment,” as used herein, means the act of treating as defined above, unless otherwise indicated. The term “to treat” also includes adjuvant and neoadjuvant treatment of a subject.

[0180] For the purposes of the present invention, beneficial or desired clinical outcomes include, but are not limited to: reducing (or destroying) the proliferation of neoplastic or cancerous cells; inhibiting metastatic or neoplastic cells; reducing or decreasing the size of tumors; achieving cancer remission; reducing symptoms resulting from cancer; improving the quality of life of people with cancer; reducing the dose of other drugs required to treat cancer; slowing the progression of cancer; curing cancer; overcoming one or more resistance mechanisms of cancer; and / or extending the survival time of cancer patients. Positive therapeutic effects in cancer can be measured by several methods (see, for example, WA Weber, Assessing tumor response to therapy, J. Nucl. Med. 50 Appendix 1:1S~10S (2009)). For example, with respect to tumor growth inhibition (T / C), according to the National Cancer Institute (NCI) criteria, a T / C of 42% or less is the lowest level of antitumor activity. A T / C ratio of less than 10% is considered a high level of antitumor activity, where T / C (%) = treated median tumor volume / control median tumor volume × 100.

[0181] In some embodiments, the treatment achieved by the compounds of the present invention is defined by referring 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).

[0182] As used herein, the term “complete response” or “CR” means the disappearance of all signs of cancer in response to treatment (e.g., the disappearance of all target lesions). This does not necessarily mean that the cancer is cured.

[0183] As used herein, the term “disease-free survival” (DFS) means the length of time a patient survives after the completion of primary treatment for cancer without any signs or symptoms of that cancer.

[0184] As used herein, the term “duration of response” (DoR) refers to the length of time that a tumor continues to respond to treatment without growing or spreading. Treatments that demonstrate an improvement in DoR can produce a sustained and meaningful delay in disease progression.

[0185] As used herein, the terms “objective response” and “overall response” refer to measurable responses, 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.

[0186] As used herein, the term “overall survival” (OS) means the length of time a patient diagnosed with a disease, such as cancer, is still alive from the date of diagnosis or the commencement of treatment for the disease. OS is typically measured as an extension of life expectancy in a patient receiving a particular treatment compared to a control group of patients (i.e., those receiving either another drug or a placebo).

[0187] As used herein, the terms “partial response” or “PR” refer to a reduction in the size of one or more tumors or lesions, or in the extent of cancer progression within the body, in response to treatment. For example, in some embodiments, PR refers to a reduction of at least 30% in the sum of the longest diameters (SLDs) of the target lesions, with reference to baseline SLDs.

[0188] As used herein, 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 is also referred to as “time to tumor progression” and may include the amount of time during which the patient experiences complete response (CR) or partial response (PR) and the amount of time during which the patient experiences stable disease (SD).

[0189] As used herein, the term "progressive disease" or "PD" refers to a growing, spreading or worsening cancer. In some embodiments, PR refers to at least a 20% increase in the SLD of a target lesion, taking the minimum SLD as a reference, recorded from the start of treatment or to the presence of one or more new lesions.

[0190] As used herein, the term "stable disease" (SD) refers to a cancer that is not decreasing or increasing in extent or severity.

[0191] As used herein, the term "sustained response" refers to a sustained effect on reducing tumor growth after a treatment break. For example, the tumor size may be the same size or smaller compared to the size at the start of the dosing phase. In some embodiments, a sustained response has a duration that is at least as long as, at least 1.5 times, 2 times, 2.5 times or 3 times as long as, or longer than, the treatment duration.

[0192] The anti-cancer effect of a method of treating cancer, including "objective response", "complete response", "partial response", "progressive disease", "stable disease", "progression-free survival", "response duration", can be defined and evaluated by the investigators using RECIST v1.1 as used herein (Eisenhauer et al., New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1), Eur J of Cancer, 2009;45(2):228-47).

[0193] In some embodiments of the methods and uses described herein, the present invention relates to neoadjuvant therapy, adjuvant therapy, first-line therapy, second-line therapy, second-line or retrospective therapy, or third-line or retrospective therapy. In each of the cases as further described herein, the cancer may be localized, progressive, or metastatic, and intervention may occur at a point in time along the continuity of the disease (i.e., at any stage of the cancer).

[0194] Treatment regimens for the compounds of the present invention, which are effective in treating cancer patients, may vary according to factors such as the patient's condition, age and weight, and the ability of the therapy to induce an anti-cancer response in the subject. While any embodiment of the aspects of the present invention may not be effective in achieving a positive therapeutic effect in all subjects, it should be effective in a statistically significant number of subjects, as determined by any statistical test known in the art, such as Student's t-test, chi-squared test, Mann-Whitney U test, Kruskal-Wallis test (H test), Yonkhiel-Tapstra test (testy), and Wilcon-on test.

[0195] The terms “treatment regimen,” “medication protocol,” and “medication regimen” may be used interchangeably to refer to the dose and timing of administration of PF-07104091, either in its crystalline or amorphous form, alone or in combination with additional anticancer agents, as described herein.

[0196] "Improvement" means reducing or improving one or more symptoms to some extent when treated with a compound or drug, such as PF-07104091 in either a crystalline or amorphous form as described in the present invention, compared to when the compound is not administered. "Improvement" also includes shortening or reducing the duration of symptoms, i.e., reducing, preferably eliminating, the symptoms to some extent.

[0197] As used herein, “abnormal cell growth” refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition), unless otherwise indicated. Abnormal cell growth can be benign (not cancerous) or malignant (cancerous). In several embodiments of the methods provided herein, the abnormal cell growth is cancerous.

[0198] Abnormal cell growth includes abnormal growth in tumors characterized by (1) amplification or overexpression of CDK2, (2) amplification or overexpression of CCNE1 and / or CCNE2, (3) loss or Rb, and (4) resistance to endocrine therapy, anti-HER2 targeted agents, CDK4 / 6 inhibitors, or chemotherapy (e.g., taxanes or platins).

[0199] In some embodiments, the methods and uses of the present invention may further include one or more additional anticancer agents. In some embodiments, the additional anticancer agents are selected from the group consisting of antitumor agents, anti-angiogenic agents, signaling inhibitors, and antiproliferative agents. In some embodiments, the additional anticancer agents are selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, insertive antibiotics, growth factor inhibitors, radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxic substances, and endocrine therapeutic agents such as antiandrogens, androgen deprivation therapy (ADT), and antiestrogens. The additional anticancer agents may include small molecule therapeutics and pharmaceutically acceptable salts or solvates thereof, therapeutic antibodies, antibody-drug conjugates (ADCs), proteolytic chimeric molecules (PROTACs), or antisense molecules.

[0200] In some embodiments, the additional anticancer agent is an anti-estrogen, where 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, SERD is selected from the group consisting of fulvestrant, elastrant (RAD-1901, Radius Health), SAR439859 (Sanofi), RG6171 (Roche), AZD9833 (AstraZeneca), AZD9496 (AstraZeneca), lintodestrant (G1 Therapeutics), ZN-c5 (Zentalis), LSZ102 (Novartis), D-0502 (Inventisbio), LY3484356 (Lilly), and SHR9549 (Jiansu Hengrui Medicine). In some such embodiments, SERD is fulvestrant. In some embodiments, the anti-estrogen agent is SERM. In some such embodiments, SERM is selected from the group consisting of tamoxifen, raloxifene, toremifene, rasofoxifen, bazedoxifen, and afimoxifen. In some such embodiments, the SERM is tamoxifen or raloxifen.

[0201] In some embodiments, additional anticancer agents are antiandrogens such as abiraterone, apalutamide, bicalutamide, cyproterone, enzalutamide, flutamide, or nilutamide. In some embodiments, the method or use further comprises androgen deprivation therapy (ADT), such as a luteinizing hormone-releasing hormone (LHRH) agonist, an LHRH antagonist, a gonadotropin-releasing hormone (GnRH) agonist, or a GnRH antagonist.

[0202] In some embodiments, the methods and uses of the present invention further include one or more additional anticancer agents selected from the following:

[0203] Anti-angiogenic agents include, for example, VEGF inhibitors, VEGFR inhibitors, TIE-2 inhibitors, PDGFR inhibitors, angiopoietin inhibitors, PKCβ inhibitors, COX-2 (cyclooxygenase II) inhibitors, integrins (alpha-v / beta-3), MMP-2 (matrix-metalloproteinase 2) inhibitors, and MMP-9 (matrix-metalloproteinase 9) inhibitors.

[0204] Signal transduction inhibitors include, for example, kinase inhibitors (e.g., inhibitors of tyrosine kinase, serine / threonine kinase, or cyclin-dependent kinase), proteasome inhibitors, PI3K / AKT / mTOR pathway inhibitors, phosphoinositide 3-kinase (PI3K) inhibitors, isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) inhibitors, B-cell lymphoma 2 (BCL2) inhibitors, neurotrophin receptor kinase (NTRK) inhibitors, reorganized-at-transfection (RET) inhibitors, Notch inhibitors, PARP inhibitors, Hedgehog pathway inhibitors, and selective inhibitors of nuclear export (SINE).

[0205] Examples of signal transduction inhibitors include acalabrutinib, afatinib, alectinib, alpelisib, axitinib, binimetinib, bortezomib, bosutinib, brigutinib, cabozantinib, carfilzomib, ceritinib, cobimetinib, copanlisib, crizotinib, dabrafenib, dacomitinib, dasatinib, duvelisib, enasidenib, encorafenib, entrectinib, erlotinib, gefitinib, gilteritinib, glassegib, ibrutinib, idelalisib, imatinib, ipa This includes, but is not limited to, tasertib, ivosidenib, ixazomib, lapatinib, lalotrectinib, lenvatinib, lorlatinib, midostaurin, neratinib, nilotinib, niraparib, olaparib, osimertinib, pazopanib, ponatinib, regorafenib, rucaparib, ruxolitinib, sonidegib, sorafenib, sunitinib, talazoparib, trametinib, vandetanib, vemurafenib, venetoclax, and bismodegib, or pharmaceutically acceptable salts and solvates thereof.

[0206] Antineoplastic agents include, for example, alkylating agents, platinum coordination complexes, cytotoxic antibiotics, antimetabolies, bio-response modifiers, histone deacetylase (HDAC) inhibitors, hormones, monoclonal antibodies, growth factor inhibitors, taxanes, topoisomerase inhibitors, vinca alkaloids, and a wide variety of other active ingredients.

[0207] Alkylating agents include altretamine, bendamustine, busulfan, carmustine, chlorambucil, cyclophosphamide, dacarbazine, ifosfamide, lomustine, mechloretamine, melphalan, procarbazine, streptozocin, temozolomide, thiotepa, and trabectedin.

[0208] Platinum coordination complexes (also referred to herein as "platinum agents") include carboplatin, cisplatin, and oxaliplatin.

[0209] Cytotoxic antibiotics include bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitomycin, mitoxantrone, plicamycin, and barurubicin.

[0210] Antimetabolites include antifolic acid agents such as methotrexate, pemetrexed, pralatrexate, and trimethrexate; purine analogs such as azathioprine, cladribine, fludarabine, mercaptopurine, and thioguanine; and pyrimidine analogs such as azacitidine, capecitabine, cytarabine, decitabine, furoxiuridine, fluorouracil, gemcitabine, and trifluridine / tipracil.

[0211] The bio-response modifiers include aldethleukin (IL-2), denileukin diffitox, and interferon gamma.

[0212] Histone deacetylase inhibitors include bellinostat, panobinostat, romidepsin, and vorinostat.

[0213] Hormone preparations include anti-androgens, anti-estrogens, gonadotropin-releasing hormone (GnRH) analogs, and peptide hormones. Examples of anti-estrogen agents include aromatase inhibitors such as letrozole, anastrozole, and exemestane; SERDs such as fulvestrant, elastrant (RAD-1901, Radius Health), SAR439859 (Sanofi), RG6171 (Roche), AZD9833 (AstraZeneca), AZD9496 (AstraZeneca), lintodestrant (G1 Therapeutics), ZN-c5 (Zentalis), LSZ102 (Novartis), D-0502 (Inventisbio), LY3484356 (Lilly), and SHR9549 (Jiansu Hengrui Medicine); and serMs such as tamoxifen, raloxifen, toremifene, rasofoxifen, bazedoxifen, and afimoxifen. Examples of GnRH analogs include degarelix, goserelin, histrelin, leuprolide, and triptorelin. Examples of peptide hormones include lanreotide, octreotide, and pasireotide. Examples of antiandrogens include abiraterone, apalutamide, bicalutamide, cyproterone, enzalutamide, flutamide, and nilutamide, as well as pharmaceutically acceptable salts and solvates thereof.

[0214] Monoclonal antibodies include alemtuzumab, atezolizumab, avelumab, bevacizumab, blinatumomab, brentuximab, semiprimab, cetuximab, daratumumab, dinutuximab, durvalumab, elotuzumab, gemtuzumab, inotuzumab ozogamicin, ipilimumab, mogamulizumab, moxetumomab pasdotox, necitumumab, nivolumab, ofatumumab, olaratumumab, panitumumab, pembrolizumab, pastozumab, ramucirumab, rituximab, tocitumomab, and trastuzumab.

[0215] Taxanes include cabazitaxel, docetaxel, paclitaxel, and paclitaxel albumin-stabilized nanoparticle formulations (Nab-paclitaxel).

[0216] Topoisomerase inhibitors include etoposide, irinotecan, teniposide, and topotecan.

[0217] Vinca alkaloids include vinblastine, vincristine, and vinorelbine, as well as pharmaceutically acceptable salts thereof.

[0218] A diverse range of antineoplastic agents include asparaginase (peguasparagase), bexarotene, eribulin, everolimus, hydroxyurea, ixabepyrone, lenalidomide, mitotane, omasetaxin, pomalidomide, taglaxofusp, tetrotristat, temsirolimus, thalidomide, and venetoclax.

[0219] In some embodiments, additional anticancer agents include abiraterone acetate, acalabrutinib, adtrastuzumab emtansine, afatinib dimaleate, afimoxifen, aldesleukin, alectinib, alemtuzumab, alpelisib, amifostine, anastrozole, apalutamide, aprepitant, arsenic trioxide, asparaginase, and Erwinia chrysanthes. Chrysanthemi), atezolizumab, avapritinib, avelumab, axicaputadine silolucell, axitinib, azacitidine, AZD9833 (AstraZeneca), AZD9496 (AstraZeneca), bazedoxifene, bellinostat, bendamustine hydrochloride, bevacizumab, bexarotene, bicalutamide, binimetinib, bleomycin sulfate, blinatumomab, bortezomib, bosutinib, brentuximab Buvedotin, briguchinib, cabazitaxel, cabozantinib S-malate, caraspargaze pegol-mknl, capecitabine, caplacizumab-yhdp, capmatinib hydrochloride, carboplatin, carfilzomib, carmustine, semiprimab-rwlc, ceritinib, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cobimetinib, copanlisib hydrochloride, crizotinib, cyclophosphamide, cytarabine, D -0502 (Inventisbio), dabrafenib mesylate, dacarbazine, dacomitinib, dactinomycin, daratumumab, daratumumab and hyaluronidase-fihj, darbepoetin alfa, darolutamide, dasatinib, daunorubicin hydrochloride, decitabine, defibrotide sodium, degarelix, denileukin diffitox, denosumab, dexamethasone, dexrazoxane hydrochloride, dinutuximab, docetaxel , doxorubicin hydrochloride, durvalumab, duvelisib, elacestrant, elotuzumab, eltrombopagolamine, emaparmab-lzsg, enasidenib mesylate, encorafenib, enfortumab vedotin-ejfv, entrectinib, enzalutamide, epirubicin hydrochloride, epoetin alfa, erdafitinib, eribulin mesylate, erlotinib hydrochloride, etoposide, etoposide phosphate, everolimus, exemestane,fam-trastuzumab deruxtecan-nxki, fedratinib hydrochloride, filgrastim, fludarabine phosphate, fluorouracil, flutamide, fosmatinib disodium, fulvestrant, gefitinib, gemcitabine hydrochloride, gemtuzumab ozogamicin, gilteritinib fumarate, gladegib maleate, glucarpidase, goserelin acetate, granisetron, granisetron hydrochloride, hydroxyurea, ibritumomab tiuxetan, ibrutinib, idarubicin hydrochloride, idelalisib, ifosfamide, imatinib mesylate Imiquimod, Inotuzumab Ozogamicin, Interferon Alpha-2b Recombinant, Iobenguan I-131, Ipatasertib, Ipilimumab, Irinotecan Hydrochloride, Isatuximab-IRFC, Ivosidenib, Ixabepyrone, Isazomib Citrate, Lanreotide Acetate, Lapatinib Tosylate, Lalotrectinib Sulfate, Lasofoxifen, Lenalidomide, Lenvatinib Mesylate, Letrozole, Leucovorin Calcium, Leuprolide Acetate, Lomustine, Lorlatinib, LSZ102 (Novartis), Lurubinecte N, LY3484356 (Lilly), megestrol acetate, melphalan, melphalan hydrochloride, mercaptopurine, methotrexate, midostaurine, mitomycin, mitoxantrone hydrochloride, mogamulizumab-kpkc, moxetumomab pasdotox-tdfk, necitumumab, nelarabine, neratinib maleate, nilotinib, nilutamide, niraparib tosylate monohydrate, nivolumab, obinutuzumab, ofatumumab, olaparib, omasetaxin mepesuccinate, ondansetron hydrochloride, osimertinib mesylate, ox Liplatin, paclitaxel, paclitaxel albumin-stabilized nanoparticle preparation, palifermin, palonosetron hydrochloride, pamidronate disodium, panitumumab, panobinostat, pazopanib hydrochloride, pegasparagase, pegfilgrastim, peginterferon alfa-2b, pembrolizumab, pemetrexed disodium, pemigatinib, patuzumab, pexidartinib hydrochloride, plerixafor, polatuzumab vedotin-piiq, pomalidomide, ponatinib hydrochloride, pralatrexate, prednisone, procarbazine hydrochloride,Propranolol hydrochloride, radium-223 dichloride, raloxifene hydrochloride, ramucirumab, rasburicase, ravulizumab-cwvz, recombinant interferon alpha-2b, regorafenib, RG6171 (Roche), lintodestrant, lipretinib, rituximab, lorapitant hydrochloride, romidepsin, romiplostim, rucaparibu cansylate, ruxolitinib sulfate, sacituzumab govitecan-hziy, SAR439859 (Sanofi), selinexol, serpercatinib, selumetinib sulfate, SHR9549 (Jiansu Hengrui Medicine), siltuximab, ciplucel-t, sonidegib, sorafenib tosylate, taglaxofusp-erzs, talazoparib tosylate, tarimozine laharpalepbec, tamoxifen citrate, tazemetostat hydrobromide, temozolomide, temsirolimus, thalidomide, thioguanine, thiotepa, tisagenlecleucel, tocilizumab, topotecan hydrochloride, toremifene, trabectedin, trametinib, trastuzumab, trastuzumab and hyaluronidase-oysk, Trifluridine and tipiracil hydrochloride, tucatinib, uridine triacetate, barrubicin, vandetanib, vemurafenib, venetoclax, vinblastine sulfate, vincristine sulfate, vinorelbine tartrate, bismodegib, vorinostat, zanubrutinib, ziv-aflibercept, ZN-c5 (Zentalis), and zoledronic acid; or the aforementioned free bases, pharmaceutically acceptable salts (including alternative salt forms of the salts listed above), or solvated forms; or combinations thereof, selected from the group.

[0220] The terms “cancer” or “malignant” refer to or describe tumors caused by malignant and / or invasive growth, or abnormal cell growth. As used herein, “cancer” refers to solid tumors named after the type of cells that make them up, and cancers of the blood, bone marrow, or lymphatic system. Examples of solid tumors include, but are not limited to, sarcomas and carcinomas. Examples of cancers of the blood include, but are not limited to, leukemia, lymphoma, and myeloma. The term “cancer” includes, but is not limited to, primary cancers, which originate in a specific site within the body; metastatic cancers, which spread from where they began to other parts of the body; recurrences of the initial primary cancer after remission; and secondary primary cancers, which are new primary cancers in a person with a history of previous cancers of a different type than the later ones.

[0221] The efficacy of the methods and uses described herein in a particular tumor may be enhanced by combination with other approved or experimental cancer therapies, such as radiation, surgery, chemotherapy agents, targeted therapies, agents that inhibit other signaling pathways that are dysregulated in tumors, and other immunostimulants such as PD-1 or PD-L1 antagonists. The methods and uses of the present invention may further comprise one or more additional anticancer agents.

[0222] The administration of the crystalline or amorphous forms of the present invention may be affected by any method that enables delivery of the compound to the site of action. These methods include oral, intraduodenal, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular, or infusion), topical, and rectal administration.

[0223] The dosage regimen may be adjusted to provide the optimal desired response. For example, the crystalline or amorphous forms of the present invention may be administered as a single bolus, as several divided doses administered over time, or the dose may be proportionally reduced or increased as indicated by the emergency of the treatment situation. Formulating the therapeutic agent in dosage unit forms may be particularly advantageous for ease of administration and uniformity of dosage. When used herein, a dosage unit form refers to a physically discontinuous unit suitable as a unit dose for treating a mammalian subject, each unit containing a predetermined amount of the active compound calculated to produce the desired therapeutic effect together with the required pharmaceutical carrier. The specifications for the dosage unit forms of the present invention may be determined by and directly depend on (a) the unique characteristics of the solid form and the specific therapeutic or protective effect to be achieved, and (b) limitations inherent in the art of compounding, such as the active compound for treating susceptibility in an individual.

[0224] Therefore, those skilled in the art will see that, based on the disclosures provided herein, doses and administration regimens are adjusted according to methods well known in the therapeutic art. That is, maximum tolerable doses can be easily established, such as temporary requirements for administering each active substance to provide a detectable therapeutic benefit to a target, and effective doses to provide a detectable therapeutic benefit can also be determined. Thus, while certain doses and administration regimens are illustrated herein, these examples do not in any way limit the doses and administration regimens that may be provided to a target when practicing the present invention.

[0225] It should be noted that dose values ​​may vary depending on the type and severity of the condition being alleviated, and may include single or multi-dose doses. It should be further understood that for any particular subject, a specific dosage regimen should be adjusted over time according to 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 disorder or condition, the rate of administration, the pharmacokinetics of the compound, and the discretion of the prescribing physician. The dosage ranges specified herein are illustrative only and are not intended to limit the scope or practice of the claimed solid form or pharmaceutical composition. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and / or laboratory values. Therefore, the present invention encompasses intra-patient dose escalation as determined by those skilled in the art. Determining appropriate dosages and regimens for the administration of chemotherapeutic agents is well known in the relevant art and will be understood to be encompassed by those skilled in the art once the teachings disclosed herein are provided.

[0226] The dosage of the crystalline or amorphous form of the present invention is typically in single or divided doses, ranging from about 0.001 to about 100 mg per kg of body weight per day, preferably from about 1 to about 35 mg / kg / day. For a 70 kg person, this would be about 0.01 to about 7 g / day, preferably from about 0.02 to about 2.5 g / day. In some cases, a dosage level below the lower limit of the above range may be more than sufficient, while in other cases, a larger dose may be used without causing any adverse side effects, however, such larger doses are first divided into several smaller doses for administration throughout the day. The dosage may be administered as a single dose (QD) or optionally subdivided into smaller doses suitable for BID (twice daily), TID (three times daily), or QID (four times daily) administration. The dosage regimen may be adjusted to provide an optimal therapeutic response. For example, the dose may be proportionally reduced or increased as directed by a treatment situation emergency, including temporary or permanent dose reduction when it is necessary to improve or prevent side effects.

[0227] Repeating or adjusting an administration or drug regimen may be done as necessary to achieve the desired treatment. “Continuous drug regimen,” as used herein, is an administration or drug regimen without interruption of treatment, for example, without treatment holidays. A repeating 21 or 28-day treatment cycle without interruption of treatment between treatment cycles is an example of a continuous drug regimen.

[0228] In some embodiments, the crystalline or amorphous form of PF-07104091 is administered in a daily dose ranging from approximately 1 mg to approximately 1000 mg. In some embodiments, the crystalline or amorphous form of the present invention is administered in a daily dose ranging from approximately 10 mg to approximately 500 mg, and in some embodiments, in a daily dose ranging from approximately 25 mg to approximately 300 mg. In some embodiments, this is approximately 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, 180, 185, It is administered in doses of 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, according to a QD, BID, TID, or QID schedule.

[0229] Repeating or adjusting an administration or drug regimen may be done as necessary to achieve the desired treatment. “Intermittent drug regimen” refers to an administration or drug regimen that includes periods of drug interruption, such as treatment holidays. A repeating 14 or 21-day treatment cycle with a 7-day treatment interruption between treatment cycles is an example of an intermittent drug schedule. Such schedules with 2 or 3 weeks of treatment and 1 week of treatment are sometimes referred to as 2 / 1 week or 3 / 1 week treatment cycles, respectively. Alternatively, intermittent drug administration may include a 7-day treatment cycle with 5 days of treatment and 2 days of treatment.

[0230] When used herein, "continuous medication schedule" refers to a regimen of administration or medication that is free from interruptions, such as treatment holidays. A repetition of 21 or 28-day treatment cycles without interruptions between treatment cycles is an example of a continuous medication schedule.

[0231] In some embodiments, either the crystalline or amorphous form of PF-07104091 described herein is administered on an intermittent dosing schedule. In other embodiments, either the crystalline or amorphous form of PF-07104091 described herein is administered on a continuous dosing schedule.

[0232] "Pharmaceutical composition" means a mixture of one or more therapeutic agents described herein as active ingredients, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and at least one pharmaceutically acceptable carrier or additive. In some embodiments, the pharmaceutical composition comprises two or more pharmaceutically acceptable carriers and / or additives.

[0233] As used herein, “pharmaceutically acceptable carrier” means a carrier or excipient that does not cause significant irritation to an organism and does not inhibit the biological activity and properties of an active compound or therapeutic agent.

[0234] Pharmaceutically acceptable carriers may include any conventional pharmaceutical carrier or excipient. The choice of carrier and / or excipient will depend to a considerable extent on factors such as the specific mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0235] In one embodiment, the present invention relates to a pharmaceutical composition comprising anhydrous crystalline PF-07104091 (Form 2) and a pharmaceutically acceptable carrier or additive.

[0236] In one embodiment, the present invention relates to a pharmaceutical composition comprising crystalline PF-07104091 monohydrate (Form 3) and a pharmaceutically acceptable carrier or additive.

[0237] In one embodiment, the present invention relates to a pharmaceutical composition comprising amorphous PF-07104091 (Form 4) and a pharmaceutically acceptable carrier or additive.

[0238] In one embodiment, the present invention relates to a pharmaceutical composition comprising anhydrous crystalline PF-07104091 (Form 5) and a pharmaceutically acceptable carrier or additive.

[0239] Suitable pharmaceutical carriers include inert excipients or fillers, water, and various organic solvents (hydrates and solvates, etc.). The pharmaceutical composition may optionally contain additional components such as flavoring agents, binders, and additives. Therefore, for oral administration, tablets containing various additives such as citric acid may be used together with various disintegrants such as starch, alginic acid, and certain complex silicates, as well as binders such as sucrose, gelatin, and acacia. Examples of additives, though not limited to these, include calcium carbonate, calcium phosphate, various sugars, and various starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are often useful for tableting purposes. Similar types of solid pharmaceutical compositions can also be used in soft and hard-filled gelatin capsules. Therefore, non-limiting examples of materials include lactose and high molecular weight polyethylene glycol. If an aqueous suspension or elixir is desired for oral administration, the active compound therein may be combined with various sweeteners or flavorings, colorants or dyes, and, if desired, emulsifiers or suspending agents, along with excipients such as water, ethanol, propylene glycol, glycerin, or combinations thereof.

[0240] The pharmaceutical composition of the present invention may be in a form suitable for oral administration, such as tablets, capsules, pills, powders, sustained-release formulations, liquids, or suspensions; for parenteral injection, such as sterile liquids, suspensions, or emulsions; for topical administration, such as ointments or creams; or for rectal administration, such as suppositories. The pharmaceutical composition may be in a unit dosage form suitable for single-dose administration of a precise dosage. The pharmaceutical composition will contain a conventional pharmaceutical carrier or additive and a compound according to the present invention as an active ingredient. In addition, the composition may contain other medicinal or pharmaceutical products, carriers, adjuvants, etc.

[0241] Exemplary parenteral administration forms include solutions or suspensions of the active compound in a sterile aqueous solution, such as an aqueous solution of propylene glycol or a dextrose solution. Such dosage forms may be preferably buffered, if desired.

[0242] Methods for preparing various pharmaceutical compositions by adding specific amounts of active compounds are known to or will become apparent to those skilled in the art. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easter, Pa., 19th edition (1995).

[0243] Either the crystalline or amorphous form of the invention described herein may be administered orally. Oral administration may involve swallowing so that the therapeutic agent enters the gastrointestinal tract, or it may be administered orally or sublingually so that the therapeutic agent enters the bloodstream directly from the mouth.

[0244] Formulations suitable for oral administration include solid formulations such as tablets, particles, capsules containing liquid or powder, candies (including liquid fillers), chewable tablets, multi- and nanoparticle formulations, gels, solid liquid formulations, liposomes, films (including mucosal adhesives), ovals, sprays, and liquid formulations.

[0245] Liquid formulations include suspensions, liquids, syrups, and elixirs. Such formulations may be used as fillers in soft or hard capsules and typically contain 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 may also be prepared, for example, by restoring a solid from a sachet.

[0246] Either the crystalline or amorphous form of the invention described herein may be used in rapidly dissolving, rapidly disintegrating dosage forms, such as those described in Expert Opinion in Therapeutic Patents, 11(6), 981-986, Liang and Chen (2001), the disclosure of which is incorporated herein by reference in its entirety.

[0247] In tablet dosage forms, the crystalline or amorphous form of PF-07104091 may constitute 1% to 80 wt% of the dosage form, more typically 5 to 60 wt%. In addition to the activator, tablets generally contain disintegrants. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch, and sodium alginate. Generally, disintegrants may constitute 1 to 25 wt% of the dosage form, preferably 5 to 20 wt%.

[0248] Binders are generally used to impart tackiness to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. Tablets may also contain excipients such as lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and calcium hydrogen phosphate dihydrate.

[0249] The tablets may optionally contain surfactants such as sodium lauryl sulfate and polysorbate 80, as well as flow enhancers such as silicon dioxide and talc. If present, the amount of surfactants is typically 0.2 wt% to 5 wt% of the tablet, and the amount of flow enhancers is typically 0.2 wt% to 1 wt% of the tablet.

[0250] The tablets generally also contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate. The lubricant is generally present in amounts from 0.25 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt%, of the tablet.

[0251] Other conventional ingredients include antioxidants, colorants, flavorings, preservatives, and taste enhancers.

[0252] An exemplary tablet may contain approximately 1 wt% to 80 wt% of an activator, approximately 10 wt% to 90 wt% of a binder, approximately 0 wt% to 85 wt% of an excipient, approximately 2 wt% to 10 wt% of a disintegrant, and approximately 0.25 wt% to 10 wt% of a lubricant.

[0253] The tablet mixture may be compressed directly or by rollers to form tablets. Alternatively, the tablet mixture or a portion of the mixture may be wet, dry, or melt-granulated, melt-solidified, or extruded before tableting. The final formulation may contain one or more layers, be coated or uncoated, or be encapsulated.

[0254] The formulation of tablets is discussed in detail in "Pharmaceutical Dosage Forms: Tablets, Vol. 1," by H. Lieberman and L. Lachman, Marcel Dekker, NY, NY, 1980 (ISBN 0-8247-6918-X), the disclosure of which is incorporated herein by reference in its entirety.

[0255] Capsules (e.g., made of gelatin or HPMC), blisters, and cartridges for use in inhalers or injectors may be formulated to contain a mixed powder of a therapeutic agent, a suitable powder base such as lactose or starch, and a performance modifier such as l-leucine, mannitol, or magnesium stearate. The lactose may be in anhydrous or monohydrate form, preferably the latter. Other suitable additives include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

[0256] Solid formulations for oral administration can be formulated to be immediate and / or regulated release. Regulated release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release.

[0257] A suitable controlled-release formulation is described in U.S. Patent No. 6,106,864. Details of other suitable release technologies, such as high-energy dispersion, permeability, and coated 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. The use of chewing gum to achieve controlled release is described in WO00 / 35298. The disclosures of these references are incorporated herein by reference in their entirety.

[0258] Either the crystalline or amorphous form of PF-07104091 described herein may be administered directly into the bloodstream, muscle, or internal organs. Preferred means for parenteral administration include intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, and subcutaneous. Preferred devices for parenteral administration include needle (including microneedle) syringes, needleless syringes, and injection techniques.

[0259] Parenteral formulations are typically aqueous solutions that may contain additives such as salts, carbohydrates, and buffers (preferably with a pH of 3 to 9), but for some applications, they may be more preferably formulated as a dry form used as a sterile non-aqueous solution or in combination with a suitable vehicle such as sterile pyrogen-free water.

[0260] The preparation of parenteral formulations under sterile conditions, for example by lyophilization, can be easily carried out using standard pharmaceutical techniques well known to those skilled in the art.

[0261] The solubility of therapeutic agents used in the preparation of parenteral solutions can potentially be increased by using appropriate formulation techniques, such as incorporating solubility enhancers.

[0262] The crystalline and amorphous forms of PF-07104091 described herein may be in the form of kits suitable for administering the pharmaceutical composition. Such kits may contain an activator in the form of a pharmaceutical composition, which comprises the activator, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. The kits may include means for separately holding the pharmaceutical composition, such as containers, divided bottles, or divided foil packets. An example of such a kit is a household blister pack used for packaging tablets, capsules, etc. To aid in medication adherence, the kits may typically include an instruction sheet and may be equipped with memory aids. The kits may further include other materials that may be useful when administering the medicine, such as excipients, filters, IV bags and lines, needles and syringes.

[0263] In some preferred embodiments, the present invention provides one or more embodiments E1 to E41.

[0264] Crystalline form (Form 3) of (1R,3S)-3-[3-({[3-(methoxymethyl)-1-methyl-1H-pyrazole-5-yl]carbonyl}amino)-1H-pyrazole-5-yl]cyclopentylpropane-2-ylcarbamate (PF-07104091) monohydrate, having a powder X-ray diffraction (PXRD) pattern including peaks at 2θ values ​​measured using CuKα radiation at E1.8.4, 10.1, and 21.5°2θ±0.2°2θ.

[0265] Crystalline form of Embodiment E1, having a PXRD pattern further including a peak at a 2θ value measured using CuKα radiation, at E2.16.9°2θ±0.2°2θ.

[0266] Crystalline form of embodiment E1 or E2, having a PXRD pattern further including a peak at a 2θ value measured using CuKα radiation at E3.27.0°2θ±0.2°2θ.

[0267] E4. 1657cm -1 ±2cm -1 wavenumber (cm -1 A crystalline form of any one of embodiments E1 to E3 having a Raman spectrum containing the value ).

[0268] E5. 1595cm -1 ±2cm -1 wavenumber (cm -1 A crystalline form of Embodiment E4 having a Raman spectrum further containing the value.

[0269] E6. 1408cm -1 ±2cm -1 wavenumber (cm -1 A crystalline form of embodiment E4 or E5 having a Raman spectrum further containing the value.

[0270] E7. Includes one, two, or three resonance (ppm) values ​​selected from the group consisting of 25.2, 37.5, and 159.3 ppm ± 0.2 ppm. 13A crystalline form having a 1C solid-state NMR spectrum, one of any one of embodiments E1 to E6.

[0271] E8. Further includes resonance (ppm) values ​​of 151.9 and 152.5 ppm ± 0.2 ppm. 13 Crystalline form of Embodiment E7 having a 1C solid-state NMR spectrum.

[0272] E9. 1657, 1595 and 1408 cm -1 ±2cm -1 wavenumber (cm -1 Crystalline form (form 3) of PF-07104091 monohydrate, having a Raman spectrum containing the ) value.

[0273] E10. Includes resonance (ppm) values ​​of 25.2 and 37.5 ppm ± 0.2 ppm, and may further include resonance (ppm) value of 159.3 ppm ± 0.2 ppm. 13 Crystalline form (Form 3) of PF-07104091 monohydrate, exhibiting a 1C solid-state NMR spectrum.

[0274] Crystalline form of embodiment E10, having a PXRD pattern including peaks at 2θ values ​​measured using CuKα radiation, at E11.8.4 and 10.1°2θ±0.2°2θ.

[0275] E12. 1657cm -1 ±2cm -1 wavenumber (cm -1 A crystalline form of embodiment E10 or E11 having a Raman spectrum containing the value ).

[0276] E13. (a) PXRD patterns including peaks at 2θ values ​​measured using CuKα radiation at 8.4, 10.1, and 21.5°2θ±0.2°2θ, (b) 1657, 1595 and 1408 cm -1 ±2cm -1 wavenumber (cm -1 ) Raman spectrum including the value, or (c) Includes resonance (ppm) values ​​of 25.2, 37.5 and 159.3 ppm ± 0.2 ppm 13 C solid-state NMR spectrum, or any combination of two or more of (a), (b), and (c) A crystalline form (form 3) of PF-07104091 monohydrate having the following characteristics.

[0277] E14. (a) A PXRD pattern that includes peaks at 2θ values ​​measured using CuKα radiation at 8.4° and 10.1°2θ±0.2°2θ, and may further include a peak at 2θ value measured using CuKα radiation at 21.5°2θ±0.2°2θ. (b) 1657cm -1 ±2cm -1 wavenumber (cm -1 ) Includes values ​​of 1595 and 1408 cm -1 ±2cm -1 wavenumber (cm -1 A Raman spectrum that may also contain values, or (c) Includes resonance (ppm) values ​​of 25.2 and 37.5 ppm ± 0.2 ppm, and may further include resonance (ppm) value of 159.3 ppm ± 0.2 ppm. 13 C solid-state NMR spectrum, or any combination of two or more of (a), (b), and (c) A crystalline form (form 3) of PF-07104091 monohydrate having the following characteristics.

[0278] E15. A crystalline form of any one of embodiments E1 to E14, which is substantially pure PF-07104091 monohydrate (form 3).

[0279] Anhydrous crystalline form (form 2) of PF-07104091, having a PXRD pattern with peaks at 2θ values ​​measured using CuKα radiation at E16.9.8, 13.3, and 17.4°2θ±0.2°2θ.

[0280] Crystalline form of embodiment E16, having a PXRD pattern further including a peak at a 2θ value measured using CuKα radiation, E17.4.2°2θ±0.2°2θ.

[0281] Crystalline form of embodiment E16 or E17, having a PXRD pattern further including a peak at a 2θ value measured using CuKα radiation, at E18.7.5°2θ±0.2°2θ.

[0282] E19. 1691cm -1 ±2cm -1 wavenumber (cm -1 A crystalline form of any one of embodiments E16 to E18 having a Raman spectrum containing the value ).

[0283] E20. 1582cm -1 ±2cm -1 wavenumber (cm -1 A crystalline form of embodiment E19 having a Raman spectrum further containing the value.

[0284] E21. 996cm -1 ±2cm -1 wavenumber (cm -1 A crystalline form of embodiment E19 or E20 having a Raman spectrum further containing the value.

[0285] E22. Includes one, two, or three resonance (ppm) values ​​selected from the group consisting of 24.1, 39.8, and 41.6 ppm ± 0.2 ppm. 13 A crystalline form having a 1C solid-state NMR spectrum, one of any one of embodiments E16 to E21.

[0286] E23. Further includes resonance (ppm) values ​​of 21.8 and 138.2 ppm ± 0.2 ppm. 13 Crystalline form of embodiment E22 having a 1C solid-state NMR spectrum.

[0287] E24. 1691, 1582 and 996 cm -1 ±2cm -1wavenumber (cm -1 Anhydrous crystalline form (form 2) of PF-07104091 having a Raman spectrum containing the ) value.

[0288] E25. Includes resonance (ppm) values ​​of 24.1, 39.8, and 41.6 ppm ± 0.2 ppm. 13 Anhydrous crystalline form (Form 2) of PF-07104091, possessing a 1C solid-state NMR spectrum.

[0289] Crystalline form of embodiment E25, having a PXRD pattern including peaks at 2θ values ​​measured using CuKα radiation, at E26.9.8 and 13.3°2θ±0.2°2θ.

[0290] E27. 1691cm -1 ±2cm -1 wavenumber (cm -1 A crystalline form of embodiment E25 or E26 having a Raman spectrum containing the value.

[0291] E28. (a) PXRD patterns including peaks at 2θ values ​​measured using CuKα radiation at 9.8, 13.3, and 17.4°2θ ± 0.2°2θ. (b) 1691, 1582 and 996 cm -1 ±2cm -1 wavenumber (cm -1 ) Raman spectrum including the value, or (c) Includes resonance (ppm) values ​​of 24.1, 39.8 and 41.6 ppm ± 0.2 ppm. 13 C solid-state NMR spectrum, or any combination of two or more of (a), (b), and (c) An anhydrous crystalline form (form 2) of PF-07104091 having the following characteristics.

[0292] E29. (a) A PXRD pattern that includes peaks at 2θ values ​​measured using CuKα radiation at 9.8° and 13.3°2θ±0.2°2θ, and may further include a peak at 2θ value measured using CuKα radiation at 17.4°2θ±0.2°2θ. (b) 1691cm -1 ±2cm -1 wavenumber (cm -1 ) Includes values ​​of 1582 and 996 cm -1 ±2cm -1 wavenumber (cm -1 A Raman spectrum that may also contain values, or (c) Includes resonance (ppm) values ​​of 24.1, 39.8 and 41.6 ppm ± 0.2 ppm. 13 C solid-state NMR spectrum, or any combination of two or more of (a), (b), and (c) An anhydrous crystalline form (form 2) of PF-07104091 having the following characteristics.

[0293] E30. A crystalline form of any one of embodiments E16 to E29, which is substantially pure PF-07104091 (form 2).

[0294] E31. Anhydrous crystalline form (form 5) of PF-07104091 having a PXRD pattern containing three or more peaks at 2θ values ​​measured using CuKα radiation, selected from the group consisting of 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.

[0295] E32. A pharmaceutical composition comprising one crystalline form from any one of Embodiments E1 to E31 and a pharmaceutically acceptable carrier or additive.

[0296] E33. A method for treating cancer in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of one crystalline form of any one embodiment E1 to E31.

[0297] E34. The method of Embodiment 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 tumor, sarcoma, and lymphoma.

[0298] E35. Amorphous form of PF-07104091 (Form 4).

[0299] E36. Amorphous morphology of Embodiment E35 having a PXRD pattern including a broad peak at diffraction angles (2θ) measured using CuKα radiation, from approximately 5 to approximately 35°2θ ± 0.2°2θ.

[0300] E37. Amorphous morphology of embodiment E35 or E36, having essentially the same PXRD pattern as Figure 4.

[0301] E38. Glass transition temperature of 59.8±5℃ (T g An amorphous form having any one of embodiments E35 to E37.

[0302] E39. A pharmaceutical composition comprising one amorphous form of any one of embodiments E35 to E38 and a pharmaceutically acceptable carrier or additive.

[0303] E40. A method for treating cancer in a subject requiring it, comprising the step of administering to the subject a therapeutically effective amount of one amorphous form of any one embodiment E35 to E38.

[0304] E41. The method of Embodiment 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 tumor, sarcoma, and lymphoma. [Examples]

[0305] The examples and preparations provided below further illustrate and demonstrate aspects and embodiments of the present invention. It should be understood that the scope of the present invention is not limited to the scope of the following examples.

[0306] (Example 1) Instrumental method General method A. Powder X-ray diffraction (PXRD) Instrument Law: Powder X-ray diffraction analysis was performed using a Bruker AXS D8 Endeavor diffractometer equipped with a Cu radiation source. The diffracted radiation was detected by a Lynx-Eye XE T detector with an electric slit. The X-ray tube voltage and amperage were set to 40 kV and 40 mA, respectively. Data were acquired using a locked-couple scanning theta-theta goniometer at a scanning speed of 1.0 second per step, with Cu K-alpha wavelengths (CuKαλ = 1.5418 Å) from 3.0 to 40.0 degrees 2-theta in 0.01 degree increments. The scatter removal screen 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 revolutions per minute during acquisition. Data were acquired using Bruker DIFFRAC Plus software.

[0307] Peak picking method: Data analysis was performed using Bruker DIFFRAC+ software (version 5.0.0). The PXRD data files were not processed before peak retrieval. The peak retrieval algorithm in the EVA software was applied, and preliminary peak assignment was performed using a threshold of 1. To ensure validity, manual adjustments were made, the output of the automatic assignment was visually verified, and peak positions were adjusted to the maximum peak value. Peaks with a relative intensity of 3% or more were generally selected. Peaks that were not split and did not match the noise were not selected. The typical error associated with peak position from PXRD as described in the USP is a maximum of + / -0.2°²-theta (USP-941).

[0308] General Method B. Raman Spectroscopy Instrument Law: Raman spectra were acquired using a Thermo Scientific iS50 FT-Raman accessory mounted on an FT-IR bench. A CaF2 beam splitter was utilized in the FT-Raman configuration. The spectrometer features a 1064 nm diode laser and a room-temperature InGaAs detector. Instrument performance and calibration validation were performed using polystyrene prior to data acquisition. Samples were analyzed as tablets in a glass NMR tube or in a suitable sample holder where they were statically held during data acquisition. Spectra were acquired using laser power between 0.1 and 0.5 W and 512 co-added scans. The acquisition range was 3700–100 cm². -1 The API spectrum was 2 cm. -1 Recording was performed using high resolution, and Hap-Gensel apodization was applied to the entire spectrum. Multiple spectra were recorded, and the reported spectra are representative of the two spots.

[0309] Peak picking method: The intensity scale was normalized to 1 before peak picking. Peaks were manually identified using Thermo Nicolette Omnic 9.7.46 software. Peak locations were picked by the peak maximum value, and peaks were identified as is only if they had slopes on both sides; peak shoulders were not included. For undiluted form 3 APIs, an absolute threshold of 0.012 with a sensitivity of 75 was used during peak picking. For undiluted form 2 APIs, an absolute threshold of 0.04 with a sensitivity of 75 was used during peak picking. Peaks with normalized peak intensities between (1~0.75), (0.74~0.30), and (0.29~0) were labeled as strong, medium, and weak, respectively. Relative peak intensity values ​​are also illustrated in this report.

[0310] General method C. 13 ¹¹¹ solid-state NMR (ssNMR) spectroscopy: Instrument Law: Solid-state NMR (ssNMR) analysis is performed using the Bruker-Biospin Avance III 500MHz. 1 The analysis was performed using a CPMAS probe positioned inside a (H-frequency) NMR spectrometer. The material was packed into a 4 mm rotor. A magic angle spinning speed of 15.0 kHz was used.

[0311] 13 C ssNMR spectra were collected using proton-decoupled cross-polarization magic angle spinning (CPMAS) experiments. A phase-modulated proton decoupling field of 80–90 kHz was applied during spectrum acquisition. The cross-polarization contact time was set to 2 ms. Recycle delays of 4.5 sec, 3.9 sec, 4.5 sec, and 2.4 sec were used for experiments for morphology 1, morphology 2, morphology 3, and morphology 5, respectively. The number of scans was adjusted to obtain a reasonable signal-to-noise ratio, and 768 or 1024 scans were collected for each API. 13 The C chemical shift scale is based on an external standard for crystalline adamantane. 13 The CPMAS experiment was used, and its high-field resonance was set to 29.5 ppm (determined from undiluted TMS) for reference.

[0312] Peak picking method: Automated peak picking was performed using Bruker-BioSpinTopSpin version 3.6 software. Generally, a 5% relative intensity threshold was used for preliminary peak selection. The output of the automated peak picking was visually verified to ensure validity, and manual adjustments were made if necessary. While specific solid-state NMR peak values ​​are reported herein, a range exists for these peak values ​​due to differences in instruments, samples, and sample preparation. This is a common practice in the art of solid-state NMR, due to inherent variations in peak position. 13 Typical variability in the x-axis value of the ¹¹C chemical shift is approximately plus or minus 0.2 ppm for crystalline solids. The solid-state NMR peak heights reported herein are relative intensities. Solid-state NMR intensities may vary depending on the actual settings of the CPMAS experimental parameters and the thermal history of the sample.

[0313] (Example 2) Preparation of anhydrous crystalline PF-07104091 (Form 2)

[0314] [ka] Anhydrous crystalline PF-07104091 (Form 2) was prepared by dissolving PF-07104091 monohydrate (Form 1) (prepared as described in U.S. Patent No. 11,014,911) in 50:50% v / v methyl isobutyl ketone:heptane at approximately 80°C. The solution was then removed from the heat and cooled to room temperature. The resulting solid was collected by filtration, rinsed with heptane, and dried under vacuum to obtain crystalline PF-07104091 (Form 2), which was confirmed to be the anhydrous free form by elemental analysis.

[0315] 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, small amounts of residual solvent were detectable by ssNMR, which is likely due to solvent trapped within crystal lattice defects during crystallization of the anhydrous form.

[0316] Differential scanning calorimetry (DSC) showed endothermic melting at an initial temperature of approximately 113°C (confirmed by a melting point analyzer).

[0317] PF-07104091 (Form 2) was found to be slightly hygroscopic by moisture sorption (DVS) studies: approximately 0.7% mass increase at 60% RH; approximately 1% mass increase at 75% RH; and approximately 1.6% mass increase at 90% RH. The PXRD of the material after moisture sorption showed no change in the solid form.

[0318] Thermogravimetric analysis (TGA) of the Form 2 reference sample crystallized from acetone:cyclohexane (1:2.1) showed a total weight loss of approximately 1%, which was confirmed by solution NMR to be the residual solvent (cyclohexane).

[0319] [Table 1]

[0320] [Table 2-1]

[0321] [Table 2-2]

[0322] [Table 3] † indicates a peak caused by trapped solvent molecules.

[0323] (Example 3) Preparation of crystalline PF-07104091 monohydrate (Form 3)

[0324] [ka] N-(5-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazole-3-yl)-3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamide (compound A) (187 g, 0.586 mol) (prepared by acidic deprotection of intermediate 13B as described in Example 13 of U.S. Patent No. 11,014,911) was dissolved in tetrahydrofuran (THF) (1.78 L) with vigorous stirring using a magnetic stirrer. 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 minutes, and then heated to 50°C at a rate of 1°C / min and held for 30 minutes. The mixture was cooled to 30°C, and then 2-propylamine (iPrNH2) (70 g, 1.184 mol) was added. The reaction mixture was heated to 50°C at 1°C / min, and then held at 50°C until the reaction was complete. If necessary, additional iPrNH2 (18 g, 0.304 mol) was added to complete the reaction. 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 held at 50°C for 5 hours. The reaction mixture was cooled to 25°C, and the reaction mixture was distilled under vacuum until the solution volume was 6 mL / g based on compound A, the internal temperature was between 45 and 50°C, and the THF was less than 0.1% according to GCHS. The mixture was cooled to 25°C, and then H2O was added until the reaction volume was 16 mL / g based on compound A. Acetonitrile (0.75 L) was added via a dropping funnel and held for 10 minutes, then 37% hydrochloric acid (29 g) in water was added over 30 minutes to adjust the pH to between 7 and 8. Additional HCl or KOH was added to adjust the pH of the mixture to between 7 and 8. The mixture was heated to 40°C and held for 3 hours. The mixture was cooled to 15°C at a rate of 0.1°C / min and stirred at 15°C for 1 hour. The mixture was filtered and the solid was rinsed with 9:1 H2O / acetonitrile (0.500 L). The solid was dried in a humidified vacuum oven at 50°C until the Karl Fischer (KF) titration was between 4.2% and 4.5% to obtain PF-07104091 monohydrate (Form 3).

[0325] [Table 4]

[0326] [Table 5]

[0327] [Table 6]

[0328] (Example 4) Preparation of anhydrous crystalline PF-07104091 (Form 5)

[0329] [ka] Anhydrous crystalline PF-07104091 (Form 5) was prepared by placing PF-07104091 monohydrate (Form 3) in an open dish in an oven at approximately 50°C and purging it with dry nitrogen gas for approximately 3 hours.

[0330] As an alternative, anhydrous crystalline PF-07104091 (Form 5) was prepared by storing PF-07104091 monohydrate (Form 3) on a desiccant (approximately 0% RH) at ambient temperature for 17 days.

[0331] The elemental analysis of PF-07104091 (Form 5) was consistent with the anhydrous form, as shown in Table 7.

[0332] [Table 7]

[0333] As shown in Figure 15, a weight loss of less than 1% was observed at 200°C by thermogravimetric analysis of PF-07104091 (Form 5), confirming that this form is anhydrous.

[0334] [Table 8]

[0335] [Table 9]

[0336] [Table 10]

[0337] (Example 5) Preparation of amorphous PF-07104091 (Form 4)

[0338] [ka] Amorphous PF-07104091 (Form 4) was prepared by in situ melting quenching of PF-07104091 monohydrate (Form 1) (prepared as described in U.S. Patent No. 11,014,911) in a differential scanning calorimeter (DSC). Large-scale preparation of amorphous Form 4 was attempted using both melting quenching and freeze-drying.

[0339] The general DSC procedure used to obtain amorphous PF-07104091 (Form 4) is provided below. 1. Weigh 3-5 mg of API into an aluminum pan and seal it with the aluminum lid without sealing it tightly. 2. Load the pan into the DSC under a nitrogen gas purge of 50 L / min. 3. Change the temperature at a rate of 20°C / min until it reaches -30°C. 4. Maintain at isothermal temperature for 1 minute. 5. Change the temperature at a rate of 10°C / min until it reaches 160°C. 6. Maintain at isothermal temperature for 1 minute. 7. Change the temperature at a rate of 20°C / min until it reaches -30°C. 8. Maintain at isothermal temperature for 1 minute. 9. Change the temperature at a rate of 10°C / min until it reaches 160°C.

[0340] A typical DSC thermogram is provided in Figure 14 from the second heating cycle (i.e., step 9 above), showing a glass transition temperature (T) of approximately 59.8 ± 5°C. g This indicates (measured by DSC at a rate of change of 10°C / min).

[0341] As shown in Figure 4, amorphous PF-07104091 (morphology 4) lacks any of the sharp peak characteristics of the crystalline morphology and has a PXRD pattern (2θ) that includes broad peaks at diffraction angles (2θ) from approximately 5 to approximately 35°2θ ± 0.2°2θ.

[0342] Comparative Example 6 Crystalline PF-07104091 monohydrate (Form 1)

[0343] [ka]

[0344] PF-07104091 monohydrate (Form 1) was prepared as described in Example 13 of U.S. Patent No. 11,014,911. PXRD, Raman and PXRD for Form 1 were performed. 13 C ssNMR characterization data are provided in Tables 11, 12, and 13, respectively.

[0345] [Table 11]

[0346] [Table 12]

[0347] [Table 13]

[0348] (Example 7) stability studies Slurry experiments were performed as follows: The indicated starting form of PF-07104091 was transferred to a 2 mL vial. The indicated solvent or solvent mixture was added, and a slurry was obtained at the specified temperature (Table 14). Additional solids were added as needed to ensure a sufficiently concentrated slurry. A magnetic stirring bar was added, and the vial was tightly capped to prevent solvent loss. The obtained slurry was stirred at the specified temperature. Aliquots were taken from the slurry periodically or after a certain period of time. The solid was separated from the liquid by centrifugal filtration, and the solid was 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.

[0349] [Table 14]

[0350] The single-crystal X-ray structure of PF-07104091 monohydrate (form 3) was determined and is shown in Figure 16. Computer analysis indicated that PF-07104091 monohydrate (form 3) has superior intermolecular shape, hydrogen bond network topology, and lack of voids compared to PF-07104091 monohydrate (form 1), and is therefore expected to be more stable. The single-crystal X-ray structure of PF-07104091 monohydrate (form 1) is provided in Figure 1 of U.S. Patent No. 11,014,911.

Claims

[Claim 1] Crystals of (1R,3S)-3-[3-({[3-(methoxymethyl)-1-methyl-1H-pyrazole-5-yl]carbonyl}amino)-1H-pyrazole-5-yl]cyclopentylpropane-2-ylcarbamate (PF-07104091) monohydrate (Form 3), having a powder X-ray diffraction (PXRD) pattern including peaks at 2θ values ​​measured using CuKα radiation at 8.4, 10.1, and 21.5°2θ ± 0.2°2θ.

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