Solid-state forms of (S)-N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and its salts

Abstract

The present disclosure relates to solid state forms of (S)-N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and salts thereof. Such solid state forms are useful in preparing pharmaceutical compositions and dosage forms for the treatment of diseases.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 178,752, filed April 23, 2021, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] RAF kinase functions by phosphorylating and activating MEK in the Ras-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) pathway (also known as the MAPK / ERK pathway). By altering the levels and activity of transcription factors, MAPK alters the transcription of genes important for the cell cycle. Deregulation of MAPK activity frequently occurs in tumors. Therefore, therapeutics targeting RAF kinase activity are desirable for use in treating cancer and other disorders characterized by aberrant MAPK / ERK pathway signaling. One such RAF kinase modulator is (S)-N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and its pharmaceutically acceptable salts. Summary of the Invention

[0003] The present disclosure relates to an amorphous solid state form of (S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, hereinafter known as Compound 1. The molecular structure of Compound 1 is shown below.

[0004] [ka]

[0005] Further disclosed herein is a crystalline form of (S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide hydrochloride, hereinafter known as Compound 2. The molecular structure of Compound 2 is shown below.

[0006] [ka]

[0007] Further disclosed herein is a crystalline form of (S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide hydrobromide, hereinafter known as Compound 3. The molecular structure of Compound 3 is shown below.

[0008] [ka]

[0009] Further disclosed herein are crystalline Forms I and II of (S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide 4-methylbenzenesulfonate, hereinafter known as Compound 4. The molecular structure of Compound 4 is shown below.

[0010] [ka]

[0011] Further disclosed herein is a crystalline form of (S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide phosphate, hereinafter known as Compound 5. The molecular structure of compound 5 is shown below.

[0012] [ka]

[0013] Further disclosed herein are crystalline Forms I and II of (S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide sulfate, hereinafter known as Compound 6. The molecular structure of Compound 6 is shown below.

[0014] [ka]

[0015] Provided herein are pharmaceutical compositions comprising a solid-state form of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, or any combination thereof, and a pharmaceutically acceptable excipient.

[0016] Further described herein is a method of inhibiting the receptor tyrosine kinase effector RAF, the method comprising administering a solid form of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, or any combination thereof, to a subject having a disease in need thereof. [Brief explanation of the drawings]

[0017] The features of the present invention are set forth with particularity in the appended claims and will be better understood by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which: [Figure 1] 1 shows the X-ray diffraction pattern of amorphous Compound 1. [Figure 2] 1 shows differential scanning calorimetry and thermogravimetric analysis of amorphous Compound 1. [Figure 3] 1 shows the X-ray diffraction pattern of crystalline Compound 2. [Figure 4] 1 shows differential scanning calorimetry and thermogravimetric analysis of crystalline Compound 2. [Figure 5] 1 shows the X-ray diffraction pattern of crystalline Compound 3. [Figure 6] 1 shows differential scanning calorimetry and thermogravimetric analysis of crystalline Compound 3. [Figure 7] 1 shows the X-ray diffraction pattern of Form I of crystalline Compound 4, crystallized from MTBE. [Figure 8] 1 shows the X-ray diffraction pattern of Form II of crystalline Compound 4, crystallized from acetone. [Figure 9] 1 shows the X-ray diffraction pattern of crystalline Compound 5. [Figure 10] 1 shows differential scanning calorimetry and thermogravimetric analysis of crystalline Compound 5. [Figure 11] 1 shows the dynamic vapor sorption of compound 1. [Figure 12] 1 shows the dynamic vapor sorption of compound 2. [Figure 13] 1 shows the dynamic vapor sorption of compound 3. [Figure 14] 1 illustrates an exemplary tablet manufacturing process. Detailed Description of the Invention

[0018] Provided herein are compositions comprising solid-state forms of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, or any combination thereof.

[0019] In some embodiments, Compound 2 has been found to have many unexpected advantages. Compound 2 is highly stable, being identified as the thermodynamic product of all competitive slurry experiments conducted with amorphous Compound 2. Although Compound 2 is anhydrous as determined by TGA, Compound 2 is minimally hygroscopic and has a high melting point, indicating the compound's high stability. An additional advantage of Compound 2 is its increased solubility in aqueous media compared to Compound 1. Compound 3 has been found to have similar endothermic data compared to Compound 2.

[0020] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications mentioned herein are incorporated by reference.

[0021] As used in this specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0022] The terms "hydrate" and "solvate" are meant to describe forms of crystalline Compound 1 that contain a certain amount of water or solvent, as supported by data from differential scanning calorimetry (DSC) experiments, thermogravimetric analysis (TGA) experiments, X-ray diffraction experiments, and / or procedures for producing solid crystalline forms. In some embodiments, the solvate or hydrate crystalline form contains at least 1.5%, 1.75%, 2.0%, 2.5%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0%, 15.0%, or 20.0% of the total weight of the sample as water, solvent, or a combination thereof, as measured by TGA. In some embodiments, the solvate or hydrate crystalline form exhibits at least one DSC endotherm onset 30° C. before or within 30° C. of the boiling point of the water or solvent used to produce the crystalline form. For example, a hydrate crystalline form may have a DSC endotherm onset at 108°C and an endotherm peak at 124°C.

[0023] The crystalline solid forms referred to as "solvates" or "hydrates" are not meant to be limiting. For example, a solvate or hydrate may comprise a combination of water and a solvent in the crystalline solid form.

[0024] The terms "type," "form," and "pattern" are intended to be used interchangeably and are meant to refer to a particular crystalline material having the properties described herein. For example, "Crystalline Hydrate Type A," "Crystalline Hydrate Form A," and "XRPD Pattern A" refer to the same crystalline substance.

[0025] When referring to a number or numerical range, the term "about" means that the referenced number or numerical range is approximate within experimental variability (or within statistical experimental error); thus, the number or numerical range will, in some cases, vary by between 1% and 15% of the stated number or numerical range.

[0026] As used herein, the term "substantially similar" means an analytical spectrum, such as an XRPD pattern, DSC thermogram, or TGA thermogram, that largely resembles a reference spectrum in both peak positions and peak intensities.

[0027] Characterization of compounds and solid-state morphology In one embodiment, the present invention provides solid-state forms of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, and Compound 6. In one embodiment, the crystalline forms are characterized by interlattice plane intervals as determined by X-ray powder diffraction (XRPD) diffractograms. Diffractograms are typically represented by plots of peak intensity versus peak position, i.e., diffraction angle 2θ (2-theta), in degrees. Characteristic peaks for a given compound can be selected according to peak position and their relative intensity to distinguish the compound and crystalline structure from others. Amorphous solid-state forms have also been characterized by XRPD. The amorphous solid-state forms exhibit an absence of interlattice plane spacing.

[0028] Both crystalline and amorphous solid-state forms have been identified for Compound 2, Compound 4, Compound 5, and Compound 6. The amorphous solid-state forms described herein are specifically designated as such. For example, the phrase "solid-state form of Compound 2" refers to the crystalline form of Compound 2, unless otherwise specified as an amorphous solid-state form.

[0029] Those skilled in the art will recognize that for a given crystalline form of the same compound, measured XRD peak positions and / or intensities may vary within a margin of error. The values ​​of degrees 2θ allow for an appropriate margin of error. Generally, the margin of error is represented by "±." For example, "8.716±0.3" in degrees 2θ represents a range from 8.716+0.3, i.e., 9.016, to 8.716-0.3, i.e., 8.416. Depending on sample preparation techniques, calibration techniques applied to the instrument, and variations due to human manipulation, those skilled in the art will recognize that the margin of error for XRD may be ±0.5, ±0.4, ±0.3, ±0.2, ±0.1, ±0.05, or less. Further details of the methods and apparatus used for XRD analysis are provided in the Examples section.

[0030] In one embodiment, the crystalline form is characterized by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). DSC thermograms are typically displayed by diagrams plotting normalized heat flow in watts / gram ("W / g") versus sample temperature measured in °C. DSC thermograms are typically evaluated for estimated onset and end (onset) temperatures, peak temperature, and heat of fusion. A single maximum in a DSC thermogram is often used as a characteristic peak to distinguish one crystalline form from another. TGA thermograms are typically displayed by diagrams plotting percent weight loss (%) versus sample temperature measured in °C. In the figures disclosed herein, DSC and TGA thermograms are plotted sharing an X-axis (temperature), but with separate Y-axes for weight % and heat flow, corresponding to TGA and DSC measurements, respectively.

[0031] Those skilled in the art will recognize that for a given crystalline form of the same compound, DSC and TGA thermogram measurements will vary within a margin of error. The value of a single maximum expressed in °C allows for an appropriate margin of error. Generally, the margin of error is expressed as "±". For example, a single maximum of "53.1°C ± 10.0" means a range from 53.1°C + 10.0, i.e., 63.1°C, to about 53.1°C - 10.0, i.e., 43.1°C. Those skilled in the art will recognize that for any of the powder diffraction reflections described herein, the appropriate margin of error for the single maximum may be ±10.0, ±7.5, ±5.0, ±2.5, ±2, ±1.5, ±1, ±0.5, or less, depending on the sample preparation technique, crystallization conditions, calibration techniques applied to the instrument, artificial operational variations, etc.

[0032] Further details of the methods and equipment used for DSC and TGA thermogram analysis are provided in the Examples section.

[0033] compound 1 In some embodiments, the present invention provides an amorphous solid state of (S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, also known as Compound 1. In some embodiments, the amorphous solid state of Compound 1 exhibits an X-ray powder diffraction pattern substantially similar to that shown in FIG.

[0034] In some embodiments, the amorphous solid state of Compound 1 exhibits a DSC thermogram substantially similar to that shown in Figure 2. In some embodiments, the amorphous solid state of Compound 1 exhibits a DSC endotherm at 97.2°C ± 5.0°C. In certain embodiments, the margin of error for the endotherm of the amorphous solid state of Compound 1 is selected from ± 15.0, ± 10.0, ± 5.0, and ± 2.0.

[0035] In some embodiments, the amorphous solid state of Compound 1 exhibits a TGA thermogram substantially similar to that shown in Figure 2. In some embodiments, the amorphous solid state of Compound 1 exhibits a TGA weight loss of 1.8%±0.5 at 150°C±10.0. In certain embodiments, the margin of error for the TGA weight loss for the amorphous solid state of Compound 1 is selected from ±5.0, ±2.0, ±1.0, ±0.5, and ±0.1.

[0036] In some embodiments herein, provided herein are compositions in which the amorphous solid state of Compound 1 is substantially free of crystalline form. In some embodiments, the amount of crystalline form is 20% (w / w) or less. In some embodiments, the amount of crystalline form is 15% (w / w) or less. In some embodiments, the amount of crystalline form is 10% (w / w) or less. In some embodiments, the amount of crystalline form is 5% (w / w) or less. In some embodiments, the amount of crystalline form is 1% (w / w) or less.

[0037] compound 2 In some embodiments, the present invention provides a crystalline solid state of (S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide hydrochloride, also known as Compound 2. In some embodiments, the crystalline solid state of Compound 2 exhibits an X-ray powder diffraction pattern substantially similar to that shown in FIG.

[0038] In some embodiments, the present invention provides a crystalline solid-state form of Compound 2. In some embodiments, the solid-state form exhibits an X-ray powder diffraction reflection at 19.7°±0.3 2θ. In some embodiments, the solid form exhibits X-ray powder diffraction reflections at 11.1°±0.3 and 21.2°±0.3 2θ. In some embodiments, the solid form exhibits X-ray powder diffraction reflections at 15.8°±0.3 and 22.0°±0.3 2θ. In some embodiments, the solid form exhibits X-ray powder diffraction reflections at 13.9°±0.3, 18.5°±0.3, 21.7°±0.3, and 22.5°±0.3 2θ. In some embodiments, the solid form exhibits X-ray powder diffraction reflections at 9.7°±0.3, 23.3°±0.3, and 23.8°±0.3 2θ.

[0039] In some embodiments, the solid form exhibits at least one X-ray powder diffraction reflection selected from 9.7°±0.3, 11.1°±0.3, 13.9°±0.3, 15.8°±0.3, 18.5°±0.3, 19.7°±0.3, 21.2°±0.3, 21.7°±0.3, 22.0°±0.3, 22.5°±0.3, 23.3°±0.3, and 23.8°±0.3. In some embodiments, the solid form exhibits at least one X-ray powder diffraction reflection selected from 20.3°±0.2, 23.4°±0.2, and 24.0°±0.2. In some embodiments, the solid form exhibits at least two X-ray powder diffraction reflections selected from 9.7°±0.3, 11.1°±0.3, 13.9°±0.3, 15.8°±0.3, 18.5°±0.3, 19.7°±0.3, 21.2°±0.3, 21.7°±0.3, 22.0°±0.3, 22.5°±0.3, 23.3°±0.3, and 23.8°±0.3. In some embodiments, the solid form exhibits at least three X-ray powder diffraction reflections selected from 9.7°±0.3, 11.1°±0.3, 13.9°±0.3, 15.8°±0.3, 18.5°±0.3, 19.7°±0.3, 21.2°±0.3, 21.7°±0.3, 22.0°±0.3, 22.5°±0.3, 23.3°±0.3, and 23.8°±0.3. In some embodiments, the solid form exhibits at least four X-ray powder diffraction reflections selected from 9.7°±0.3, 11.1°±0.3, 13.9°±0.3, 15.8°±0.3, 18.5°±0.3, 19.7°±0.3, 21.2°±0.3, 21.7°±0.3, 22.0°±0.3, 22.5°±0.3, 23.3°±0.3, and 23.8°±0.3. In some embodiments, the solid form exhibits at least five X-ray powder diffraction reflections selected from 9.7°±0.3, 11.1°±0.3, 13.9°±0.3, 15.8°±0.3, 18.5°±0.3, 19.7°±0.3, 21.2°±0.3, 21.7°±0.3, 22.0°±0.3, 22.5°±0.3, 23.3°±0.3, and 23.8°±0.3.In some embodiments, the solid form exhibits at least six X-ray powder diffraction reflections selected from 9.7°±0.3, 11.1°±0.3, 13.9°±0.3, 15.8°±0.3, 18.5°±0.3, 19.7°±0.3, 21.2°±0.3, 21.7°±0.3, 22.0°±0.3, 22.5°±0.3, 23.3°±0.3, and 23.8°±0.3. In certain embodiments, the margin of error for any one of the reflections of Compound 2 is selected from ±0.5, ±0.4, ±0.3, ±0.2, ±0.1, and ±0.05. In some embodiments, Compound 2 exhibits an X-ray powder diffraction pattern substantially similar to that shown in FIG. In some embodiments, Compound 2 exhibits at least one of the X-ray powder diffraction pattern reflections in Table 1.

[0040] [Table 1-1]

[0041] [Table 1-2]

[0042] In some embodiments, the crystalline solid state of Compound 2 exhibits a DSC thermogram substantially similar to that shown in Figure 4. In some embodiments, the crystalline solid state of Compound 2 exhibits a DSC endotherm at 229.9°C ± 5.0°C. In certain embodiments, the margin of error for the endotherm of the crystalline solid state of Compound 2 is selected from ± 15.0, ± 10.0, ± 5.0, and ± 2.0.

[0043] In some embodiments, the crystalline solid state of Compound 2 exhibits a TGA thermogram substantially similar to that shown in Figure 4. In some embodiments, the crystalline solid state of Compound 2 exhibits a weight loss of less than 1.0% ±0.5 by 160°C ±10.0. In certain embodiments, the margin of error for the TGA weight loss of the crystalline solid state of Compound 2 is selected from ±5.0, ±2.0, ±1.0, ±0.5, and ±0.1.

[0044] In some embodiments, provided herein are compositions wherein the crystalline solid state form of Compound 2 is substantially free of other crystalline or amorphous forms. In some embodiments, the amount of other crystalline or amorphous forms is 20% (w / w) or less. In some embodiments, the amount of other crystalline or amorphous forms is 15% (w / w) or less. In some embodiments, the amount of other crystalline or amorphous forms is 10% (w / w) or less. In some embodiments, the amount of other crystalline or amorphous forms is 5% (w / w) or less. In some embodiments, the amount of other crystalline or amorphous forms is 1% (w / w) or less.

[0045] compound 3 In some embodiments, the present invention provides a crystalline solid state of (S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide hydrobromide, also known as Compound 3. In some embodiments, the crystalline solid state of Compound 3 exhibits an X-ray powder diffraction pattern substantially similar to that shown in FIG.

[0046] In some embodiments, the present invention provides a crystalline solid-state form of Compound 3. In some embodiments, the solid-state form exhibits an X-ray powder diffraction reflection at 21.9°±0.3 2θ. In some embodiments, the solid form exhibits X-ray powder diffraction reflections at 19.7°±0.3 and 21.1°±0.3 2θ. In some embodiments, the solid form exhibits X-ray powder diffraction reflections at 19.3°±0.3, 20.1°±0.3, and 21.3°±0.3 2θ. In some embodiments, the solid form exhibits X-ray powder diffraction reflections at 12.2°±0.3, 23.2°±0.3, and 24.0°±0.3 2θ. In some embodiments, the solid form exhibits X-ray powder diffraction reflections at 17.1°±0.3, 27.3°±0.3, and 28.7°±0.3 2θ.

[0047] In some embodiments, the solid form exhibits at least one X-ray powder diffraction reflection selected from 12.2°±0.3, 17.1°±0.3, 19.7°±0.3, 21.1°±0.3, 21.9°±0.3, 23.2°±0.3, 24.0°±0.3, 27.3°±0.3, and 28.7°±0.3. In some embodiments, the solid form exhibits at least two X-ray powder diffraction reflections selected from 12.2°±0.3, 17.1°±0.3, 19.7°±0.3, 21.1°±0.3, 21.9°±0.3, 23.2°±0.3, 24.0°±0.3, 27.3°±0.3, and 28.7°±0.3. In some embodiments, the solid form exhibits at least three X-ray powder diffraction reflections selected from 12.2°±0.3, 17.1°±0.3, 19.7°±0.3, 21.1°±0.3, 21.9°±0.3, 23.2°±0.3, 24.0°±0.3, 27.3°±0.3, and 28.7°±0.3. In some embodiments, the solid form exhibits at least four X-ray powder diffraction reflections selected from 12.2°±0.3, 17.1°±0.3, 19.7°±0.3, 21.1°±0.3, 21.9°±0.3, 23.2°±0.3, 24.0°±0.3, 27.3°±0.3, and 28.7°±0.3. In some embodiments, the solid form exhibits at least five X-ray powder diffraction reflections selected from 12.2°±0.3, 17.1°±0.3, 19.7°±0.3, 21.1°±0.3, 21.9°±0.3, 23.2°±0.3, 24.0°±0.3, 27.3°±0.3, and 28.7°±0.3. In some embodiments, the solid form exhibits at least six X-ray powder diffraction reflections selected from 12.2°±0.3, 17.1°±0.3, 19.7°±0.3, 21.1°±0.3, 21.9°±0.3, 23.2°±0.3, 24.0°±0.3, 27.3°±0.3, and 28.7°±0.3. In certain embodiments, the margin of error for any one of the reflections of Compound 3 is selected from ±0.5, ±0.4, ±0.3, ±0.2, ±0.1, and ±0.05. In some embodiments, Compound 3 exhibits an X-ray powder diffraction pattern substantially similar to that shown in Figure 5. In some embodiments, Compound 3 exhibits at least one of the X-ray powder diffraction pattern reflections in Table 2.

[0048] [Table 2-1]

[0049] [Table 2-2]

[0050] In some embodiments, the crystalline solid state of Compound 3 exhibits a DSC thermogram substantially similar to that shown in Figure 6. In some embodiments, the crystalline solid state of Compound 3 exhibits a DSC endotherm at 222.2°C ± 5.0°C. In certain embodiments, the margin of error for the endotherm of the crystalline solid state of Compound 3 is selected from ±15.0, ±10.0, ±5.0, and ±2.0.

[0051] In some embodiments, the crystalline solid state of Compound 3 exhibits a TGA thermogram substantially similar to that shown in Figure 6. In some embodiments, the crystalline solid state of Compound 3 exhibits a weight loss of less than 1.0% ± 0.5% by 150°C ± 10.0°C. In certain embodiments, the margin of error for the TGA weight loss of the crystalline solid state of Compound 3 is selected from ± 5.0, ± 2.0, ± 1.0, ± 0.5, and ± 0.1.

[0052] In some embodiments, provided herein are compositions wherein the crystalline solid state form of Compound 3 is substantially free of other crystalline or amorphous forms. In some embodiments, the amount of other crystalline or amorphous forms is 20% (w / w) or less. In some embodiments, the amount of other crystalline or amorphous forms is 15% (w / w) or less. In some embodiments, the amount of other crystalline or amorphous forms is 10% (w / w) or less. In some embodiments, the amount of other crystalline or amorphous forms is 5% (w / w) or less. In some embodiments, the amount of other crystalline or amorphous forms is 1% (w / w) or less.

[0053] compound 4 In some embodiments, the present invention provides a crystalline solid state of (S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide 4-methylbenzenesulfonate, also known as Compound 4. In some embodiments, the crystalline solid state of Compound 4 is crystallized in the presence of MTBE (Form I) and exhibits an X-ray powder diffraction pattern substantially similar to that shown in FIG. 6. In some embodiments, the crystalline solid state of Compound 4 is crystallized in the presence of acetone (Form II) and exhibits an X-ray powder diffraction pattern substantially similar to that shown in FIG. 7.

[0054] Compound 4 - Form I crystallized with MTBE In some embodiments, the present invention provides Form I, a crystalline solid-state form of Compound 4, crystallized in the presence of MTBE. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 6.1°±0.3 2θ. In some embodiments, the solid form exhibits X-ray powder diffraction reflections at 15.0°±0.3 and 17.9°±0.3 2θ. In some embodiments, the solid form exhibits X-ray powder diffraction reflections at 5.7°±0.3, 7.2°±0.3, and 18.5°±0.3 2θ. In some embodiments, the solid form exhibits X-ray powder diffraction reflections at 9.3°±0.3, 12.1°±0.3, 12.7°±0.3, and 19.9°±0.3 2θ. In some embodiments, the solid form exhibits X-ray powder diffraction reflections at 14.5°±0.3, 15.5°±0.3, and 16.6°±0.3 2θ.

[0055] In some embodiments, the solid form exhibits at least one X-ray powder diffraction reflection selected from 5.7°±0.3, 6.1°±0.3, 7.2°±0.3, 9.3°±0.3, 12.1°±0.3, 12.7°±0.3, 14.5°±0.3, 15.0°±0.3, 15.5°±0.3, 16.6°±0.3, 17.9°±0.3, 18.5°±0.3, and 19.9°±0.3. In some embodiments, the solid form exhibits at least two X-ray powder diffraction reflections selected from 5.7°±0.3, 6.1°±0.3, 7.2°±0.3, 9.3°±0.3, 12.1°±0.3, 12.7°±0.3, 14.5°±0.3, 15.0°±0.3, 15.5°±0.3, 16.6°±0.3, 17.9°±0.3, 18.5°±0.3, and 19.9°±0.3. In some embodiments, the solid form exhibits at least three X-ray powder diffraction reflections selected from 5.7°±0.3, 6.1°±0.3, 7.2°±0.3, 9.3°±0.3, 12.1°±0.3, 12.7°±0.3, 14.5°±0.3, 15.0°±0.3, 15.5°±0.3, 16.6°±0.3, 17.9°±0.3, 18.5°±0.3, and 19.9°±0.3. In some embodiments, the solid form exhibits at least four X-ray powder diffraction reflections selected from 5.7°±0.3, 6.1°±0.3, 7.2°±0.3, 9.3°±0.3, 12.1°±0.3, 12.7°±0.3, 14.5°±0.3, 15.0°±0.3, 15.5°±0.3, 16.6°±0.3, 17.9°±0.3, 18.5°±0.3, and 19.9°±0.3. In some embodiments, the solid form exhibits at least five X-ray powder diffraction reflections selected from 5.7°±0.3, 6.1°±0.3, 7.2°±0.3, 9.3°±0.3, 12.1°±0.3, 12.7°±0.3, 14.5°±0.3, 15.0°±0.3, 15.5°±0.3, 16.6°±0.3, 17.9°±0.3, 18.5°±0.3, and 19.9°±0.3.In some embodiments, the solid form exhibits at least six X-ray powder diffraction reflections selected from 5.7°±0.3, 6.1°±0.3, 7.2°±0.3, 9.3°±0.3, 12.1°±0.3, 12.7°±0.3, 14.5°±0.3, 15.0°±0.3, 15.5°±0.3, 16.6°±0.3, 17.9°±0.3, 18.5°±0.3, and 19.9°±0.3. In certain embodiments, the margin of error for any one of the reflections of Compound 4 is selected from ±0.5, ±0.4, ±0.3, ±0.2, ±0.1, and ±0.05. In some embodiments, Form I of Compound 4 exhibits an X-ray powder diffraction pattern substantially similar to that shown in FIG. 7. In some embodiments, Form I of Compound 4 exhibits at least one of the X-ray powder diffraction pattern reflections in Table 3.

[0056] [Table 3]

[0057] In some embodiments, provided herein are compositions in which Form I, the crystalline solid state form of Compound 4, is substantially free of other crystalline or amorphous forms. In some embodiments, the amount of other crystalline or amorphous forms is 20% (w / w) or less. In some embodiments, the amount of other crystalline or amorphous forms is 15% (w / w) or less. In some embodiments, the amount of other crystalline or amorphous forms is 10% (w / w) or less. In some embodiments, the amount of other crystalline or amorphous forms is 5% (w / w) or less. In some embodiments, the amount of other crystalline or amorphous forms is 1% (w / w) or less.

[0058] Compound 4 - Form II crystallized from acetone In some embodiments, the present invention provides Form II, a crystalline solid state form of Compound 4 crystallized in the presence of acetone. In some embodiments, the present invention provides Form II, a crystalline solid state form of Compound 4. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 6.8°±0.3 2θ. In some embodiments, the solid form exhibits X-ray powder diffraction reflections at 5.2°±0.3, 6.1°±0.3, and 18.8°±0.3 2θ. In some embodiments, the solid form exhibits X-ray powder diffraction reflections at 16.3°±0.3, 17.1°±0.3, and 21.1°±0.3 2θ. In some embodiments, the solid form exhibits X-ray powder diffraction reflections at 12.5°±0.3, 17.2°±0.3, 18.5°±0.3, and 19.2°±0.3 2θ. In some embodiments, the solid form exhibits X-ray powder diffraction reflections at 2θ values ​​of 10.5°±0.3, 11.9°±0.3, and 12.9°±0.3.

[0059] In some embodiments, the solid form exhibits at least one X-ray powder diffraction reflection selected from 5.2°±0.3, 6.1°±0.3, 6.8°±0.3, 10.5°±0.3, 11.9°±0.3, 12.5°±0.3, 12.9°±0.3, 16.3°±0.3, 17.1°±0.3, 17.2°±0.3, 18.5°±0.3, 18.8°±0.3, 19.2°±0.3, and 21.1°±0.3. In some embodiments, the solid form exhibits at least two X-ray powder diffraction reflections selected from 5.2°±0.3, 6.1°±0.3, 6.8°±0.3, 10.5°±0.3, 11.9°±0.3, 12.5°±0.3, 12.9°±0.3, 16.3°±0.3, 17.1°±0.3, 17.2°±0.3, 18.5°±0.3, 18.8°±0.3, 19.2°±0.3, and 21.1°±0.3. In some embodiments, the solid form exhibits at least three X-ray powder diffraction reflections selected from 5.2°±0.3, 6.1°±0.3, 6.8°±0.3, 10.5°±0.3, 11.9°±0.3, 12.5°±0.3, 12.9°±0.3, 16.3°±0.3, 17.1°±0.3, 17.2°±0.3, 18.5°±0.3, 18.8°±0.3, 19.2°±0.3, and 21.1°±0.3. In some embodiments, the solid form exhibits at least four X-ray powder diffraction reflections selected from 5.2°±0.3, 6.1°±0.3, 6.8°±0.3, 10.5°±0.3, 11.9°±0.3, 12.5°±0.3, 12.9°±0.3, 16.3°±0.3, 17.1°±0.3, 17.2°±0.3, 18.5°±0.3, 18.8°±0.3, 19.2°±0.3, and 21.1°±0.3. In some embodiments, the solid form exhibits at least five X-ray powder diffraction reflections selected from 5.2°±0.3, 6.1°±0.3, 6.8°±0.3, 10.5°±0.3, 11.9°±0.3, 12.5°±0.3, 12.9°±0.3, 16.3°±0.3, 17.1°±0.3, 17.2°±0.3, 18.5°±0.3, 18.8°±0.3, 19.2°±0.3, and 21.1°±0.3.In some embodiments, the solid form exhibits at least six X-ray powder diffraction reflections selected from 5.2°±0.3, 6.1°±0.3, 6.8°±0.3, 10.5°±0.3, 11.9°±0.3, 12.5°±0.3, 12.9°±0.3, 16.3°±0.3, 17.1°±0.3, 17.2°±0.3, 18.5°±0.3, 18.8°±0.3, 19.2°±0.3, and 21.1°±0.3. In certain embodiments, the margin of error for any one of the reflections of Compound 4 is selected from ±0.5, ±0.4, ±0.3, ±0.2, ±0.1, and ±0.05. In some embodiments, Form II of Compound 4 exhibits an X-ray powder diffraction pattern substantially similar to that shown in FIG. In some embodiments, Form II of Compound 4 exhibits at least one of the X-ray powder diffraction pattern reflections in Table 4.

[0060] [Table 4]

[0061] In some embodiments, provided herein are compositions in which Form II, a crystalline solid state form of Compound 4, is substantially free of other crystalline or amorphous forms. In some embodiments, the amount of other crystalline or amorphous forms is 20% (w / w) or less. In some embodiments, the amount of other crystalline or amorphous forms is 15% (w / w) or less. In some embodiments, the amount of other crystalline or amorphous forms is 10% (w / w) or less. In some embodiments, the amount of other crystalline or amorphous forms is 5% (w / w) or less. In some embodiments, the amount of other crystalline or amorphous forms is 1% (w / w) or less.

[0062] compound 5 In some embodiments, the present invention provides a crystalline solid state of (S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide phosphate, also known as Compound 5. In some embodiments, the crystalline solid state of Compound 5 exhibits an X-ray powder diffraction pattern substantially similar to that shown in FIG.

[0063] In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 6.9°±0.3 2θ. In some embodiments, the solid form exhibits X-ray powder diffraction reflections at 18.3°±0.3 and 24.0°±0.3 2θ. In some embodiments, the solid form exhibits X-ray powder diffraction reflections at 9.1°±0.3, 20.7°±0.3, and 22.7°±0.3 2θ. In some embodiments, the solid form exhibits X-ray powder diffraction reflections at 5.9°±0.3, 11.9°±0.3, 13.8°±0.3, and 21.9°±0.3 2θ. In some embodiments, the solid form exhibits X-ray powder diffraction reflections at 19.2°±0.3, 20.4°±0.3, 25.8°±0.3, and 26.6°±0.3 2θ.

[0064] In some embodiments, the solid form exhibits at least one X-ray powder diffraction reflection selected from 5.9°±0.3, 6.9°±0.3, 9.1°±0.3, 11.9°±0.3, 13.8°±0.3, 18.3°±0.3, 19.2°±0.3, 20.4°±0.3, 20.7°±0.3, 21.9°±0.3, 22.7°±0.3, 24.0°±0.3, 25.8°±0.3, and 26.6°±0.3. In some embodiments, the solid form exhibits at least two X-ray powder diffraction reflections selected from 5.9°±0.3, 6.9°±0.3, 9.1°±0.3, 11.9°±0.3, 13.8°±0.3, 18.3°±0.3, 19.2°±0.3, 20.4°±0.3, 20.7°±0.3, 21.9°±0.3, 22.7°±0.3, 24.0°±0.3, 25.8°±0.3, and 26.6°±0.3. In some embodiments, the solid form exhibits at least three X-ray powder diffraction reflections selected from 5.9°±0.3, 6.9°±0.3, 9.1°±0.3, 11.9°±0.3, 13.8°±0.3, 18.3°±0.3, 19.2°±0.3, 20.4°±0.3, 20.7°±0.3, 21.9°±0.3, 22.7°±0.3, 24.0°±0.3, 25.8°±0.3, and 26.6°±0.3. In some embodiments, the solid form exhibits at least four X-ray powder diffraction reflections selected from 5.9°±0.3, 6.9°±0.3, 9.1°±0.3, 11.9°±0.3, 13.8°±0.3, 18.3°±0.3, 19.2°±0.3, 20.4°±0.3, 20.7°±0.3, 21.9°±0.3, 22.7°±0.3, 24.0°±0.3, 25.8°±0.3, and 26.6°±0.3. In some embodiments, the solid form exhibits at least five X-ray powder diffraction reflections selected from 5.9°±0.3, 6.9°±0.3, 9.1°±0.3, 11.9°±0.3, 13.8°±0.3, 18.3°±0.3, 19.2°±0.3, 20.4°±0.3, 20.7°±0.3, 21.9°±0.3, 22.7°±0.3, 24.0°±0.3, 25.8°±0.3, and 26.6°±0.3.In some embodiments, the solid form exhibits at least six X-ray powder diffraction reflections selected from 5.9°±0.3, 6.9°±0.3, 9.1°±0.3, 11.9°±0.3, 13.8°±0.3, 18.3°±0.3, 19.2°±0.3, 20.4°±0.3, 20.7°±0.3, 21.9°±0.3, 22.7°±0.3, 24.0°±0.3, 25.8°±0.3, and 26.6°±0.3. In certain embodiments, the margin of error for any one of the reflections of Compound 5 is selected from ±0.5, ±0.4, ±0.3, ±0.2, ±0.1, and ±0.05. In some embodiments, Compound 5 exhibits an X-ray powder diffraction pattern substantially similar to that shown in FIG. In some embodiments, compound 5 exhibits at least one of the X-ray powder diffraction pattern reflections in Table 5.

[0065] [Table 5]

[0066] In some embodiments, the crystalline solid state of Compound 5 exhibits a DSC thermogram substantially similar to that shown in Figure 10. In some embodiments, the crystalline solid state of Compound 5 exhibits a DSC endotherm at 150.6°C ± 5.0°C. In certain embodiments, the margin of error for the endotherm of the crystalline solid state of Compound 5 is selected from ± 15.0, ± 10.0, ± 5.0, and ± 2.0.

[0067] In some embodiments, the crystalline solid state of Compound 5 exhibits a TGA thermogram substantially similar to that shown in Figure 10. In some embodiments, the crystalline solid state of Compound 5 exhibits a weight loss of less than 6.2% ±0.5 by 170°C ±10.0. In certain embodiments, the margin of error for the TGA weight loss of the crystalline solid state of Compound 5 is selected from ±5.0, ±2.0, ±1.0, ±0.5, and ±0.1.

[0068] In some embodiments, provided herein are compositions in which the crystalline solid state form of Compound 5 is substantially free of other crystalline or amorphous forms. In some embodiments, the amount of other crystalline or amorphous forms is 20% (w / w) or less. In some embodiments, the amount of other crystalline or amorphous forms is 15% (w / w) or less. In some embodiments, the amount of other crystalline or amorphous forms is 10% (w / w) or less. In some embodiments, the amount of other crystalline or amorphous forms is 5% (w / w) or less. In some embodiments, the amount of other crystalline or amorphous forms is 1% (w / w) or less.

[0069] compound 6 In some embodiments, the present invention provides a crystalline solid state of (S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide sulfate, also known as Compound 6. In some embodiments, the crystalline solid state of Compound 6 is crystallized in the presence of acetonitrile (Form I). In some embodiments, the crystalline solid state of Compound 6 is crystallized in the presence of isopropyl alcohol (Form II).

[0070] Compound 6 - Form I crystallized in acetonitrile In some embodiments, the present invention provides Form I, a crystalline solid-state form of Compound 6, crystallized in the presence of acetonitrile. In some embodiments, the solid form exhibits X-ray powder diffraction reflections at 2θ values, and in some embodiments, the solid form exhibits X-ray powder diffraction reflections at 2θ values ​​of 3.2°±0.3. In some embodiments, the solid form exhibits X-ray powder diffraction reflections at 2θ values ​​of 3.3°±0.3 and 6.8°±0.3. In some embodiments, the solid form exhibits X-ray powder diffraction reflections at 2θ values ​​of 4.6°±0.3 and 7.1°±0.3. In some embodiments, the solid form exhibits X-ray powder diffraction reflections at 2θ values ​​of 8.0°±0.3, 12.5°±0.3, 15.7°±0.3, 16.0°±0.3, and 19.9°±0.3.

[0071] In some embodiments, the solid form exhibits at least one X-ray powder diffraction reflection selected from 3.2°±0.3, 3.3°±0.3, 4.6°±0.3, 6.8°±0.3, 7.1°±0.3, 8.0°±0.3, 12.5°±0.3, 15.7°±0.3, 16.0°±0.3, and 19.9°±0.3. In some embodiments, the solid form exhibits at least two X-ray powder diffraction reflections selected from 3.2°±0.3, 3.3°±0.3, 4.6°±0.3, 6.8°±0.3, 7.1°±0.3, 8.0°±0.3, 12.5°±0.3, 15.7°±0.3, 16.0°±0.3, and 19.9°±0.3. In some embodiments, the solid form exhibits at least three X-ray powder diffraction reflections selected from 3.2°±0.3, 3.3°±0.3, 4.6°±0.3, 6.8°±0.3, 7.1°±0.3, 8.0°±0.3, 12.5°±0.3, 15.7°±0.3, 16.0°±0.3, and 19.9°±0.3. In some embodiments, the solid form exhibits at least four X-ray powder diffraction reflections selected from 3.2°±0.3, 3.3°±0.3, 4.6°±0.3, 6.8°±0.3, 7.1°±0.3, 8.0°±0.3, 12.5°±0.3, 15.7°±0.3, 16.0°±0.3, and 19.9°±0.3. In some embodiments, the solid form exhibits at least five X-ray powder diffraction reflections selected from 3.2°±0.3, 3.3°±0.3, 4.6°±0.3, 6.8°±0.3, 7.1°±0.3, 8.0°±0.3, 12.5°±0.3, 15.7°±0.3, 16.0°±0.3, and 19.9°±0.3. In some embodiments, the solid form exhibits at least six X-ray powder diffraction reflections selected from 3.2°±0.3, 3.3°±0.3, 4.6°±0.3, 6.8°±0.3, 7.1°±0.3, 8.0°±0.3, 12.5°±0.3, 15.7°±0.3, 16.0°±0.3, and 19.9°±0.3. In certain embodiments, the margin of error for any one of the reflections of Compound 6 is selected from ±0.5, ±0.4, ±0.3, ±0.2, ±0.1, and ±0.05. In some embodiments, Form I of Compound 6 exhibits at least one of the X-ray powder diffraction pattern reflections in Table 6.

[0072] [Table 6]

[0073] In some embodiments, provided herein are compositions in which Form I, the crystalline solid state form of Compound 6, is substantially free of other crystalline or amorphous forms. In some embodiments, the amount of other crystalline or amorphous forms is 20% (w / w) or less. In some embodiments, the amount of other crystalline or amorphous forms is 15% (w / w) or less. In some embodiments, the amount of other crystalline or amorphous forms is 10% (w / w) or less. In some embodiments, the amount of other crystalline or amorphous forms is 5% (w / w) or less. In some embodiments, the amount of other crystalline or amorphous forms is 1% (w / w) or less.

[0074] Compound 6 - Form II crystallized in isopropanol In some embodiments, the present invention provides Form II, a crystalline solid state form of Compound 6, which is crystallized in the presence of acetonitrile. In some embodiments, the present invention provides Form II, a crystalline solid state form of Compound 6. In some embodiments, the solid form exhibits an X-ray powder diffraction reflection at 7.2°±0.3 2θ. In some embodiments, the solid form exhibits X-ray powder diffraction reflections at 14.5°±0.3 and 16.1°±0.3 2θ. In some embodiments, the solid form exhibits X-ray powder diffraction reflections at 15.8°±0.3 and 19.9°±0.3 2θ. In some embodiments, the solid form exhibits X-ray powder diffraction reflections at 9.5°±0.3, 19.1°±0.3, 19.3°±0.3, and 21.9±0.3 2θ.

[0075] In some embodiments, the solid form exhibits at least one X-ray powder diffraction reflection selected from 7.2°±0.3, 9.5°±0.3, 14.5°±0.3, 15.8°±0.3, 16.1°±0.3, 19.1°±0.3, 19.3°±0.3, 19.9°±0.3, and 21.9°±0.3. In some embodiments, the solid form exhibits at least two X-ray powder diffraction reflections selected from 7.2°±0.3, 9.5°±0.3, 14.5°±0.3, 15.8°±0.3, 16.1°±0.3, 19.1°±0.3, 19.3°±0.3, 19.9°±0.3, and 21.9°±0.3. In some embodiments, the solid form exhibits at least three X-ray powder diffraction reflections selected from 7.2°±0.3, 9.5°±0.3, 14.5°±0.3, 15.8°±0.3, 16.1°±0.3, 19.1°±0.3, 19.3°±0.3, 19.9°±0.3, and 21.9°±0.3. In some embodiments, the solid form exhibits at least four X-ray powder diffraction reflections selected from 7.2°±0.3, 9.5°±0.3, 14.5°±0.3, 15.8°±0.3, 16.1°±0.3, 19.1°±0.3, 19.3°±0.3, 19.9°±0.3, and 21.9°±0.3. In some embodiments, the solid form exhibits at least five X-ray powder diffraction reflections selected from 7.2°±0.3, 9.5°±0.3, 14.5°±0.3, 15.8°±0.3, 16.1°±0.3, 19.1°±0.3, 19.3°±0.3, 19.9°±0.3, and 21.9°±0.3. In some embodiments, the solid form exhibits at least six X-ray powder diffraction reflections selected from 7.2°±0.3, 9.5°±0.3, 14.5°±0.3, 15.8°±0.3, 16.1°±0.3, 19.1°±0.3, 19.3°±0.3, 19.9°±0.3, and 21.9°±0.3. In certain embodiments, the margin of error for any one of the reflections of Compound 6 is selected from ±0.5, ±0.4, ±0.3, ±0.2, ±0.1, and ±0.05. In some embodiments, Form II of Compound 6 exhibits at least one of the X-ray powder diffraction pattern reflections in Table 7.

[0076] [Table 7]

[0077] In some embodiments, provided herein are compositions in which Form II, a crystalline solid state form of Compound 6, is substantially free of other crystalline or amorphous forms. In some embodiments, the amount of other crystalline or amorphous forms is 20% (w / w) or less. In some embodiments, the amount of other crystalline or amorphous forms is 15% (w / w) or less. In some embodiments, the amount of other crystalline or amorphous forms is 10% (w / w) or less. In some embodiments, the amount of other crystalline or amorphous forms is 5% (w / w) or less. In some embodiments, the amount of other crystalline or amorphous forms is 1% (w / w) or less.

[0078] Pharmaceutical Composition In certain embodiments, Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 is administered as a pure chemical. In other embodiments, Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 is administered in a manner that is consistent with the chosen route of administration and the dosage regimen described in, for example, Remington: The Science and Practice of Pharmacy (Gennaro, 2011). st The pharmaceutical composition is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier), selected on the basis of standard pharmaceutical practice, such as that described in "Pharmaceutical Compositions and Methods for Promoting and Promoting the Development of Novel Pharmaceuticals," Ed. Mack Pub. Co., Easton, PA (2005)).

[0079] Provided herein are pharmaceutical compositions comprising at least one of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 and one or more pharmaceutically acceptable carriers. A carrier (or excipient) is acceptable or suitable if it is compatible with the other ingredients of the composition and not deleterious to the recipient (subject or patient) of the composition.

[0080] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6.

[0081] One embodiment provides a method for preparing a pharmaceutical composition, comprising mixing Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 with a pharmaceutically acceptable carrier.

[0082] In certain embodiments, Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 is substantially pure, meaning that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other small organic molecules, such as, for example, unreacted intermediates or synthetic by-products generated in one or more steps of the synthetic method.

[0083] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules made of hard or soft gelatin, methylcellulose, or another suitable material that dissolves easily in the digestive tract. In some embodiments, suitable non-toxic solid carriers are used, including, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 2012) st See Ed. Mack Pub. Co., Easton, PA (2005).

[0084] In some embodiments, the formulation comprises Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6, a pharmaceutically acceptable carrier, and a disintegrant. In some embodiments, the disintegrant is selected from the group consisting of natural starch, pregelatinized starch, sodium starch, methylcrystalline cellulose, methylcellulose, croscarmellose, croscarmellose sodium, cross-linked starch such as sodium carboxymethylcellulose, cross-linked carboxymethylcellulose, cross-linked croscarmellose, sodium starch glycolate, cross-linked polymers such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, clay, or gum. In some embodiments, the disintegrant is croscarmellose sodium.

[0085] In some embodiments, Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 is formulated for administration by injection. In some examples, the injection formulation is an aqueous formulation. In some examples, the injection formulation is a non-aqueous formulation. In some examples, the injection formulation is an oily formulation such as sesame oil.

[0086] The dose of a composition comprising Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 will vary depending on the disease of the subject or patient (e.g., human). In some embodiments, such factors include general health, age, and other factors.

[0087] The pharmaceutical composition is administered in a manner appropriate for the disease to be treated (or prevented). The appropriate dose and the appropriate duration and frequency of administration will be determined by factors such as the patient's disease, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides a sufficient amount of the composition to provide a therapeutic and / or preventive effect (e.g., improved clinical results such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or reduced severity of symptoms). The optimal dose is generally determined using experimental models and / or clinical trials. The optimal dose depends on the patient's obesity, body weight, or blood volume.

[0088] Oral doses generally range from about 1.0 mg to about 1000 mg, one to four or more times per day.

[0089] Treatment method One embodiment provides Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 for use in a method of treatment of the human or animal body.

[0090] One embodiment provides Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 for use in a method of treating cancer or a neoplastic disease.

[0091] One embodiment provides the use of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 in the manufacture of a medicament for the treatment of cancer or a neoplastic disease.

[0092] In some embodiments, described herein are methods of treating cancer in a patient in need thereof, the methods comprising administering to the patient Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6. In some embodiments, described herein are methods of treating cancer in a patient in need thereof, the methods comprising administering to the patient a pharmaceutical composition comprising Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6 and a pharmaceutically acceptable excipient.

[0093] Provided herein are methods wherein the pharmaceutical composition is administered orally. Provided herein are methods wherein the pharmaceutical composition is administered by injection.

[0094] Other embodiments and uses will be apparent to those skilled in the art in light of the present disclosure. The following examples are provided merely as illustrations of various embodiments and are not to be construed as limiting the invention in any way. [Example]

[0095] The present disclosure is further illustrated by the following examples, which should not be construed as limiting in any way. The experimental procedures for generating the data shown are described in more detail below. It is to be understood that the present disclosure has been described in an illustrative manner and that the terminology used is intended to be in the nature of description rather than of limitation.

[0096] General experimental, equipment, and methodological details The general synthesis of (S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide is described in paragraph PCT / US2020 / 057132.

[0097] X-ray powder diffraction (XRPD) A Bruker D8 Advance X-ray powder diffractometer equipped with a LynxEye detector was used for XRPD analysis. The XRPD parameters used are listed in Table 8.

[0098] [Table 8]

[0099] Differential scanning calorimetry (DSC) DSC was performed using a Discovery DSC 250 (TA Instruments, US). Samples were placed in aluminum pin-hole hermetic pans and the weight was accurately recorded. The samples were heated at a rate of 10°C / min from 25°C to the final temperature. The DSC parameters used are listed in Table 9.

[0100] [Table 9]

[0101] Thermogravimetric analysis (TGA) TGA was performed on a Discovery TGA 55 (TA Instruments, US). Samples were placed in tared open aluminum pans, automatically weighed, and inserted into the TGA oven. Samples were heated at a rate of 10°C / min from ambient temperature to the final temperature. The TGA parameters used are listed in Table 10.

[0102] [Table 10]

[0103] Dynamic Vapor Sorption (DVS) Moisture sorption / desorption data were collected on a DVS Intrinsic PLUS (SMS, UK). Samples were placed in a tared sample chamber and automatically weighed. Samples were dried at 40°C / 0% RH until dm / dt was less than 0.002% and cooled to 25°C. The DVS parameters used are listed in Table 11.

[0104] [Table 11]

[0105] Polarized Light Microscopy (PLM) Optical microscopy was performed using a polarizing microscope ECLIPSE LV100POL (Nikon, JPN).

[0106] Proton Nuclear Magnetic Resonance (1H-NMR) 1 H-NMR was performed using a Bruker Advance 300 equipped with an autosampler (B-ACS 120).

[0107] Ultra-Performance Liquid Chromatography (UPLC) Method The UPLC methods for solubility and stability testing are listed in Table 12.

[0108] [Table 12]

[0109] Example 1. Characterization of (S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (Compound 1) The amorphous form of Compound 1 was identified by XRPD, as shown in Figure 1. The thermogram in Figure 2 showed that the sample had a weight loss of -1.8% between room temperature and 150 °C, with a broad endothermic peak at 97.2 °C ± 5.0 °C. The amorphous material was slightly hygroscopic, taking up 2% water at 80% RH (Figure 11). The material remained amorphous after DVS testing.

[0110] Compound 1 is insoluble in n-heptane and water (<1 mg / mL), and soluble in methanol, ethanol, acetone, tetrahydrofuran, methyl ethyl ketone, ethyl acetate, acetonitrile, isobutanol, isopropyl alcohol, and isopropyl acetate (>100 mg / mL). Compound 1 has a solubility of approximately 60 mg / mL in methyl t-butyl ether.

[0111] Example 2. Characterization of (S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide hydrochloride (Compound 2) Approximately 390 mg of compound 1 was added to 10 V acetone at room temperature to obtain a clear solution. Then, 69.3 μL of concentrated HCl (1.1 equiv.) was added, and precipitation occurred after 1 min. The resulting suspension was kept at room temperature for 3 h. The solid was collected by filtration and dried overnight under vacuum at 50 °C. Compound 2 was obtained as an off-white solid in ~81% yield. Compound 2 was highly crystalline, as shown in Figure 3. Compound 2 was slightly hygroscopic, uptake of 0.66% water at 80% relative humidity and 0.95% water at 90% relative humidity, as measured by DVS (Figure 12). Compound 2 showed a DSC peak at 229.94 °C ± 5.0 °C, and a weight loss of less than 1.0% ± 5.0 °C by 160 °C ± 10.0 °C, as measured by TGA (Figure 4).

[0112] Amorphous solid-state forms of (S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide hydrochloride are achievable. However, unless specifically designated as amorphous, "Compound 2" refers to the crystalline form shown in FIG. 3. Amorphous (S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide hydrochloride was formed by rapid evaporation of 15 mg of Compound 2 dissolved in 0.5 mL of methanol. XRPD confirmed the solid was amorphous. Slurries of amorphous (S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide hydrochloride in 0.5 mL of a solvent from Table 13 were prepared. Each suspension was stirred at 50° C. and room temperature for 1 day. Each suspension was filtered and analyzed by XRPD. In each experiment, conversion of amorphous (S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide hydrochloride to crystalline Compound 2 was observed.

[0113] [Table 13]

[0114] Compound 1 and Compound 2 were evaluated for stability at 60°C and 40°C at 75% relative humidity for 9 days. On days 0, 3, and 9, samples were dissolved in diluent to prepare solutions for purity analysis by UPLC. Solid samples were also analyzed by XRPD to determine crystalline form. The results of the study are summarized in Table 14 below.

[0115] [Table 14]

[0116] A solution of Compound 2 was evaluated for stability in 0.5% MC / 0.1% Tween 80 at 10 mg / mL. 10.7 mg of Compound 2 was weighed into a sample vial, and then 500 μL of 1% MC and 500 μL of 0.2% Tween 80 were added to obtain a 10 mg / mL suspension (calculated as the free base). The mixture was left stirring at room temperature for 15 minutes, and the suspension was allowed to stand at room temperature for 7 days. No morphological changes occurred, but the purity, as measured by UPLC, decreased by 0.13% after 7 days.

[0117] The thermodynamic solubility of compound 2 was measured by UPLC in 13 solvents at room temperature and 50°C, respectively. The results are summarized in Table 15. Compound 2 showed the highest solubility in MeOH, at approximately 102 mg / mL at 50°C and 55 mg / mL at room temperature. In most of the other selected solvents, the compound was nearly insoluble (<0.5 mg / mL), except for EtOH and water, where it was slightly soluble (6-9 mg / mL). The solid form of the residual solid from the solubility test was examined by XRPD, and no form change occurred during the solubility test.

[0118] [Table 15]

[0119] A comparative dissolution study was performed on Compounds 1 and 2. Approximately 20 mg of each sample was weighed into a sample vial, and then 4 mL of medium was added to form a suspension. All suspensions were shaken at 37°C and 200 rpm. At 0.5, 2, and 24 hours, each suspension was filtered, and the filtrate was analyzed by UPLC to test solubility. The pH of the filtrate was measured, and the filter cake was analyzed by XRPD. Compound 1 has very low solubility in water (<9 μg / mL), while Compound 2 exhibits a solubility of approximately 2.5 mg / mL in water. The solubilities of Compounds 1 and 2 were similar in the biorelevant dissolution media, FaSSIF and FeSSIF. Compound 1 was converted to Compound 2 in FaSSGF. The experimental results are summarized in Table 16.

[0120] [Table 16]

[0121] Example 3. Characterization of (S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide hydrobromide (Compound 3) Compound 3 was synthesized by dissolving 26 mg of compound 1 in acetone and adding 1 equivalent of hydrobromic acid at room temperature. Stirring for 30 minutes produced a slurry, and the solid was isolated by filtration. The solid was highly crystalline, as shown in Figure 5. Compound 3 was slightly hygroscopic, picking up 0.27% water at 80% relative humidity and 0.45% water at 90% relative humidity, as measured by DVS (Figure 13). Compound 3 exhibited a DSC peak at 222.2°C ± 5.0°C, and a weight loss of less than 1.0% ± 0.5°C by 150°C ± 10.0°C, as measured by TGA (Figure 6).

[0122] Example 4. Characterization of (S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide 4-methylbenzenesulfonate (Compound 4) Compound 4 was prepared by adding 1 equivalent of p-toluenesulfonic acid to Compound 1 in acetone or MTBE. In MTBE, the reagents were stirred at 50° C. for 1 hour, after which a solid appeared and was isolated by filtration to give Form I of crystalline Compound 4, as shown in FIG. 7. In acetone, the reagents were stirred for 2 hours, after which a solid appeared and was isolated by filtration to give Form II of crystalline Compound 4, as shown in FIG. 8. When the synthesis was performed in ethyl acetate and the solvent was evaporated, an amorphous form of (S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide 4-methylbenzenesulfonate was obtained, as determined by XRPD.

[0123] Example 5. Characterization of (S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide phosphate (Compound 5) Compound 5 was prepared by adding 1 equivalent of phosphoric acid to compound 1 in methanol at room temperature. The reagents were stirred overnight, after which a solid appeared and was isolated by filtration to give crystalline compound 5, as shown in Figure 9. Compound 5 exhibited a DSC desolvation / dehydration curve between 37 and 66°C ± 5.0°C and an endothermic melting peak at 150.6°C ± 5.0°C. Two-step weight losses of approximately 3.3% ± 0.5°C and 2.9% ± 0.5°C occurred upon heating to 177°C ± 10.0°C, as measured by TGA (Figure 10). Amorphous forms of (S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide phosphate were obtained when the synthesis was carried out in acetonitrile or ethyl acetate and the solvent was evaporated, as determined by XRPD.

[0124] Example 6. Characterization of (S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide sulfate (Compound 6) Compound 6 was prepared by adding 1 equivalent of sulfuric acid to Compound 1 in acetonitrile or isopropyl alcohol. The reagents were combined in acetonitrile and stirred, resulting in the appearance of a solid, which was isolated by filtration to provide Form I of crystalline Compound 6. The reagents were combined in isopropyl alcohol and stirred, resulting in the appearance of a solid, which was isolated by filtration to provide Form II of crystalline Compound 6. The reaction was carried out in acetone containing 0.5 equivalents of sulfuric acid, and the acetone was evaporated to provide an amorphous form of (S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide sulfate, as determined by XRPD.

[0125] Example 7. Pharmaceutical Formulation and Manufacturing Process The pharmaceutical formulation provides immediate release of Compound 2 over a period of approximately one hour. When the tablet is exposed to water and begins to disintegrate, the drug substance is rapidly released from the tablet core. The tablet is intended to dissolve completely in the stomach, where solubility is highest. To enable rapid dissolution, a superdisintegrant such as croscarmellose sodium is added to the formulation. Other components of the formulation include fillers such as microcrystalline cellulose, mannitol, and hypromellose acetate succinate, anti-adherents such as talc, glidants such as silicon dioxide, and lubricants such as sodium stearyl fumarate. The tablets are film-coated with a non-functional coating containing plasticizers such as polyvinyl alcohol, PEG, titanium dioxide, and other color pigments.

[0126] Figure 14 shows the manufacturing process used for an exemplary pharmaceutical product. A dry granulation process was selected for tablet production to improve blend flowability in the tablet press and weight uniformity of the tablet core formulation. The tablet manufacturing process begins by blending Compound 2, microcrystalline cellulose, mannitol, hypromellose acetate succinate, talc, croscarmellose sodium, and silicon dioxide in a blender. The blended material is passed through a Comil to break down agglomerates, after which sodium stearyl fumarate is added and further blended. The lubricated blend is dry granulated in a roller compactor to increase the material's density, followed by milling. Croscarmellose sodium, silicon dioxide, and sodium stearyl fumarate are added to the milled material, which forms granules representing approximately 97% of the formulation by weight. This granule and extragranular excipient mixture is blended to prepare the final composition for tableting. The tablet cores are compressed using a rotary tablet press. Different tablet strengths can be made by adjusting the tablet weight (e.g., 25 and 100 mg strength tablets). After compression, the tablet cores are coated using an aqueous film coating system in a pan coater.

[0127] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the invention. It is understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. The following claims define the scope of the invention, and it is intended that methods and structures within the scope of these claims and their equivalents be covered therein. Furthermore, the present invention includes the following aspects. [Aspect 1] A solid form of (S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide hydrochloride, represented below as Compound 2, [ka] A crystalline, solid form. [Aspect 2] 2. The solid form of embodiment 1, wherein the solid form exhibits an X-ray powder diffraction reflection with a 2θ value of 19.7°±0.3. [Aspect 3] 3. The solid form of embodiment 2, wherein the solid form exhibits X-ray powder diffraction reflections at 2θ values ​​of 11.1°±0.3 and 21.2°±0.3. [Aspect 4] 4. The solid form of embodiment 2 or 3, exhibiting X-ray powder diffraction reflections at 2θ values ​​of 15.8°±0.3 and 22.0°±0.3. [Aspect 5] A solid form of any one of embodiments 2-4, exhibiting X-ray powder diffraction reflections at 2θ values ​​of 13.9°±0.3, 18.5°±0.3, 21.7°±0.3, and 22.5°±0.3. [Aspect 6] 6. The solid form of any one of embodiments 2-5, wherein the solid form exhibits X-ray powder diffraction reflections at 2θ values ​​of 9.7°±0.3, 23.3°±0.3, and 23.8°±0.3. [Aspect 7] 2. The solid form of embodiment 1, wherein the solid form exhibits at least one X-ray powder diffraction reflection selected from 9.7°±0.3, 11.1°±0.3, 13.9°±0.3, 15.8°±0.3, 18.5°±0.3, 19.7°±0.3, 21.2°±0.3, 21.7°±0.3, 22.0°±0.3, 22.5°±0.3, 23.3°±0.3, and 23.8°±0.3. [Aspect 8] 8. The solid form of embodiment 7, wherein the solid form exhibits at least two X-ray powder diffraction reflections selected from 9.7°±0.3, 11.1°±0.3, 13.9°±0.3, 15.8°±0.3, 18.5°±0.3, 19.7°±0.3, 21.2°±0.3, 21.7°±0.3, 22.0°±0.3, 22.5°±0.3, 23.3°±0.3, and 23.8°±0.3. [Aspect 9] 9. The solid form of embodiment 8, wherein the solid form exhibits at least three X-ray powder diffraction reflections selected from 9.7°±0.3, 11.1°±0.3, 13.9°±0.3, 15.8°±0.3, 18.5°±0.3, 19.7°±0.3, 21.2°±0.3, 21.7°±0.3, 22.0°±0.3, 22.5°±0.3, 23.3°±0.3, and 23.8°±0.3. [Aspect 10] 10. The solid form of embodiment 9, wherein the solid form exhibits at least four X-ray powder diffraction reflections selected from 9.7°±0.3, 11.1°±0.3, 13.9°±0.3, 15.8°±0.3, 18.5°±0.3, 19.7°±0.3, 21.2°±0.3, 21.7°±0.3, 22.0°±0.3, 22.5°±0.3, 23.3°±0.3, and 23.8°±0.3. [Aspect 11] 11. The solid form of embodiment 10, wherein the solid form exhibits at least five X-ray powder diffraction reflections selected from 9.7°±0.3, 11.1°±0.3, 13.9°±0.3, 15.8°±0.3, 18.5°±0.3, 19.7°±0.3, 21.2°±0.3, 21.7°±0.3, 22.0°±0.3, 22.5°±0.3, 23.3°±0.3, and 23.8°±0.3. [Aspect 12] 12. The solid form of embodiment 11, wherein the solid form exhibits at least six X-ray powder diffraction reflections selected from 9.7°±0.3, 11.1°±0.3, 13.9°±0.3, 15.8°±0.3, 18.5°±0.3, 19.7°±0.3, 21.2°±0.3, 21.7°±0.3, 22.0°±0.3, 22.5°±0.3, 23.3°±0.3, and 23.8°±0.3. [Aspect 13] 2. The solid form of embodiment 1, wherein the solid form exhibits X-ray powder diffraction reflections at 2θ values, wherein the crystalline solid state form of Compound 2 exhibits at least one X-ray powder diffraction reflection selected from 20.3°±0.2, 23.4°±0.2, and 24.0°±0.2. [Aspect 14] 4. The solid form of embodiment 1, which exhibits the X-ray powder diffraction pattern shown in FIG. 3. [Aspect 15] 15. The solid form of any one of embodiments 1-14, which exhibits a differential scanning calorimetry thermogram comprising an endothermic peak at 229.9°C ± 5.0°C. [Aspect 16] 15. The solid form of any one of embodiments 1-14, which exhibits the differential scanning calorimetry thermogram shown in FIG. [Aspect 17] 16. The solid form of any one of embodiments 1-15, which exhibits a weight loss of less than 1.0%±0.5 by 160° C.±10.0 as determined by thermogravimetric analysis. [Aspect 18] 16. The solid form of any one of embodiments 1-15, which exhibits the thermogravimetric analysis thermogram shown in FIG. 4. [Aspect 19] A solid form of (S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, represented below as Compound 1,

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Claims

1. A crystalline form of (S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide hydrochloride, represented below as Compound 2, 【Chemistry 1】 The crystal exhibits X-ray powder diffraction reflections at 2θ values ​​of 19.7°±0.2, 11.1°±0.2, 21.2°±0.2, and 15.8°±0.

2.

2. A crystal described in claim 1, wherein the X-ray powder diffraction reflections of the crystal further show an X-ray powder diffraction reflection with a 2θ value of 22.0°±0.

2.

3. A crystal as described in claim 2, wherein the X-ray powder diffraction reflections of the crystal further exhibit X-ray powder diffraction reflections at 2θ values ​​of 13.9°±0.2, 18.5°±0.2, 21.7°±0.2, and 22.5°±0.

2.

4. A crystal as described in claim 1, wherein the X-ray powder diffraction reflections of the crystal further exhibit X-ray powder diffraction reflections at 2θ values ​​of 9.7°±0.2, 23.3°±0.2, and 23.8°±0.

2.

5. The crystal described in claim 1, wherein the crystal exhibits at least five X-ray powder diffraction reflections selected from 9.7°±0.2, 11.1°±0.2, 13.9°±0.2, 15.8°±0.2, 18.5°±0.2, 19.7°±0.2, 21.2°±0.2, 21.7°±0.2, 22.0°±0.2, 22.5°±0.2, 23.3°±0.2, and 23.8°±0.

2.

6. The crystal described in claim 1, wherein the crystal exhibits at least six X-ray powder diffraction reflections selected from 9.7°±0.2, 11.1°±0.2, 13.9°±0.2, 15.8°±0.2, 18.5°±0.2, 19.7°±0.2, 21.2°±0.2, 21.7°±0.2, 22.0°±0.2, 22.5°±0.2, 23.3°±0.2, and 23.8°±0.

2.

7. A crystal described in claim 1 exhibiting the X-ray powder diffraction pattern shown in the figure below.

8. 2. The crystal according to claim 1, which exhibits a differential scanning calorimetry thermogram including an endothermic peak at 229.9°C ± 5.0°C.

9. A crystal described in claim 1, exhibiting a differential scanning calorimetry thermogram as shown in the following figure.

10. 10. The crystal of claim 1, which exhibits a weight loss of less than 1.0%±0.5 up to 160° C.±10.0° C. as determined by thermogravimetric analysis.

11. A crystal described in claim 1, exhibiting the thermogravimetric analysis thermogram shown in the following figure.

12. A crystalline form of (S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide hydrobromide, represented below as Compound 3, 【Chemistry 2】 The crystal exhibits X-ray powder diffraction reflections at 2θ values ​​of 21.9°±0.2, 19.7°±0.2, 21.1°±0.2, and 19.3°±0.

2.

13. A crystalline form of (S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide 4-methylbenzenesulfonate, represented below as Compound 4, 【Transformation 3】 the crystals exhibit X-ray powder diffraction reflections at 2θ values ​​of 6.1°±0.2, 15.0°±0.2, 17.9°±0.2, and 7.1°±0.2; or The crystal exhibits X-ray powder diffraction reflections at 2θ values ​​of 6.8°±0.2, 5.2°±0.2, 6.1°±0.2, and 18.8°±0.

2.

14. A crystalline form of (S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide phosphate, represented below as Compound 5, 【Chemistry 4】 The crystal exhibits X-ray powder diffraction reflections at 2θ values ​​of 6.9°±0.2, 18.3°±0.2, 24.0°±0.2, and 20.7°±0.

2.

15. A crystalline form of (S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide sulfate, represented below as Compound 6, 【Transformation 5】 the crystals exhibit X-ray powder diffraction reflections at 2θ values ​​of 3.2°±0.2, 3.3°±0.2, 6.8°±0.2, and 4.6°±0.2; or The crystal exhibits X-ray powder diffraction reflections at 2θ values ​​of 7.2°±0.2, 14.5°±0.2, 16.1°±0.2, and 15.8°±0.

2.

16. 16. A pharmaceutical composition comprising the crystal of any one of claims 1, 12, 13, 14, or 15 and a pharmaceutically acceptable excipient.

17. 17. The pharmaceutical composition of claim 16, further comprising a disintegrant.

18. 18. The pharmaceutical composition of claim 17, wherein the disintegrant is croscarmellose sodium.

19. A pharmaceutical for inhibiting the receptor tyrosine kinase effector RAF in a subject having a disease requiring inhibition of the receptor tyrosine kinase effector RAF, comprising the crystal of any one of claims 1, 12, 13, 14, or 15.

20. The pharmaceutical composition of claim 19, wherein the disease is cancer or a tumor disease.

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