Crystalline form of (S)-5-((3-(4-(4-fluorophenyl)-1H-imidazol-2-yl)chroman-6-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one

Abstract

The present disclosure relates to (S)-5-((3-(4-(4-fluorophenyl)-1H-imidazol-2-yl)chroman-6-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one [Formula 1] JPEG2025539426000023.jpg58165, or a crystalline form of a salt, solvate or solvate salt thereof.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 428,604, filed November 29, 2022, which is incorporated by reference in its entirety. [Background technology]

[0002] Mutations leading to uncontrolled signaling through the RAS-RAF-MAPK pathway are found in over one-third of all cancers. RAF kinases (A-RAF, B-RAF, and C-RAF) are essential parts of this pathway, and B-RAF mutations are common in clinical trials. While most B-RAF V600E-mutant skin cancers are sensitive to approved B-RAF-selective drugs, B-RAF V600E-mutant colorectal cancers are surprisingly insensitive to these drugs as monotherapy, necessitating combination therapy, due to the function of other RAF family members. B-RAF-selective therapies have failed to demonstrate clinical benefit against atypical B-RAF (non-V600E) and other RAF- and RAS-driven tumors.

[0003] U.S. Patent No. 10,183,939, the disclosure of which is incorporated herein by reference in its entirety, discloses pan-RAF inhibitors that exhibit binding affinity to V600E of B-RAF and C-RAF. These pan-RAF inhibitors have been identified as promising candidates for overcoming resistance mechanisms associated with clinically approved B-RAF-selective drugs.

[0004] Crystallization of an active pharmaceutical ingredient can provide benefits to its physicochemical properties. Such physicochemical properties include, among others, solubility, bioavailability, stability, melting point, flow properties, and hygroscopicity. Therefore, crystalline forms can be advantageous for pharmaceuticals. Therefore, there is a need for crystalline forms of RAF inhibitors. Summary of the Invention

[0005] An embodiment of the present disclosure is Compound I

[0006] [ka] or a crystalline form of a salt, solvate, or salt of a solvate thereof.

[0007] In embodiments, the crystalline form of Compound I is Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, or Form M, or any combination thereof.

[0008] In embodiments, the crystalline form of Compound I is Form A.

[0009] In embodiments, Form A is characterized by peaks in an X-ray powder diffraction (XRPD) pattern at 5.8±0.2, 11.8±0.2, 16.6±0.2, and 23.1±0.2 degrees 2θ. In embodiments, Form A is further characterized by at least one peak in an XRPD pattern selected from 11.4±0.2, 17.3±0.2, 17.5±0.2, 17.9±0.2, and 24.2±0.2 degrees 2θ. In embodiments, Form A has the following concentrations: 5.8±0.2, 6.0±0.2, 7.1±0.2, 9.3±0.2, 11.4±0.2, 11.8±0.2, 14.1±0.2, 16.6±0.2, 17.3±0.2, 17.5±0.2, 17.9±0.2, 18.5±0.2, 19.1±0.2, 19.8±0.2, 20.0±0.2, 21.0±0.2, 22.0±0.2, 23.0±0.2, 24.0±0.2, 25.0±0.2, 26.0±0.2, 27.0±0.2, 28.0±0.2, 29.0±0.2, 30.0±0.2, 31.0±0.2, 32.0±0.2, 33.0±0.2, 34.0±0.2, 35.0±0.2, 36.0±0.2, 37.0±0.2, 38.0±0.2, 39.0±0.2, 40.0±0.2, 41.0±0.2, 42.0±0.2, 43.0±0.2, 44.0±0.2, 45.0±0.2, 46.0±0.2, 47.0±0.2, 48.0±0.2, 49.0±0.2, 50.0±0.2, 51.0±0.2, 52.0±0.2, 53.0±0.2, 54.0±0.2, 55.0±0.2, 56.0 and 35.8±0.2 degrees 2θ. In an embodiment, Form A is characterized by an XRPD pattern substantially similar to the XRPD pattern shown in FIG. 1A.

[0010] In embodiments, Form A exhibits a differential scanning calorimetry (DSC) thermogram comprising peaks at 77±5° C., 243±5° C., 271±5° C., or 285±5° C., or any combination thereof. In embodiments, Form A exhibits a differential scanning calorimetry (DSC) thermogram comprising peaks at 77±5° C., 243±5° C., 245±5° C., 271±5° C., or 285±5° C., or any combination thereof. In embodiments, the peak at 67±5° C. is associated with an enthalpy of 61±5 Joules per gram (J / g); the peak at 239±5° C. is associated with an enthalpy of 78±5 J / g; the peak at 245±5° C. is associated with an enthalpy of 67±5 J / g; and the peak at 277±5° C. is associated with an enthalpy of 84±5 J / g. In embodiments, Form A exhibits a DSC thermogram comprising an endothermic peak with an onset at 46±5° C., 231±5° C., or 271±5° C., or any combination thereof. In embodiments, Form A exhibits a DSC thermogram comprising an exothermic peak with an onset at 242±5° C.

[0011] In embodiments, Form A exhibits a 3% weight loss at a temperature of 120±5° C., a 1% weight loss at 220±5° C., or both, as measured by thermogravimetric (TGA) analysis.

[0012] In an embodiment, Form A is a hydrate.

[0013] In embodiments, the crystalline form of Compound I is Form B. In embodiments, Form B is characterized by peaks in an XRPD pattern at 6.2±0.2, 12.6±0.2, and 23.4±0.2 degrees 2θ. In embodiments, Form B is characterized by an XRPD pattern substantially similar to the XRPD pattern shown in Figure 2A.

[0014] In embodiments, Form B exhibits a DSC thermogram comprising a peak at 71±5° C., or 170±5° C., or a combination thereof. In embodiments, the peak at 71±5° C. is associated with an enthalpy of 107±5 J / g, and the peak at 170±5° C. is associated with an enthalpy of 2±5 J / g. In embodiments, Form B exhibits a DSC thermogram comprising an endothermic peak with an onset at 33±5° C., or 165±5° C., or a combination thereof.

[0015] In an embodiment, Form B exhibits a weight loss of 8% at a temperature of 110±5° C. as determined by TGA analysis.

[0016] In an embodiment, Form B is a hydrate.

[0017] In embodiments, the crystalline form of Compound I is Form C.

[0018] In embodiments, Form C is characterized by peaks in an XRPD pattern at 16.8±0.2, 23.1±0.2, and 24.2±0.2 degrees 2θ. In embodiments, Form C is further characterized by at least one peak in an XRPD pattern selected from 5.8±0.2, 11.5±0.2, 17.2±0.2, 17.5±0.2, and 18.4±0.2 degrees 2θ. In embodiments, Form C has the following concentrations: 5.8±0.2, 7.1±0.2, 9.4±0.2, 11.5±0.2, 11.7±0.2, 12.8±0.2, 14.1±0.2, 16.8±0.2, 17.2±0.2, 17.5±0.2, 17.9±0.2, 18.2±0.2, 18.4±0.2, 19.0±0.2, 19.6±0.2, 20.4±0.2, and 36.2±0.2 °2θ. In an embodiment, Form C is characterized by an XRPD pattern substantially similar to the XRPD pattern shown in Figure 3A.

[0019] In embodiments, Form C exhibits a DSC thermogram comprising peaks at 92±5, 154±5, 231±5, or 242±5°C, or combinations thereof. In embodiments, the peak at 92±5°C is associated with an enthalpy of 301±5 Joules per gram (J / g); the peak at 154±5°C is associated with an enthalpy of 63±5 J / g; the peak at 231±5°C is associated with an enthalpy of 614±5 J / g; and the peak at 242±5°C is associated with an enthalpy of 14±5 J / g. In embodiments, Form C exhibits a DSC thermogram comprising endothermic peaks with onset at 56±5, 133±5, 229±5, or 239±5°C, or any combination thereof.

[0020] In an embodiment, Form C exhibits a weight loss of 16% at a temperature of 75±5° C. as measured by TGA analysis.

[0021] In embodiments, Form C is a hydrate. In embodiments, the solvate is a dimethyl sulfoxide (DMSO) solvate. In embodiments, the solvate is a DMSO / water, dimethylacetamide (DMAc) / water, N-methyl-2-pyrrolidone (NMP), and NMP / water solvate.

[0022] In embodiments, the crystalline form of Compound I is Form D.

[0023] In embodiments, Form D is characterized by peaks in an XRPD pattern at 12.5±0.2, and 23.4±0.2 degrees 2θ. In embodiments, Form D is further characterized by at least one peak in an XRPD pattern selected from 11.5±0.2, 21.3±0.2, and 26.4±0.2 degrees 2θ. In embodiments, Form D is characterized by peaks in an XRPD pattern at 6.1±0.2, 8.9±0.2, 21.3±0.2, 23.4±0.2, and 26.4±0.2 degrees 2θ. In embodiments, Form D is characterized by an XRPD pattern substantially similar to the XRPD pattern shown in Figure 4A.

[0024] In embodiments, Form D exhibits a DSC thermogram comprising a peak at 84±5° C., or 191±5° C., or a combination thereof. In embodiments, the peak at 84±5° C. is associated with an enthalpy of 300±5 J / g, and the peak at 191±5° C. is associated with an enthalpy of 8±5 J / g. In embodiments, Form D exhibits a DSC thermogram comprising an endothermic peak with an onset at 52±5° C., or 179±5° C., or a combination thereof.

[0025] In embodiments, Form D exhibits a 5% weight loss at a temperature of 110±5° C., a 2% weight loss at 170±5° C., or both, as measured by TGA analysis.

[0026] In embodiments, Form D is a solvate. In embodiments, the solvate is a dimethyl sulfoxide (DMSO) solvate.

[0027] In embodiments, the crystalline form of Compound I is Form E.

[0028] In embodiments, Form E is characterized by peaks in an XRPD pattern at 5.8±0.2, 17.4±0.2, and 22.9±0.2 degrees 2θ. In embodiments, Form E is further characterized by at least one peak in an XRPD pattern selected from 11.6±0.2, 16.7±0.2, 17.1±0.2, 23.3±0.2, and 24.0±0.2 degrees 2θ. In embodiments, Form E has the following concentrations: 5.8±0.2, 7.0±0.2, 9.4±0.2, 11.4±0.2, 11.6±0.2, 14.1±0.2, 16.7±0.2, 17.1±0.2, 17.4±0.2, 17.8±0.2, 18.1±0.2, 18.3±0.2, 18.8±0.2, 19.4±0.2, 20.2±0.2, 5A. In an embodiment, Form E is characterized by peaks in an XRPD pattern at 20.9±0.2, 21.1±0.2, 21.8±0.2, 22.1±0.2, 22.9±0.2, 23.3±0.2, 24.0±0.2, 25.4±0.2, 25.9±0.2, 26.3±0.2, 28.3±0.2, 33.3±0.2, and 35.7±0.2 degrees 2θ. In an embodiment, Form E is characterized by an XRPD pattern substantially similar to the XRPD pattern shown in FIG. 5A.

[0029] In embodiments, Form E exhibits a DSC thermogram comprising peaks at 176±5°C, 239±5°C, or 276±5°C, or combinations thereof. In embodiments, the peak at 176±5°C is associated with an enthalpy of 75±5 J / g; the peak at 239±5°C is associated with an enthalpy of 32±5 J / g; and the peak at 276±5°C is associated with an enthalpy of 17±5 J / g. In embodiments, Form E exhibits a DSC thermogram comprising endothermic peaks with onset at 139±5°C, 233±5°C, or 271±5°C, or any combination thereof.

[0030] In embodiments, Form E exhibits a 2% weight loss at a temperature of 80±5° C., a 16% weight loss at 140±5° C., or both, as measured by TGA analysis.

[0031] In an embodiment, Form E is a solvate.

[0032] In embodiments, the crystalline form of Compound I is Form F.

[0033] In embodiments, Form F is characterized by peaks in its XRPD pattern at 13.0±0.2, 17.0±0.2, and 19.3±0.2 degrees 2θ. In embodiments, Form F is further characterized by at least one peak in its XRPD pattern selected from 20.0±0.2, 22.5±0.2, and 23.3±0.2 degrees 2θ. In embodiments, Form E is characterized by peaks at 11.8±0.2, 13.0±0.2, 13.9±0.2, 14.2±0.2, 14.5±0.2, 15.8±0.2, 17.0±0.2, 19.3±0.2, 20.0±0.2, 21.0±0.2, 21.8±0.2, 22.1±0.2, 22.5±0.2, 23.3±0.2, 25. 6A. In an embodiment, Form F is characterized by peaks in an XRPD pattern at: 3±0.2, 25.5±0.2, 26.3±0.2, 26.8±0.2, 27.2±0.2, 27.9±0.2, 28.3±0.2, 30.4±0.2, 31.7±0.2, 32.2±0.2, 32.6±0.2, 35.9±0.2, and 39.5±0.2 degrees 2θ. In an embodiment, Form F is characterized by an XRPD pattern substantially similar to the XRPD pattern displayed in FIG. 6A.

[0034] In an embodiment, Form A exhibits a DSC thermogram comprising a peak at 280±5° C. In an embodiment, the peak at 277±5° C. is associated with an enthalpy of 113±5 J / g. In an embodiment, Form F exhibits a DSC thermogram comprising an endothermic peak with an onset at 269±5° C.

[0035] In an embodiment, Form F exhibits a weight loss of 1% at a temperature of 100±5° C. as measured by TGA analysis.

[0036] In an embodiment, Form F is anhydrous.

[0037] In embodiments, the crystalline form of Compound I is Form G.

[0038] In embodiments, Form G is characterized by peaks in its XRPD pattern at 12.6±0.2, 21.2±0.2, and 23.5±0.2 degrees 2θ. In embodiments, Form G is further characterized by at least one peak in its XRPD pattern selected from 6.2±0.2, 13.4±0.2, 19.0±0.2, 26.2±0.2, and 26.5±0.2 degrees 2θ. In embodiments, Form G is characterized by peaks in its XRPD pattern at 6.2±0.2, 11.4±0.2, 12.6±0.2, 13.4±0.2, 19.0±0.2, 21.2±0.2, 23.5±0.2, 26.2±0.2, 26.5±0.2, 28.0±0.2, 31.4±0.2, and 36.0±0.2 degrees 2θ. In embodiments, Form G is characterized by an XRPD pattern substantially similar to the XRPD pattern shown in Figure 7A.

[0039] In an embodiment, Form G is a solvate. In an embodiment, the solvate is a DMSO solvate.

[0040] In embodiments, the crystalline form of Compound I is Form H.

[0041] In embodiments, Form H is characterized by peaks in an XRPD pattern at 5.7±0.2, 6.0±0.2, and 11.7±0.2 degrees two-theta. In embodiments, Form H is further characterized by at least one peak in an XRPD pattern selected from 7.1±0.2, 11.4±0.2, 17.2±0.2, 23.0±0.2, and 24.0±0.2 degrees two-theta. In embodiments, Form H is characterized by peaks in an XRPD pattern at 5.7±0.2, 6.0±0.2, 7.1±0.2, 9.2±0.2, 11.4±0.2, 11.7±0.2, 14.1±0.2, 16.5±0.2, 17.2±0.2, 17.8±0.2, 18.4±0.2, 19.1±0.2, 19.7±0.2, 20.1±0.2, 20.6±0.2, 22.0±0.2, 23.0±0.2, 24.0±0.2, 25.4±0.2, 26.0±0.2, and 28.2±0.2 degrees 2θ. In embodiments, Form H is characterized by an XRPD pattern substantially similar to the XRPD pattern shown in Figure 8A.

[0042] In an embodiment, Form H is anhydrous.

[0043] In embodiments, the crystalline form of Compound I is Form J.

[0044] In an embodiment, Form J is characterized by peaks in an XRPD pattern at 11.1±0.2, 11.6±0.2, and 17.1±0.2 degrees 2θ.

[0045] In embodiments, Form J is further characterized by at least one peak in an XRPD pattern selected from 5.6±0.2, 6.9±0.2, 16.2±0.2, 17.8±0.2, and 18.3±0.2 degrees 2θ.

[0046] In embodiments, Form J is 5.6±0.2, 6.9±0.2, 9.1±0.2, 11.1±0.2, 11.6±0.2, 12.9±0.2, 13.9±0.2, 16.2±0.2, 16.8±0.2, 17.1±0.2, 17.5±0.2, 17.8±0.2, 18.29±0.2, 19.2±0.2, 19.7±0.2, 20.6±0.2, 21.0±0.2, 21.6±0.2, It is characterized by peaks in the XRPD pattern at 22.4±0.2, 22.9±0.2, 23.4±0.2, 23.9±0.2, 25.9±0.2, 26.2±0.2, 27.5±0.2, 27.7±0.2, 28.0±0.2, 29.0±0.2, 30.1±0.2, 31.0±0.2, 31.7±0.2, 32.9±0.2, 37.2±0.2, and 38.4±0.2 degrees 2θ.

[0047] In embodiments, Form J is characterized by an XRPD pattern substantially similar to the XRPD pattern shown in Figure 10A.

[0048] In embodiments, Form J exhibits a DSC thermogram comprising peaks at 83±5°C, 196±5°C, and 285±5°C.

[0049] In embodiments, the crystalline form of Compound I is Form K.

[0050] In an embodiment, Form K is characterized by peaks in an XRPD pattern at 5.4±0.2, 13.4±0.2, and 17.9±0.2 degrees 2θ.

[0051] In embodiments, Form K is 5.5±0.2, 7.3±0.2, 11.4±0.2, 12.0±0.2, 12.9±0.2, 13.4±0.2, 14.6±0.2, 16.1±0.2, 16.9±0.2, 17.4±0.2, 17.9±0.2, 18.4±0.2, 19.0±0.2, 19.9±0.2, 21.1±0.2, 21.5±0.2, 21.7±0.2, 21.9±0.2, 22.2±0.2, 22.9±0.2 The XRPD patterns are characterized by peaks at ±0.2, 23.2±0.2, 24.1±0.2, 24.8±0.2, 25.1±0.2, 27.8±0.2, 26.3±0.2, 26.7±0.2, 27.3±0.2, 27.6±0.2, 28.5±0.2, 29.7±0.2, 32.5±0.2, 33.9±0.2, 34.7±0.2, 35.3±0.2, 37.3±0.2, and 38.3±0.2 degrees 2θ.

[0052] In an embodiment, Form K is characterized by an XRPD pattern substantially similar to the XRPD pattern shown in FIG.

[0053] In embodiments, the crystalline form of Compound I is Form L.

[0054] In an embodiment, Form L is characterized by peaks in an XRPD pattern at 4.3±0.2, 8.2±0.2, and 8.6±0.2 degrees 2θ.

[0055] In embodiments, Form L is 4.3±0.2, 8.2±0.2, 8.6±0.2, 12.9±0.2, 13.4±0.2, 15.4±0.2, 15.9±0.2, 17.2±0.2, 17.7±0.2, 18.2±0.2, 18.6±0.2, 19.2±0.2, 20.5±0.2, 21.5±0.2, 22.2± The XRPD pattern is characterized by peaks at 0.2, 24.1±0.2, 24.9±0.2, 25.7±0.2, 26.0±0.2, 26.6±0.2, 27.1±0.2, 27.5±0.2, 28.1±0.2, 29.2±0.2, 30.2±0.2, 31.2±0.2, and 38.5±0.2 degrees 2θ.

[0056] In an embodiment, Form L is characterized by an XRPD pattern substantially similar to the XRPD pattern shown in FIG.

[0057] In embodiments, the crystalline form of Compound I is Form M.

[0058] In an embodiment, Form M is characterized by peaks in an XRPD pattern at 7.3±0.2, 10.4±0.2, and 12.7±0.2 degrees 2θ.

[0059] In embodiments, Form M is characterized by peaks in an XRPD pattern at 7.3±0.2, 9.2±0.2, 10.4±0.2, 11.8±0.2, 12.7±0.2, 14.8±0.2, 16.2±0.2, 17.5±0.2, 18.6±0.2, 19.0±0.2, 19.9±0.2, 21.0±0.2, 22.3±0.2, 23.6±0.2, 29.2±0.2, 31.2±0.2, 32.5±0.2, and 33.5±0.2 degrees 2θ.

[0060] In an embodiment, Form M is characterized by an XRPD pattern substantially similar to the XRPD pattern shown in FIG.

[0061] In embodiments, the present disclosure provides a composition comprising a crystalline form of Compound 1 and a pharmaceutically acceptable excipient. [Brief explanation of the drawings]

[0062] [Figure 1A] 1 shows an XRPD diffractogram of a sample of crystalline Form A of Compound I. [Figure 1B] 1 shows a differential scanning calorimetry (DSC) plot of crystalline Form A of Compound I. [Figure 1C] 1 shows a thermogravimetric analysis (TGA) plot of crystalline Form A of Compound I. [Figure 1D] 1 shows a dynamic vapor sorption (DVS) plot of crystalline Form A of Compound I. [Figure 1E] 1 shows the XRPD spectrum of a sample of crystalline form A* of Compound I. [Figure 1F] 1 shows a DCS plot of crystalline form A* of Compound I. [Figure 2A] 1 shows an XRPD diffractogram of a sample of crystalline form B of Compound I. [Figure 2B] 1 shows a DCS plot of crystalline form B of Compound I. [Figure 2C] 1 shows a TGA plot of crystalline form B of Compound I. [Figure 3A] 1 shows an XRPD diffractogram of a sample of crystalline form C of Compound I. [Figure 3B] 1 shows a DCS plot of crystalline Form C of Compound I. [Figure 3C] 1 shows a TGA plot of crystalline Form C of Compound I. [Figure 4A] 1 shows an XRPD diffractogram of a sample of crystalline form D of Compound I. [Figure 4B] 1 shows the DCS plot of crystalline form D of Compound I. [Figure 4C] 1 shows a TGA plot of crystalline form D of Compound I. [Figure 5A] 1 shows an XRPD diffractogram of a sample of crystalline form E of Compound I. [Figure 5B] 1 shows a DCS plot of crystalline form E of Compound I. [Figure 5C] 1 shows a TGA plot of crystalline form E of Compound I. [Figure 6A]1 shows an XRPD diffractogram of a sample of crystalline form F of Compound I. [Figure 6B] 1 shows a DCS plot of crystalline form F of Compound I. [Figure 6C] 1 shows a TGA plot of crystalline form F of Compound I. [Figure 6D] 1 shows a DVS plot of crystalline form F of Compound I. [Figure 7] 1 shows an XRPD diffractogram of a sample of crystalline form G of Compound I. [Figure 8] 1 shows an XRPD diffractogram of a sample of crystalline form H of Compound I. [Figure 9A] 1 shows an XRPD diffractogram of a sample of crystalline Form I of Compound I. [Figure 9B] 1 shows a DCS plot of crystalline Form I of Compound I. [Figure 10A] 1 shows an XRPD diffractogram of a sample of crystalline form J of Compound I. [Figure 10B] 1 shows a DCS plot of crystalline form J of Compound I. [Figure 11] 1 shows an XRPD diffractogram of a sample of crystalline form K of Compound I. [Figure 12] 1 shows an XRPD diffractogram of a sample of crystalline form L of Compound I. [Figure 13] 1 shows an XRPD diffractogram of a sample of crystalline form M of Compound I. [Figure 14A] 1 shows dissolution data for 10 mg capsules containing Form A. [Figure 14B] Dissolution data for capsules containing Form A and 10% Form F are shown. [Figure 14C] 1 shows dissolution data for capsules containing Form F. [Figure 15A] 1 shows dissolution data for 50 mg capsules containing Form A. [Figure 15B] Dissolution data for Form A and capsules containing 10% Form F are shown. [Figure 15C] 1 shows dissolution data for capsules containing Form F. DETAILED DESCRIPTION OF THE INVENTION

[0063] The present disclosure relates to crystalline forms of RAF inhibitors, including crystalline forms A, B, C, D, E, F, G, H, I, J, K, L, and M. Crystalline forms A and F exhibit increased crystallinity and stability compared to crystalline forms C, D, E, F, G, H, I, J, K, L, and M, and crystalline forms A and F are suitable for large-scale manufacturing, meaning that forms A and F have desirable properties for further pharmaceutical development.

[0064] All publications, patents, and patent applications in this specification, including any drawings and exhibits, are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent or patent application, drawing, or exhibit was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.

[0065] definition Although the following terms are believed to be well understood by those of ordinary skill in the art, the following definitions are provided to facilitate the description of the subject matter disclosed herein.

[0066] Compound I is (S)-5-((3-(4-(4-fluorophenyl)-1H-imidazol-2-yl)chroman-6-yl)oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one, having the structure shown below. In an embodiment, Compound I is a pan-RAF inhibitor.

[0067] [ka]

[0068] As used herein, the term "substantially" means greater than 85% (i.e., greater than 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100%).

[0069] The term "substantially similar," as used herein with respect to analytical spectra such as XRPD patterns, means that the spectrum is similar to a reference spectrum in both peak positions and their relative intensities, allowing for appropriate variability within the art. For example, two spectra may be considered "substantially similar" if they share sufficient defining characteristics to distinguish them from spectra obtained with different solid forms. In embodiments, spectra or characterization data that are substantially similar to those of a reference crystalline form would be understood by one of skill in the art to correspond to the same crystalline form as the particular reference. When analyzing whether spectra or characterization data are substantially similar, one of skill in the art will understand that certain characterization data points may vary within reasonable limits while describing a given solid form, for example, due to experimental error or routine sample-to-sample analysis.

[0070] Polymorphism can be characterized as the ability of a compound to crystallize into different crystalline forms while maintaining the same chemical formula. Polymorphs of a given drug substance are chemically identical to other polymorphs of that drug substance in that the same atoms are bonded to each other in the same way, but their lattice arrangements differ, which may affect one or more physical properties such as stability, solubility, melting point, bulk density, flow properties, and bioavailability.

[0071] The term "effective" is used to describe an amount of a compound, composition, or ingredient that, when used in the context of its intended use, produces an intended result. The term "effective" encompasses all other effective amount or effective concentration terms described or used herein.

[0072] As used herein, the phrase "therapeutically effective amount" and like phrases refer to the amount necessary to administer to a patient, or to a patient's cells, tissues, or organs, to obtain a therapeutic effect, such as an ameliorative or curative effect in the treatment of cancer. A therapeutically effective amount is an amount sufficient to elicit the biological or medical response in a cell, tissue, system, animal, or human that is desired by a researcher, veterinarian, physician, or clinician.

[0073] All XRPD peaks and patterns are expressed in degrees 2θ using Cu Kα1 radiation with a wavelength of 1.5406 Å. The values ​​of degrees 2θ allow for a reasonable margin of error. For example, a degree 2θ of approximately 17.48±0.2 indicates a range of approximately 17.46 to 17.50 degrees 2θ. Depending on sample preparation techniques, calibration techniques applied to the instrument, and operational variations, those skilled in the art will recognize that a reasonable margin of error for XRPD is ±0.2, including any value less than ±0.2, such as ±0.1.

[0074] TGA and DSC thermograms of a given crystalline form of the same compound can differ within a range of error. The value of a single peak, expressed in degrees Celsius, provides an appropriate error range. Typically, the error range is expressed as "±." For example, a single peak characteristic value of "120±5" indicates a range of 115 to 125. Depending on sample preparation techniques, calibration techniques applied to the instrument, and human operating variability, those skilled in the art will recognize that an appropriate error range for a single peak characteristic value may be ±5, including any value below ±5, such as ±4, ±3.5, ±3, ±2.5; ±2.0; ±1.5; ±1.0; or less than ±0.5.

[0075] The following description contains information that may be useful in understanding the present invention. No admission is made that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.

[0076] Crystalline Form of Compound I Aspects of the present disclosure relate to crystalline forms of Compound I, or a salt, solvate, or solvated salt thereof. In embodiments, the crystalline form of Compound I is Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, or any combination thereof.

[0077] In embodiments, the crystalline form of Compound I (Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, or Form M) is a salt. Examples of salts include, but are not limited to, hydrochloride, maleate, fumarate, citrate, malate, sulfate, acetate, phosphate, L-(+)-tartrate, D-glucuronate, benzoate, succinate, ethanesulfonate, methanesulfonate, p-toluenesulfonate, malonate, benzenesulfonate, and 1-hydroxy-2-naphthoate.

[0078] In embodiments, the crystalline forms of Compound I (Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, and / or Form M) are solvates. Non-limiting examples of suitable solvates include dimethylformamide (DMF), acetone, dimethyl sulfoxide (DMSO), methanol, isopropanol, ethanol, and ethyl acetate.

[0079] In embodiments, the crystalline form of Compound I (Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, or Form M) is anhydrous.

[0080] In embodiments, the crystalline form of Compound I (Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, or Form M) is a hydrate. Non-limiting examples of hydrates include a hemihydrate, a monohydrate, a dihydrate, a trihydrate, and a hexahydrate.

[0081] In embodiments, the crystalline form of Compound I may consist of a mixture of one or more forms (e.g., Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, or Form M) of Compound I. In some embodiments, the crystalline form of Compound I may consist of a substantially pure form of one form of Compound I.

[0082] In embodiments, a crystalline form of Compound I may consist of more than about 99.9%, more than about 99.8%, more than about 99.7%, more than about 99.6%, more than about 99.5%, more than about 99.4%, more than about 99.3%, more than about 99.2%, more than about 99.1%, or more than about 99.0% of a form of Compound I (e.g., Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, and / or Form M).

[0083] In embodiments, a crystalline form of Compound I may consist of greater than about 99%, greater than 98%, greater than 97%, greater than 96%, greater than 95%, greater than 94%, greater than 93%, greater than 92%, greater than 91%, or greater than 90% of a form of Compound I. In some embodiments, a crystalline form of Compound I may consist of greater than about 90%, greater than 85%, greater than 80%, greater than 75%, greater than 70%, greater than 65%, greater than 60%, greater than 55%, greater than 50%, greater than 45%, or greater than 40% of a form of Compound I (e.g., Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, and / or Form M).

[0084] I. Form A In embodiments, the crystalline form of Compound I is Form A.

[0085] In an embodiment, Form A is characterized by peaks in its XRPD pattern at 5.8±0.2, 11.8±0.2, 23.1±0.2, and 24.2±0.2 degrees 2θ. In an embodiment, the variance around any of these peaks is ±0.1 degrees 2θ.

[0086] In an embodiment, Form A is characterized by peaks in an XRPD pattern at 11.8±0.2, 23.1±0.2, and 24.2±0.2 degrees 2θ, and at least one peak in the XRPD pattern selected from 5.8±0.2, 11.4±0.2, 17.3±0.2, 17.5±0.2, and 17.9±0.2 degrees 2θ (e.g., 1, 2, 3, 4, or 5). In an embodiment, the variance around any of these peaks is ±0.1 degrees 2θ.

[0087] In embodiments, Form A is 5.8±0.2, 6.0±0.2, 7.1±0.2, 9.3±0.2, 11.4±0.2, 11.8±0.2, 14.1±0.2, 16.6±0.2, 17.3±0.2, 17.5±0.2, 17.9±0.2, 18.5±0.2, 19.1±0.2, 19.8±0.2, 20.0±0.2, 21.0±0.2, 22.0±0.2, 23.0±0.2, 24.0±0.2, 25.0±0.2, 26.0±0.2, 27.0±0.2, 28.0±0.2, 29.0±0.2, 30.0±0.2, 31.0±0.2, 32.0±0.2, 33.0±0.2, 34.0±0.2, 35.0±0.2, 36.0±0.2, 37.0±0.2, 38.0±0.2, 39.0±0.2, 40.0±0.2, 41.0±0.2, 42.0±0.2, 43.0±0.2, 44.0±0.2, 45.0±0.2, 46.0±0.2, 47.0±0.2, 48.0±0.2, 49.0±0.2, 50.0±0.2, 51.0±0.2, 52.0±0.2, 53.0±0.2, 54.0±0.2, 55.0±0.2, 56.0±0.2 and 35.8±0.2 degrees 2Θ. In an embodiment, the variance at any of these peaks is ±0.1 degrees 2Θ.

[0088] In an embodiment, Form A is characterized by peaks in an XRPD pattern at 11.8±0.2, 23.1±0.2, and 24.2±0.2 degrees 2θ.

[0089] In embodiments, Form A is characterized by peaks in an XRPD pattern at 11.8±0.1, 23.1±0.1, and 24.2±0.1 degrees 2θ, and at least one peak in an XRPD pattern selected from 5.8±0.1, 11.4±0.1, 17.3±0.1, 17.5±0.1, and 17.9±0.1 degrees 2θ (e.g., 1, 2, 3, 4, or 5).

[0090] In embodiments, Form A is 5.8±0.1, 6.0±0.1, 7.1±0.1, 9.3±0.1, 11.4±0.1, 11.8±0.1, 14.1±0.1, 16.6±0.1, 17.3±0.1, 17.5±0.1, 17.9±0.1, 18.5±0.1, 19.1±0.1, 19.8±0.1, 20.0±0.1, 21.0±0.1, 22.0±0.1, 23.0±0.1, 24.0±0.1, 25.0±0.1, 26.0±0.1, 27.0±0.1, 28.0±0.1, 29.0±0.1, 30.0±0.1, 31.0±0.1, 32.0±0.1, 33.0±0.1, 34.0±0.1, 35.0±0.1, 36.0±0.1, 37.0±0.1, 38.0±0.1, 39.0±0.1, 40.0±0.1, 41.0±0.1, 42.0±0.1, 43.0±0.1, 44.0±0.1, 45.0±0.1, 46.0±0.1, 47.0±0.1, 48.0±0.1, 49.0±0.1, 50.0±0.1, 51.0±0.1, 52.0±0.1, 53.0±0.1, 54.0±0.1, 55.0±0.1, 56.0±0.1 It is characterized by peaks in the XRPD pattern at 0.7±0.1, 21.3±0.1, 21.6±0.1, 22.1±0.1, 23.1±0.1, 24.2±0.1, 25.6±0.1, 26.1±0.1, 26.5±0.1, 27.3±0.1, 28.4±0.1, and 35.8±0.1 degrees 2θ.

[0091] In embodiments, Form A is characterized by at least one peak in an XRPD pattern selected from 5.8±0.2, 7.1±0.2, 9.3±0.2, 11.4±0.2, 11.8±0.2, 14.1±0.2, 16.6±0.2, 17.3±0.2, 17.5±0.2, 17.9±0.2, 18.5±0.2, 20.7±0.2, 21.3±0.2, 21.6±0.2, 22.1±0.2, 24.2±0.2, 25.6±0.2, 27.3±0.2, 28.4±0.2, and 35.8±0.2 degrees 2θ that is not present in Form B described herein.

[0092] In embodiments, Form A is characterized by at least one peak in an XRPD pattern selected from 5.8±0.2 or 27.3±0.2 degrees 2θ that is not present in Form C described herein.

[0093] In embodiments, Form A is characterized by at least one peak in an XRPD pattern selected from 9.3±0.2, 14.1±0.2, 20.7±0.2, 22.1±0.2, 25.6±0.2, 27.3±0.2, 28.4±0.2, or 35.8±0.2 degrees 2θ that is not present in Form D described herein.

[0094] In embodiments, Form A is characterized by a peak in its XRPD pattern at 27.3±0.2 degrees 2θ that is not present in Form E described herein.

[0095] In embodiments, Form A is characterized by at least one peak in an XRPD pattern selected from 5.8±0.2, 6.0±0.2, 7.1±0.2, 9.3±0.2, 17.5±0.2, 17.9±0.2, or 18.5±0.2 degrees 2θ that is not present in Form F described herein.

[0096] In embodiments, Form A is characterized by at least one peak in an XRPD pattern selected from 7.1±0.2, 9.3±0.2, 14.1±0.2, 17.3±0.2, 17.5±0.2, 17.9±0.2, 18.5±0.2, 19.8±0.2, 20.7±0.2, 22.1±0.2, 23.1±0.2, 24.2±0.2, 25.6±0.2, or 27.3±0.2 degrees 2θ that is not present in Form G described herein.

[0097] In embodiments, Form A is characterized by at least one peak in an XRPD pattern selected from 17.9±0.2, 26.5±0.2, or 35.8±0.2 degrees 2θ that is not present in Form H described herein.

[0098] In embodiments, Form A is characterized by an XRPD pattern substantially similar to the XRPD pattern shown in Figure 1A.

[0099] In embodiments, Form A is characterized by an XRPD pattern comprising the peaks shown in Table 1.

[0100] In embodiments, Form A is characterized by having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or more XRPD peaks listed in Table 1.

[0101] In embodiments, Form A exhibits a DSC thermogram comprising peaks at 67±5, 239±5, 245±5, or 277±5° C., or any combination thereof. In embodiments, the peak at 67±5° C. is associated with an enthalpy of 61±5 Joules per gram (J / g); the peak at 239±5° C. is associated with an enthalpy of 78±5 J / g; the peak at 245±5° C. is associated with an enthalpy of 67±5 J / g; and the peak at 277±5° C. is associated with an enthalpy of 84±5 J / g.

[0102] In embodiments, Form A exhibits a DSC thermogram comprising an endothermic peak with an onset at 46±5° C., 231±5° C., or 271±5° C., or any combination thereof. In embodiments, Form A exhibits a DSC thermogram comprising an exothermic peak with an onset at 242±5° C.

[0103] In embodiments, Form A exhibits a DSC thermogram comprising peaks at 67±3, 239±3, 245±3, or 277±3° C., or any combination thereof. In embodiments, the peak at 67±5° C. is associated with an enthalpy of 61±5 J / g, the peak at 239±3° C. is associated with an enthalpy of 78±5 J / g; the peak at 245±3° C. is associated with an enthalpy of 67±5 J / g; and the peak at 277±3° C. is associated with an enthalpy of 84±5 J / g.

[0104] In embodiments, Form A exhibits a DSC thermogram comprising an endothermic peak with an onset at 46±3° C., 231±3° C., or 271±3° C., or any combination thereof. In embodiments, Form A exhibits a DSC thermogram comprising an exothermic peak with an onset at 242±3° C.

[0105] In embodiments, Form A exhibits a DSC thermogram substantially similar to the DSC thermogram shown in Figure 1B.

[0106] In embodiments, Form A exhibits a weight loss of about 1% to about 10% at a temperature of 120±5° C. as measured by thermogravimetric (TGA) analysis. For example, Form A exhibits a weight loss of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% (including all values ​​therebetween) at a temperature of 120±5° C. as measured by TGA.

[0107] In embodiments, Form A exhibits a weight loss of about 0.01% to about 5% as measured by TGA analysis at 220±5° C. For example, Form A exhibits a weight loss of about 0.01%, about 0.1%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, or about 5% (including all values ​​therebetween) at a temperature of 220±5° C. as measured by TGA.

[0108] In embodiments, Form A exhibits substantially no weight loss at a temperature of 220±5° C. as determined by TGA analysis.

[0109] In embodiments, Form A exhibits a weight loss of about 1% to about 10% at a temperature of 120±5° C., a weight loss of about 0.01% to about 5% at 220±5° C., or both, as measured by TGA analysis.

[0110] In embodiments, Form A exhibits a 3% weight loss at a temperature of 120±3° C., a 1% weight loss at 220±3° C., or both, as measured by TGA analysis.

[0111] In embodiments, Form A exhibits a TGA thermogram substantially similar to the TGA thermogram shown in Figure 1C.

[0112] II.Form B In embodiments, the crystalline form of Compound I is Form B.

[0113] In an embodiment, Form B is characterized by a peak in an XRPD pattern at 39.1±0.2 degrees 2θ.

[0114] In an embodiment, Form B is characterized by peaks in its XRPD pattern at 12.7±0.2, 13.4±0.2, and 23.4±0.2 degrees 2θ. In an embodiment, the variance around any of these peaks is ±0.1 degrees 2θ.

[0115] In embodiments, the crystalline form of Compound I is Form B. In embodiments, Form B is characterized by peaks in its XRPD pattern at 6.2±0.2, 12.6±0.2, and 23.4±0.2 degrees 2θ. In embodiments, the variance around any of these peaks is ±0.1 degrees 2θ.

[0116] In an embodiment, Form B is characterized by peaks in an XRPD pattern at 12.7±0.2, 13.4±0.2, and 23.4±0.2 degrees 2θ, and at least one peak in the XRPD pattern selected from 6.2±0.2, 13.6±0.2, 23.3±0.2, 26.1±0.2, and 26.3±0.2 degrees 2θ (e.g., 1, 2, 3, 4, or 5). In an embodiment, the variance around any of these peaks is ±0.1 degrees 2θ.

[0117] In an embodiment, Form B is characterized by peaks in its XRPD pattern at 6.2±0.2, 12.7±0.2, 13.4±0.2, 13.6±0.2, 19.0±0.2, 19.8±0.2, 23.3±0.2, 23.4±0.2, 26.1±0.2, 26.3±0.2, and 39.1±0.2 degrees 2θ. In an embodiment, the variance around any of these peaks is ±0.1 degrees 2θ.

[0118] In an embodiment, Form B is characterized by peaks in an XRPD pattern at 12.7±0.1, 13.4±0.1, and 23.4±0.1 degrees 2θ.

[0119] In an embodiment, Form B is characterized by peaks in an XRPD pattern at 12.7±0.1, 13.4±0.1, and 23.4±0.1 degrees 2θ, and at least one peak in an XRPD pattern selected from 6.2±0.1, 13.6±0.1, 23.3±0.1, 26.1±0.1, and 26.3±0.1 degrees 2θ (e.g., 1, 2, 3, 4, or 5).

[0120] In an embodiment, Form B is characterized by peaks in an XRPD pattern at 6.2±0.1, 12.7±0.1, 13.4±0.1, 13.6±0.1, 19.0±0.1, 19.8±0.1, 23.3±0.1, 23.4±0.1, 26.1±0.1, 26.3±0.1, and 39.1±0.1 degrees 2θ.

[0121] In embodiments, Form B is characterized by an XRPD pattern substantially similar to the XRPD pattern shown in Figure 2A.

[0122] In embodiments, Form B is characterized by an XRPD pattern comprising the peaks shown in Table 4.

[0123] In embodiments, Form B is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or more XRPD peaks listed in Table 4.

[0124] In embodiments, Form B is characterized by at least one peak in an XRPD pattern selected from 12.7±0.2, 13.4±0.2, 13.6±0.2, or 39.1±0.2 degrees 2θ that is not present in Form A described herein.

[0125] In embodiments, Form B is characterized by at least one peak in an XRPD pattern selected from 13.4±0.2, 13.6±0.2, or 39.1±0.2 degrees 2θ that is not present in Form C described herein.

[0126] In embodiments, Form B is characterized by at least one peak in an XRPD pattern selected from 13.62±0.2 or 39.11±0.2 degrees 2θ that is not present in Form D described herein.

[0127] In embodiments, Form B is characterized by at least one peak in an XRPD pattern selected from 12.6±0.2, 13.4±0.2, 13.6±0.2, or 39.1±0.2 degrees 2θ that is not present in Form E described herein.

[0128] In embodiments, Form B is characterized by at least one peak in an XRPD pattern selected from 6.2±0.2, 13.4±0.2, or 39.11±0.2 degrees 2θ that is not present in Form F described herein.

[0129] In embodiments, Form B is characterized by at least one peak in an XRPD pattern selected from 19.8±0.2 or 39.1±0.2 degrees 2θ that is not present in Form G described herein.

[0130] In embodiments, Form B is characterized by at least one peak in an XRPD pattern selected from 6.2±0.2, 12.7±0.2, 13.4±0.2, 13.6±0.2, or 39.1±0.2 degrees 2θ that is not present in Form H described herein.

[0131] In embodiments, Form B is characterized by at least one peak in an XRPD pattern selected from 6.2±0.2, 12.7±0.2, 13.4±0.2, 13.6±0.2, or 39.1±0.2 degrees 2θ that is not present in Form H described herein.

[0132] In an embodiment, Form B exhibits a DSC thermogram comprising a peak at 71±5° C., or 170±5° C., or a combination thereof. In an embodiment, the peak at 71±5° C. is associated with an enthalpy of 107±5 J / g, and the peak at 170±5° C. is associated with an enthalpy of 2±5 J / g.

[0133] In embodiments, Form B exhibits a DSC thermogram comprising an endothermic peak with an onset at 33±5° C., or 165±5° C., or a combination thereof.

[0134] In an embodiment, Form B exhibits a DSC thermogram comprising a peak at 71±3° C., or 170±3° C., or a combination thereof. In an embodiment, the peak at 71±3° C. is associated with an enthalpy of 107±3 J / g, and the peak at 170±3° C. is associated with an enthalpy of 2±3 J / g.

[0135] In embodiments, Form B exhibits a DSC thermogram comprising an endothermic peak with an onset at 33±3° C., or 165±3° C., or a combination thereof.

[0136] In embodiments, Form B exhibits a DSC thermogram substantially similar to the DSC thermogram shown in Figure 2B.

[0137] In embodiments, Form B exhibits a weight loss of about 5% to about 15% at a temperature of 110±5° C., as measured by TGA analysis. For example, Form B exhibits a weight loss of about 5%, about 7%, about 9%, about 11%, about 13%, or about 15% (including all values ​​therebetween) at a temperature of 110±5° C., as measured by TGA.

[0138] In an embodiment, Form B exhibits a weight loss of 8% at a temperature of 110±5° C. as determined by TGA analysis.

[0139] In embodiments, Form B exhibits a TGA thermogram substantially similar to the TGA thermogram shown in Figure 2C.

[0140] III.Form C In embodiments, the crystalline form of Compound I is Form C.

[0141] In an embodiment, Form C is characterized by peaks in its XRPD pattern at 3.6±0.2 and / or 4.23.6±0.2 degrees 2θ. In an embodiment, the variance around either of these peaks is ±0.1 degrees 2θ.

[0142] In an embodiment, Form C is characterized by peaks in its XRPD pattern at 16.8±0.2, 23.1±0.2, and 24.2±0.2 degrees 2θ. In an embodiment, the variance around any of these peaks is ±0.1 degrees 2θ.

[0143] In embodiments, Form C is characterized by peaks in its XRPD pattern at 16.8±0.2, 23.1±0.2, and 24.2±0.2 degrees 2θ, and at least one peak in its XRPD pattern selected from 5.8±0.2, 11.5±0.2, 17.2±0.2, 17.5±0.2, and 18.4±0.2 degrees 2θ (e.g., 1, 2, 3, 4, or 5). In embodiments, the variance around any of these peaks is ±0.1 degrees 2θ.

[0144] In embodiments, Form C has the following concentrations: 3.6±0.2, 4.2±0.2, 5.8±0.2, 7.1±0.2, 9.4±0.2, 11.5±0.2, 11.7±0.2, 12.8±0.2, 14.1±0.2, 16.8±0.2, 17.2±0.2, 17.5±0.2, 17.9±0.2, 18.2±0.2, 18.4±0.2, 19.0±0.2, 19.6±0.2, 20.4±0.2 and 36.2±0.2 degrees 2θ. In an embodiment, the variance at any of these peaks is ±0.1 degrees 2θ.

[0145] In an embodiment, Form C is characterized by peaks in an XRPD pattern at 16.8±0.1, 23.1±0.1, and 24.2±0.1 degrees 2θ.

[0146] In embodiments, Form C is characterized by peaks in an XRPD pattern at 16.8±0.1, 23.1±0.1, and 24.2±0.1 degrees 2θ, and at least one peak in an XRPD pattern selected from 5.8±0.1, 11.5±0.1, 17.2±0.1, 17.5±0.1, and 18.4±0.1 degrees 2θ (e.g., 1, 2, 3, 4, or 5).

[0147] In embodiments, Form C is 3.6±0.1, 4.2±0.1, 5.8±0.1, 7.1±0.1, 9.4±0.1, 11.5±0.1, 11.7±0.1, 12.8±0.1, 14.1±0.1, 16.8±0.1, 17.2±0.1, 17.5±0.1, 17.9±0.1, 18.2±0.1, 18.4±0.1, 19.0±0.1, 19.6±0.1, 20.4±0.1 The XRPD pattern is characterized by peaks at 0.1, 21.3±0.1, 22.1±0.1, 22.6±0.1, 23.1±0.1, 23.4±0.1, 24.2±0.1, 25.7±0.1, 26.2±0.1, 26.6±0.1, 28.5±0.1, 30.3±0.1, 31.0±0.1, 32.4±0.1, 34.0±0.1, and 36.2±0.1 degrees 2θ.

[0148] In embodiments, Form C is characterized by at least one peak in an XRPD pattern selected from 3.6±0.2, 4.2±0.2, 12.8±0.2, 22.6±0.2, 30.3±0.2, 31.0±0.2, 32.4±0.2, or 33.5±0.2 degrees 2θ that is not present in Form A described herein.

[0149] In embodiments, Form A is absent from Form B described herein, 3.6±0.2, 4.2±0.2, 7.1±0.2, 9.4±0.2, 11.5±0.2, 11.7±0.2, 12.8±0.2, 14.1±0.2, 16.8±0.2, 17.2±0.2, 17.5±0.2, 17.9±0.2, 18.2±0.2, 18. 4±0.2, 20.4±0.2, 21.3±0.2, 22.1±0.2, 22.6±0.2, 24.2±0.2, 25.7±0.2, 28.5±0.2, 30.3±0.2, 31.0±0.2, 32.4±0.2, 33.5±0.2, or 36.2±0.2 degrees 2θ.

[0150] In embodiments, Form C is characterized by at least one peak in an XRPD pattern selected from 3.6±0.2, 4.2±0.2, 9.4±0.2, 14.1±0.2, 20.4±0.2, 22.1±0.2, 22.6±0.2, 28.5±0.2, 30.3±0.2, 31.0±0.2, 32.4±0.2, 33.5±0.2, or 36.3±0.2 degrees 2θ that is not present in Form D described herein.

[0151] In embodiments, Form C is characterized by at least one peak in an XRPD pattern selected from 3.6±0.2, 4.2±0.2, 12.8±0.2, 30.3±0.2, 31.0±0.2, 32.4±0.2, or 36.2±0.2 degrees 2θ that is not present in Form E described herein.

[0152] In embodiments, Form C is characterized by at least one peak in an XRPD pattern selected from 3.6±0.2, 4.2±0.2, 5.8±0.2, 7.1±0.2, 9.4±0.2, 17.5±0.2, 17.9±0.2, 18.2±0.2, 18.4±0.2, or 31.0±0.2, 33.5±0.2 degrees 2θ that is not present in Form F described herein.

[0153] In embodiments, Form C is characterized by at least one peak in an XRPD pattern selected from 3.6±0.2, 4.2±0.2, 7.1±0.2, 9.4±0.2, 14.1±0.2, 16.8±0.2, 17.2±0.2, 17.5±0.2, 17.9±0.2, 18.2±0.2, 18.4±0.2, 22.1±0.2, 22.6±0.2, 24.2±0.2, 25.7±0.2, 28.5±0.2, 30.3±0.2, 32.4±0.2, or 33.5±0.2 degrees 2θ that is not present in Form G described herein.

[0154] In embodiments, Form C is characterized by at least one peak in an XRPD pattern selected from 3.6±0.2, 4.2±0.2, 12.8±0.2, 26.6±0.2, 31.0±0.2, 32.4±0.2, 33.5±0.2, or 36.2±0.2 degrees 2θ that is not present in Form H described herein.

[0155] In embodiments, Form C is characterized by an XRPD pattern substantially similar to the XRPD pattern shown in Figure 3A.

[0156] In embodiments, Form C is characterized by an XRPD pattern comprising the peaks shown in Table 5.

[0157] In embodiments, Form C is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or more XRPD peaks listed in Table 5.

[0158] In embodiments, Form C exhibits a DSC thermogram comprising peaks at 92±5, 154±5, 231±5, or 242±5° C., or combinations thereof. In embodiments, the peak at 92±5° C. is associated with an enthalpy of 301±5 J / g; the peak at 154±5° C. is associated with an enthalpy of 63±5 J / g; the peak at 231±5° C. is associated with an enthalpy of 14±5 J / g; and the peak at 242±5° C. is associated with an enthalpy of 14±5 J / g.

[0159] In embodiments, Form C is characterized by a DSC thermogram comprising an endothermic peak with an onset at 56±5, 133±5, 229±5, or 239±5° C., or any combination thereof.

[0160] In embodiments, Form C exhibits a DSC thermogram comprising peaks at 92±3, 154±3, 231±3, or 242±3° C., or combinations thereof. In embodiments, the peak at 92±3° C. is associated with an enthalpy of 301±5 J / g; the peak at 154±3° C. is associated with an enthalpy of 63±5 J / g; the peak at 231±3° C. is associated with an enthalpy of 14±5 J / g; and the peak at 242±3° C. is associated with an enthalpy of 14±5 J / g.

[0161] In embodiments, Form C is characterized by a DSC thermogram comprising an endothermic peak with an onset at 56±3, 133±3, 229±3, or 239±3° C., or any combination thereof.

[0162] In embodiments, Form C exhibits a DSC thermogram substantially similar to the DSC thermogram shown in Figure 3B.

[0163] In embodiments, Form C exhibits a weight loss of about 10% to about 20% at a temperature of 75±5° C., as measured by TGA analysis. For example, Form C exhibits a weight loss of about 10%, about 12%, about 14%, about 16%, about 18%, or about 20% (including all values ​​therebetween) at a temperature of 75±5° C., as measured by TGA.

[0164] In an embodiment, Form C exhibits a weight loss of 16% at a temperature of 75±5° C. as measured by TGA analysis.

[0165] In embodiments, Form C exhibits a TGA thermogram substantially similar to the TGA thermogram shown in Figure 3C.

[0166] IV.Form D In embodiments, the crystalline form of Compound I is Form D.

[0167] In an embodiment, Form D is characterized by peaks in its XRPD pattern at 5.8±0.2, 11.8±0.2, and 23.1±0.2 degrees 2θ. In an embodiment, the variance around any of these peaks is ±0.1 degrees 2θ.

[0168] In an embodiment, Form D is characterized by peaks in an XRPD pattern at 5.8±0.2, 11.8±0.2, and 23.1±0.2 degrees 2θ, and at least one peak in the XRPD pattern selected from 11.7±0.2, 12.5±0.2, 17.3±0.2, 23.4±0.2, and 24.1±0.2 degrees 2θ (e.g., 1, 2, 3, 4, or 5). In an embodiment, the variance around any of these peaks is ±0.1 degrees 2θ.

[0169] In embodiments, Form D is characterized by peaks in its XRPD pattern at 5.8±0.2, 6.0±0.2, 7.2±0.2, 8.9±0.2, 11.7±0.2, 11.8±0.2, 12.5±0.2, 13.0±0.2, 16.9±0.2, 17.3±0.2, 17.8±0.2, 18.5±0.2, 19.1±0.2, 19.7±0.2, 21.3±0.2, 23.1±0.2, 23.4±0.2, 24.1±0.2, 26.2±0.2, and 26.4±0.2 degrees 2θ. In embodiments, the variance around any of these peaks is ±0.1 degrees 2θ.

[0170] In an embodiment, Form D is characterized by peaks in an XRPD pattern at 5.8±0.1, 11.8±0.1, and 23.1±0.1 degrees 2θ.

[0171] In embodiments, Form D is characterized by peaks in an XRPD pattern at 5.8±0.1, 11.8±0.1, and 23.1±0.1 degrees 2θ, and at least one peak in an XRPD pattern selected from 11.7±0.1, 12.5±0.1, 17.3±0.1, 23.4±0.1, and 24.1±0.1 degrees 2θ (e.g., 1, 2, 3, 4, or 5).

[0172] In embodiments, Form D is characterized by peaks in an XRPD pattern at 5.8±0.1, 6.0±0.1, 7.2±0.1, 8.9±0.1, 11.7±0.1, 11.8±0.1, 12.5±0.1, 13.0±0.1, 16.9±0.1, 17.3±0.1, 17.8±0.1, 18.5±0.1, 19.1±0.1, 19.7±0.1, 21.3±0.1, 23.1±0.1, 23.4±0.1, 24.1±0.1, 26.2±0.1, and 26.4±0.1 degrees 2θ.

[0173] In embodiments, Form D is characterized by peaks in an XRPD pattern at 12.5±0.2, and 23.4±0.2 degrees 2θ. In embodiments, Form D is further characterized by at least one peak in an XRPD pattern selected from 11.5±0.2, 21.3±0.2, and 26.4±0.2 degrees 2θ. In embodiments, Form D is characterized by peaks in an XRPD pattern at 6.1±0.2, 8.9±0.2, 21.3±0.2, 23.4±0.2, and 26.4±0.2 degrees 2θ.

[0174] In embodiments, Form D is characterized by at least one peak in an XRPD pattern selected from 12.5±0.2 and 13.0±0.2 degrees 2θ that is not present in Form A described herein.

[0175] In embodiments, Form D is characterized by at least one peak in an XRPD pattern selected from 7.2±0.2, 8.9±0.2, 11.7±0.2, 11.8±0.2, 12.5±0.2, 16.9±0.2, 17.3±0.2, 17.8±0.2, 18.5±0.2, 19.1±0.2, 21.3±0.2, or 24.1±0.2 degrees 2θ that is not present in Form B described herein.

[0176] In embodiments, Form D is characterized by an XRPD pattern at 8.9±0.2 degrees 2θ, which is not present in Form C described herein.

[0177] In embodiments, Form D is characterized by at least one peak in an XRPD pattern selected from 8.9±0.2, 12.5±0.2, or 13.0±0.2 degrees 2θ that is not present in Form E described herein.

[0178] In embodiments, Form D is characterized by at least one peak in an XRPD pattern selected from 5.8±0.2, 6.0±0.2, 7.2±0.2, 8.9±0.2, 12.5±0.2, 13.0±0.2, 17.8±0.2, or 18.5±0.2 degrees 2θ that is not present in Form F described herein.

[0179] In embodiments, Form D is characterized by at least one peak in an XRPD pattern selected from 7.2±0.2, 8.9±0.2, 16.9±0.2, 17.3±0.2, 17.8±0.2, 18.5±0.2, or 24.1±0.2 degrees 2θ that is not present in Form G described herein.

[0180] In embodiments, Form D is characterized by at least one peak in an XRPD pattern selected from 12.5±0.2, 13.04±0.2, 26.2±0.2, or 26.4±0.2 degrees 2θ that is not present in Form H described herein.

[0181] In embodiments, Form D is characterized by an XRPD pattern substantially similar to the XRPD pattern shown in Figure 4A.

[0182] In embodiments, Form D is characterized by an XRPD pattern comprising the peaks shown in Table 6.

[0183] In embodiments, Form D is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or more XRPD peaks listed in Table 6.

[0184] In embodiments, Form D exhibits a DSC thermogram comprising a peak at 84±5° C., or 191±5° C., or a combination thereof. In embodiments, the peak at 84±5° C. is associated with an enthalpy of 300±5 J / g, and the peak at 191±5° C. is associated with an enthalpy of 8±5 J / g.

[0185] In embodiments, Form D exhibits a DSC thermogram comprising an endothermic peak with an onset at 52±5° C., or 179±5° C., or a combination thereof.

[0186] In embodiments, Form D exhibits a DSC thermogram comprising a peak at 84±3° C., or 191±3° C., or a combination thereof. In embodiments, the peak at 84±3° C. is associated with an enthalpy of 300±5 J / g, and the peak at 191±3° C. is associated with an enthalpy of 8±5 J / g.

[0187] In embodiments, Form D exhibits a DSC thermogram comprising an endothermic peak with an onset at 52±3° C., or 179±3° C., or a combination thereof.

[0188] In embodiments, Form D exhibits a DSC thermogram substantially similar to the DSC thermogram shown in Figure 4B.

[0189] In embodiments, Form D exhibits a weight loss of about 1% to about 10% at a temperature of 110±5° C., as measured by TGA analysis. For example, Form D exhibits a weight loss of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% (including all values ​​therebetween) at a temperature of 110±5° C., as measured by TGA analysis.

[0190] In embodiments, Form D exhibits a weight loss of about 0.1% to about 5% at a temperature of 170±5° C., as measured by TGA analysis. For example, Form D exhibits a weight loss of about 0.1%, about 1%, about 2%, about 3%, about 4%, or about 5% (including all values ​​therebetween) at a temperature of 170±5° C., as measured by TGA analysis.

[0191] In some embodiments, Form D exhibits substantially no weight loss at a temperature of 170±5° C. as determined by TGA analysis.

[0192] In embodiments, Form D exhibits a weight loss of about 1% to about 10% at a temperature of 110±5° C., a weight loss of about 0.1% to about 2% at 170±5° C., or both, as measured by TGA analysis.

[0193] In embodiments, Form D exhibits a 5% weight loss at a temperature of 110±5° C., a 2% weight loss at 170±5° C., or both, as measured by TGA analysis.

[0194] In embodiments, Form D exhibits a TGA thermogram substantially similar to the TGA thermogram shown in Figure 4C.

[0195] V. Form E In embodiments, the crystalline form of Compound I is Form E.

[0196] In an embodiment, Form E is characterized by peaks in its XRPD pattern at 5.8±0.2, 17.4±0.2, and 22.9±0.2 degrees 2θ. In an embodiment, the variance around any of these peaks is ±0.1 degrees 2θ.

[0197] In an embodiment, Form E is characterized by peaks in an XRPD pattern at 5.8±0.2, 17.4±0.2, and 22.9±0.2 degrees 2θ, and at least one peak in the XRPD pattern selected from 11.6±0.2, 16.7±0.2, 17.1±0.2, 23.3±0.2, and 24.0±0.2 degrees 2θ (e.g., 1, 2, 3, 4, or 5). In an embodiment, the variance around any of these peaks is ±0.1 degrees 2θ.

[0198] In embodiments, Form E has the following concentrations: 5.8±0.2, 7.0±0.2, 9.4±0.2, 11.4±0.2, 11.6±0.2, 14.1±0.2, 16.7±0.2, 17.1±0.2, 17.4±0.2, 17.8±0.2, 18.1±0.2, 18.3±0.2, 18.8±0.2, 19.4±0.2, 20.2±0.2, and 35.7±0.2 degrees 2Θ. In an embodiment, the variance at any of these peaks is ±0.1 degrees 2Θ.

[0199] In an embodiment, Form E is characterized by peaks in an XRPD pattern at 5.8±0.1, 17.4±0.1, and 22.9±0.1 degrees 2θ.

[0200] In embodiments, Form E is characterized by peaks in an XRPD pattern at 5.8±0.1, 17.4±0.1, and 22.9±0.1 degrees 2θ, and at least one peak in an XRPD pattern selected from 11.6±0.1, 16.7±0.1, 17.1±0.1, 23.3±0.1, and 24.0±0.1 degrees 2θ (e.g., 1, 2, 3, 4, or 5).

[0201] In embodiments, Form E is characterized by at least one peak in an XRPD pattern selected from 12.5±0.2 or 13.0±0.2 degrees 2θ that is not present in Form A described herein.

[0202] In embodiments, Form E is characterized by at least one peak in an XRPD pattern selected from 7.0±0.2, 9.4±0.2, 11.4±0.2, 11.6±0.2, 14.1±0.2, 16.7±0.2, 17.1±0.2, 17.4±0.2, 17.8±0.2, 18.1±0.2, 18.3±0.2, 18.8±0.2, 19.4±0.2, 20.2±0.2, 20.9±0.2, 21.1±0.2, 21.8±0.2, 22.1±0.2, 22.9±0.2, 24.0±0.2, 25.4±0.2, 28.3±0.2, 33.3±0.2, or 35.7±0.2 degrees 2θ that is not present in Form B described herein.

[0203] In embodiments, Form E is characterized by at least one peak in an XRPD pattern selected from 20.9±0.2 or 35.7±0.2 degrees 2θ that is not present in Form C described herein.

[0204] In embodiments, Form E is characterized by at least one peak in an XRPD pattern selected from 9.4±0.2, 14.1±0.2, 20.2±0.2, 21.8±0.2, 22.1±0.2, 25.4±0.2, 28.3±0.2, 33.3±0.2, or 35.7±0.2 degrees 2θ that is not present in Form D described herein.

[0205] In embodiments, Form E is characterized by at least one peak in an XRPD pattern selected from 5.8±0.2, 7.0±0.2, 9.4±0.2, 17.8±0.2, 18.1±0.2, 18.3±0.2, 18.8±0.2, or 33.3±0.2 degrees 2θ that is not present in Form F described herein.

[0206] In embodiments, Form E is characterized by at least one peak in an XRPD pattern selected from 7.0±0.2, 9.4±0.2, 14.1±0.2, 17.1±0.2, 17.4±0.2, 17.8±0.2, 18.1±0.2, 18.3±0.2, 20.2±0.2, 21.8±0.2, 22.1±0.2, 22.9±0.2, 24.0±0.2, 25.4±0.2, 28.3±0.2, or 33.3±0.2 degrees 2θ that is not present in Form G described herein.

[0207] In embodiments, Form E is characterized by at least one peak in an XRPD pattern selected from 33.3±0.2 or 35.7±0.2 degrees 2θ that is not present in Form H described herein.

[0208] In embodiments, Form E is characterized by an XRPD pattern substantially similar to the XRPD pattern shown in Figure 5A.

[0209] In embodiments, Form E is characterized by an XRPD pattern comprising the peaks shown in Table 7.

[0210] In embodiments, Form E is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or more XRPD peaks listed in Table 7.

[0211] In embodiments, Form E exhibits a DSC thermogram comprising peaks at 176±5, 239±5, or 276±5° C., or combinations thereof. In embodiments, the peak at 176±5° C. is associated with an enthalpy of 75±5 J / g; the peak at 239±5° C. is associated with an enthalpy of 32±5 J / g; and the peak at 276±5° C. is associated with an enthalpy of 17±5 J / g.

[0212] In embodiments, Form E exhibits a DSC thermogram comprising an endothermic peak with an onset at 139±5° C., 233±5° C., or 271±5° C., or any combination thereof.

[0213] In embodiments, Form E exhibits a DSC thermogram comprising peaks at 176±3, 239±3, or 276±3° C., or any combination thereof. In embodiments, the peak at 176±3° C. is associated with an enthalpy of 75±5 J / g; the peak at 239±3° C. is associated with an enthalpy of 32±5 J / g; and the peak at 276±3° C. is associated with an enthalpy of 17±5 J / g.

[0214] In embodiments, Form E exhibits a DSC thermogram comprising an endothermic peak with an onset at 139±3° C., 233±3° C., or 271±3° C., or any combination thereof.

[0215] In an embodiment, Form E exhibits a DSC thermogram substantially similar to the DSC thermogram shown in Figure 5B.

[0216] In embodiments, Form E exhibits a weight loss of about 0.1% to about 5% at a temperature of 80±5° C., as measured by TGA analysis. For example, Form E exhibits a weight loss of about 0.1%, about 1%, about 2%, about 3%, about 4%, or about 5% (including all values ​​therebetween) at a temperature of 80±5° C., as measured by TGA analysis.

[0217] In some embodiments, Form E exhibits substantially no weight loss at a temperature of 80±5° C. as measured by TGA analysis.

[0218] In embodiments, Form E exhibits a weight loss of about 10% to about 20% at a temperature of 140±5° C., as measured by TGA analysis. For example, Form E exhibits a weight loss of about 10%, about 12%, about 14%, about 16%, about 18%, or about 20% (including all values ​​therebetween) at a temperature of 140±5° C., as measured by TGA.

[0219] In embodiments, Form E exhibits a weight loss of about 0.1% to about 5% at a temperature of 80±5° C., a weight loss of about 10% to about 20% at 140±5° C., or both, as measured by TGA analysis.

[0220] In embodiments, Form E exhibits a weight loss of about 2% at a temperature of 80±5° C., a weight loss of about 16% at 140±5° C., or both, as measured by TGA analysis.

[0221] In embodiments, Form E exhibits a TGA thermogram substantially similar to the TGA thermogram shown in Figure 4C.

[0222] VI.Form F In embodiments, the crystalline form of Compound I is Form F.

[0223] In an embodiment, Form F is characterized by at least one peak in an XRPD pattern selected from 15.8±0.2 or 29.4±0.2 degrees 2θ. In an embodiment, the variance around any of these peaks is ±0.1 degrees 2θ.

[0224] In an embodiment, Form F is characterized by peaks in an XRPD pattern at 13.0±0.2, 17.0±0.2, and 19.3±0.2 degrees 2θ. In an embodiment, the variance around any of these peaks is ±0.1 degrees 2θ.

[0225] In embodiments, Form F is characterized by peaks in an XRPD pattern at 13.0±0.2, 17.0±0.2, and 19.3±0.2 degrees 2θ, and at least one peak in the XRPD pattern (e.g., 1, 2, 3, 4, or 5) selected from 20.0±0.2, 22.5±0.2, 22.6±0.2, 23.3±0.2, and 23.9±0.2 degrees 2θ. In embodiments, the variance around any of these peaks is ±0.1 degrees 2θ.

[0226] In embodiments, Form F has the following concentrations: 11.8±0.2, 13.0±0.2, 13.9±0.2, 14.2±0.2, 14.5±0.2, 15.8±0.2, 16.4±0.2, 17.0±0.2, 19.3±0.2, 20.0±0.2, 21.0±0.2, 21.8±0.2, 22.1±0.2, 22.5±0.2, 22.6±0.2, 23.3±0.2, 23.7±0.2, 23.9±0.2, 24. and 39.5±0.2 degrees 2θ. In an embodiment, the variance at any of these peaks is ±0.1 degrees 2θ.

[0227] In an embodiment, Form F is characterized by peaks in an XRPD pattern at 13.0±0.1, 17.0±0.1, and 19.3±0.1 degrees 2θ.

[0228] In embodiments, Form F is characterized by peaks in an XRPD pattern at 13.0±0.1, 17.0±0.1, and 19.3±0.1 degrees 2θ, and at least one peak in an XRPD pattern selected from 20.0±0.1, 22.5±0.1, 22.6±0.1, 23.3±0.1, and 23.9±0.1 degrees 2θ (e.g., 1, 2, 3, 4, or 5).

[0229] In embodiments, Form F is 11.8±0.1, 13.0±0.1, 13.9±0.1, 14.2±0.1, 14.5±0.1, 15.8±0.1, 16.4±0.1, 17.0±0.1, 19.3±0.1, 20.0±0.1, 21.0±0.1, 21.8±0.1, 22.1±0.1, 22.5±0.1, 22.6±0.1, 23.3±0.1, 23.7±0.1, 23.9±0.1, 24.1±0.1, 24.2±0.1, 24.5±0.1, 25.8±0.1, 26.4±0.1, 27.0±0.1, 27.0±0.1, 28.0±0.1, 28.1±0.1, 29.0±0.1, 30.0±0.1, 30.1±0.1, 30.2±0.1, 30.3±0.1, 30.4±0.1, 30.5±0.1, 30.6±0.1, 30.7±0.1, 30.8±0.1, 30.9±0.1, 31.0±0.1, 31.1±0.1, 31.2±0.1, 31.3±0.1, 31.4±0.1, 31.5±0.1, 31.6±0.1, 31.7±0.1, 31.8±0.1, 31.9±0.1, 32.1±0.1, 32.2±0.1, 32.3 The XRPD patterns are characterized by peaks at ±0.1, 25.3±0.1, 25.5±0.1, 26.3±0.1, 26.8±0.1, 27.2±0.1, 27.9±0.1, 28.3±0.1, 29.4±0.1, 30.4±0.1, 31.7±0.1, 31.8±0.1, 32.2±0.1, 32.6±0.1, 35.6±0.1, 35.9±0.1, and 39.5±0.1 degrees 2θ.

[0230] In embodiments, Form F is characterized by at least one peak in an XRPD pattern selected from 13.0±0.2, 15.8±0.2, 22.6±0.2, 23.7±0.2, 29.4±0.2, 30.4±0.2, 31.7±0.2, 31.8±0.2, 32.2±0.2, 32.6±0.2, or 39.5±0.2 degrees 2θ that is not present in Form A described herein.

[0231] In embodiments, Form F is absent from Form B described herein, 11.8±0.2, 14.2±0.2, 14.5±0.2, 15.8±0.2, 16.4±0.2, 17.0±0.2, 19.3±0.2, 21.0±0.2, 21.8±0.2, 22.1±0.2, 22.5±0.2, 22.6±0.2, 23.9±0.2, 24.1±0.2, 25. The compound is characterized by at least one peak in an XRPD pattern selected from: 25.3±0.2, 25.5±0.2, 26.8±0.2, 27.2±0.2, 27.9±0.2, 28.3±0.2, 29.4±0.2, 30.4±0.2, 31.7±0.2, 31.8±0.2, 32.2±0.2, 32.6±0.2, 35.6±0.2, 35.9±0.2°2θ.

[0232] In embodiments, Form F is characterized by peaks in its XRPD pattern at 15.8±0.2, 27.2±0.2, 27.9±0.2, 29.4±0.2, 31.7±0.2, 31.8, 35.6±0.2, or 38.5±0.2 degrees 2θ that are not present in Form C described herein.

[0233] In embodiments, Form F is characterized by peaks in an XRPD pattern at 13.9±0.2, 14.2±0.2, 14.5±0.2, 15.8±0.2, 16.4±0.2, 21.8±0.2, 22.5±0.2, 22.6±0.2, 25.3±0.2, 25.5±0.2, 26.8±0.2, 27.2±0.2, 27.9±0.2, 28.3±0.2, 29.4±0.2, 30.4±0.2, 31.7±0.2, 31.8±0.2, 32.2±0.2, 32.6±0.2, 35.6±0.2, 35.9±0.2, or 39.5±0.2 degrees 2θ that are not present in Form D described herein.

[0234] In embodiments, Form F is characterized by peaks in its XRPD pattern at 13.0±0.2, 15.8±0.2, 29.4±0.2, 30.4±0.2, 31.7±0.2, 31.8±0.2, 32.2±0.2, 32.6±0.2, or 39.5±0.2 degrees 2θ that are not present in Form E described herein.

[0235] In embodiments, Form F is characterized by peaks in an XRPD pattern at 13.9±0.2, 14.2±0.2, 14.5±0.2, 15.8±0.2, 16.4±0.2, 17.0±0.2, 20.0±0.2, 21.8±0.2, 22.5±0.2, 22.6±0.2, 23.9±0.2, 24.1±0.2, 25.3±0.2, 25.5±0.2, 27.2±0.2, 29.4±0.2, 30.4±0.2, 32.2±0.2, 32.6±0.2, 35.6±0.2, or 39.5±0.2 degrees 2θ that are not present in Form G described herein.

[0236] In embodiments, Form F is characterized by peaks in its XRPD pattern at 13.0±0.2, 15.8±0.2, 22.5±0.2, 23.25±0.2, 23.7±0.2, 29.4±0.2, 31.7±0.2, 31.8±0.2, 32.2±0.2, 32.6±0.2, 35.6±0.2, 35.9±0.2, or 39.5±0.2 degrees 2θ that are not present in Form H described herein.

[0237] In embodiments, Form F is characterized by an XRPD pattern substantially similar to the XRPD pattern displayed in Figure 6A.

[0238] In embodiments, Form F is characterized by an XRPD pattern comprising the peaks shown in Table 8.

[0239] In embodiments, Form F is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or more XRPD peaks listed in Table 8.

[0240] In an embodiment, Form F exhibits a DSC thermogram comprising a peak at 277±5° C. In an embodiment, the peak at 277±5° C. is associated with an enthalpy of 113±5 J / g.

[0241] In embodiments, Form F exhibits a DSC thermogram comprising an endothermic peak with an onset at 269±5°C.

[0242] In an embodiment, Form F exhibits a DSC thermogram comprising a peak at 277±3° C. In an embodiment, the peak at 277±3° C. is associated with an enthalpy of 113±5 J / g.

[0243] In embodiments, Form F exhibits a DSC thermogram comprising an endothermic peak with an onset at 269±3°C.

[0244] In an embodiment, Form F exhibits a DSC thermogram substantially similar to the DSC thermogram shown in Figure 6B.

[0245] In embodiments, Form F exhibits less than about 1% weight loss as measured by TGA at a temperature of 100±5° C. For example, Form F exhibits less than about 1%, less than about 0.1%, less than about 0.01%, or less than about 0.001% weight loss as measured by TGA.

[0246] In embodiments, Form F exhibits substantially no weight loss at a temperature of 100±5° C. as measured by TGA.

[0247] In embodiments, Form F exhibits a TGA thermogram substantially similar to the TGA thermogram shown in Figure 6C.

[0248] VII.Form G In embodiments, the crystalline form of Compound I is Form G.

[0249] In an embodiment, Form G is characterized by peaks in its XRPD pattern at 12.6±0.2, 21.2±0.2, and 23.5±0.2 degrees 2θ. In an embodiment, the variance around any of these peaks is ±0.1 degrees 2θ.

[0250] In embodiments, Form G is characterized by peaks in its XRPD pattern at 12.6±0.2, 21.2±0.2, and 23.5±0.2 degrees 2θ, and at least one peak in its XRPD pattern selected from 6.2±0.2, 13.4±0.2, 19.0±0.2, 26.2±0.2, and 26.5±0.2 degrees 2θ (e.g., 1, 2, 3, 4, or 5). In embodiments, the variance around any of these peaks is ±0.1 degrees 2θ.

[0251] In embodiments, Form G is characterized by peaks in its XRPD pattern at 6.2±0.2, 11.4±0.2, 12.6±0.2, 13.4±0.2, 19.0±0.2, 21.2±0.2, 23.5±0.2, 26.2±0.2, 26.5±0.2, 28.0±0.2, 31.4±0.2, and 36.0±0.2 degrees 2Θ. In embodiments, the variance around any of these peaks is ±0.1 degrees 2Θ.

[0252] In an embodiment, Form G is characterized by peaks in an XRPD pattern at 12.6±0.1, 21.2±0.1, and 23.5±0.1 degrees 2θ.

[0253] In embodiments, Form G is characterized by peaks in an XRPD pattern at 12.6±0.1, 21.2±0.1, and 23.5±0.1 degrees 2θ, and at least one peak in an XRPD pattern selected from 6.2±0.1, 13.4±0.1, 19.0±0.1, 26.2±0.1, and 26.5±0.1 degrees 2θ (e.g., 1, 2, 3, 4, or 5).

[0254] In an embodiment, Form G is characterized by peaks in an XRPD pattern at 6.2±0.1, 11.4±0.1, 12.6±0.1, 13.4±0.1, 19.0±0.1, 21.2±0.1, 23.5±0.1, 26.2±0.1, 26.5±0.1, 28.0±0.1, 31.4±0.1, and 36.0±0.1 degrees 2θ.

[0255] In embodiments, Form G is characterized by at least one peak in an XRPD pattern selected from 12.6±0.2, 13.4±0.2, or 31.4±0.2 degrees 2θ that is not present in Form A described herein.

[0256] In embodiments, Form G is characterized by at least one peak in an XRPD pattern selected from 11.4±0.2, 21.2±0.2, 23.5±0.2, 28.0±0.2, 31.4±0.2, or 36.0±0.2 degrees 2θ that is not present in Form B described herein.

[0257] In embodiments, Form G is characterized by at least one peak in an XRPD pattern selected from 13.4±0.2 or 28.0±0.2 degrees 2θ that is not present in Form C described herein.

[0258] In embodiments, Form G is characterized by at least one peak in an XRPD pattern selected from 28.0±0.2, 31.4±0.2, or 36.0±0.2 degrees 2θ that is not present in Form D described herein.

[0259] In embodiments, Form G is characterized by at least one peak in an XRPD pattern selected from 12.6±0.2, 13.4±0.2, or 31.4±0.2 degrees 2θ that is not present in Form E described herein.

[0260] In embodiments, Form G is characterized by at least one peak in an XRPD pattern selected from 13.4±0.2 or 19.0±0.2 degrees 2θ that is not present in Form E described herein.

[0261] In embodiments, Form G is characterized by at least one peak in an XRPD pattern selected from 12.6±0.2, 13.4±0.2, 23.5±0.2, 26.5±0.2, 31.4±0.2, or 36.0±0.2 degrees 2θ that is not present in Form H described herein.

[0262] In embodiments, Form G is characterized by an XRPD pattern substantially similar to the XRPD pattern shown in Figure 7A.

[0263] In embodiments, Form G is characterized by an XRPD pattern comprising the peaks shown in Table 10.

[0264] In embodiments, Form G is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or more XRPD peaks listed in Table 10.

[0265] VIII.Form H In embodiments, the crystalline form of Compound I is Form H.

[0266] In embodiments, Form H is characterized by a peak in its XRPD pattern at 30.3±0.2 degrees 2θ that is not present in Form A described herein. In embodiments, the variance around any of these peaks is ±0.1 degrees 2θ.

[0267] In an embodiment, Form H is characterized by peaks in its XRPD pattern at 5.7±0.2, 6.0±0.2, and 11.7±0.2 degrees 2θ. In an embodiment, the variance around any of these peaks is ±0.1 degrees 2θ.

[0268] In an embodiment, Form H is characterized by peaks in an XRPD pattern at 5.7±0.2, 6.0±0.2, and 11.7±0.2 degrees 2θ, and at least one peak in the XRPD pattern selected from 7.1±0.2, 11.4±0.2, 17.2±0.2, 23.0±0.2, and 24.0±0.2 degrees 2θ (e.g., 1, 2, 3, 4, or 5). In an embodiment, the variance around any of these peaks is ±0.1 degrees 2θ.

[0269] In embodiments, Form H is characterized by peaks in an XRPD pattern at 5.7±0.2, 6.0±0.2, 7.1±0.2, 9.2±0.2, 11.4±0.2, 11.7±0.2, 14.1±0.2, 16.5±0.2, 17.2±0.2, 17.8±0.2, 18.4±0.2, 19.1±0.2, 19.7±0.2, 20.1±0.2, 20.6±0.2, 21.4±0.2, 22.0±0.2, 23.0±0.2, 24.0±0.2, 25.4±0.2, 26.0±0.2, 27.1±0.2, 28.2±0.2, and 30.3±0.2 degrees 2θ. In an embodiment, the variance at any of these peaks is ±0.1 degrees 2θ.

[0270] In an embodiment, Form H is characterized by peaks in an XRPD pattern at 5.7±0.1, 6.0±0.1, and 11.7±0.1 degrees 2θ.

[0271] In embodiments, Form H is characterized by peaks in an XRPD pattern at 5.7±0.1, 6.0±0.1, and 11.7±0.1 degrees 2θ, and at least one peak in an XRPD pattern selected from 7.1±0.1, 11.4±0.1, 17.2±0.1, 23.0±0.1, and 24.0±0.1 degrees 2θ (e.g., 1, 2, 3, 4, or 5).

[0272] In embodiments, Form H is characterized by peaks in an XRPD pattern at 5.7±0.1, 6.0±0.1, 7.1±0.1, 9.2±0.1, 11.4±0.1, 11.7±0.1, 14.1±0.1, 16.5±0.1, 17.2±0.1, 17.8±0.1, 18.4±0.1, 19.1±0.1, 19.7±0.1, 20.1±0.1, 20.6±0.1, 21.4±0.1, 22.0±0.1, 23.0±0.1, 24.0±0.1, 25.4±0.1, 26.0±0.1, 27.1±0.1, 28.2±0.1, and 30.3±0.1 degrees 2θ.

[0273] In embodiments, Form H is characterized by at least one peak in an XRPD pattern selected from 9.2±0.2, 11.4±0.2, 11.7±0.2, 14.1±0.2, 16.5±0.2, 17.2±0.2, 17.8±0.2, 18.4±0.2, 20.1±0.2, 20.6±0.2, 21.4±0.2, 22.0±0.2, 24.0±0.2, 25.4±0.2, 27.1±0.2, 28.2±0.2, or 30.3±0.2 degrees 2θ that is not present in Form B described herein.

[0274] In embodiments, Form H is characterized by a peak in its XRPD pattern at 27.1±0.2 degrees 2θ that is not present in Form C described herein.

[0275] In embodiments, Form H is characterized by at least one peak in an XRPD pattern selected from 14.1±0.2, 20.1±0.2, 20.6±0.2, 22.0±0.2, 25.4±0.2, 27.1±0.2, 28.2±0.2, or 30.3±0.2 degrees 2θ that is not present in Form D described herein.

[0276] In embodiments, Form H is characterized by at least one peak in an XRPD pattern selected from 27.1±0.2 or 30.3±0.2 degrees 2θ that is not present in Form E described herein.

[0277] In embodiments, Form H is characterized by at least one peak in an XRPD pattern selected from 17.8±0.2, 18.4±0.2, or 20.57±0.2 degrees 2θ that is not present in Form F described herein.

[0278] In embodiments, Form H is characterized by at least one peak in an XRPD pattern selected from 7.1±0.2, 9.2±0.2, 14.1±0.2, 16.5±0.2, 17.2±0.2, 17.8±0.2, 18.4±0.2, 19.7±0.2, 20.1±0.2, 20.6±0.2, 22.0±0.2, 23.0±0.2, 24.0±0.2, 25.4±0.2, 27.1±0.2, or 30.3±0.2 degrees 2θ that is not present in Form G described herein.

[0279] In embodiments, Form H is characterized by an XRPD pattern substantially similar to the XRPD pattern shown in Figure 8A.

[0280] In embodiments, Form H is characterized by an XRPD pattern comprising the peaks shown in Table 11.

[0281] In embodiments, Form H is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or more XRPD peaks listed in Table 11.

[0282] IX.Form I In embodiments, the crystalline form of Compound I is Form I.

[0283] In an embodiment, Form I is characterized by a peak in its XRPD pattern at 6.3±0.2 degrees 2θ. In an embodiment, the variance of this peak is ±0.1 degrees 2θ.

[0284] In embodiments, Form I is characterized by an XRPD pattern substantially similar to the XRPD pattern shown in Figure 9A.

[0285] In an embodiment, Form I exhibits a DSC thermogram comprising a peak at 260±5°C.

[0286] In an embodiment, Form I exhibits a DSC thermogram substantially similar to the DSC thermogram shown in Figure 9B.

[0287] X. Form J In embodiments, the crystalline form of Compound I is Form J.

[0288] In an embodiment, Form J is characterized by peaks in its XRPD pattern at 11.1±0.2, 11.6±0.2, and 17.1±0.2 degrees 2θ. In an embodiment, the variance around any of these peaks is ±0.1 degrees 2θ.

[0289] In embodiments, Form J is 5.8±0.2, 7.1±0.2, 9.4±0.2, 11.5±0.2, 11.7±0.2, 12.8±0.2, 14.1±0.2, 16.8±0.2, 17.2±0.2, 17.5±0.2, 17.9±0.2, 18.2±0.2, 18.4±0.2, 19.0±0.2, 19.6±0.2, 20.4±0.2, and 36.2±0.2 degrees 2Θ. In an embodiment, the variance at any of these peaks is ±0.1 degrees 2Θ.

[0290] In embodiments, Form J is characterized by an XRPD pattern substantially similar to the XRPD pattern shown in Figure 10A.

[0291] In embodiments, Form J is characterized by an XRPD pattern comprising the peaks shown in Table 13.

[0292] In embodiments, Form J is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or more XRPD peaks listed in Table 13.

[0293] In embodiments, Form J exhibits a DSC thermogram comprising peaks at 83±5°C, 196±5°C, and 285±5°C.

[0294] In an embodiment, Form J exhibits a DSC thermogram substantially similar to the DSC thermogram shown in Figure 10B.

[0295] XI.Form K In embodiments, the crystalline form of Compound I is Form K.

[0296] In an embodiment, Form K is characterized by peaks in its XRPD pattern at 5.4±0.2, 13.4±0.2, and 17.9±0.2 degrees 2θ. In an embodiment, the variance around any of these peaks is ±0.1 degrees 2θ.

[0297] In embodiments, Form K is 5.5±0.2, 7.3±0.2, 11.4±0.2, 12.0±0.2, 12.9±0.2, 13.4±0.2, 14.6±0.2, 16.1±0.2, 16.9±0.2, 17.4±0.2, 17.9±0.2, 18.4±0.2, 19.0±0.2, 19.9±0.2, 21.1±0.2, 21.5±0.2, 21.7±0.2, 21.9±0.2, 22.2±0.2, 22.9±0.2 and 38.3±0.2 degrees 2θ. In an embodiment, the variance at any of these peaks is ±0.1 degrees 2θ.

[0298] In an embodiment, Form K is characterized by an XRPD pattern substantially similar to the XRPD pattern shown in FIG.

[0299] In embodiments, Form K is characterized by an XRPD pattern comprising the peaks shown in Table 14.

[0300] In embodiments, Form K is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or more XRPD peaks listed in Table 14.

[0301] XII.Form L In embodiments, the crystalline form of Compound I is Form L.

[0302] In an embodiment, Form L is characterized by peaks in its XRPD pattern at 4.3±0.2, 8.2±0.2, and 8.6±0.2 degrees 2θ. In an embodiment, the variance around any of these peaks is ±0.1 degrees 2θ.

[0303] In embodiments, Form L is 4.3±0.2, 8.2±0.2, 8.6±0.2, 12.9±0.2, 13.4±0.2, 15.4±0.2, 15.9±0.2, 17.2±0.2, 17.7±0.2, 18.2±0.2, 18.6±0.2, 19.2±0.2, 20.5±0.2, 21.5±0.2, 22.2± and 38.5±0.2 degrees 2Θ. In an embodiment, the variance at any of these peaks is ±0.1 degrees 2Θ.

[0304] In an embodiment, Form L is characterized by an XRPD pattern substantially similar to the XRPD pattern shown in FIG.

[0305] In embodiments, Form L is characterized by an XRPD pattern comprising the peaks shown in Table 15.

[0306] In embodiments, Form L is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or more XRPD peaks listed in Table 15.

[0307] XIII.Form M In embodiments, the crystalline form of Compound I is Form M.

[0308] In an embodiment, Form M is characterized by peaks in its XRPD pattern at 7.3±0.2, 10.4±0.2, and 12.7±0.2 degrees 2θ. In an embodiment, the variance around any of these peaks is ±0.1 degrees 2θ.

[0309] In embodiments, Form M is characterized by peaks in its XRPD pattern at 7.3±0.2, 9.2±0.2, 10.4±0.2, 11.8±0.2, 12.7±0.2, 14.8±0.2, 16.2±0.2, 17.5±0.2, 18.6±0.2, 19.0±0.2, 19.9±0.2, 21.0±0.2, 22.3±0.2, 23.6±0.2, 29.2±0.2, 31.2±0.2, 32.5±0.2, and 33.5±0.2 degrees 2θ. In embodiments, the variance around any of these peaks is ±0.1 degrees 2θ.

[0310] In an embodiment, Form M is characterized by an XRPD pattern substantially similar to the XRPD pattern shown in FIG.

[0311] In embodiments, Form M is characterized by an XRPD pattern comprising the peaks shown in Table 16.

[0312] In embodiments, Form M is characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or more XRPD peaks listed in Table 16.

[0313] Pharmaceutical Composition An embodiment of the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of at least one crystalline form (e.g., Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, or Form M) of Compound I or a salt, solvate, or solvate salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0314] The dosage of Compound I or a crystalline form of its salt, solvate, or solvate salt (e.g., Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, or Form M) will, of course, vary depending on the mode of administration, the desired treatment, and the disorder indicated. For example, when Compound I is administered orally, the daily dosage of the compound may range from about 0.01 microgram per kilogram of body weight (μg / kg) to about 100 milligrams per kilogram of body weight (mg / kg).

[0315] Although a crystalline form of Compound I or a salt, solvate, or solvate salt thereof (including, for example, Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, or Form M) may be used per se, the compound is generally administered in the form of a pharmaceutical composition together with a pharmaceutically acceptable adjuvant, diluent, or carrier. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described, for example, in "Pharmaceuticals - The Science of Dosage Form Designs", M.E. Aulton, Churchill Livingstone, 1988.

[0316] Depending on the mode of administration, the pharmaceutical composition used for administration contains 0.05-99% w (weight %), 0.05-80%, 0.10-70%, or 0.10-50% of a crystalline form of Compound I, or a salt, solvate, or solvate salt thereof (e.g., Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, or Form M), all weight % being based on the total composition.

[0317] Pharmaceutical compositions may be administered topically (e.g., to the skin), for example, in the form of creams, gels, lotions, solutions, suspensions, or systemically, for example, by oral administration in the form of tablets, capsules, syrups, powders, or granules; by parenteral administration in the form of sterile injectable (including intravenous, subcutaneous, intramuscular, intravascular, infusion) solutions, suspensions, emulsions; by rectal administration in the form of suppositories; or by inhalation administration in the form of an aerosol.

[0318] For oral administration, Compound I, or a crystalline form of its salt, solvate, or solvate salt (e.g., Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, or Form M) may be mixed with an adjuvant or carrier, such as lactose, saccharose, sorbitol, mannitol; starch, such as potato starch, corn starch, or amylopectin; cellulose derivatives; binders, such as gelatin or polyvinylpyrrolidone; and / or lubricants, such as magnesium stearate, calcium stearate, polyethylene glycol, wax, paraffin, etc., and compressed into tablets. If coated tablets are required, the cores prepared as described above may be coated with a concentrated sugar solution, which may contain, for example, gum arabic, gelatin, talcum, and titanium dioxide. Alternatively, the tablets may be coated with a suitable polymer dissolved in a readily volatile organic solvent.

[0319] For the preparation of soft gelatin capsules, Compound I, or a crystalline form of its salt, solvate, or solvate salt (e.g., Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, or Form M) may be blended with, for example, vegetable oil or polyethylene glycol. Hard gelatin capsules may contain granules of the compound using any of the tablet excipients described above. Alternatively, liquid or semi-solid formulations of Compound I, or a crystalline form of its salt, solvate, or solvate salt (e.g., Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, or Form M) may be filled into hard gelatin capsules. Liquid formulations for oral administration may be in the form of a syrup or suspension, e.g., a solution, containing a crystalline form of Compound I, or a salt, solvate, or solvate salt thereof (e.g., Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, or Form M), with the remainder being sugar and a mixture of ethanol, water, glycerol, and propylene glycol. Optionally, such liquid formulations may contain colorants, flavors, sweeteners (e.g., saccharin), preservatives, and / or carboxymethylcellulose as a thickening agent, or other excipients known to those skilled in the art.

[0320] For intravenous (parenteral) administration, Compound I, or a crystalline form of a salt, solvate, or solvate salt thereof (e.g., Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, or Form M) may be administered as a sterile aqueous or oily solution.

[0321] The size of a dose of Compound I, or a crystalline form of a salt, solvate, or solvated salt thereof (e.g., Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, or Form M) for therapeutic purposes will naturally vary according to well-known principles of medicine and depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

[0322] The dosage level, frequency of administration, and duration of treatment with Compound I, or a crystalline form of its salt, solvate, or solvated salt (e.g., Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, or Form M) are expected to vary depending on the formulation and clinical indication, the age of the patient, and any coexisting medical conditions. The typical duration of treatment with Compound I, or a crystalline form of its salt, solvate, or solvated salt (e.g., Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, or Form M) is expected to vary between 1 and 7 days for most clinical indications. In the case of recurrent infections or infections associated with tissues or implanted materials with poor blood supply, including bone / joints, airways, endocardium, and dental tissues, treatment duration may need to be extended beyond 7 days.

[0323] Treatment method Embodiments of the present disclosure relate to methods of using at least one crystalline form of Compound I or a salt, solvate, or solvated salt thereof (e.g., Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, or Form M) to treat various diseases and conditions. Embodiments of the present disclosure also relate to methods of treating various diseases or conditions, comprising administering at least one crystalline form of Compound I or a salt, solvate, or solvated salt thereof (e.g., Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, or Form M) to a subject in need thereof.

[0324] In embodiments, the methods or uses disclosed herein comprise administering Compound I or a crystalline form of its salt, solvate, or solvated salt (e.g., Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, or Form M) to treat a disease or condition involving the abnormal activity of one or more RAF kinases. In embodiments, the methods or uses comprise administering Compound I or a crystalline form of its salt, solvate, or solvated salt (e.g., Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, or Form M) to treat a disease or condition treatable by inhibition of one or more Raf kinases. RAF kinase inhibition is relevant to the treatment of many different diseases associated with the abnormal activity of the MAPK pathway. In embodiments, the condition is treatable by inhibition of a RAF kinase, such as B-RAF or C-RAF.

[0325] In embodiments, the disease or condition is cancer.In embodiments, the disease or condition is selected from Barrett's adenocarcinoma, biliary tract cancer, breast cancer, cervical cancer, cholangiocarcinoma, central nervous system tumor, primary CNS tumor, glioblastoma, astrocytoma, glioblastoma multiforme, ependymoma, secondary CNS tumor (metastasis of tumors outside the central nervous system to the central nervous system), brain tumor, brain metastasis, colorectal cancer, colon cancer, gastric cancer, head and neck cancer, head and neck squamous cell carcinoma, acute lymphoblastic leukemia, acute myeloid leukemia (AML), myelodysplastic syndrome, chronic myeloid leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, megakaryoblastic leukemia, multiple myeloma, erythroleukemia, hepatocellular carcinoma, lung cancer, small cell lung cancer, non-small cell lung cancer, ovarian cancer, endometrial cancer, pancreatic cancer, pituitary adenoma, prostate cancer, renal cancer, metastatic melanoma or thyroid cancer.

[0326] In embodiments, the disease or condition is melanoma, non-small cell carcinoma, colorectal cancer, ovarian cancer, thyroid cancer, breast cancer, or cholangiocarcinoma. In embodiments, the disease or condition is colon cancer. In embodiments, the disease or condition is melanoma.

[0327] In embodiments, the present disclosure provides a method of treating small lung cancer, comprising administering at least one crystalline form of Compound I or a salt, solvate, or solvated salt thereof (e.g., Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, or Form M) to a subject in need thereof.

[0328] In embodiments, the present disclosure provides a method of treating colon cancer, comprising administering at least one crystalline form of Compound I or a salt, solvate, or solvated salt thereof (e.g., Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, or Form M) to a subject in need thereof.

[0329] In embodiments, the present disclosure provides a method of treating melanoma, comprising administering at least one crystalline form of Compound I or a salt, solvate, or solvated salt thereof (e.g., Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, or Form M) to a subject in need thereof.

[0330] In embodiments, the present disclosure provides a method of treating pancreatic cancer, comprising administering at least one crystalline form of Compound I or a salt, solvate, or solvated salt thereof (e.g., Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, or Form M) to a subject in need thereof.

[0331] In embodiments, the disease or condition is BRAF V600E In embodiments, the disease or condition is a cancer comprising a BRAF mutation. V600E In embodiments, the disease or condition is regulated by BRAF V600E Melanoma, BRAF V600E Colorectal cancer, BRAF V600E Papillary thyroid cancer, BRAF V600E Low-grade serous ovarian cancer, BRAF V600E Glioma, BRAF V600E Hepatobiliary cancer, BRAF V600Ehairy cell leukemia, BRAF V600E Non-small cell carcinoma, or BRAF V600E It is a pilocytic astrocytoma.

[0332] In embodiments, the disease or condition is cardiofacial cutaneous syndrome and polycystic kidney disease.

[0333] In embodiments, a crystalline form of Compound I or a salt, solvate, or solvated salt thereof (e.g., Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, or Form M) is used in combination with one or more pharmaceutically active agents.

[0334] In an embodiment, the other pharmaceutically active agent is an anti-tumor agent.

[0335] In embodiments, the additional pharmaceutically active agent is an antiproliferative / anti-tumor agent. In embodiments, the antiproliferative / anti-tumor agent is selected from the group consisting of alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, bendamustine, melphalan, chlorambucil, busulfan, temozolamide, and nitrosoureas); antimetabolites (e.g., gemcitabine, fluoropyrimidines such as 5-fluorouracil and tegafur, folate antagonists such as raltitrexed, methotrexate, pemetrexed, cytosine arabinoside, and hydroxyurea); antibiotics (e.g., adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, fluticasone, fluoxetine ... anthracyclines such as bicine, idarubicin, mitomycin-C, dactinomycin, and mithramycin; mitotic inhibitors (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, taxoids such as taxol and taxotere, and polo kinase inhibitors); proteasome inhibitors such as carfilzomib and bortezomib; interferon therapy; or topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, mitoxantrone, and camptothecin).

[0336] In embodiments, the additional pharmaceutically active agent is a cytostatic agent, which in embodiments is an anti-estrogen (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodoxifene), an anti-androgen (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), an LHRH antagonist or agonist (e.g., goserelin, leuprorelin, and buserelin), a progestogen (e.g., megestrol acetate), an aromatase inhibitor (e.g., anastrozole, letrozole, vorazole, and exemestane), or an inhibitor of 5α-reductase, such as finasteride.

[0337] In embodiments, the other pharmaceutically active agent is an anti-invasive agent, hi embodiments, the anti-invasive agent is dasatinib and bosutinib (SKI-606), a metalloproteinase inhibitor, or an inhibitor of urokinase plasminogen activator receptor function, or an antibody against heparanase.

[0338] In embodiments, the additional pharmaceutically active agent is an inhibitor of growth factor function. In embodiments, inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies, such as the anti-erbB2 antibody trastuzumab (Herceptin™), the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab, tyrosine kinase inhibitors, such as inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors such as gefitinib, erlotinib, and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI1033), erbB2 tyrosine kinase inhibitors such as lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; proteins involved in cellular apoptosis. inhibitors of the platelet-derived growth factor family such as imatinib and / or nilotinib (AMN107); inhibitors of serine / threonine kinases (e.g., farnesyltransferase inhibitors, RAS / RAF signaling inhibitors such as sorafenib, tipifarnib, and lonafarnib); inhibitors of cell signaling via MEK and / or AKT kinases, C-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor kinase inhibitors; cyclin-dependent kinase inhibitors such as Aurora kinase inhibitors or CDK2 and / or CDK4 inhibitors.

[0339] In embodiments, the other pharmaceutically active agent is an anti-angiogenic agent that inhibits the effects of vascular endothelial growth factor, such as the anti-vascular endothelial growth factor antibody bevacizumab (Avastin™); thalidomide; lenalidomide; and VEGF receptor tyrosine kinase inhibitors, such as vandetanib, vatalanib, sunitinib, axitinib, and pazopanib.

[0340] In embodiments, the additional pharmaceutically active agent is, in embodiments, a cytotoxic agent, fludarivine (Fludara), cladribine, or pentostatin (Nipent™).

[0341] In embodiments, the additional pharmaceutically active agent is a steroid. In embodiments, the steroid is a corticosteroid, including glucocorticoids and mineralocorticoids, such as aclometasone, aclometasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol propionate, cloprednol, cortisone, cortisone acetate, cortivazol, deoxycortone, desonide, deoxymethasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinolone acetonide ... Examples of suitable steroids include fluocortin butyl, fluorocortisone, fluorocortolone, flucortolone caproate, fluocortolone pivalate, fluorometholone, fluprednidene, fluprednidene acetate, flurandrenolone, fluticasone, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone aceponate, icometasone embutate, meprednisone, methylprednisolone, paramethasone mometasone, mometasone furoate monohydrate, prednicarbate, prednisolone, prednisone, tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide, triamcinolone alcohol, and their respective pharmaceutically acceptable derivatives. Combinations of steroids, such as combinations of two or more of the steroids described herein, may also be used.

[0342] In embodiments, the additional pharmaceutically active agent is a targeted therapeutic agent, hi embodiments, the targeted therapeutic agent is a PI3Kd inhibitor, e.g., idelalisib and perifosine.

[0343] In embodiments, the other pharmaceutically active agent is an immunotherapeutic agent. In embodiments, the immunotherapeutic agent is an antibody therapeutic agent such as alemtuzumab, rituximab, ibritumomab tiuxetan (Zevalin®), and ofatumumab; an interferon such as interferon alpha; an interleukin such as IL-2 (aldesleukin); an interleukin inhibitor, such as an IRAK4 inhibitor; a cancer vaccine, including prophylactic and therapeutic vaccines such as HPV vaccines, for example, Gardasil, Cervarix, Oncophage, and Sipuleucel-T (Provenge); a Toll-like receptor modulator, such as a TLR-7 or TLR-9 agonist; and a PD-1 antagonist, a PDL-1 antagonist, and an IDO-1 antagonist.

[0344] In embodiments, the pharmaceutical composition may be used in combination with another therapy, which in embodiments is gene therapy, including approaches to replace abnormal genes, such as abnormal p53 or abnormal BRCA1 or BRCA2.

[0345] In embodiments, the other therapy is an immunotherapeutic approach, including, for example, antibody therapy such as alemtuzumab, rituximab, ibritumomab tiuxetan (Zevalin®), and ofatumumab; interferons such as interferon alpha; interleukins such as IL-2 (aldesleukin); interleukin inhibitors, e.g., IRAK4 inhibitors; cancer vaccines, including prophylactic and therapeutic vaccines such as HPV vaccines, e.g., Gardasil, Cervarix, Oncophage, and Sipuleucel-T (Provenge); Toll-like receptor modulators, e.g., TLR-7 or TLR-9 agonists; and PD-1 antagonists, PDL-1 antagonists, and IDO-1 antagonists.

[0346] [Example]

[0347] Compound I can be prepared according to the method disclosed in WIPO Patent Application Publication No. 2022 / 023450, which is incorporated herein for all purposes.The following examples are used to assist in the explanation of the present disclosure, but should not be considered as limiting the present disclosure in any way.

[0348] Example 1: Unless otherwise specified, all characterization data was obtained using the following procedures:

[0349] X-ray powder diffraction (XRPD) XRPD analysis was performed on a Bruker D8 Advance equipped with a LYNXYE_XE_T 1D detector, scanning the sample between 3 and 40° 2θ. For analysis, the material was ground on a single-crystal silicon holder. It was then analyzed using Cu K radiation (αλ = 1.54060 Å; α = 1.54443 Å; β = 1.39225 Å; α:α ratio = 0.5), applying a step size of 0.02° and a scan time of 0.12 s / step. The primary beam path slit was 10.0 mm across the sample, with a 2.5° axial SollerMount angle. The secondary beam path slit was 5.2 mm.

[0350] Differential scanning calorimetry (DSC) Approximately 1-2 mg of material was weighed into a pinned aluminum DSC pan. The sample pan was placed in a differential scanning calorimeter (TA Discovery 2500) and protected with a nitrogen flow of 50 mL / min. The sample was heated from 30°C to 250°C at a rate of 10°C / min, and the heat flow was recorded.

[0351] Thermogravimetric analysis (TGA) Approximately 2 mg of material was weighed into an open aluminum pan and loaded into a simultaneous thermogravimetric / differential thermal analyzer (TG Discovery 5500) and kept at room temperature. The nitrogen flow rate for the balance was 10 mL / min, and the nitrogen flow rate for the sample was 25 mL / min. The sample was then heated from 30°C to 300°C at a rate of 10°C / min, and the change in sample weight was recorded.

[0352] Dynamic Vapor Sorption (DVS) Approximately 10 mg of material was analyzed at 25°C using an automated dynamic vapor sorption analyzer (Intrinsic / Advantage). Method 1 for the anhydrous material involved a humidity cycle of 40-0-95-0-40% RH in 10% RH stepwise fashion, during which the mass change was recorded. Method 2 for the hydrate material involved a humidity cycle of 40-95-0-95-40% RH in 10% RH stepwise fashion, during which the mass change was recorded. The equilibrium setting was 0.002 dm / dt (% / min). The minimum dm / dt stabilization time was 60 minutes, and the maximum dm / dt stabilization time was 360 minutes.

[0353] Form A Compound 1 was dissolved in DMSO (18 volumes) at 25°C. Water (2.5 volumes) was added, followed by 0.5% Compound 1 Form A seeds. The slurry was stirred at 25°C for 2 hours. Water (6.5 volumes) was added over 6 hours, and the slurry was stirred at 25°C for 12 hours. The slurry was filtered, and the solid was washed four times with water (5.6 volumes). The solid material was then slurried in water (15 volumes) at 25°C for 18 hours. The solid was washed three times with water (5.6 volumes) and then dried under vacuum at 40°C. Form A was then characterized by XRPD (Figure 1A, Table 1), DSC (Figure 1B), TGA (Figure 1C), and DVS (Figure 1D, Table 2).

[0354] A summary of the XRPD peaks for Form A can be seen in Table 1 below.

[0355] [Table 1]

[0356] A summary of the DVS isothermal analysis of Form A can be seen in Table 2 below.

[0357] [Table 2]

[0358] Form A * Form A of Compound 1 was equilibrated in acetone at 25° C. for 2 weeks with stirring. The resulting suspension was filtered. The dehydrated cake was analyzed and Form A was subsequently * was characterized by XRPD (Fig. 1E, Table 3) and DSC (Fig. 1F).

[0359] Form A * A summary of the XRPD peaks can be seen in Table 3 below.

[0360] [Table 3]

[0361] Form B Compound 1 phosphate Form A was equilibrated in water (2 mg / mL concentration) at 25°C for 2 days. The resulting suspension was filtered and the dehydrated cake was analyzed. Form B was then characterized by XRPD (Figure 2A, Table 4), DSC (Figure 2B), and TGA (Figure 2C).

[0362] A summary of the XRPD peaks for Form B can be found in Table 4 below.

[0363] [Table 4]

[0364] Form C Form A of Compound 1 was equilibrated in DMSO with stirring for 2 weeks at 25° C. The precipitate was filtered, and the resulting Form C was then characterized by XRPD (FIG. 3A, Table 5), DSC (FIG. 3B), and TGA (FIG. 3C).

[0365] A summary of the XRPD peaks for Form C can be found in Table 5 below.

[0366] [Table 5]

[0367] Form D Form A was dissolved in a minimum amount of DMF to form a saturated solution. Water was slowly added to form a suspension (DMF:water 1:3). The precipitate was filtered and the dehydrated cake was analyzed. Form D was then characterized by XRPD (Figure 4A, Table 6), DSC (Figure 4B), and TGA (Figure 4C).

[0368] A summary of the XRPD peaks for Form D can be found in Table 6 below.

[0369] [Table 6]

[0370] Form E Form A of Compound 1 was dissolved in a minimum amount of acetone. The solution was filtered through a 0.45 μm syringe membrane filter. The clear solution was then allowed to slowly evaporate under ambient conditions. The solid residue was analyzed, and Form E was then characterized by XRPD (FIG. 5A, Table 7), DSC (FIG. 5B), and TGA (FIG. 5C).

[0371] A summary of the XRPD peaks for Form E can be found in Table 7 below.

[0372] [Table 7]

[0373] Form F Form A of Compound 1 was dissolved in 11.5 volumes of DMSO / ethyl acetate (1:1) at 70°C. The solution was polish filtered and washed with 0.5 volumes of DMSO / ethyl acetate (1:1). The solution was cooled to 60°C over 30 minutes, and methanol (4 volumes) was added. 0.5% Form F seeds were added, and the slurry was stirred at 60°C for 4 hours. Methanol (12 volumes) was added over 6 hours. The slurry was then cooled to 10°C over 5 hours and held at 10°C for 9 hours. The slurry was filtered and washed twice with methanol (4 volumes). Form F was then characterized by XRPD (Figure 6A, Table 8), DSC (Figure 6B), TGA (Figure 6C), and DVS (Figure 6D, Table 9).

[0374] A summary of the XRPD peaks for Form F can be found in Table 8 below.

[0375] [Table 8]

[0376] A summary of the DVS isothermal analysis of Form F can be seen in Table 9 below.

[0377] [Table 9]

[0378] Form G Form A of Compound 1 was dissolved in DMSO. The clear solution was quickly added to water (DMSO:water 1:3). The precipitate was collected by filtration, and then Form G was characterized by XRPD (Figure 7, Table 10).

[0379] A summary of the XRPD peaks for Form G can be found in Table 10 below.

[0380] [Table 10]

[0381] Form H: Form H of Compound 1 was observed when Form A of Compound 1 was heated to 110° C. in VT-XRPD or at 110° C. at 0% RH in VH-XRPD. Form H was then characterized by XRPD (FIG. 8, Table 11).

[0382] A summary of the XRPD peaks for Form H can be found in Table 11 below.

[0383] [Table 11]

[0384] Form I Form I of Compound 1 was observed during VT-XRPD or when Form A of Compound 1 was heated to 252° C. at 0% RH during VH-XRPD. Form I was then characterized by XRPD ( FIG. 9A , Table 12) and DSC ( FIG. 9B).

[0385] A summary of the XRPD peaks for Form I can be seen below in Table 12. The characteristic peak for Form I was identified at 6.2-6.3 degrees 2θ as shown in Figure 9A and Table 12.

[0386] [Table 12]

[0387] Form J Form J of Compound 1 was formed from acetic acid and acetone. Form I was then characterized by XRPD (FIG. 10A, Table 13) and DSC (FIG. 10B).

[0388] A summary of the XRPD peaks for Form J can be found in Table 13 below.

[0389] [Table 13]

[0390] Form K The compound 1 form K formed was characterized by XRPD (Figure 12, Table 14).

[0391] A summary of the XRPD peaks for Form K can be found in Table 14 below.

[0392] [Table 14]

[0393] Form L The formed Compound 1 Form L was characterized by XRPD (Figure 13, Table 15).

[0394] A summary of the XRPD peaks for Form L can be found in Table 15 below.

[0395] [Table 15]

[0396] Form M The compound 1 form M formed was characterized by XRPD (Figure 14, Table 16).

[0397] A summary of the XRPD peaks for Form M can be found in Table 16 below.

[0398] [Table 16]

[0399] A summary of the DSC and TGA thermograms of the various forms can be seen in Table 17 below.

[0400] [Table 17]

[0401] conclusion Various crystalline forms of Compound I were identified: Forms A, B, C, D, E, F, G, H, I, J, K, L, and M. Among these forms, Forms A and F were selected for further pharmaceutical development due to their suitability for large-scale manufacturing, stability, and crystallinity compared to Forms B, C, D, E, and G. In particular, compared to Forms B, C, D, E, G, H, I, J, K, L, and M, Forms A and F exhibit a higher degree of crystallinity (e.g., compare Figures 1A and 6A (Forms A and F) to Figures 2A and 4A (Forms B and D)) and also offer enhanced stability, as evidenced by DSC and TGA thermograms (Table 17 and Figures 1B and 6B).

[0402] Example 2: In vitro dissolution profiles were analyzed for Form A and Form F. In vitro drug dissolution and release studies can provide insight into the in vivo performance of a drug, such as bioavailability. Biorelevant media was used to predict the bioavailability of Compound I, an otherwise poorly soluble drug.

[0403] Forms A and F were selected for further pharmaceutical development, and dissolution studies were performed on these forms. Studies were performed at different pHs and in biorelevant media: hydrochloric acid (HCl), fasting simulated gastric fluid (FaSSGF), fasting simulated intestinal fluid (FaSSIF), and fed simulated intestinal fluid (FeSSIF) (75 rpm, 900 mL). Three 10 mg and 50 mg capsules were analyzed as shown in Table 18 below. Capsules included Form A only, 90% Form A mixed with 10% Form F, and Form F. The results are shown in Figures 14A-14C (10 mg capsules) and Figures 15A-15C (50 mg capsules).

[0404] [Table 18]

Claims

1. Compound I: 【Chemistry 1】 or a crystalline form of a salt or solvate thereof.

2. 2. The crystalline form of claim 1, wherein the crystalline form of Compound I is Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form J, Form K, Form L, or Form M.

3. 3. The crystalline form of claim 2, wherein said crystalline form of Compound I is Form A.

4. 4. The crystalline form of claim 3, wherein Form A is characterized by peaks in an X-ray diffraction (XRPD) pattern at 5.8±0.2, 11.8±0.2, 16.6±0.2, and 23.1±0.2 degrees 2θ.

5. 5. The crystalline form of claim 4, wherein Form A is further characterized by at least one peak in an XRPD pattern selected from 5.8±0.2, 11.4±0.2, 17.3±0.2, 17.5±0.2, and 17.9±0.2 degrees 2θ.

6. Form A showed the following results: 5.8±0.2, 6.0±0.2, 7.1±0.2, 9.3±0.2, 11.4±0.2, 11.8±0.2, 14.1±0.2, 16.6±0.2, 17.3±0.2, 17.5±0.2, 17.9±0.2, 18.5±0.2, 19.1±0.2, 19.8±0.2, 20.7±0.2, 21.

6. The crystalline form of claims 3-5, characterized by peaks in an XRPD pattern at 3±0.2, 21.6±0.2, 22.1±0.2, 23.1±0.2, 24.2±0.2, 25.6±0.2, 26.1±0.2, 26.5±0.2, 27.3±0.2, 28.4±0.2, and 35.8±0.2 degrees two-theta.

7. 7. The crystalline form of claims 3-6, characterized by an XRPD pattern substantially similar to the XRPD pattern shown in Figure 1A.

8. 8. The crystalline form of claims 3-7, exhibiting a differential scanning calorimetry (DSC) thermogram comprising peaks at 77±5, 239±5, 243±5°C, 271±5°C, 285±5°C, or any combination thereof.

9. 9. The crystalline form of claim 8, wherein the peak at 67±5°C is associated with an enthalpy of 61±5 Joules per gram (J / g); the peak at 239±5°C is associated with an enthalpy of 78±5 J / g; the peak at 245±5°C is associated with an enthalpy of 67±5 J / g; and the peak at 277±5°C is associated with an enthalpy of 84±5 J / g.

10. 10. The crystalline form of claims 3-9, exhibiting a DSC thermogram comprising an endothermic peak with an onset at 46±5, 231±5, or 271±5°C, or any combination thereof.

11. 11. The crystalline form of claims 3-10, exhibiting a DSC thermogram comprising an exothermic peak with an onset at 242±5°C.

12. 12. The crystalline form of claims 3-11, which exhibits a weight loss of 3% at a temperature of 120±5°C, a weight loss of 1% at 220±5°C, or both, as measured by thermogravimetric (TGA) analysis.

13. The crystalline form of claims 3 to 12, wherein Compound I is a hydrate.

14. 3. The crystalline form of claim 2, wherein said crystalline form of Compound I is Form B.

15. 15. The crystalline form of claim 14, wherein Form B is characterized by peaks in an XRPD pattern at 12.7±0.2, 13.4±0.2, and 23.4±0.2 degrees 2θ.

16. 16. The crystalline form of claim 15, wherein Form B is further characterized by at least one peak in an XRPD pattern selected from 6.2±0.2, 13.6±0.2, 23.3±0.2, 26.1±0.2, and 26.3±0.2 degrees 2θ.

17. 17. The crystalline form of claims 14-16, wherein Form B is characterized by peaks in an XRPD pattern at 6.2±0.2, 12.7±0.2, 13.4±0.2, 13.6±0.2, 19.0±0.2, 19.8±0.2, 23.3±0.2, 23.4±0.2, 26.1±0.2, 26.3±0.2, and 39.1±0.2 degrees two-theta.

18. 18. The crystalline form of claims 14-17, characterized by an XRPD pattern substantially similar to the XRPD pattern shown in Figure 2A.

19. 19. The crystalline form of claims 14-18, exhibiting a DSC thermogram comprising a peak at 71±5°C, or 170±5°C, or a combination thereof.

20. 20. The crystalline form of claim 19, wherein the peak at 71±5°C is associated with an enthalpy of 107±5 J / g and the peak at 170±5°C is associated with an enthalpy of 2±5 J / g.

21. 21. The crystalline form of claims 14-20, exhibiting a DSC thermogram comprising an endothermic peak with an onset at 33±5°C, or 165±5°C, or a combination thereof.

22. 22. The crystalline form of claims 14 to 21, which exhibits a weight loss of 8% at a temperature of 110±5°C as measured by TGA analysis.

23. The crystalline form of claims 14 to 22, wherein Compound I is a hydrate.

24. 3. The crystalline form of claim 2, wherein said crystalline form of Compound I is Form C.

25. 25. The crystalline form of claim 24, wherein Form C is characterized by peaks in an XRPD pattern at 16.8±0.2, 23.1±0.2, and 24.2±0.2 degrees 2θ.

26. 26. The crystalline form of claim 25, wherein Form C is further characterized by at least one peak in an XRPD pattern selected from 5.8±0.2, 11.5±0.2, 17.2±0.2, 17.5±0.2, and 18.4±0.2 degrees 2θ.

27. Form C: 3.6±0.2, 4.2±0.2, 5.8±0.2, 7.1±0.2, 9.4±0.2, 11.5±0.2, 11.7±0.2, 12.8±0.2, 14.1±0.2, 16.8±0.2, 17.2±0.2, 17.5±0.2, 17.9±0.2, 18.2±0.2, 18.4±0.2, 19.0±0.2, 19.6±0.2, 20.4±0.2, 21.3±0.2; 27. The crystalline form of claims 24-26, characterized by peaks in an XRPD pattern at 22.1±0.2, 22.6±0.2, 23.1±0.2, 23.4±0.2, 24.2±0.2, 25.7±0.2, 26.2±0.2, 26.6±0.2, 28.5±0.2, 30.3±0.2, 31.0±0.2, 32.4±0.2, 34.0±0.2, and 36.2±0.2 degrees two-theta.

28. 28. The crystalline form of claims 24-27, characterized by an XRPD pattern substantially similar to the XRPD pattern shown in Figure 3A.

29. 29. The crystalline form of claims 24-28, exhibiting a DSC thermogram comprising peaks at 92±5, 154±5, 231±5, or 242±5°C, or a combination thereof.

30. 30. The crystalline form of claim 29, wherein the peak at 92±5°C is associated with an enthalpy of 301±5 J / g; the peak at 154±5°C is associated with an enthalpy of 63±5 J / g; the peak at 231±5°C is associated with an enthalpy of 14±5 J / g; and the peak at 242±5°C is associated with an enthalpy of 14±5 J / g.

31. 31. The crystalline form of claims 28-30, exhibiting a DSC thermogram comprising an endothermic peak with an onset at 56±5, 133±5, 229±5, or 239±5°C, or any combination thereof.

32. 32. The crystalline form of claims 28-31, which exhibits a weight loss of 16% at a temperature of 75±5°C as measured by TGA analysis.

33. The crystalline form of claims 28-32, wherein Compound I is a solvate.

34. 34. The crystalline form of claim 33, wherein the solvate is a dimethyl sulfoxide (DMSO) solvate.

35. 3. The crystalline form of claim 2, wherein said crystalline form of Compound I is Form D.

36. 36. The crystalline form of claim 35, wherein Form D is characterized by peaks in an XRPD pattern at 12.5±0.2, 23.4±0.2, and 23.1±0.2 degrees 2θ.

37. 37. The crystalline form of claim 36, wherein Form D is further characterized by at least one peak in an XRPD pattern selected from 11.5±0.2 and 21.3±0.2 degrees 2θ.

38. 38. The crystalline form of claims 35-37, wherein Form D is characterized by peaks in an XRPD pattern at 5.8±0.2, 6.0±0.2, 7.2±0.2, 8.9±0.2, 11.7±0.2, 11.8±0.2, 12.5±0.2, 13.0±0.2, 16.9±0.2, 17.3±0.2, 17.8±0.2, 18.5±0.2, 19.1±0.2, 19.7±0.2, 21.3±0.2, 23.1±0.2, 23.4±0.2, 24.1±0.2, 26.2±0.2, and 26.4±0.2 degrees 2θ.

39. 39. The crystalline form of claims 35-38, characterized by an XRPD pattern substantially similar to the XRPD pattern shown in Figure 4A.

40. 40. The crystalline form of claims 35-39, exhibiting a DSC thermogram comprising a peak at 84±5, or 191±5, or a combination thereof.

41. 41. The crystalline form of claim 40, wherein the peak at 84±5°C is associated with an enthalpy of 300±5 J / g and the peak at 191±5°C is associated with an enthalpy of 8±5 J / g.

42. 42. The crystalline form of claims 35-41, exhibiting a DSC thermogram comprising an endothermic peak with an onset at 52±5, or 179±5°C, or a combination thereof.

43. 43. The crystalline form of claims 35-42, which exhibits a 5% weight loss at a temperature of 110±5°C, a 2% weight loss at 170±5°C, or both, as measured by TGA analysis.

44. 44. The crystalline form of claims 35-43, wherein Compound I is a solvate.

45. 45. The crystalline form of claim 44, wherein the solvate is a dimethylformamide (DMF) solvate.

46. 3. The crystalline form of claim 2, wherein said crystalline form of Compound I is Form E.

47. 47. The crystalline form of claim 46, wherein Form E is characterized by peaks in an XRPD pattern at 5.8±0.2, 17.4±0.2, and 22.9±0.2 degrees 2θ.

48. 48. The crystalline form of claim 47, wherein Form E is further characterized by at least one peak in an XRPD pattern selected from 11.6±0.2, 16.7±0.2, 17.1±0.2, 23.3±0.2, and 24.0±0.2 degrees 2θ.

49. Form E showed the following results: 5.8±0.2, 7.0±0.2, 9.4±0.2, 11.4±0.2, 11.6±0.2, 14.1±0.2, 16.7±0.2, 17.1±0.2, 17.4±0.2, 17.8±0.2, 18.1±0.2, 18.3±0.2, 18.8±0.2, 19.4±0.2, 20.2±0.2, 20.9±0.2, 21.

49. The crystalline form of claims 46-48, characterized by peaks in an XRPD pattern at 1±0.2, 21.8±0.2, 22.1±0.2, 22.9±0.2, 23.3±0.2, 24.0±0.2, 25.4±0.2, 25.9±0.2, 26.3±0.2, 28.3±0.2, 33.3±0.2, and 35.7±0.2 degrees two-theta.

50. 50. The crystalline form of claims 46-49, characterized by an XRPD pattern substantially similar to the XRPD pattern shown in Figure 5A.

51. 51. The crystalline form of claims 46-50, exhibiting a DSC thermogram comprising peaks at 176±5, 239±5, 231±5, or 276±5°C, or combinations thereof.

52. 52. The crystalline form of claim 51, wherein the peak at 176±5°C is associated with an enthalpy of 75±5 J / g; the peak at 239±5°C is associated with an enthalpy of 32±5 J / g; and the peak at 276±5°C is associated with an enthalpy of 17±5 J / g.

53. 53. The crystalline form of claims 46-52, exhibiting a DSC thermogram comprising an endothermic peak with an onset at 139±5, 233±5, or 271±5°C, or any combination thereof.

54. 54. The crystalline form of claims 46-53, which exhibits a weight loss of 2% at a temperature of 80±5°C, a weight loss of 16% at 140±5°C, or both, as measured by TGA analysis.

55. 55. The crystalline form of claims 46-54, wherein Compound I is a solvate.

56. 3. The crystalline form of claim 2, wherein said crystalline form of Compound I is Form F.

57. 57. The crystalline form of claim 56, wherein form F is characterized by peaks in an XRPD pattern at 13.0±0.2, 17.0±0.2, and 19.3±0.2 degrees 2θ.

58. 58. The crystalline form of claim 57, wherein Form F is further characterized by at least one peak in an XRPD pattern selected from 20.0±0.2, 22.5±0.2, 22.6±0.2, 23.3±0.2, and 23.9±0.2 degrees 2θ.

59. Form F was 11.8±0.2, 13.0±0.2, 13.9±0.2, 14.2±0.2, 14.5±0.2, 15.8±0.2, 16.4±0.2, 17.0±0.2, 19.3±0.2, 20.0±0.2, 21.0±0.2, 21.8±0.2, 22.1±0.2, 22.5±0.2, 22.6±0.2, 23.3±0.2, 23.7±0.2, 23.9±0.2, 24.1±0.2, 25.3±0.2 59. The crystalline form of claims 56-58, characterized by peaks in an XRPD pattern at 2, 25.5±0.2, 26.3±0.2, 26.8±0.2, 27.2±0.2, 27.9±0.2, 28.3±0.2, 29.4±0.2, 30.4±0.2, 31.7±0.2, 31.8±0.2, 32.2±0.2, 32.6±0.2, 35.6±0.2, 35.9±0.2, and 39.5±0.2 degrees 2θ.

60. 60. The crystalline form of claims 56-59, characterized by an XRPD pattern substantially similar to the XRPD pattern shown in Figure 6A.

61. 61. The crystalline form of claims 56-60, exhibiting a DSC thermogram comprising a peak at 277±5°C.

62. 62. The crystalline form of claim 61, wherein the peak at 277±5°C is associated with an enthalpy of 113±5 J / g.

63. 63. The crystalline form of claims 56-62, exhibiting a DSC thermogram comprising an endothermic peak with an onset at 269±5°C.

64. 64. The crystalline form of claims 56-63, which exhibits less than 1% weight loss at a temperature of 100±5°C as measured by TGA.

65. 65. The crystalline form of claims 56-64, wherein Compound I is an anhydrate.

66. 3. The crystalline form of claim 2, wherein said crystalline form of Compound I is Form G.

67. 67. The crystalline form of claim 66, wherein form G is characterized by peaks in an XRPD pattern at 12.6±0.2, 21.2±0.2, and 23.5±0.2 degrees 2θ.

68. 68. The crystalline form of claim 67, wherein form G is further characterized by at least one peak in an XRPD pattern selected from 6.2±0.2, 13.4±0.2, 19.0±0.2, 26.2±0.2, and 26.5±0.2 degrees 2θ.

69. 69. The crystalline form of claims 66-68, wherein form G is characterized by peaks in an XRPD pattern at 6.2±0.2, 11.4±0.2, 12.6±0.2, 13.4±0.2, 19.0±0.2, 21.2±0.2, 23.5±0.2, 26.2±0.2, 26.5±0.2, 28.0±0.2, 31.4±0.2, and 36.0±0.2 degrees two-theta.

70. 70. The crystalline form of claims 66-69, characterized by an XRPD pattern substantially similar to the XRPD pattern shown in Figure 7A.

71. 71. The crystalline form of claims 66-70, wherein Compound I is a solvate.

72. 72. The crystalline form of claim 71, wherein the solvate is a DMSO solvate.

73. 3. The crystalline form of claim 2, wherein said crystalline form of Compound I is Form H.

74. 74. The crystalline form of claim 73, wherein Form H is characterized by peaks in an XRPD pattern at 5.7±0.2, 6.0±0.2, and 11.7±0.2 degrees 2θ.

75. 75. The crystalline form of claim 74, wherein Form H is further characterized by at least one peak in an XRPD pattern selected from 7.1±0.2, 11.4±0.2, 17.2±0.2, 23.0±0.2, and 24.0±0.2 degrees 2θ.

76. 76. The crystalline form of claims 73-75, wherein Form H is characterized by peaks in an XRPD pattern at 5.7±0.2, 6.0±0.2, 7.1±0.2, 9.2±0.2, 11.4±0.2, 11.7±0.2, 14.1±0.2, 16.5±0.2, 17.2±0.2, 17.8±0.2, 18.4±0.2, 19.1±0.2, 19.7±0.2, 20.1±0.2, 20.6±0.2, 21.4±0.2, 22.0±0.2, 23.0±0.2, 24.0±0.2, 25.4±0.2, 26.0±0.2, 27.1±0.2, 28.2±0.2, and 30.3±0.2 degrees 2θ.

77. 77. The crystalline form of claims 73-76, characterized by an XRPD pattern substantially similar to the XRPD pattern shown in Figure 8A.

78. 78. The crystalline form of claims 73-77, wherein Compound I is an anhydrate.

79. 3. The crystalline form of claim 2, wherein said crystalline form of Compound I is Form J.

80. 80. The crystalline form of claim 79, wherein Form J is characterized by peaks in an XRPD pattern at 11.1±0.2, 11.6±0.2, and 17.1±0.2 degrees 2θ.

81. 81. The crystalline form of claim 80, further characterized by at least one peak in an XRPD pattern selected from 5.6±0.2, 6.9±0.2, 16.2±0.2, 17.8±0.2, and 18.3±0.2 degrees 2θ.

82. Form J was 5.6±0.2, 6.9±0.2, 9.1±0.2, 11.1±0.2, 11.6±0.2, 12.9±0.2, 13.9±0.2, 16.2±0.2, 16.8±0.2, 17.1±0.2, 17.5±0.2, 17.8±0.2, 18.29±0.2, 19.2±0.2, 19.7±0.2, 20.6±0.2, 21.0±0.2, 21.6±0.2, 22.4±0.2, 22.

82. The crystalline form of claims 79-81, characterized by peaks in an XRPD pattern at 9±0.2, 23.4±0.2, 23.9±0.2, 25.9±0.2, 26.2±0.2, 27.5±0.2, 27.7±0.2, 28.0±0.2, 29.0±0.2, 30.1±0.2, 31.0±0.2, 31.7±0.2, 32.9±0.2, 37.2±0.2, and 38.4±0.2 degrees two-theta.

83. 82. The crystalline form of claims 79-81, characterized by an XRPD pattern substantially similar to the XRPD pattern shown in Figure 10A.

84. 82. The crystalline form of claims 79-81, exhibiting a DSC thermogram comprising peaks at 83±5°C, 196±5°C, and 285±5°C.

85. 3. The crystalline form of claim 2, wherein said crystalline form of Compound I is Form K.

86. 86. The crystalline form of claim 85, wherein form K is characterized by peaks in an XRPD pattern at 5.4±0.2, 13.4±0.2, and 17.9±0.2 degrees 2θ.

87. Form K: 5.5±0.2, 7.3±0.2, 11.4±0.2, 12.0±0.2, 12.9±0.2, 13.4±0.2, 14.6±0.2, 16.1±0.2, 16.9±0.2, 17.4±0.2, 17.9±0.2, 18.4±0.2, 19.0±0.2, 19.9±0.2, 21.1±0.2, 21.5±0.2, 21.7±0.2, 21.9±0.2, 22.2±0.2, 22.9±0.2, 23.2±0.2 87. The crystalline form of claim 85 or 86, characterized by peaks in an XRPD pattern at 24.1±0.2, 24.8±0.2, 25.1±0.2, 27.8±0.2, 26.3±0.2, 26.7±0.2, 27.3±0.2, 27.6±0.2, 28.5±0.2, 29.7±0.2, 32.5±0.2, 33.9±0.2, 34.7±0.2, 35.3±0.2, 37.3±0.2, and 38.3±0.2 degrees 2θ.

88. 88. The crystalline form of claims 85-87, characterized by an XRPD pattern substantially similar to the XRPD pattern shown in Figure 11.

89. 3. The crystalline form of claim 2, wherein said crystalline form of Compound I is Form L.

90. 90. The crystalline form of claim 89, wherein form L is characterized by peaks in an XRPD pattern at 4.3±0.2, 8.2±0.2, and 8.6±0.2 degrees 2θ.

91. Form L: 4.3±0.2, 8.2±0.2, 8.6±0.2, 12.9±0.2, 13.4±0.2, 15.4±0.2, 15.9±0.2, 17.2±0.2, 17.7±0.2, 18.2±0.2, 18.6±0.2, 19.2±0.2, 20.5±0.2, 21.5±0.2, 22.2±0.2, 24.1±0.2; 91. The crystalline form of claim 89 or 90, characterized by peaks in an XRPD pattern at 24.9±0.2, 25.7±0.2, 26.0±0.2, 26.6±0.2, 27.1±0.2, 27.5±0.2, 28.1±0.2, 29.2±0.2, 30.2±0.2, 31.2±0.2, and 38.5±0.2 degrees 2θ.

92. 92. The crystalline form of claims 89-91, characterized by an XRPD pattern substantially similar to the XRPD pattern shown in Figure 12.

93. 3. The crystalline form of claim 2, wherein the crystalline form of Compound I is Form M.

94. 94. The crystalline form of claim 93, wherein Form M is characterized by peaks in an XRPD pattern at 7.3±0.2, 10.4±0.2, and 12.7±0.2 degrees 2θ.

95. 91. The crystalline form of claim 89 or 90, wherein Form M is characterized by peaks in an XRPD pattern at 7.3±0.2, 9.2±0.2, 10.4±0.2, 11.8±0.2, 12.7±0.2, 14.8±0.2, 16.2±0.2, 17.5±0.2, 18.6±0.2, 19.0±0.2, 19.9±0.2, 21.0±0.2, 22.3±0.2, 23.6±0.2, 29.2±0.2, 31.2±0.2, 32.5±0.2, and 33.5±0.2 degrees 2θ.

96. 96. The crystalline form of claims 93-95, characterized by an XRPD pattern substantially similar to the XRPD pattern shown in Figure 13.

97. 97. A composition comprising the crystalline form of any one of claims 1 to 96 and a pharmaceutically acceptable excipient.

98. 97. A method of treating a disease or condition, comprising administering to a subject in need thereof a therapeutically effective amount of the crystalline form of any one of claims 1 to 96.

99. 100. The method of claim 99, wherein the disease or condition involves the abnormal activity of one or more RAF kinases.

100. 101. The method of claim 100, wherein said one or more RAF kinases is B-RAF.

101. 102. The method of any one of claims 99 to 101, wherein the disease or condition is cancer.

102. The cancer may be Barrett's adenocarcinoma; biliary tract cancer; breast cancer; cervical cancer; cholangiocarcinoma; central nervous system tumors; primary CNS tumors; glioblastoma, astrocytoma; glioblastoma multiforme; ependymoma; secondary CNS tumors (metastasis of tumors originating outside the central nervous system to the central nervous system); brain tumors; brain metastases; colorectal cancer; colorectal cancer; gastric cancer; head and neck cancer; head and neck squamous cell carcinoma; acute lymphoblastic leukemia; acute myeloid leukemia (AML); myelodysplastic syndrome; chronic myeloid leukemia; Hodgkin's lymphoma; non-Hodgkin's lymphoma; megakaryoblastic leukemia; multiple myeloma; erythroleukemia; hepatocellular carcinoma; lung cancer; small cell lung cancer; 103. The method of claim 102, wherein the cancer is non-small cell lung cancer; ovarian cancer; endometrial cancer; pancreatic cancer; pituitary adenoma; prostate cancer; renal cancer; metastatic melanoma; or thyroid cancer.

103. 103. The method of claim 102, wherein the cancer is melanoma, non-small cell carcinoma, colon cancer, or pancreatic cancer.

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