Crystalline solid forms of salts of N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, processes for making, and methods of use

Abstract

To provide methods of treating diseases.SOLUTION: The invention relates to novel crystalline solid forms of salts of the chemical compound N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and solvates thereof, including hydrates, that are useful for treatment of cancer. Also disclosed are pharmaceutical compositions comprising the crystalline solid forms, and production processes of the crystalline solid forms, and methods of using them for treatment of cancer, particularly renal cell carcinoma (RCC) and medullary thyroid cancer (MTC).SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] Related Applications This application claims priority to U.S. Application No. 62 / 511,714, filed May 26, 2017, the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to novel crystalline solid forms of salts of the compound N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-l,l-dicarboxamide, and solvates thereof, including hydrates, useful for the treatment of cancer. Pharmaceutical compositions containing said crystalline solid forms and processes for the preparation of said crystalline solid forms, as well as methods of their use for the treatment of cancer, particularly renal cell carcinoma (RCC) and medullary thyroid carcinoma (MTC), are also disclosed. [Background technology]

[0003] Commonly assigned PCT Patent Publication No. WO2005 / 030140, the entirety of which is incorporated herein by reference, discloses novel inhibitors of multiple receptor tyrosine kinases (RTKs) involved in tumor growth and angiogenesis, pathological bone remodeling, and metastatic progression of cancer. In particular, the compound N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide is specifically described as an RTK inhibitor in WO2005 / 030140. N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide is also known in the art as cabozantinib. The chemical structure of N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (cabozantinib) is compound 1. [ka] It is expressed as:

[0004] Compound 1 has an enzyme Ret IC of approximately 5.2 nM. 50 value (dihydrate), and the enzyme c-Met IC of approximately 1.3 nM 50 The assay used to measure this c-Met activity is described in paragraph

[0458] of WO2005 / 030140.

[0005] During early development experiments, compound 1 (free base) was found to be a BCS Class II compound with low solubility and high permeability. Due to its observed low aqueous solubility, compound 1 was initially deemed unsuitable for development into a solid oral dosage form, and therefore the drug development was focused on finding a salt with suitable hygroscopicity, thermal stability, chemical stability, physical stability, and solubility. He scored a point.

[0006] The malate salt of Compound 1, described in WO2010 / 083414 (the entire contents of which are incorporated by reference), was subsequently found to have an acceptable combination of crystallinity, solubility, and stability compared to the free base of Compound 1. The S-malate salt of N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (also known as cabozantinib or COMETRIQ®) was approved by the U.S. Food and Drug Administration on November 29, 2012 for the treatment of advanced metastatic medullary thyroid carcinoma (MTC). In December 2013, the European Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion on the Marketing Authorization Application (MAA) for COMETRIQ® submitted to the European Medicines Agency, or EMA, for the proposed indications of progressive, unresectable, locally advanced, or metastatic MTC. More recently, in 2015, cabozantinib as the S-malate salt was approved as CABOMETYX® for the treatment of advanced renal cell carcinoma. Applicants continue to strive to provide suitable forms of Compound 1 that have favorable properties related to processing stability, manufacturing stability, storage stability, and / or drug utility, in addition to therapeutic efficacy. Thus, the discovery of novel crystalline solid forms of Compound 1 that have some or all of these desirable properties remains essential for drug development. Thus, disclosed herein are novel crystalline solid forms of Compound 1 that can be used in pharmaceutical compositions for the treatment of proliferative diseases, such as cancer. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] International Publication No. 2005 / 030140 [Patent Document 2] International Publication No. 2010 / 083414 Summary of the Invention [Means for solving the problem]

[0008] The present invention is directed to novel crystalline solid forms of salts of Compound 1, as well as pharmaceutical compositions containing such crystalline solid forms, methods of using the crystalline solid forms, and processes for their manufacture, thereby satisfying these and other needs. The crystalline solid forms include solvated solid forms, including hydrates. The crystalline solid forms of Compound 1 are useful in the preparation of pharmaceutical compositions that are expected to be useful in the treatment of cancer, among other uses. Thus, one aspect of the present invention relates to pharmaceutical compositions comprising a pharma-ceutically acceptable carrier and a therapeutically effective amount of a solid form of Compound 1.

[0009] As previously shown, Compound 1 inhibits multiple receptor tyrosine kinases (RTKs) involved in tumor growth and angiogenesis, pathological bone remodeling, and cancer metastasis progression. Thus, crystalline solid forms of Compound 1 are useful for treating cancer. Accordingly, another aspect of the present invention relates to a method for treating cancer, comprising administering to a subject a therapeutically effective amount of a solid form of Compound 1 disclosed herein. The present invention is also directed to a process for preparing the crystalline solid form of Compound 1.

[0010] The solid forms are summarized in Table 1. Table 1. Novel crystalline solid forms of salts of N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide [Table 1]

[0011] A total of 27 forms were observed during the screening. One of the patterns (Form 8) was associated with the free base. The remaining 26 solids were evaluated according to their crystallinity, state of solvation, stoichiometry, ease of preparation, deliquescence, stability against desolvation, molecular weight, and acceptability / tolerability for oral administration. Water solubility determinations and optical microscopy were also performed.

[0012] In a particular embodiment, the present invention provides a method for producing a method for the treatment of a cancer A crystalline solid salt of N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1), N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (compound 1) pyruvate; N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (compound 1) glutarate, N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (compound 1) isethionate monohydrate and The present invention relates to a salt selected from the group consisting of:

[0013] Forms 14, 19, and 20 (pyruvate, glutarate, and isethionate) were prepared on a 250-1000 mg scale and confirmed to be identical to those observed in the initial screening. XRPD, DSC, TG / DTA, DVS, and 1 Detailed characterization by H NMR spectroscopy was also performed. The crystal habits of these compounds were also investigated. Compound 1 pyruvate and glutarate salts were irregular particles with low aspect ratios, while compound 1 isethionate salt showed a crystal habit of needle-like morphology.

[0014] The salt forms described herein have many advantageous properties, including lower molecular weights conferring higher activity / weight ratios, higher solubility, improved filterability and flow properties due to particle morphology / aspect ratios, and low hygroscopicity. Furthermore, many of the salts described herein are natural human metabolites and therefore are well tolerated in vivo. [Brief description of the drawings]

[0015] [Figure 1] FIG. 1 shows XRPD spectra of Forms 1, 2, and 3. [Diagram 2] FIG. 1 shows the XRPD spectra of Forms 4, 5, and 6. [Diagram 3] FIG. 1 shows the XRPD spectra of Forms 7, 8, and 9. [Figure 4] FIG. 1 shows the XRPD spectra of Forms 10, 11, and 12. [Diagram 5] FIG. 1 shows the XRPD spectra of Forms 13, 14, and 15. [Figure 6]FIG. 1 shows the XRPD spectra of Forms 16, 17, and 18. [Figure 7] FIG. 1 shows the XRPD spectra of Forms 19, 20, and 21. [Figure 8] FIG. 1 shows the XRPD spectra of Forms 22, 23, and 24. [Figure 9] FIG. 1 shows the XRPD spectra of Forms 25, 26, and 27. [Figure 10] FIG. 2 is a diagram showing the TG / DTA curve of Form 1. [Figure 11] FIG. 2 is a diagram showing the TG / DTA curve of Form 2. [Figure 12] FIG. 2 shows the TG / DTA curve of Form 3. [Figure 13] FIG. 1 shows the TG / DTA curve of Form 5. [Figure 14] FIG. 1 shows the TG / DTA curve of Form 6. [Figure 15] FIG. 1 shows the TG / DTA curve of Form 7. [Figure 16] FIG. 1 shows the TG / DTA curve of Form 9. [Figure 17] FIG. 1 shows the TG / DTA curve of Form 10. [Figure 18] FIG. 1 shows the TG / DTA curve of Form 11. [Figure 19] FIG. 1 shows the TG / DTA curve of Form 12. [Figure 20] FIG. 13 shows the TG / DTA curve of Form 13. [Figure 21] FIG. 1 shows the TG / DTA curve of Form 15. [Figure 22] FIG. 1 shows the TG / DTA curve of Form 16. [Figure 23] FIG. 17 shows the TG / DTA curve of Form 17. [Figure 24] FIG. 16 shows the TG / DTA curve of Form 18. [Diagram 25] FIG. 2 shows the TG / DTA curve of Form 21. [Figure 26] FIG. 2 shows the TG / DTA curve of Form 22. [Figure 27] FIG. 2 shows the TG / DTA curve of Form 24. [Figure 28] FIG. 2 shows the TG / DTA curve of Form 25. [Figure 29] FIG. 23 shows the TG / DTA curve of Form 26. [Diagram 30] FIG. 1 shows the NMR spectrum of Form 1 in DMSO-d6. [Diagram 31] FIG. 1 shows the NMR spectrum of Form 2 in DMSO-d6. [Diagram 32] FIG. 1 shows the NMR spectrum of Form 3 in DMSO-d6. [Diagram 33] FIG. 1 shows the NMR spectrum of Form 5 in DMSO-d6. [Diagram 34] FIG. 1 shows the NMR spectrum of Form 6 in DMSO-d6. [Diagram 35] FIG. 1 shows the NMR spectrum of Form 7 in DMSO-d6. [Diagram 36] FIG. 1 shows the NMR spectrum of Form 8 in DMSO-d6. [Figure 37] FIG. 1 shows the NMR spectrum of Form 9 in DMSO-d6. [Figure 38] FIG. 1 shows the NMR spectrum of Form 10 in DMSO-d6. [Figure 39] FIG. 1 shows the NMR spectrum of Form 11 in DMSO-d6. [Diagram 40] FIG. 1 shows the NMR spectrum of Form 12 in DMSO-d6. [Diagram 41] FIG. 1 shows the NMR spectrum of Form 13 in DMSO-d6. [Diagram 42] FIG. 1 shows the NMR spectrum of Form 15 in DMSO-d6. [Diagram 43] FIG. 1 shows the NMR spectrum of Form 16 in DMSO-d6. [Diagram 44] FIG. 1 shows the NMR spectrum of Form 17 in DMSO-d6. [Diagram 45]FIG. 1 shows the NMR spectrum of Form 18 in DMSO-d6. [Figure 46] FIG. 1 shows the NMR spectrum of Form 19 in DMSO-d6. [Figure 47] FIG. 1 shows the NMR spectrum of Form 21 in DMSO-d6. [Figure 48] FIG. 1 shows the NMR spectrum of Form 22 in DMSO-d6. [Figure 49] FIG. 1 shows the NMR spectrum of Form 23 in DMSO-d6. [Figure 50] FIG. 1 shows the NMR spectrum of Form 24 in DMSO-d6. [Figure 51] FIG. 1 shows the NMR spectrum of Form 25 in DMSO-d6. [Figure 52] FIG. 1 shows the NMR spectrum of Form 26 in DMSO-d6. [Figure 53-1] A is an XRPD spectrum of Compound 1 pyruvate in Form 14. B is a DSC curve of Compound 1 pyruvate in Form 14. C is a TG / DTA thermogram of Compound 1 pyruvate in Form 14. D is a DVS isotherm of Compound 1 pyruvate in Form 14. E is a pre-DVS (top) and post-DVS (bottom) XRPD spectrum of Compound 1 pyruvate in Form 14. F is a FT-IR spectrum of Compound 1 pyruvate in Form 14. G is a 1H-NMR (DMSO-d6) of Compound 1 pyruvate in Form 14. [Figure 53-2] Same as above [Figure 53-3] Same as above [Figure 53-4] Same as above [Figure 53-5] Same as above [Figure 54-1]A is an XRPD spectrum of compound 1 glutarate in form 20. B is a DSC curve of compound 1 glutarate in form 20. C is a TG / DTA thermogram of compound 1 glutarate in form 20. D is a DVS isotherm of compound 1 glutarate in form 20. E is a pre-DVS (top) and post-DVS (bottom) XRPD spectrum of compound 1 glutarate in form 20. F is an infrared (IR) spectrum of compound 1 glutarate in form 20. G is a 1H-NMR (DMSO-d6) of compound 1 glutarate in form 20. [Figure 54-2] Same as above [Figure 54-3] Same as above [Figure 54-4] Same as above [Figure 54-5] Same as above [Figure 55-1] A is an XRPD spectrum of Compound 1 isethionate monohydrate in Form 27. B is a DSC curve of Compound 1 isethionate monohydrate in Form 27. C is a TG / DTA thermogram of Compound 1 isethionate monohydrate in Form 27. D is a DVS isotherm of Compound 1 isethionate monohydrate in Form 27. E is an XRPD spectrum of Compound 1 isethionate monohydrate in Form 27, pre-DVS (top) and post-DVS (bottom). F is an infrared (IR) spectrum of Compound 1 isethionate monohydrate in Form 27. G is a 1H-NMR (DMSO-d6) of Compound 1 isethionate monohydrate in Form 27. [Figure 55-2] Same as above [Figure 55-3] Same as above [Figure 55-4] Same as above [Figure 55-5] Same as above DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] Definition of Terms The compositions of the present invention can be prepared using the manufacturing processes described herein, the amounts and characteristics of the ingredients used in said manufacturing processes will be as described herein.

[0017] When describing the compounds, compositions, methods and processes of the invention, the following terms have the following meanings unless otherwise indicated.

[0018] The term "solvate" refers to a complex or aggregate formed by one or more molecules of a solute, i.e., crystalline compound 1, and one or more molecules of a solvent. Such solvates generally have a substantially fixed molar ratio of solute and solvent. The term also includes clathrates, including clathrates containing water. Representative solvents include, for example, water, methanol, ethanol, isopropanol, acetic acid, etc. When the solvent is water, the solvate formed is a hydrate.

[0019] A "therapeutically effective amount" refers to an amount sufficient to effect treatment when administered to a subject in need of treatment. The amount of the compound of the present invention that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the age of the subject to be treated, and the like. A therapeutically effective amount can be routinely determined by one of ordinary skill in the art in light of their own knowledge and this disclosure. Thus, a "therapeutically effective amount" of Compound 1 refers to an amount sufficient to treat a subject suffering from any of a variety of cancers involving abnormal cell proliferation and angiogenesis. A therapeutically effective amount according to the present disclosure is an amount that is therapeutically useful for treating or preventing the disease states and disorders discussed herein. Compound 1 (including the solid state disclosed herein) has therapeutic activity to inhibit, regulate, and / or modulate kinase signal transduction as described in WO2005 / 030140.

[0020] As used herein, "treating" or "treatment" refers to the treatment of a human disease condition characterized by abnormal cell proliferation and invasion and includes at least one of: (i) preventing the development of said disease condition in a human, particularly at a stage when such a human is susceptible to, but has not yet been diagnosed with, said disease condition; (ii) inhibiting said disease condition, i.e., preventing the onset of said disease condition; and (iii) alleviating said disease condition, i.e., causing regression of said disease condition.

[0021] The term "pharmaceutically acceptable" refers to a substance that is not biologically or otherwise undesirable. For example, the term "pharmaceutically acceptable carrier" refers to a substance that can be incorporated into a composition and administered to a subject without producing undesirable biological effects or interacting in a harmful manner with other components of the composition. Such pharmaceutically acceptable substances typically meet the necessary standards of toxicological and manufacturing testing, and include substances identified by the U.S. Food and Drug Administration as suitable inactive ingredients.

[0022] The term "dosage form" refers to physically discrete units suitable for administration to a subject, i.e., each unit containing a predetermined amount of a compound of the invention calculated to produce a desired therapeutic effect, either alone or in combination with one or more additional units. For example, such unit dosage forms can be capsules, tablets, pills, etc.

[0023] As used herein, "amorphous" refers to a solid form of molecules and / or ions that is not crystalline. Amorphous solids do not exhibit distinct X-ray diffraction patterns with sharp peaks.

[0024] As used herein, the term "substantially pure" means that the solid form of Compound 1 referred to contains at least about 90 weight percent based on the weight of such solid form. The term "at least about 90 weight percent" is not intended to limit the applicability of the doctrine of equivalents to the claims, but includes, but is not limited to, for example, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99, and about 100 weight percent based on the weight of the solid form referred to. The remainder of the solid form of Compound 1 may contain other solid form(s) of Compound 1 and / or reaction-derived impurities and / or process-derived impurities that occur, for example, when the crystalline form is prepared. The presence of reaction-derived impurities and / or process-derived impurities can be measured by analytical techniques known in the art, such as, for example, chromatography, nuclear magnetic resonance spectroscopy, mass spectroscopy, and / or infrared spectroscopy.

[0025] As used herein, "crystalline solid" refers to a compound or composition in which the structural units are arranged in a fixed geometric pattern or lattice, such that the crystalline solid has a rigid long-range order. The structural units that make up the crystal structure may be atoms, molecules, or ions. Crystalline solids exhibit a definite melting point.

[0026] As used herein, the "European Pharmacopoeia Classification" is a system for classifying compounds based on their hygroscopicity. The classification is determined according to Table 2. [Table 2] The hygroscopicity of a compound can be determined by techniques known to those of skill in the art, such as, but not limited to, dynamic vapor sorption (DVS).

[0027] Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, one or more hydrogen atoms have been replaced by deuterium or tritium, or one or more carbon atoms have been replaced by 13 C or 14 Compound 1 substituted with C-enriched carbons is within the scope of the present invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or compounds with improved therapeutic profiles. Embodiment

[0028] In one aspect, the present invention provides a crystalline solid N-{4-[(6 ,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1) citrate monohydrate, wherein the crystalline solid comprises Compound 1 and citrate in a 1:1 molar ratio. In one embodiment, Form 1 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 4.02, 9.61, 13.35, 13.50, 15.52, 16.45, 18.49, 20.94, 21.29, 21.50, 21.59, 23.85, 26.83, and 27.12 degrees on the 2θ scale. In another embodiment, Form 1 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 9.61, 13.35, 13.50, 21.50, 23.85, 26.83, and 27.12 degrees. In a further embodiment, Form 1 is characterized by peaks in an XRPD pattern at 9.61, 13.35, 13.50, 21.50, 23.85, 26.83, and 27.12 degrees on the 2-theta scale. In yet a further embodiment, Form 1 is characterized by the XRPD pattern of Figure 1. In another further embodiment, Form 1 is characterized by an XRPD pattern having peak values ​​in Table 3. [Table 3]

[0029] In one aspect, the invention comprises a crystalline solid N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1) malonate (3.6 molar equivalents of water) characterized as Form 2, wherein the crystalline solid comprises Compound 1 and malonate in a 1:1 molar ratio. In one embodiment, Form 2 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 6.36, 7.97, 11.99, 12.09, 12.75, 13.64, 17.52, 19.58, 20.57, 21.82, 23.43, 24.73, 24.79, 25.01, 26.09, 26.93, 27.36, 27.42, and 27.61 degrees on the 2-theta scale. In another embodiment, Form 2 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 6.36, 7.97, 12.75, 19.58, 20.57, 23.43, 25.01, 26.93, 27.36, and 27.42 degrees on the 2-theta scale. In a further embodiment, Form 2 has the following molecular weights on the 2θ scale: 6.36, 7.97, 12.75, 19.58, 20 Form 2 is characterized by an XRPD pattern having peaks at: 0.57, 23.43, 25.01, 26.93, 27.36, and 27.42 degrees. In yet a further embodiment, Form 2 is characterized by the XRPD pattern of Figure 1. In another further embodiment, Form 2 is characterized by an XRPD pattern having the peak values ​​in Table 4. [Table 4-1] [Table 4-2]

[0030] In one aspect, the invention comprises a crystalline solid N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1) oxalate (anhydrous) characterized as Form 3, wherein the crystalline solid comprises Compound 1 and oxalate in a 1:1 molar ratio. In one embodiment, Form 3 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 7.40, 9.44, 9.78, 10.36, 12.67, 12.97, 13.60, 14.42, 15.87, 18.65, 19.06, 21.21, 22.05, 22.76, 23.07, 24.89, and 25.69 degrees on the 2θ scale. In another embodiment, Form 3 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 9.78, 10.36, 12.97, 13.60, 23.07, and 25.69 degrees. In a further embodiment, Form 3 is characterized by peaks in an XRPD pattern at 9.78, 10.36, 12.97, 13.60, 23.07, and 25.69 degrees on the 2-theta scale. In yet a further embodiment, Form 3 is characterized by the XRPD pattern of Figure 1. In another further embodiment, Form 3 is characterized by an XRPD pattern having peak values ​​in Table 5. [Table 5-1] [Table 5-2]

[0031] In one aspect, the invention comprises a crystalline solid N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1) ethane disulfonate (deliquescent), characterized as Form 4, wherein the crystalline solid comprises Compound 1 and ethane disulfonate in a 1:1 molar ratio. In one embodiment, Form 4 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 6.83, 8.37, 11.67, 13.10, 13.65, 22.09, 22.48, 22.70, 24.66, and 27.19 degrees on the 2θ scale. In another embodiment, Form 4 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 8.37, 11.67, 13.10, 22.48, 22.70, 24.66, and 27.19 degrees. In a further embodiment, Form 4 is characterized by peaks in an XRPD pattern at 8.37, 11.67, 13.10, 22.48, 22.70, 24.66, and 27.19 degrees on the 2θ scale. In yet a further embodiment, Form 4 is characterized by the XRPD pattern of Figure 2. In another further embodiment, Form 4 is characterized by an XRPD pattern having peak values ​​in Table 6. [Table 6]

[0032] In one aspect, the invention comprises a crystalline solid N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1) sulfate (3.7 molar equivalents of water) characterized as Form 5, wherein the crystalline solid comprises Compound 1 and sulfate in a 1:1 molar ratio. In one embodiment, Form 5 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 9.56, 10.08, 13.29, 13.86, 14.17, 22.27, 22.60, 22.93, 25.16, and 27.70 degrees on the 2θ scale. In another embodiment, Form 5 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 8.37, 11.67, 13.10, 22.48, 22.70, 24.66, and 27.19 degrees. In a further embodiment, Form 5 is characterized by peaks in an XRPD pattern at 9.56, 10.08, 13.29, 13.86, 22.60, and 25.16 degrees on the 2-theta scale. In yet a further embodiment, Form 5 is characterized by the XRPD pattern of Figure 2. In another further embodiment, Form 5 is characterized by an XRPD pattern having peak values ​​in Table 7. [Table 7]

[0033] In one aspect, the present invention provides a crystalline solid, N-{4-[(6 {N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1) besylate salt (anhydrous), wherein the crystalline solid comprises Compound 1 and besylate in a 1:1 molar ratio. In one embodiment, Form 6 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 9.77, 10.52, 13.26, 14.34, 15.90, 15.98, 17.93, 18.69, 19.54, 22.83, 26.78, and 26.85 degrees on the 2θ scale. In another embodiment, Form 6 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 9.77, 10.52, 13.26, 14.34, 15.90, 18.69, 19.54, 22.83, 26.78, and 26.85 degrees. In a further embodiment, Form 6 is characterized by peaks in an XRPD pattern at 9.77, 10.52, 13.26, 14.34, 15.90, 18.69, 19.54, 22.83, 26.78, and 26.85 degrees on the 2-theta scale. In yet a further embodiment, Form 6 is characterized by the XRPD pattern of Figure 2. In another further embodiment, Form 6 is characterized by an XRPD pattern having peak values ​​in Table 8. [Table 8]

[0034] In one aspect, the present invention comprises a crystalline solid N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1) esylate (anhydrous) characterized as Form 7, wherein the crystalline solid comprises Compound 1 and esylate in a 1:1 molar ratio. In one embodiment, Form 7 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 5.18, 11.63, 14.09, 14.79, 16.89, 19.92, 21.05, and 26.46 degrees on the 2θ scale. In another embodiment, Form 7 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 14.79 and 19.92 degrees. In a further embodiment, Form 7 is characterized by peaks in an XRPD pattern at 14.79 and 19.92 degrees on the 2θ scale. In yet a further embodiment, Form 7 is characterized by the XRPD pattern of Figure 3. In another further embodiment, Form 7 is characterized by an XRPD pattern having the peak values ​​in Table 9. [Table 9]

[0035] In one aspect, the present invention comprises a crystalline solid N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1), characterized as Form 8 (free base). In one embodiment, Form 8 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 6.76, 12.35, 12.85, 18.88, 21.01, 22.83, 23.59, 25.10, 26.30, 27.96, and 28.02 degrees on the 2-theta scale. In another embodiment, Form 8 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 12.35, 12.85, 18.88, 21.01, 22.83, 23.59, 25.10, and 26.30 degrees. In a further embodiment, Form 8 is characterized by peaks in an XRPD pattern at 12.35, 12.85, 18.88, 21.01, 22.83, 23.59, 25.10, and 26.30 degrees on the 2-theta scale. In yet a further embodiment, Form 8 is characterized by the XRPD pattern of Figure 3. In another further embodiment, Form 7 is characterized by an XRPD pattern having the peak values ​​in Table 10. [Table 10]

[0036] In one aspect, the present invention provides a crystalline solid N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1) mesylate salt (anhydrous) characterized as Form 9, wherein the crystalline solid comprises Compound 1 and mesylate in a 1:1 molar ratio. In one embodiment, Form 9 is characterized by one or more peaks in its XRPD pattern selected from the group consisting of 5.75, 11.33, 15.57, 16.19, 16.34, 16.76, 17.36, 17.90, 20.87, 22.69, and 23.08 degrees on the 2-theta scale. In another embodiment, Form 9 is characterized by one or more peaks in its XRPD pattern selected from the group consisting of 5.75, 15.57, 16.19, 17.90, 20.87, 22.69, and 23.08 degrees on the 2-theta scale. In a further embodiment, Form 9 is characterized by peaks in its XRPD pattern selected from the group consisting of 5.75, 15.57, 16.19, 17.90, 20.87, 22.69, and 23.08 degrees on the 2-theta scale. In yet a further embodiment, Form 9 is characterized by the XRPD pattern of Figure 3. In another further embodiment, Form 9 is characterized by an XRPD pattern having the peak values ​​in Table 11. [Table 11]

[0037] In one aspect, the invention comprises a crystalline solid N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1) tosylate salt (anhydrous), characterized as Form 10, wherein the crystalline solid comprises Compound 1 and tosylate in a 1:1 molar ratio. In one embodiment, Form 10 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 4.77, 9.58, 14.17, 14.26, 15.55, 15.61, 18.20, 18.29, 19.30, 20.12, 26.13, 26.20, 27.11, and 28.99 degrees on the 2θ scale. In another embodiment, Form 10 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 15.55, 18.29, 19.30, 20.12, 26.13, and 26.20 degrees. In a further embodiment, Form 10 is characterized by peaks in an XRPD pattern at 15.55, 18.29, 19.30, 20.12, 26.13, and 26.20 degrees on the 2-theta scale. In yet a further embodiment, Form 10 is characterized by the XRPD pattern of Figure 4. In another further embodiment, Form 10 is characterized by an XRPD pattern having peak values ​​in Table 12. [Table 12-1] [Table 12-2]

[0038] In one aspect, the invention comprises a crystalline solid N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1) sulfate (2.4 molar equivalents of water) characterized as Form 11, wherein the crystalline solid comprises Compound 1 and sulfate in a 1:1 molar ratio. In one embodiment, Form 11 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 6.75, 9.64, 11.06, 12.70, 13.70, 13.92, 14.76, 21.13, 23.58, 24.46, 24.52, 26.66, 27.62, and 29.81 degrees on the 2θ scale. In another embodiment, Form 11 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 12.70, 13.92, 23.58, 24.46, 24.52, and 26.66 degrees. In a further embodiment, Form 11 is characterized by peaks in an XRPD pattern at 12.70, 13.92, 23.58, 24.46, 24.52, and 26.66 degrees on the 2-theta scale. In yet a further embodiment, Form 11 is characterized by the XRPD pattern of Figure 4. In another further embodiment, Form 11 is characterized by an XRPD pattern having the peak values ​​in Table 13. [Table 13]

[0039] In one aspect, the invention comprises a crystalline solid N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1) ethane disulfonate (anhydrous), characterized as Form 12, wherein the crystalline solid comprises Compound 1 and ethane disulfonate in a 2:1 molar ratio. In one embodiment, Form 12 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 13.20, 13.75, 14.56, 16.45, 16.74, 18.07, 18.23, 20.18, 22.28, 23.46, 24.98, 25.69, 27.62, and 31.26 degrees on the 2θ scale. In another embodiment, Form 12 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 13.20, 13.75, 14.56, 20.18, 22.28, 24.98, and 25.69 degrees on the 2-theta scale. In a further embodiment, Form 12 is characterized by peaks in an XRPD pattern at 13.20, 13.75, 14.56, 20.18, 22.28, 24.98, and 25.69 degrees on the 2-theta scale. In another further embodiment, Form 12 is characterized by peaks in an XRPD pattern at 13.20, 14.56, 20.18, 22.28, 24.98, and 25.69 degrees on the 2-theta scale. In yet a further embodiment, Form 12 is characterized by the XRPD pattern of FIG. In another further embodiment, Form 12 is characterized by an XRPD pattern having the peak values ​​in Table 14. [Table 14]

[0040] In one aspect, the invention comprises a crystalline solid N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1) oxalate (anhydrous) characterized as Form 13, wherein the crystalline solid comprises Compound 1 and oxalate in a 1:1 molar ratio. In one embodiment, Form 13 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 12.67, 12.86, 13.63, 20.83, 21.28, 22.65, 23.59, 25.89, 26.55, and 26.60 degrees on the 2θ scale. In another embodiment, Form 13 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 12.67, 13.63, 20.83, 22.65, 23.59, and 26.55 degrees on the 2-theta scale. In another further embodiment, Form 13 is characterized by peaks in an XRPD pattern at 12.67, 13.63, 20.83, 22.65, 23.59, and 26.55 degrees on the 2-theta scale. In yet a further embodiment, Form 13 is characterized by the XRPD pattern of Figure 5. In another further embodiment, Form 13 is characterized by an XRPD pattern having peak values ​​in Table 15. [Table 15]

[0041] In one aspect, the invention comprises a crystalline solid N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1) pyruvate (anhydrous), characterized as Form 14, wherein the crystalline solid comprises Compound 1 and pyruvate in a 1:1 molar ratio. In one embodiment, Form 14 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 7.84, 8.81, 11.58, 15.67, 16.30, 16.55, 17.67, 17.92, 18.00, 18.20, 18.62, 19.66, 20.54, 20.75, 23.84, 26.35, and 26.42 degrees on the 2θ scale. In another embodiment, Form 14 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 8.81, 17.67, 23.84, and 26.42 degrees on the 2-theta scale. In another further embodiment, Form 14 is characterized by peaks in an XRPD pattern at 8.81, 17.67, 23.84, and 26.42 degrees on the 2-theta scale. In another further embodiment, Form 14 is characterized by peaks in an XRPD pattern at 8.81, 11.58, 17.67, 18.00, 23.84, and 26.35 degrees on the 2-theta scale. In yet a further embodiment, Form 14 is characterized by the XRPD pattern of Figure 5. In another further embodiment, Form 14 is characterized by an XRPD pattern having peak values ​​in Table 16. [Table 16]

[0042] In one aspect, the invention comprises a crystalline solid N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1) besylate salt (1.4 molar equivalents of tetrahydrofuran), characterized as Form 15, wherein the crystalline solid comprises Compound 1 and besylate in a 1:1 molar ratio. In one embodiment, Form 15 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 5.75, 10.42, 13.04, 15.59, 16.47, 17.95, 18.17, 18.85, 19.41, 20.90, 22.50, 23.24, and 24.36 degrees on the 2θ scale. In another embodiment, Form 15 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 5.75, 10.42, 15.59, 16.47, and 24.36 degrees on the 2-theta scale. In another further embodiment, Form 15 is characterized by peaks in an XRPD pattern at 5.75, 10.42, 15.59, 16.47, and 24.36 degrees on the 2-theta scale. In another further embodiment, Form 15 is characterized by peaks in an XRPD pattern at 5.75, 10.42, 15.59, 16.47, 17.95, 18.17, and 24.36 degrees on the 2-theta scale. In yet a further embodiment, Form 15 is characterized by the XRPD pattern of FIG. 5. In another further embodiment, Form 15 is characterized by an XRPD pattern having peak values ​​in Table 17. [Table 17-1] [Table 17-2]

[0043] In one aspect, the invention comprises a crystalline solid N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1) mesylate dihydrate characterized as Form 16, wherein the crystalline solid comprises Compound 1 and mesylate in a 1:1 molar ratio. In one embodiment, Form 16 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 6.71, 9.70, 10.76, 13.35, 13.47, 15.67, 16.20, 18.65, 19.09, 19.33, 21.77, 21.87, 23.00, 23.98, 25.25, 26.86, and 27.19 degrees on the 2θ scale. In another embodiment, Form 16 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 9.70, 13.47, 21.77, 21.87, 23.98, and 26.86 degrees on the 2-theta scale. In another further embodiment, Form 16 is characterized by peaks in an XRPD pattern at 9.70, 13.47, 21.77, 21.87, 23.98, and 26.86 degrees on the 2-theta scale. In yet a further embodiment, Form 16 is characterized by the XRPD pattern of Figure 6. In another further embodiment, Form 16 is characterized by an XRPD pattern having peak values ​​in Table 18. [Table 18-1] [Table 18-2]

[0044] In one aspect, the invention comprises a crystalline solid N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1) succinate salt (0.4 molar equivalents of acetonitrile and 0.86 molar equivalents of water), characterized as Form 17, wherein the crystalline solid comprises Compound 1 and succinate in a molar ratio of 1:0.7 (Compound 1 to succinate salt). In one embodiment, Form 17 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 5.96, 6.74, 11.88, 12.15, 13.69, 13.74, 16.47, 20.43, 20.70, 22.85, 24.69, 24.76, and 26.59 degrees on the 2θ scale. In another embodiment, Form 17 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 5.96, 6.74, 11.88, 13.74, 20.70, and 24.76 degrees on the 2-theta scale. In another further embodiment, Form 17 is characterized by peaks in an XRPD pattern at 5.96, 6.74, 11.88, 13.74, 20.70, and 24.76 degrees on the 2-theta scale. In another further embodiment, Form 17 is characterized by peaks in an XRPD pattern at 6.74, 11.88, 20.70, 24.69, 24.76, and 26.59 degrees on the 2-theta scale. In yet a further embodiment, Form 17 is characterized by the XRPD pattern of FIG. 6. In another further embodiment, Form 17 is characterized by an XRPD pattern having peak values ​​in Table 19. [Table 19-1] [Table 19-2]

[0045] In one aspect, the present invention comprises a crystalline solid N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1) esylate salt (0.4 molar equivalents of acetonitrile), characterized as Form 18, wherein the crystalline solid comprises Compound 1 and esylate in a 1:1 molar ratio. In one embodiment, Form 18 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 9.45, 9.86, 15.31, 16.85, 20.83, 21.72, 22.82, and 24.60 degrees on the 2-theta scale. In another embodiment, Form 18 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 9.45, 9.86, 20.83, and 21.72 degrees. In a further embodiment, Form 18 is characterized by peaks in an XRPD pattern at 9.45, 9.86, 20.83, and 21.72 degrees on the 2-theta scale. In another further embodiment, Form 18 is characterized by peaks in an XRPD pattern at 9.45, 9.86, 20.83, 21.72, and 24.60 degrees on the 2-theta scale. In yet a further embodiment, Form 18 is characterized by the XRPD pattern of Figure 6. In another further embodiment, Form 18 is characterized by an XRPD pattern having peak values ​​in Table 20. [Table 20]

[0046] In one aspect, the invention comprises a crystalline solid N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1) isethionate monohydrate characterized as Form 19, wherein the crystalline solid comprises Compound 1 and isethionate in a 1:1 molar ratio. In one embodiment, Form 19 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 8.54, 11.10, 12.22, 12.67, 14.12, 17.19, 18.73, 22.19, and 24.33 degrees on the 2-theta scale. In another embodiment, Form 19 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 8.54, 12.67, 22.19, and 24.33 degrees on the 2θ scale. In a further embodiment, Form 19 has an XRPD pattern of 8.54, 12.67, 22.19, and 24.33 degrees on the 2θ scale. 3. In another further embodiment, Form 19 is characterized by peaks in an XRPD pattern at 8.54, 11.10, 12.67, 14.12, 22.19, and 24.33 degrees on the 2θ scale. In yet a further embodiment, Form 19 is characterized by the XRPD pattern of FIG. 7. In another further embodiment, Form 19 is characterized by an XRPD pattern having peak values ​​in Table 21. [Table 21]

[0047] In one aspect, the invention comprises a crystalline solid N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1) glutarate (0.59 molar equivalents of water) characterized as Form 20, wherein the crystalline solid comprises Compound 1 and glutarate in a 1:1 molar ratio. In one embodiment, Form 20 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 8.06, 11.77, 19.97, 20.21, 22.27, 23.11, 23.17, 25.81, 25.87, 26.00, and 26.06 degrees on the 2θ scale. In another embodiment, Form 20 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 8.06, 11.77, 20.21, 22.27, and 26.06 degrees on the 2-theta scale. In a further embodiment, Form 20 is characterized by peaks in an XRPD pattern at 8.06, 11.77, 20.21, 22.27, and 26.06 degrees on the 2-theta scale. In another further embodiment, Form 20 is characterized by peaks in an XRPD pattern at 8.06, 11.77, 20.21, 22.27, 23.11, 25.81, 25.87, and 26.00 degrees on the 2-theta scale. In yet a further embodiment, Form 20 is characterized by the XRPD pattern of FIG. 7. In another further embodiment, Form 20 is characterized by an XRPD pattern having peak values ​​in Table 22. [Table 22]

[0048] In one aspect, the invention comprises a crystalline solid N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1) sulfate monohydrate characterized as Form 21, wherein the crystalline solid comprises Compound 1 and sulfate in a 1:1 molar ratio. In one embodiment, Form 21 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 6.61, 13.26, 13.60, 14.67, 16.40, 17.66, 19.96, 20.37, 20.76, 21.09, 21.25, and 23.30 degrees on the 2θ scale. In another embodiment, Form 21 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 6.61, 13.60, 20.37, 20.76, 21.09, and 23.30 degrees on the 2-theta scale. In another further embodiment, Form 21 is characterized by peaks in an XRPD pattern at 6.61, 13.60, 20.37, 20.76, 21.09, and 23.30 degrees on the 2-theta scale. In another further embodiment, Form 21 is characterized by peaks in an XRPD pattern at 13.60, 20.37, 20.76, 21.09, and 23.30 degrees on the 2-theta scale. In yet a further embodiment, Form 21 is characterized by the XRPD pattern of FIG. 7. In another further embodiment, Form 21 is characterized by an XRPD pattern having peak values ​​in Table 23. [Table 23-1] [Table 23-2]

[0049] In one aspect, the present invention comprises a crystalline solid N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1) tosylate (0.8 molar equivalents of water) characterized as Form 22, wherein the crystalline solid comprises Compound 1 and tosylate in a 1:1 molar ratio. In one embodiment, Form 22 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 13.75, 14.20, 14.77, 18.05, 19.28, 19.88, 20.51, 22.63, 25.41, 25.48, and 27.29 degrees on the 2θ scale. In another embodiment, Form 22 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 13.75, 14.77, 18.05, 19.88, 22.63, and 25.41 degrees on the 2-theta scale. In a further embodiment, Form 22 is characterized by peaks in an XRPD pattern at 13.75, 14.77, 18.05, 19.88, 22.63, and 25.41 degrees on the 2-theta scale. In yet a further embodiment, Form 22 is characterized by the XRPD pattern of Figure 8. In another further embodiment, Form 22 is characterized by an XRPD pattern having the peak values ​​in Table 24. [Table 24]

[0050] In one aspect, the invention comprises a crystalline solid N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1) succinate (0.8 molar equivalents of water) characterized as Form 23, wherein the crystalline solid comprises Compound 1 and succinate in a molar ratio of 1:0.6. In one embodiment, Form 23 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 6.35, 11.82, 12.20, 12.47, 13.76, 17.86, 18.04, 20.96, 21.96, 22.96, 23.79, 24.10, 24.96, and 25.59 degrees on the 2θ scale. In another embodiment, Form 23 has one or more peaks in an XRPD pattern selected from the group consisting of 11.82, 12.47, 22.96, and 24.96 degrees. In a further embodiment, Form 23 is characterized by peaks in an XRPD pattern at 11.82, 12.47, 22.96, and 24.96 degrees on the 2-theta scale. In another further embodiment, Form 23 is characterized by peaks in an XRPD pattern at 11.82, 12.47, 17.86, 22.96, 23.79, and 24.96 degrees on the 2-theta scale. In yet a further embodiment, Form 23 is characterized by the XRPD pattern of Figure 8. In another further embodiment, Form 23 is characterized by an XRPD pattern having peak values ​​in Table 25. [Table 25]

[0051] In one aspect, the invention comprises a crystalline solid N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1) malonate (anhydrous), characterized as Form 24, wherein the crystalline solid comprises Compound 1 and malonate in a 1:1 molar ratio. In one embodiment, Form 24 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 6.77, 12.36, 12.86, 21.02, 22.85, 23.61, 25.12, 26.31, 28.01, and 30.36 degrees on the 2-theta scale. In another embodiment, Form 24 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 12.36, 12.86, 21.02, 22.85, 23.61, and 25.12 degrees on the 2-theta scale. In a further embodiment, Form 24 is characterized by peaks in an XRPD pattern at 12.36, 12.86, 21.02, 22.85, 23.61, and 25.12 degrees on the 2-theta scale. In yet a further embodiment, Form 24 is characterized by the XRPD pattern of Figure 8. In another further embodiment, Form 24 is characterized by an XRPD pattern having peak values ​​in Table 26. [Table 26]

[0052] In one aspect, the invention comprises a crystalline solid N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1) mesylate salt (0.3 molar equivalents of acetonitrile), characterized as Form 25, wherein the crystalline solid comprises Compound 1 and mesylate in a 1:1 molar ratio. In one embodiment, Form 25 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 9.42, 9.75, 10.72, 11.98, 15.52, 17.71, 19.51, 19.66, 21.65, 21.96, 22.54, 23.35, 24.55, and 25.92 degrees on the 2θ scale. In another embodiment, Form 25 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 9.42, 9.75, 19.66, 21.65, 22.54, 23.35, and 24.55 degrees. In a further embodiment, Form 25 is characterized by peaks in an XRPD pattern at 9.42, 9.75, 19.66, 21.65, 22.54, 23.35, and 24.55 degrees on the 2-theta scale. In yet a further embodiment, Form 25 is characterized by the XRPD pattern of Figure 9. In another further embodiment, Form 25 is characterized by an XRPD pattern having peak values ​​in Table 27. [Table 27-1] [Table 27-2]

[0053] In one aspect, the present invention comprises a crystalline solid N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1) gluconate (2.6 molar equivalents of water) characterized as Form 26, wherein the crystalline solid comprises Compound 1 and gluconate in a 1:1 molar ratio. In one embodiment, Form 26 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 10.50, 10.59, 13.58, 13.98, 14.05, 18.71, 21.01, 22.59, 23.24, 24.35, 25.38, 25.46, 26.73, 26.88, 27.40, and 27.96 degrees on the 2θ scale. In another embodiment, Form 26 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 13.58, 13.98, 22.59, and 25.46 degrees on the 2-theta scale. In another further embodiment, Form 26 is characterized by peaks in an XRPD pattern at 13.58, 13.98, 22.59, and 25.46 degrees on the 2-theta scale. In another further embodiment, Form 26 is characterized by peaks in an XRPD pattern at 13.58, 13.98, 14.05, 22.59, 25.35, and 25.46 degrees on the 2-theta scale. In yet a further embodiment, Form 26 is characterized by the XRPD pattern of Figure 9. In another further embodiment, Form 26 is characterized by an XRPD pattern having peak values ​​in Table 28. [Table 28-1] [Table 28-2]

[0054] In one aspect, the invention comprises a crystalline solid N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1) isethionate monohydrate characterized as Form 27, wherein the crystalline solid comprises Compound 1 and isethionate in a 1:1 molar ratio. In one embodiment, Form 27 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 6.56, 12.39, 12.59, 13.14, 16.57, 17.55, 21.68, 23.66, 24.33, 26.09, 26.53, 26.69, and 27.40 degrees on the 2-theta scale. In another embodiment, Form 27 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 12.39, 12.59, 17.55, 21.68, 23.66, and 26.09 degrees on the 2-theta scale. In another further embodiment, Form 27 is characterized by peaks in an XRPD pattern at 12.39, 12.59, 17.55, 21.68, 23.66, 24.33, and 26.09 degrees on the 2-theta scale. In yet a further embodiment, Form 27 is characterized by the XRPD pattern of FIG. 9. In another further embodiment, Form 27 is characterized by an XRPD pattern having peak values ​​in Table 29. [Table 29]

[0055] In another aspect, the present invention includes a pharmaceutical composition comprising a therapeutically effective amount of a substantially pure crystalline solid form of a salt of Compound 1, as described herein, and a pharma- ceutically acceptable carrier.

[0056] In yet another aspect, the present invention includes a pharmaceutical composition comprising a therapeutically effective amount of a mixture of a crystalline solid form of a salt of Compound 1, as described herein, and a pharma- ceutically acceptable carrier.

[0057] In another aspect, the present invention provides a method for the preparation of a crystalline form of a salt of Compound 1 as described herein, comprising administering to a subject a therapeutically effective amount of the salt of Compound 1 as described herein. The present invention includes a method of treating cancer comprising administering a solid form to a subject.

[0058] In yet another aspect, the present invention includes a method for treating cancer comprising administering to a subject a pharmaceutical composition described herein.

[0059] In one embodiment of this aspect, the cancer is selected from thyroid cancer, gastric cancer, esophageal cancer, kidney cancer, liver cancer, ovarian cancer, cervical cancer, colon cancer, small intestine cancer, brain cancer, lung cancer, bone cancer, prostate cancer, pancreatic cancer, skin cancer, bone cancer, lymphoma, a solid tumor, Hodgkin's disease, or non-Hodgkin's lymphoma.

[0060] In further embodiments, the thyroid cancer is medullary thyroid cancer.

[0061] In another further embodiment, the kidney cancer is renal cell carcinoma.

[0062] In a further embodiment, the liver cancer is hepatocellular carcinoma.

[0063] In further embodiments, the brain cancer is an astrocytic tumor.

[0064] In further embodiments, the astrocytic tumor is selected from glioblastoma, giant cell glioblastoma, and gliosarcoma.

[0065] In still further embodiments, the glioblastoma has an oligodendrocyte component.

[0066] In one embodiment, the lung cancer is non-small cell lung cancer.

[0067] In another embodiment, the prostate cancer is castration-resistant prostate cancer.

[0068] In another aspect, the present invention includes a method for treating a disease or disorder associated with uncontrolled, abnormal, and / or unwanted cellular activity resulting from overexpression of cMET or RET, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one solid form of Compound 1 as described herein.

[0069] In yet another aspect, the present invention includes a method for treating a disease or disorder associated with uncontrolled, abnormal, and / or unwanted cellular activity resulting from overexpression of cMET or RET, comprising administering to a subject in need of such treatment a therapeutically effective amount of a pharmaceutical composition described herein.

[0070] Pharmaceutical compositions and methods of treatment Another aspect of the present disclosure relates to a pharmaceutical composition comprising at least one crystalline solid form of Compound 1, as described herein in any of the above aspects and / or embodiments, or combinations thereof, and a pharma- ceutically acceptable excipient. Pharmaceutical compositions of Compound 1 are disclosed, for example, in commonly assigned PCT Patent Publications WO2005 / 030140, WO2012 / 009722, and WO2012 / 109510, each of which is incorporated herein by reference in its entirety.

[0071] The amount of the crystalline solid form of Compound 1 or a combination thereof in the pharmaceutical composition may be a therapeutically effective amount. The crystalline solid forms of Compound 1 may be present individually or in combination in the pharmaceutical composition. Crystalline solid forms disclosed herein include Forms 1-27. Accordingly, another aspect of the present disclosure provides a pharmaceutical composition comprising at least one solid form of Compound 1, as described herein in any of the above aspects and / or embodiments, or combinations thereof, in a therapeutically effective amount, and a pharma- ceutical acceptable excipient. The present invention relates to a solid or dispersion pharmaceutical composition comprising an excipient.

[0072] Pharmaceutical compositions such as those disclosed herein may be any pharmaceutical form containing the active crystalline solid form of Compound 1. The pharmaceutical composition may be, for example, a tablet, capsule, suspension, injectable, topical, or transdermal formulation. The pharmaceutical composition generally contains about 1% to about 99% by weight of the active compound(s) or a solid form of the active compound(s) and 99% to 1% by weight of suitable pharmaceutical excipients. In one example, the composition will be between about 5% to about 75% by weight of the active compound, with the remainder being suitable pharmaceutical excipients or other adjuvants as described below.

[0073] The actual amount required to treat any particular subject will depend on a variety of factors, including the disease state being treated and its severity, the particular pharmaceutical composition used, the age, weight, general health, sex, and diet of the subject, the dosage form, time of administration, route of administration, and rate of excretion of the active compound(s) of the present disclosure or solid forms of the active compound(s), duration of treatment, any drugs used in conjunction with the particular compound used or which happen to be used concomitantly, and other such factors well known in the medical arts. These factors are discussed in detail in Goodman and Gilman's "The Pharmacological Basis of Therapeutics," Tenth Edition, A. Gilman, J.Hardman and L. Limbird, eds., McGraw-Hill Press, pp. 155-173, 2001, which is incorporated herein by reference. The active compound(s) of the present disclosure, or solid forms of the active compound(s), and pharmaceutical compositions containing them, may be combined with anti-cancer agents or other agents commonly administered to subjects undergoing treatment for cancer. They may also be co-formulated with one or more such agents in a single pharmaceutical composition.

[0074] Depending on the type of pharmaceutical composition, the pharma- ceutically acceptable carrier can be selected from any one or combination of carriers known in the art. The choice of the pharma- ceutically acceptable carrier depends in part on the desired administration method to be used. For the pharmaceutical composition of the present disclosure, i.e., one of the active compound(s) of the present disclosure, or the solid form of the active compound(s), the carrier should be selected to substantially maintain the specific form of the active compound(s), whether it is solid or not. In other words, the carrier should not substantially change the form of the active compound(s). Moreover, the carrier should not be otherwise incompatible with the form of the active compound(s), such as by causing any undesirable biological effects or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition.

[0075] Filler As mentioned above, the pharmaceutical composition containing Compound 1 includes a filler. Fillers are inactive ingredients added to adjust the bulk powder to produce a practical size for tableting. Examples of fillers include sodium starch glycolate, corn starch, talc, sucrose, dextrose, glucose, lactose, xylitol, fructose, sorbitol, calcium phosphate, calcium sulfate, calcium carbonate, and the like, or mixtures thereof. Microcrystalline cellulose can also be used as a filler, and may be any suitable form of microcrystalline cellulose known and used in tabletting technology. A mixture of lactose and microcrystalline cellulose is preferably used as the filler. In one embodiment, the lactose is anhydrous lactose sold as Lactose 60M, which is readily available commercially from a number of suppliers. In one embodiment, the microcrystalline cellulose is Avicel PH-102, which is also commercially available. There are.

[0076] Preferably, the filler(s) are present in an amount of about 50 to about 70 weight percent, more preferably about 57 to about 67 weight percent, based on the solids content of the direct compression moldable formulation. Preferably, lactose is present in an amount of about 18 to 22 weight percent. Preferably, the microcrystalline cellulose is present in an amount of about 38 to 40 weight percent.

[0077] Binder The pharmaceutical composition containing Compound 1 also contains a binder. The binder is added to the powder to impart adhesion to the powder, which allows the tablet to maintain its integrity when compressed. The binder can be any pharma- ceutically acceptable binder that can be used in tableting technology, such as gum arabic, alginic acid, carbomer, sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oil (type I), hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylate, povidone, pregelatinized starch, sodium alginate, starch, zein, etc., or mixtures thereof.

[0078] A preferred binder is hydroxypropylcellulose, preferably in an amount of about 2 to about 4 weight percent based on the solids content of the direct compression moldable formulation, hi one embodiment, the hydroxypropylcellulose is commercially available Klucel EXF.

[0079] Disintegrants The pharmaceutical composition containing Compound 1 also contains a disintegrant. Disintegrant is a substance or mixture of substances that is added to facilitate disintegration or disintegration after administration. Disintegrant can be any pharma- ceutically acceptable disintegrant that can be used in tableting technology, including alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, polyacrylin potassium, powdered cellulose, pregelatinized starch, sodium alginate, starch, etc., or mixtures thereof.

[0080] A preferred disintegrant is croscarmellose sodium in an amount of about 4 to about 8 weight percent based on the solids content of the direct compression moldable formulation, hi one embodiment, the croscarmellose sodium is commercially available Ac-Di-Sol.

[0081] Superplasticizer The pharmaceutical composition containing Compound 1 also contains a glidant. The glidant may be any pharma- ceutically acceptable glidant that contributes to the tabletability, flowability, and uniformity of the formulation, minimizes segregation, and does not significantly interfere with the release mechanism of the binder described above. The glidant is preferably selected to improve the flowability of the formulation. The glidant is preferably silicon dioxide, particularly colloidal silicon dioxide.

[0082] The glidants are used in an amount of about 0.2 to about 0.6 weight percent based on the solid content of the direct compressible formulation. More specifically, silicon dioxide, especially colloidal silicon dioxide, is used in an amount of about 0.2 to about 0.6 weight percent based on the solid content of the direct compressible formulation.

[0083] lubricant The pharmaceutical composition containing Compound 1 also contains a lubricant. The lubricant acts to adhere the tablet to the surfaces of the die and push rod. The lubricant is used to prevent adhesion of the formulation material. The lubricant may be any pharma- ceutically acceptable lubricant that contributes to the uniformity of the blend, thereby substantially preventing separation of the powder and exhibiting good flow properties. The lubricant preferably functions to facilitate tablet compression and ejection of the tablet from the die recesses. Such lubricants may be hydrophilic or hydrophobic, and examples include magnesium stearate, Lubritab®, stearic acid, talc, and other lubricants known in the art or hereafter developed that exhibit acceptable or equivalent properties, or mixtures thereof. Examples of lubricants include calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate, and the like, or mixtures thereof.

[0084] The lubricant should be selected to promote the flow of the powder into the hopper and into the die. Magnesium stearate shows excellent properties in combination with other preferred excipients of the formulation. Magnesium stearate contributes to reducing the friction between the die wall and the tablet formulation during tablet compression and facilitating the ejection of the Compound 1 tablets. It also inhibits adhesion to the push rod and die.

[0085] The lubricant is magnesium stearate (non-bovine) used in an amount of about 0.5 to about 1.0 weight percent based on the solids content of the direct compression moldable formulation.

[0086] Film Coating Agent The pharmaceutical composition containing Compound 1 also includes an optional film coating agent. The film coat may be present in a concentration of about 1 to about 10 weight percent based on the solids content of the direct compressible formulation. The film coating agent suspension may include a combination of the following ingredients: hypromellose, sodium carboxymethylcellulose, carnauba wax, cellulose acetate phthalate, cetyl alcohol, powdered sugar, ethylcellulose, gelatin, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, liquid glucose, maltodextrin, methylcellulose, microcrystalline wax, Opadry and Opadry II, polymethacrylic acid esters, polyvinyl alcohol, shellac, sucrose, talc, titanium dioxide, and zein.

[0087] Other adjuvants Other pharma- ceutically acceptable adjuvants known in the art of pharmaceutical formulations can also be used in the pharmaceutical compositions of the present disclosure. These adjuvants include, but are not limited to, preservatives, wetting agents, suspending agents, sweeteners, flavorings, perfuming agents, emulsifying agents, and dispersing agents. Prevention of microbial action can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like. If necessary, the pharmaceutical compositions of the present disclosure may also contain minor amounts of auxiliary substances, such as wetting or emulsifying agents, pH buffers, and antioxidants, such as citric acid, sorbitan monolaurate, triethanolamine oleate, and butylated hydroxytoluene.

[0088] The pharmaceutical compositions of the present disclosure can be prepared by methods known in the art of pharmaceutical formulation, see, for example, Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 1990). In solid dosage forms, any of Forms 1-27, or combinations thereof, may be added with sodium citrate or dicalcium phosphate. or (a) fillers or extenders, such as, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as, for example, cellulose derivatives, starches, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as, for example, glycerin; (d) disintegrating agents, such as, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate; (e) solution retarders, such as, for example, paraffin; (f) absorption accelerators, such as, for example, quaternary ammonium compounds; (g) wetting agents, such as, for example, cetyl alcohol, glyceryl monostearate, and magnesium stearate; (h) adsorbents, such as, for example, kaolin and bentonite; and (i) lubricants, such as, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0089] In some cases, the pharmaceutical dosage form may be a solid dispersion. The term "solid dispersion" refers to a solid-state system that includes at least two components, where one component is dispersed throughout one or more other components. For example, the solid dispersion may be an amorphous solid dispersion. As used herein, the term "amorphous solid dispersion" refers to a stable solid dispersion that includes an amorphous drug substance (compound 1) and a stabilizing polymer. "Amorphous drug substance" means that the amorphous solid dispersion contains a substantially amorphous solid form of the drug substance, i.e., at least 80% of the drug substance in the dispersion is in amorphous form. More preferably, at least 90% of the drug substance in the dispersion is in amorphous form, and most preferably at least 95%. The term "stabilizing polymer" refers to any polymer known to those of skill in the art that is used to stabilize amorphous drug substances in solid dispersions, such as, for example, those described in Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 1990).

[0090] The manufacturing processes for such solid dispersions are also available to those skilled in the art and include, for example, spray drying, melt extrusion, freeze drying, rotary evaporation, drum drying, or other solvent removal processes. In the spray drying process, the amorphous dispersion is formed by dispersing or dissolving the drug substance and the stabilizing polymer in a suitable solvent to form a feed solution, which is pumped through an atomizer into a drying chamber where the solvent is removed to form an amorphous solid dispersion powder. In the drying chamber, the particles are dried using hot gas such as forced air, nitrogen, nitrogen-enriched air, or argon. The feed solution can be atomized by conventional means known in the art, such as two-fluid sonicating nozzles and two-fluid non-sonicating nozzles.

[0091] The above-mentioned solid dosage forms can be prepared with coatings and shells, such as enteric coatings and other coatings known in the art.These dosage forms can also contain sedatives, and can be of a composition that releases the active compound or active compounds in a delayed manner in a certain part of the intestinal tract.Examples of the embedding composition that can be used are polymeric substances and waxes.The active compound can also be in the form of microencapsulation, if appropriate, with one or more of the above-mentioned excipients.

[0092] Suspensions may contain, in addition to the active compound, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, hydroxyaluminum oxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances.

[0093] Compositions for rectal administration include, for example, the active compound(s) or the active compound(s) Suppositories can be prepared by mixing the solid form of the active ingredient (e.g., sucrose, glycerin, sorbitol, sorbitol derivatives ...

[0094] Solid dosage forms are preferred for the pharmaceutical compositions of the present disclosure. Particularly preferred are solid dosage forms for oral administration, including capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound(s) are mixed with at least one inert, pharma- ceutically acceptable excipient (also known as pharma-ceutically acceptable carrier). The administration of the active compound(s) or solid forms of the active compound(s), in pure form or in a suitable pharmaceutical composition, can be carried out by any of the commonly accepted modes of administration or agents that provide similar utility. Thus, administration can be carried out, for example, orally, nasally, parenterally (intravenously, intramuscularly, or subcutaneously), topically, transdermally, intravaginally, intravesically, intracisternally, or rectally, in the form of solid, semisolid, lyophilized powder, such as, for example, tablets, suppositories, pills, soft and hard gelatin capsules, powders, solutions, suspensions, and aerosols, or in liquid dosage forms, preferably in unit dosage forms suitable for simple administration of precise dosage amounts. One preferred route of administration is oral administration, using a convenient dosage regimen that can be adjusted according to the severity of the disease state being treated. For example, the dosage regimen can be as a capsule or tablet for oral administration.

[0095] Those skilled in the art will recognize that to provide a certain amount of Compound 1, there will be a greater amount of Compound 1 as one of the salt forms described herein. For example, the molecular weight of Compound 1 is 501.51, and the molecular weight of Compound 1 pyruvate is 589.56. Therefore, to provide 100 mg of Compound 1, 117.56 mg of Compound 1 pyruvate is required. The "free base equivalent" (fbe) of a tablet containing 117.56 mg of Compound 1 pyruvate is 100 mg of Compound 1. For tablet compositions with less or more Compound 1, proportionally less or more Compound 1 L-malate is required.

[0096] In another aspect, the present disclosure relates to a pharmaceutical composition comprising at least one compound 1 in the form disclosed herein and a pharma- ceutically acceptable carrier having less than 100 ppm of 6,7-dimethoxyquinolin-4-ol, the structure of which is: [ka] It is desirable to minimize the concentration of degradation products, contaminants, or by-products, such as 6,7-dimethoxyquinolin-4-ol, in pharmaceutical compositions for administration to humans. In one embodiment, a pharmaceutical composition comprising at least one compound 1 in a form disclosed herein and a pharma- ceutically acceptable carrier having a content of 6,7-dimethoxyquinolin-4-ol of less than 90 ppm, less than 80 ppm, less than 70 ppm, less than 60 ppm, less than 50 ppm, less than 40 ppm, less than 30 ppm, less than 20 ppm, less than 10 ppm, less than 5 ppm, or less than 2.5 ppm. The structure of 6,7-dimethoxyquinolin-4-ol is: [ka] It is.

[0097] In another embodiment, a pharmaceutical composition comprising at least one compound 1 in a form disclosed herein and a pharma- ceutically acceptable carrier having a content of 1-100 ppm, 1-80 ppm, 1-60 ppm, 1-40 ppm, 1-20 ppm, 1-10 ppm, 1-5 ppm, or 1-2.5 ppm of 6,7-dimethoxyquinolin-4-ol, the structure of which is: [ka] It is.

[0098] In another aspect, a pharmaceutical composition comprising at least one compound 1 in a form disclosed herein and a pharma- ceutically acceptable carrier having a content of 0.1-100 ppm, 0.1-80 ppm, 0.1-60 ppm, 0.1-40 ppm, 0.1-20 ppm, 0.1-10 ppm, 0.1-5 ppm, 0.1-2.5 ppm, or 0.1-1 ppm of 6,7-dimethoxyquinolin-4-ol, the structure of which is: [ka] It is.

[0099] Capsule formulation In one embodiment, the dosage regimen is as a capsule formulation for oral administration.

[0100] In one embodiment, the capsule formulation comprises: 5 to 60 weight percent of at least one compound 1 in a form disclosed herein; 30 to 80 weight percent of one or more fillers; 1 to 15 weight percent of one or more disintegrants; 0.1 to 1.0 weight percent of a superplasticizer; 0.1 to 4.0 weight percent of a lubricant; Includes.

[0101] In another embodiment, the capsule formulation comprises: 5 to 60 weight percent of at least one compound 1 in a form disclosed herein; 30 to 80 weight percent of one or more fillers; 2 to 12 weight percent of one or more disintegrants; 0.1 to 0.6 weight percent of a superplasticizer; 0.1 to 3.0 weight percent of a lubricant Includes.

[0102] In another embodiment, the capsule formulation comprises: 5 to 15 weight percent of at least one compound 1 in a form disclosed herein; 70 to 80 weight percent of one or more fillers; 8 to 12 weight percent of one or more disintegrants; 0.1 to 0.4 weight percent of a superplasticizer; 0.1 to 2.0 weight percent of a lubricant Includes.

[0103] In another embodiment, the capsule formulation comprises: 5 to 15 weight percent of at least one compound 1 in a form disclosed herein; 70 to 80 weight percent of one or more fillers; 9 to 11 weight percent of one or more disintegrants; 0.2 to 0.4 weight percent of a superplasticizer; 0.5 to 1.5 weight percent of a lubricant Includes.

[0104] In another embodiment, the capsule formulation comprises: 40 to 60 weight percent of at least one compound 1 in a form disclosed herein; 30 to 50 weight percent of one or more fillers; 2 to 12 weight percent of one or more disintegrants; 0.1 to 0.6 weight percent of a superplasticizer; 0.1 to 3.0 weight percent of a lubricant Includes.

[0105] In another embodiment, the capsule formulation comprises: 45 to 55 weight percent of at least one compound 1 in a form disclosed herein; 35 to 40 weight percent of one or more fillers; 8 to 12 weight percent of one or more disintegrants; 0.2 to 0.5 weight percent of a superplasticizer; 0.5 to 2.5 weight percent of a lubricant Includes.

[0106] In another embodiment, the capsule formulation comprises: 5 to 60 weight percent of at least one compound 1 in a form disclosed herein; 30 to 80 weight percent microcrystalline cellulose; 2 to 7 weight percent of croscarmellose sodium; 2 to 7 weight percent sodium starch glycolate; 0.1 to 1.0 weight percent fumed silica; 0.1 to 4.0 weight percent stearic acid; Includes.

[0107] In another embodiment, the capsule formulation comprises: 5 to 60 weight percent of at least one compound 1 in a form disclosed herein; 30 to 80 weight percent microcrystalline cellulose; 3 to 6 weight percent croscarmellose sodium; 3 to 6 weight percent sodium starch glycolate; 0.1 to 0.6 weight percent fumed silica; 0.1 to 3.0 weight percent stearic acid Includes.

[0108] In another embodiment, the capsule formulation comprises: 5 to 15 weight percent of at least one compound 1 in a form disclosed herein; 70 to 80 weight percent microcrystalline cellulose; 4 to 6 weight percent croscarmellose sodium; 4 to 6 weight percent sodium starch glycolate; 0.1 to 0.4 weight percent fumed silica; 0.1 to 2.0 weight percent stearic acid Includes.

[0109] In another embodiment, the capsule formulation comprises: 5 to 15 weight percent of at least one compound 1 in a form disclosed herein; 70 to 80 weight percent microcrystalline cellulose; 4.5 to 5.5 weight percent croscarmellose sodium; 4.5 to 5.5 weight percent sodium starch glycolate; 0.2 to 0.4 weight percent fumed silica; 0.5 to 1.5 weight percent stearic acid Includes.

[0110] In another embodiment, the capsule formulation comprises: 40 to 60 weight percent of at least one compound 1 in a form disclosed herein; 30 to 50 weight percent microcrystalline cellulose; 2 to 7 weight percent of croscarmellose sodium; 2 to 7 weight percent sodium starch glycolate; 0.1 to 0.6 weight percent fumed silica; 0.1 to 3.0 weight percent stearic acid Includes.

[0111] In another embodiment, the capsule formulation comprises: 45 to 55 weight percent of at least one compound 1 in a form disclosed herein; 35 to 40 weight percent microcrystalline cellulose; 3 to 6 weight percent croscarmellose sodium; 3 to 6 weight percent sodium starch glycolate; 0.2 to 0.5 weight percent fumed silica; 0.5 to 2.5 weight percent stearic acid Includes.

[0112] In one embodiment, the capsule composition of the present disclosure contains 5 to about 200 mg of at least one compound 1 in a form described herein. In another embodiment, the capsule composition of the present disclosure contains 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200 mg of compound 1. In another embodiment, the capsule composition of the present disclosure contains 105 to 200 mg of compound 1. In another embodiment, the capsule composition of the present disclosure contains 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200 mg of compound 1. In another embodiment, the capsule composition of the present disclosure contains 20-100 mg of compound 1. In another embodiment, the capsule composition of the present disclosure contains 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg of compound 1. In another embodiment, the capsule composition of the present disclosure contains 20-60 mg of compound 1. In another embodiment, the capsule composition of the present disclosure contains 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 mg of compound 1. In another embodiment, the capsule composition of the present disclosure contains 20, 25, 40, 50, 60, 75, 80, or 100 mg of compound 1. In another embodiment, the capsule composition of the present disclosure contains 20 mg of compound 1. In another embodiment, the capsule composition of the present disclosure contains 40 mg of compound 1. In another embodiment, the capsule composition of the present disclosure contains 60 mg of compound 1. In another embodiment, the capsule composition of the present disclosure contains 80 mg of compound 1.

[0113] In another embodiment, the disclosure provides the pharmaceutical capsule compositions of Table 30. [Table 30]

[0114] In another embodiment, the disclosure provides the pharmaceutical capsule compositions of Table 31. [Table 31]

[0115] The capsule formulation can be prepared by blending and mixing the ingredients of the formulation and filling a two-part hard gelatin capsule according to methods available to one of skill in the art. The capsule shell components include gelatin and optionally a colorant.

[0116] Tablet formulation In one embodiment, the dosage regimen is as a tablet formulation for oral administration.

[0117] In one embodiment, the tablet formulation comprises: 25 to 40 weight percent of at least one compound 1 in a form disclosed herein; 45 to 75 weight percent of one or more diluents; 1 to 5 weight percent of a binder; 2 to 10 weight percent of a disintegrant; 0.05 to 1.0 weight percent of a superplasticizer; 0.5 to 1 weight percent of a lubricant Includes.

[0118] In another embodiment, the tablet composition comprises: 28 to 38 weight percent of at least one compound 1 in a form disclosed herein; 48 to 68 weight percent of one or more diluents; 1.5 to 4.5 weight percent of a binder; 3 to 9 weight percent of a disintegrant; 0.1 to 0.8 weight percent of a superplasticizer; 0.5 to 1 weight percent of a lubricant Includes.

[0119] In another embodiment, the tablet composition comprises: 28 to 38 weight percent of at least one compound 1 in a form disclosed herein; 48 to 68 weight percent of one or more diluents; 1.5 to 4.5 weight percent of a binder; 3 to 9 weight percent of a disintegrant; 0.1 to 0.8 weight percent of a superplasticizer; 0.5 to 1 weight percent of a lubricant Includes.

[0120] In another embodiment, the tablet composition comprises: 30 to 32 weight percent of at least one compound 1 in a form disclosed herein; 50 to 70 weight percent of one or more diluents; 2 to 4 weight percent of a binder; 4 to 8 weight percent of a disintegrant; 0.2 to 0.6 weight percent of a superplasticizer; 0.5 to 1 weight percent of a lubricant Including, The composition is coated.

[0121] In another embodiment, the tablet composition comprises: 25 to 40 weight percent of at least one compound 1 in a form disclosed herein; 35 to 45 weight percent microcrystalline cellulose; 15 to 25 weight percent anhydrous lactose; 1 to 5 weight percent hydroxypropyl cellulose; 2 to 10 weight percent of croscarmellose sodium; 0.05 to 1.0 weight percent colloidal silicon dioxide; 0.5 to 1 percent by weight of magnesium stearate; Includes.

[0122] In another embodiment, the tablet composition comprises: 28 to 38 weight percent of at least one compound 1 in a form disclosed herein; 36 to 42 weight percent microcrystalline cellulose; 18 to 22 weight percent anhydrous lactose; 1.5 to 4.5 weight percent hydroxypropyl cellulose; 3 to 9 weight percent of croscarmellose sodium; 0.1 to 0.8 weight percent colloidal silicon dioxide; 0.5 to 1 percent by weight of magnesium stearate; Includes.

[0123] In another embodiment, the tablet composition comprises: 28 to 38 weight percent of at least one compound 1 in a form disclosed herein; 37 to 39 weight percent microcrystalline cellulose; 18 to 20 weight percent anhydrous lactose; 1.5 to 4.5 weight percent hydroxypropyl cellulose; 3 to 9 weight percent of croscarmellose sodium; 0.1 to 0.8 weight percent colloidal silicon dioxide; 0.5 to 1 percent by weight of magnesium stearate; Includes.

[0124] In another embodiment, the tablet composition comprises: 30 to 32 weight percent of at least one compound 1 in a form disclosed herein; 38 to 39 weight percent microcrystalline cellulose; 19 to 20 weight percent anhydrous lactose; 2 to 4 weight percent hydroxypropyl cellulose; 4 to 8 weight percent croscarmellose sodium; 0.2 to 0.6 weight percent colloidal silicon dioxide; 0.5 to 1 percent by weight of magnesium stearate; Includes.

[0125] The tablet compositions of these and other embodiments can be coated. Many coatings are known to those skilled in the art. An example of a coating is OPADRY Yellow, which contains hypromellose, titanium dioxide, triacetin, and iron oxide yellow pigment.

[0126] In one embodiment, the tablet composition of the present disclosure contains 5 to about 200 mg of at least one compound 1 in a form described herein. In another embodiment, the tablet composition of the present disclosure contains 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200 mg of compound 1. In an embodiment, the tablet composition of the present disclosure contains 105-200 mg of compound 1. In another embodiment, the tablet composition of the present disclosure contains 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200 mg of compound 1. In another embodiment, the tablet composition of the present disclosure contains 20-100 mg of compound 1. In another embodiment, the tablet composition of the present disclosure contains 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg of compound 1. In another embodiment, the tablet composition of the present disclosure contains 20-60 mg of compound 1. In another embodiment, the tablet composition of the present disclosure contains 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 mg of compound 1. In another embodiment, the tablet composition of the present disclosure contains 20, 25, 40, 50, 60, 75, 80, or 100 mg of compound 1. In another embodiment, the tablet composition of the present disclosure contains 20 mg of compound 1. In another embodiment, the tablet composition of the present disclosure contains 40 mg of compound 1. In another embodiment, the tablet composition of the present disclosure contains 60 mg of compound 1.

[0127] In another embodiment, the once-daily tablet contains: [Table 41]

[0128] In another embodiment, the once-daily tablet contains: [Table 42]

[0129] In another embodiment, the once-daily tablet or capsule contains: [Table 43]

[0130] In another embodiment, the once-daily tablet or capsule contains: [Table 44]

[0131] The present disclosure is also directed to a process for making a tablet pharmaceutical formulation that includes Compound 1 as one of the salts disclosed herein.

[0132] In one embodiment, the manufacturing process of the tablet formulation includes mixing Compound 1 with one or more pharmaceutical excipients. The mixture is then skimmed into an aqueous solution containing a binder to form a binder solution. The binder solution is granulated using granulation techniques known in the art. For example, the granulation method may include wet high shear granulation using a wet high shear granulator. The resulting wet granules are then sieved and dried, such as by fluidized bed drying. The dried granules are then milled. The resulting dried milled granules are then mixed with a flow agent and a disintegrant to form an extragranular blend. A lubricant is then blended with the extragranular blend to form a final blend. The final blend is then compressed to form a compressed tablet, which may be film coated.

[0133] More specifically, the manufacturing process of the tablet formulation may include, if necessary, mixing the tablet formulation with the excipients. The method includes delumping Compound 1. Delumping ensures that Compound 1 is mixed uniformly with other excipients during the formulation process. The delumped Compound 1 is then mixed with microcrystalline cellulose such as Avicel PH102, lactose (anhydrous, 60M), and croscarmellose sodium. This mixture is then blended with EXF grade hydroxypropylcellulose in water to form a binder solution, which is then wet high shear granulated. The resulting wet granules are wet sieved and then fluid bed dried according to methods available to those skilled in the art. The resulting dry granules are milled and blended with colloidal silicon dioxide and croscarmellose sodium. Magnesium stearate is added to the mixture. This final blend can be tableted. The resulting uncoated core tablets are then film coated. The film coating agent includes Opadry Yellow, which includes hypromellose, titanium dioxide, triacetin, and iron oxide yellow pigment.

[0134] More specifically, the formulation process comprises: a) de-clumping unground Compound 1; b) premixing the delumped Compound 1 with Avicel PH102, anhydrous lactose 60M, and croscarmellose sodium to form a binder solution; c) wet high shear granulating the binder solution to form wet granules; d) wet sieving the wet granules to form wet sieved granules; e) fluid bed drying the wet sieved granules to produce dried granules; f) dry-milling the dried granules to produce dried milled granules; g) blending the dry milled granules with colloidal silicon dioxide and croscarmellose to form an extragranular blend; h) lubricating the above extragranular blend with magnesium stearate to form the final blend; i) compressing the final blend to form uncoated core tablets; j) film-coating the uncoated core tablets; Includes.

[0135] Treatment method Another aspect of the present disclosure relates to a method of treating cancer comprising administering at least one solid form of Compound 1 as described herein in any aspect and / or embodiment, or combination thereof, to a subject in need thereof. Methods of treatment comprising administering Compound 1 are disclosed, for example, in commonly assigned PCT Patent Publication Nos. WO2005 / 030140, WO2011 / 017639, WO2012 / 044572, WO2012 / 044577, WO2012 / 151326, WO2013 / 043840, WO2013 / 070890, WO2013 / 070903, and WO2013 / 066296, and U.S. Patent Application Publication Nos. US2012 / 0070368 and US2012 / 0252840, each of which is incorporated herein by reference in its entirety. The amount of the solid form of Compound 1 or combinations thereof administered may be a therapeutically effective amount.

[0136] Another aspect of the present disclosure relates to a method for treating a disease or disorder associated with uncontrolled, abnormal, and / or unwanted cellular activity associated with overexpression of a RTK, particularly overexpression of cMET or RET, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one solid form of Compound 1 as described herein in any aspect and / or embodiment, or combination thereof, such as those described above.

[0137] Another aspect of the present disclosure relates to the use of a solid compound 1 according to any of the above embodiments for the manufacture of a medicament for treating the above-mentioned diseases or disorders. Upon dissolution, the solid compound 1 according to the present disclosure The amorphous or amorphous form loses its solid state structure and is therefore referred to, for example, as a solution of Compound 1. At least one solid form disclosed herein can be used to prepare at least one liquid formulation in which at least one solid form according to the present disclosure is dissolved and / or suspended.

[0138] In another aspect, the present invention is directed to a method of treating cancer comprising administering a pharmaceutical dosage form comprising one or more of Forms 1-27, or a pharmaceutical composition comprising one or more of Forms 1-27 and a pharma- ceutically acceptable carrier.

[0139] In one embodiment of this aspect, the invention relates to a method of treating cancer comprising administering to a patient in need of such treatment a pharmaceutical dosage form comprising Compound 1 as one or more of Forms 1-27, as described herein in a pharmaceutical dosage form. In some embodiments, the dosage form is administered orally once daily on an empty stomach as a tablet or capsule. In some embodiments, one or more of Forms 1-27, or a pharmaceutical composition comprising one or more of Forms 1-27, is administered as a tablet. In other embodiments, one or more of Forms 1-27, or a pharmaceutical composition comprising one or more of Forms 1-27, is administered as a capsule.

[0140] Any of the tablet or capsule formulations provided above can be adjusted according to the desired dose of Compound 1. Thus, the amounts of each component of the formulation can be adjusted proportionally to provide tablet formulations containing various amounts of Compound 1, as provided in the previous paragraph. In another embodiment, the formulation can contain 20, 40, 60, or 80 mg of free base equivalent of one or more of Forms 1-27.

[0141] In this method, the desired dosage of Compound 1, in one or more of Forms 1-27 described herein, can be obtained using a combination of tablets or capsules as needed. For example, to obtain a target dose of 20 mg, one 20 mg free base equivalent tablet or capsule would be required to be administered. To obtain a target dose of 100 mg free base equivalent, one 80 mg free base equivalent tablet or capsule and one 20 mg free base equivalent tablet or capsule would be required to be administered. To obtain a target dose of 80 mg free base equivalent, one 80 mg free base equivalent tablet or capsule would be required to be administered. To obtain a target dose of 60 mg free base equivalent, three 20 mg free base equivalent tablets or capsules would be required to be administered.

[0142] In another embodiment of this method, 60 mg of free base equivalent of Compound 1 is administered once a day to a patient with cancer in need of treatment. To obtain a dose of 60 mg of free base equivalent of Compound 1, the patient is administered three tablets of 20 mg of free base equivalent. The three tablets of 20 mg of free base equivalent can be taken simultaneously or sequentially. In a further embodiment, Compound 1 is administered orally in a fasted state (i.e., without food) for about 2 hours before and 1 hour after administration. Compound 1 is preferably administered with a glass of water (about 8 ounces / 240 mL).

[0143] In another embodiment of this method, 40 mg of free base equivalent of Compound 1 is administered once a day to a cancer patient in need of treatment. To obtain a dose of 40 mg of free base equivalent of Compound 1, the patient is administered two 20 mg free base equivalent tablets. The two 20 mg free base equivalent tablets can be taken simultaneously or sequentially. In a further embodiment, one of the crystalline solid forms disclosed herein (i.e., one or more Compound 1, as any of the following Forms 1-27, is administered orally in a fasted (i.e., without food) state for about 2 hours before and 1 hour after administration. Compound 1 is preferably administered with a full glass of water (about 8 ounces / 240 mL).

[0144] In another embodiment of this method, 20 mg of free base equivalent of Compound 1 is administered once a day to a cancer patient in need of treatment. To obtain a dose of 20 mg of free base equivalent of Compound 1, the patient is administered one 20 mg free base equivalent tablet. In a further embodiment, Compound 1 is administered orally in a fasted state (i.e., without food) for about 2 hours before and 1 hour after administration. Compound 1 is preferably administered with a glass of water (about 8 oz / 240 mL).

[0145] In another embodiment, the method comprises orally administering one or more of Forms 1-27 once daily as a tablet or capsule.

[0146] In another embodiment, the method comprises orally administering one or more of Forms 1-27 once daily as capsules as provided in the table below.

[0147] In another embodiment, the method comprises orally administering one or more of Forms 1-27 once daily as tablets as given in the table below. [Table 45]

[0148] In another embodiment, the method comprises administering one of the following tablets once daily: Or, a plurality of Forms 1-27 are orally administered. [Table 46-1] [Table 46-2]

[0149] In another embodiment, the method comprises administering one of the following tablets once daily: Or, a plurality of Forms 1-27 are orally administered. [Table 47]

[0150] In another embodiment, the method comprises administering one of the following tablets once daily: Or, a plurality of Forms 1-27 are orally administered. [Table 48]

[0151] "Cancer" means a cell proliferative disease state, including, but not limited to, Heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung: bronchogenic carcinoma (squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenocar ... tumor, sarcoma, lymphoma, chondromatous hamartoma, inesothelioma; digestive tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (tubular adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, VIPoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract: kidney (adenocarcinoma, Wilms' tumor [neoblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver: hepatocellular carcinoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondroma exostosis), benign chondroma, chondroblastoma, chondromyofibroma, osteoid osteoma, and giant cell tumor; Neurological: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma) [pineal gland], glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma); gynecology: uterus (endometrial cancer), cervix (cervical cancer, precancerous cervical dysplasia), ovary (ovarian cancer [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva ( These include, but are not limited to, squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, acicular sarcoma (embryonic rhabdomyosarcoma), fallopian tube (carcinoma); hematology: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, lentigo dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis, and adrenal gland: neuroblastoma.Thus, the term "cancer cell" as used herein includes a cell afflicted by any one of the above-identified diseases.

[0152] In one embodiment, the cancer to be treated is selected from gastric cancer, esophageal cancer, renal cancer, liver cancer, bladder cancer, ovarian cancer, cervical cancer, colon cancer, small intestine cancer, brain cancer (including astrocytic tumors, which astrocytic tumors include glioblastoma, giant cell glioblastoma, gliosarcoma, and glioblastoma with oligodendroglial components), lung cancer (including non-small cell lung cancer), bone cancer, prostate cancer, pancreatic cancer, skin cancer, bone cancer, lymphoma, solid tumors, Hodgkin's disease, non-Hodgkin's lymphoma, or thyroid cancer (including medullary thyroid carcinoma). More particularly, the cancer is pancreatic cancer, hepatocellular carcinoma (HCC), renal cell carcinoma, castration-resistant prostate cancer (CRPC), gastric or gastroesophageal junction cancer, melanoma, small cell lung cancer (SCLC), ovarian cancer, primary peritoneal or fallopian tube cancer, estrogen receptor positive breast cancer, estrogen receptor / progesterone receptor / HER2 negative (triple negative) breast cancer, inflammatory breast cancer (regardless of receptor status), non-small cell lung cancer (NSCLC), or medullary thyroid cancer.

[0153] Another aspect of the present disclosure relates to a method of treating astrocytic tumors (including glioblastoma, giant cell glioblastoma, gliosarcoma, and glioblastoma with oligodendroglial components) comprising administering to a subject in need of said treatment a therapeutically effective amount of at least one Compound 1 in a form described herein, pharmacologic formulated as described herein.

[0154] Another aspect of the present disclosure relates to a method of treating thyroid cancer (including medullary thyroid cancer), comprising administering to a subject in need of said treatment a therapeutically effective amount of at least one Compound 1 in a form described herein, pharmacologic formulated as described herein.

[0155] Another aspect of the present disclosure relates to a method for treating hepatocellular carcinoma, comprising administering to a subject in need of said treatment a therapeutically effective amount of at least one compound 1 in a form described herein, pharma- ceutical formulated as described herein.

[0156] Another aspect of the present disclosure relates to a method of treating renal cell carcinoma, comprising administering to a subject in need of said treatment a therapeutically effective amount of at least one compound 1 in a form described herein, pharmacologic formulated as described herein.

[0157] Another aspect of the present disclosure relates to a method for treating castration-resistant prostate cancer, comprising administering to a subject in need of said treatment a therapeutically effective amount of at least one compound 1 in a form as described herein, pharmacologic formulation as described herein. The amount administered may be a therapeutically effective amount.

[0158] Another aspect of the present disclosure relates to a method of treating breast cancer, comprising administering to a subject in need of said treatment a therapeutically effective amount of at least one compound 1 in a form described herein, pharmacologic formulated as described herein.

[0159] Another aspect of the present disclosure relates to a method of treating ovarian cancer, comprising administering to a subject in need of said treatment a therapeutically effective amount of at least one compound 1 in a form described herein, pharmacologic formulated as described herein.

[0160] Another aspect of the present disclosure relates to a method of treating bladder cancer, comprising administering to a subject in need of said treatment a therapeutically effective amount of at least one compound 1 in a form described herein, pharmacologic formulated as described herein.

[0161] Another aspect of the present disclosure relates to a method for treating a disease or disorder associated with uncontrolled, abnormal, and / or undesirable cellular activity, comprising administering to a subject in need of said treatment a therapeutically effective amount of at least one compound 1 in a form as described herein, pharma- ceutical formulated as described herein.

[0162] In one embodiment, the cancer is thyroid cancer.

[0163] More particularly, the thyroid cancer is medullary thyroid cancer.

[0164] In one embodiment, the cancer is liver cancer.

[0165] More particularly, the liver cancer is hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, or hematoma.

[0166] In one embodiment, the cancer is a gastrointestinal cancer.

[0167] More particularly, the gastrointestinal cancer is a cancer of the esophagus that is a squamous cell carcinoma, adenocarcinoma, or leiomyosarcoma; a cancer of the stomach that is a carcinoma or lymphoma; a cancer of the pancreas that is a tubular adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, or VIPoma; a cancer of the small intestine that is an adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hematoma, or lipoma; or a cancer of the large intestine that is an adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, or leiomyoma.

[0168] In one embodiment, the cancer is pancreatic cancer.

[0169] More specifically, the pancreatic cancer is selected from the group consisting of tubular adenocarcinoma, insulinoma, gonadotropic carcinoma, gastritis cancer, and pancreatic cancer. The tumor is a cytoma, a carcinoid tumor, or a VIP-secreting tumor.

[0170] In another embodiment, the cancer is bladder cancer. In a further embodiment, the bladder cancer is squamous cell carcinoma, transitional cell carcinoma, or adenocarcinoma.

[0171] In one embodiment, the cancer is bone cancer.

[0172] More particularly, the bone cancer is osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant reticulum cell sarcoma, malignant giant cell tumor chordoma, osteochondral exostosis, chondroblastoma, chondromyofibroma, or osteoid osteoma.

[0173] In one embodiment, the cancer is a hematological cancer.

[0174] More particularly, the hematological cancer is myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disease, multiple myeloma, or myelodysplastic syndrome.

[0175] In one embodiment, the cancer is skin cancer.

[0176] More particularly, the skin cancer is malignant melanoma, basal cell carcinoma, squamous cell carcinoma, or Kaposi's sarcoma.

[0177] In one embodiment, the cancer is renal cancer.

[0178] More particularly, said renal cancer is a renal tumor.

[0179] In one embodiment, the cancer is breast cancer.

[0180] More particularly, said breast cancer is a breast tumor.

[0181] In one embodiment, the cancer is colon cancer.

[0182] More particularly, said colon cancer is a colon cancer tumor.

[0183] In one embodiment, the cancer is fallopian tube cancer.

[0184] More particularly, said fallopian tube cancer is fallopian tube carcinoma.

[0185] In one embodiment, the cancer is ovarian cancer.

[0186] More particularly, the ovarian cancer is ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, or melanoma).

[0187] In another embodiment, the cancer is prostate cancer.

[0188] More particularly, said prostate cancer is an adenocarcinoma or a sarcoma.

[0189] In another embodiment, the prostate cancer is castration-resistant prostate cancer (CRPC).

[0190] In another embodiment, the cancer is lung cancer.

[0191] More particularly, the lung cancer is bronchial carcinoma (squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hanlartoma, or inesothelioma mesothelioma.

[0192] Another aspect of the present disclosure relates to a method for treating cancer, comprising administering a therapeutically effective amount of at least one compound 1 in the form described herein, pharmacopoeically formulated as described herein, optionally in combination with another agent, to a subject in need of said treatment. The method may be carried out by administering a tablet formulation of at least one compound 1 in the form described herein, pharmacopoeically formulated as described herein.

[0193] The antitumor efficacy of the above formulations of the compounds as pharma- ceutically acceptable salts is measured using serological and / or x-ray imaging methods available to one skilled in the art. For serological methods, the relative concentration of a cancer biomarker is measured before and after administration of one or more of Forms 1-27. A positive response means that the serological concentration of the biomarker after treatment is lower compared to the concentration before treatment.

[0194] Complete serologic response: Marker levels <0.2 ng / mL on two consecutive measurements at least 4 weeks apart.

[0195] Serological partial response (PR): ≥50% reduction in marker value compared to pre-study level on two consecutive measurements at least 2 weeks apart.

[0196] Stable disease: Patients who do not meet criteria for response (CR or PR) or serologic progression.

[0197] Serologic Progression (PD): Serologic progression is noted when the marker level increases by more than 50% from the lowest recorded level since the start of treatment. Two consecutive increases must be recorded, with each measurement taken at least 2 weeks apart. Intermediate fluctuations may be seen in some cases. the Recommendations of Cancer Clinical Trials According to the Working Group, these midpoints do not trigger a new evaluation period unless they fall below the previous lowest level. These serologic response levels can be modified as needed based on the biomarkers of interest.

[0198] In one embodiment, patients treated with the dosage form experience a complete serological response. In another embodiment, patients treated with the dosage form experience a partial serological response. In a further embodiment, patients treated with the dosage form experience stable disease.

[0199] For X-ray imaging, disease progression based on X-ray imaging is defined as RECIST 1.1 for soft tissue disease, or the appearance of 2 or more new bone lesions on bone scan. If there is no clear symptomatic deterioration at the first scheduled reassessment after starting treatment, a scan at a later time point is required to confirm progression. Standard imaging techniques available to those skilled in the art can be used to evaluate the results of X-ray imaging, including technetium bone scan and CT scan. Other X-ray imaging such as NaF and FDG-PET can also be used to evaluate the results of X-ray imaging.

[0200] As noted above, the amount of one or more Forms 1-27 administered as a free base equivalent can be adjusted to avoid adverse events. For example, in one embodiment, a patient who experiences one or more adverse events at doses above 60 mg is administered a pharmaceutical dosage form comprising 60 mg of the free base equivalent of one or more Forms 1-27.

[0201] In another embodiment, patients experiencing one or more adverse events at doses between 80 mg and 160 mg are administered one or more of Forms 1-27 at a free base equivalent of 60 mg.

[0202] In another embodiment, patients who experience one or more adverse events at the 70 mg dose are administered 60 mg of the free base equivalent of one or more of Forms 1-27.

[0203] In another embodiment, patients experiencing one or more adverse events at the 80 mg dose are administered 60 mg of the free base equivalent of one or more of Forms 1-27.

[0204] In another embodiment, patients who experience one or more adverse events at the 90 mg dose are administered 60 mg of the free base equivalent of one or more of Forms 1-27.

[0205] In another embodiment, patients experiencing one or more adverse events at the 100 mg dose are administered 60 mg of the free base equivalent of one or more of Forms 1-27.

[0206] In another embodiment, patients who experience one or more adverse events at the 110 mg dose are administered 60 mg of the free base equivalent of one or more of Forms 1-27.

[0207] In another embodiment, patients who experience one or more adverse events at the 120 mg dose are administered 60 mg of the free base equivalent of one or more of Forms 1-27.

[0208] In another embodiment, patients who experience one or more adverse events at the 130 mg dose are administered 60 mg of the free base equivalent of one or more of Forms 1-27.

[0209] In another embodiment, patients who experience one or more adverse events at the 140 mg dose are administered 60 mg of the free base equivalent of one or more of Forms 1-27.

[0210] In another embodiment, patients experiencing one or more adverse events at the 150 mg dose are administered 60 mg of the free base equivalent of one or more of Forms 1-27.

[0211] In another embodiment, patients who experience one or more adverse events at the 160 mg dose are administered 60 mg of the free base equivalent of one or more of Forms 1-27.

[0212] In another embodiment, patients who experience one or more adverse events at doses of 140 mg or 100 mg free base equivalent are administered one or more of Forms 1-27 at 60 mg free base equivalent.

[0213] In another embodiment, patients who experience one or more adverse events at doses greater than 40 mg are administered a pharmaceutical dosage form containing 40 mg of the free base equivalent of one or more of Forms 1-27.

[0214] In another embodiment, patients experiencing one or more adverse events at doses between 60 mg and 160 mg are administered one or more of Forms 1-27 at a free base equivalent of 40 mg.

[0215] In another embodiment, patients experiencing one or more adverse events at the 50 mg dose are administered 40 mg of the free base equivalent of one or more of Forms 1-27.

[0216] In another embodiment, patients experiencing one or more adverse events at the 60 mg dose are administered 40 mg of the free base equivalent of one or more of Forms 1-27.

[0217] In another embodiment, patients experiencing one or more adverse events at the 70 mg dose are administered 40 mg of the free base equivalent of one or more of Forms 1-27.

[0218] In another embodiment, patients experiencing one or more adverse events at the 80 mg dose are administered 40 mg of the free base equivalent of one or more of Forms 1-27.

[0219] In another embodiment, patients experiencing one or more adverse events at the 90 mg dose are administered 40 mg of the free base equivalent of one or more of Forms 1-27.

[0220] In another embodiment, patients experiencing one or more adverse events at the 100 mg dose are administered 40 mg of the free base equivalent of one or more of Forms 1-27.

[0221] In another embodiment, patients who experience one or more adverse events at the 110 mg dose are administered 40 mg of the free base equivalent of one or more of Forms 1-27.

[0222] In another embodiment, patients who experience one or more adverse events at the 120 mg dose are administered 40 mg of the free base equivalent of one or more of Forms 1-27.

[0223] In another embodiment, patients who experience one or more adverse events at the 130 mg dose are administered 40 mg of the free base equivalent of one or more of Forms 1-27.

[0224] In another embodiment, patients who experience one or more adverse events at the 140 mg dose are administered 40 mg of the free base equivalent of one or more of Forms 1-27.

[0225] In another embodiment, patients experiencing one or more adverse events at the 150 mg dose are administered 40 mg of the free base equivalent of one or more of Forms 1-27.

[0226] In another embodiment, patients who experience one or more adverse events at the 160 mg dose are administered 40 mg of the free base equivalent of one or more of Forms 1-27.

[0227] In another embodiment, patients who experience one or more adverse events at doses of 140 mg, 100 mg, or 60 mg free base equivalent are administered one or more of Forms 1-27 at 40 mg free base equivalent.

[0228] In another embodiment, patients who experience one or more adverse events at doses greater than 60 mg are administered a pharmaceutical dosage form containing one or more of Forms 1-27 at a free base equivalent of 20 mg.

[0229] In another embodiment, patients experiencing one or more adverse events at doses between 40 mg and 160 mg are administered one or more of Forms 1-27 at a free base equivalent of 20 mg.

[0230] In another embodiment, patients who experienced one or more adverse events at the 30 mg dose. is administered 20 mg of the free base equivalent of one or more of Forms 1-27.

[0231] In another embodiment, patients experiencing one or more adverse events at the 40 mg dose are administered 20 mg of the free base equivalent of one or more of Forms 1-27.

[0232] In another embodiment, patients experiencing one or more adverse events at the 50 mg dose are administered 20 mg of the free base equivalent of one or more of Forms 1-27.

[0233] In another embodiment, patients experiencing one or more adverse events at the 60 mg dose are administered 20 mg of the free base equivalent of one or more of Forms 1-27.

[0234] In another embodiment, patients experiencing one or more adverse events at the 70 mg dose are administered 20 mg of the free base equivalent of one or more of Forms 1-27.

[0235] In another embodiment, patients experiencing one or more adverse events at the 80 mg dose are administered 20 mg of the free base equivalent of one or more of Forms 1-27.

[0236] In another embodiment, patients experiencing one or more adverse events at the 90 mg dose are administered 20 mg of the free base equivalent of one or more of Forms 1-27.

[0237] In another embodiment, patients experiencing one or more adverse events at the 100 mg dose are administered 20 mg of the free base equivalent of one or more of Forms 1-27.

[0238] In another embodiment, patients who experience one or more adverse events at the 110 mg dose are administered 20 mg of the free base equivalent of one or more of Forms 1-27.

[0239] In another embodiment, patients who experience one or more adverse events at the 120 mg dose are administered 20 mg of the free base equivalent of one or more of Forms 1-27.

[0240] In another embodiment, patients experiencing one or more adverse events at the 130 mg dose are administered 20 mg of the free base equivalent of one or more of Forms 1-27.

[0241] In another embodiment, patients who experience one or more adverse events at the 140 mg dose are administered 20 mg of the free base equivalent of one or more of Forms 1-27.

[0242] In another embodiment, patients experiencing one or more adverse events at the 150 mg dose are administered 20 mg of the free base equivalent of one or more of Forms 1-27.

[0243] In another embodiment, patients experiencing one or more adverse events at the 160 mg dose are administered 20 mg of the free base equivalent of one or more of Forms 1-27.

[0244] In another embodiment, patients who experience one or more adverse events at doses of 140 mg, 100 mg, 60 mg, or 40 mg free base equivalent are administered one or more of Forms 1-27 at a 20 mg free base equivalent.

[0245] In some embodiments, the adverse events are diarrhea, stomatitis, palmar-plantar erythema syndrome (PPES), weight loss, decreased appetite, nausea, fatigue, oral pain, changes in hair color, dysgeusia, hypertension, abdominal pain, constipation, increased AST, increased ALT, lymphopenia, elevated alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, hyperbilirubinemia, perforation, fistula, bleeding, thromboembolic events, wound complications, osteonecrosis of the jaw, proteinuria, reversible posterior leukoencephalopathy. These include one or more of: relapsing pulmonary syndrome (RPLS), and embryo-fetal toxicity.

[0246] In some embodiments, the adverse event is grade 1. In some embodiments, the adverse event is grade 2. In some embodiments, the adverse event is grade 3. In some embodiments, the adverse event is grade 4. In some embodiments, the adverse event is grade 5.

[0247] In one embodiment, treatment of a patient experiencing a grade 4 adverse event is temporarily interrupted. In another embodiment, upon resolution or improvement of the grade 4 adverse event, administration of Compound 1 is resumed at the same or a reduced dose. In some embodiments, resolution or improvement of a grade 4 adverse event refers to a return to baseline. In other embodiments, resolution or improvement of a grade 4 adverse event refers to resolution of a grade 1 adverse event.

[0248] In one embodiment, treatment of patients experiencing a grade 3 adverse event is temporarily interrupted. In another embodiment, upon resolution or improvement of the grade 3 adverse event, administration of Compound 1 is resumed at the same or reduced dosage. In some embodiments, resolution or improvement of a grade 3 adverse event refers to a return to baseline. In other embodiments, resolution or improvement of a grade 4 adverse event refers to resolution of a grade 1 adverse event.

[0249] In one embodiment, treatment of a patient experiencing a grade 2 adverse event is temporarily interrupted. In another embodiment, upon resolution or improvement of the grade 2 adverse event, administration of Compound 1 is resumed at the same or reduced dosage. In some embodiments, resolution or improvement of the grade 2 adverse event refers to a return to baseline. In other embodiments, resolution or improvement of the grade 2 adverse event refers to the resolution of the grade 1 adverse event.

[0250] In one embodiment, treatment is temporarily interrupted for patients who experience a Grade 1 adverse event. In another embodiment, upon resolution or amelioration of the Grade 1 adverse event, administration of Compound 1 is resumed at the same or a reduced dosage. In some embodiments, resolution or amelioration of the Grade 1 adverse event refers to a return to baseline.

[0251] In some embodiments, the dose is further reduced one or more times following a first reduction as a result of one or more adverse events. In one embodiment, the dose is reduced a first time. In another embodiment, the dose is reduced a first and a second time. In another embodiment, the dose is reduced a first, a second, and a third time.

[0252] General Preparation Method for Preparing Crystalline Solid Forms 1-27 Crystalline solid forms can be produced by various methods, including, but not limited to, crystallization or recrystallization from a suitable solvent mixture; sublimation; growth from the melt; transformation of the solid state from another phase; crystallization from supercritical fluids; and jet atomization. Techniques for crystallization or recrystallization of crystalline solid forms from a solvent mixture include, but are not limited to, evaporation of the solvent; lowering the temperature of the solvent mixture; seeding with crystals of a supersaturated solvent mixture of the compound and / or its salt; seeding with crystals of a supersaturated solvent mixture of the compound and / or its salt; freeze-drying the solvent mixture; and adding a poor solvent (countersolvent) to the solvent mixture. High-throughput crystallization techniques can be used to prepare crystalline solid forms, including polymorphs.

[0253] Drug crystals, including polymorphs, methods for preparing drug crystals, and characterization of drug crystals These are discussed in Solid-State Chemistry of Drugs, SR Byrn, RR Pfeiffer, and JG Stowell, 2nd Edition, SSCI, West Lafayette, Indiana (1999).

[0254] In the crystallization technique using solvent, the solvent(s) is generally selected based on one or more factors, including but not limited to, for example, the solubility of the compound, the crystallization technique used, and the vapor pressure of the solvent. A combination of solvents may also be used. For example, the compound may be solubilized in a first solvent to obtain a solution, and then an anti-solvent may be added to the solution to reduce the solubility of compound 1 in the solution and precipitate the formation of crystals. An anti-solvent is a solvent in which the solubility of the compound is low.

[0255] In one method that can be used to prepare crystals, compound 1 can be suspended and / or stirred in a suitable solvent to obtain a slurry, which can be heated to promote dissolution. As used herein, the term "slurry" refers to a saturated solution of the compound, which contains an excess amount of compound, providing a heterogeneous mixture of compound and solvent at a given temperature.

[0256] Seed crystals may be added to any crystallization mixture to promote crystallization. Seeding may be used to control the growth of a particular polymorph and / or to control the particle size distribution of the solid product. Thus, calculation of the amount of seed required is described in, for example, “Programmed Cooling Batch Crystallizers,” J. W. Mullin, “Crystallization of Crystallization of Solids,” 1999, 144:1311-1325, 1999. and J. Nyvlt, Chemical Engineering Science, 1971, 26, 3690377, it depends on the size of the available seeds and the desired size of the average product particles. Generally, small size seeds are required to effectively control the growth of crystals in a batch. Small size crystal grains can be produced by sieving, grinding, or micronizing larger crystals or by microcrystallizing a solution. In grinding or micronizing crystals, care must be taken to avoid changing the crystallinity from the desired solid form (i.e., changing it to amorphous or other polymorphic forms).

[0257] The cooled crystallization mixture may be filtered under vacuum and the isolated solid product may be washed with a suitable solvent, such as a cold recrystallization solvent. After washing, the product may be dried under a nitrogen purge to obtain the desired solid form. The product may be analyzed by suitable spectroscopic or analytical techniques, including, but not limited to, differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and thermogravimetric analysis (TGA), to confirm that a solid form of the compound is formed. The resulting solid form may be produced in an amount greater than about 70 percent by weight isolated yield, preferably greater than about 90 percent by weight isolated yield, based on the weight of compound used at the start of the crystallization operation. Optionally, the product may be de-agglomerated by co-grinding or passing through a mesh screen.

[0258] The features and advantages of the present disclosure can be readily understood by those skilled in the art upon reading the following detailed description. It should be understood that certain features of the present invention that are described above and below in the context of separate embodiments for clarity may be combined to form a single embodiment. Conversely, various features of the present disclosure that are described in the context of a single embodiment for brevity may be combined to form subcombinations thereof. The present disclosure is further illustrated by the following examples, which should not be construed as limiting the scope or spirit of the present disclosure to the specific procedures described therein. EXAMPLES

[0259] Experimental Technique X-ray Powder Diffraction (XRPD) XRPD analysis was performed using a Panalytical Xpert Pro diffractometer equipped with a Cu X-ray tube and a Pixcel detector system. Isothermal samples were analyzed in transmission mode and were sandwiched between low density polyethylene films. The Almac default XRPD program was used (range 3-40° 2θ, step size 0.013°, count time 99 s, measurement time approximately 22 min). XRPD patterns were sorted and manipulated using HighScore Plus 2.2c software.

[0260] Differential Scanning Calorimetry (DSC) DSC analysis was performed on a PerkinElmer Jade Differential Scanning Calorimeter. Precision weighed samples were placed in crimped aluminum pans. Each sample was heated under nitrogen at a rate of 10°C / min up to 300°C. Indium metal was used as the calibration standard. Temperatures at the onset of the transition were reported to the nearest 0.01°C. Note that the DSC curves reported may include automated peak integration to calculate the DH of melting. These DH values ​​are prone to significant error when multiple thermal events are observed at similar temperatures.

[0261] Thermogravimetric analysis / differential thermal analysis (TG / DTA) Thermogravimetric analysis was performed on a Mettler Toledo TG / DTA / DSC l STARe. Calibration standards were indium and tin. Samples were placed in aluminum sample pans, inserted into the TG furnace and weighed. The heat flow signal was stabilized at 30°C for 1 min and then heated to 300°C at a rate of 10°C / min in a nitrogen stream.

[0262] Dynamic Vapor Sorption (DVS) Dynamic vapor sorption (DVS) was performed using a Hiden Analytical Instruments IGAsorp water vapor sorption balance. Approximately 30 mg of sample was placed in a wire mesh water vapor sorption balance pan and loaded into the IGAsorp water vapor sorption balance and held at 25°C ± 0.1°C. The sample was subjected to a step profile from 0% RH to 90% RH in 10% increments and then desorbed from 80% RH to 0% RH in 10% increments. The criterion for reaching equilibrium was set to reach 99.0% of the step within a minimum of 60 minutes and a maximum of 5 hours for each increment. Weight change was monitored during the adsorption cycle to allow for a measurement of the hygroscopicity of the sample. Data collection was at intervals in seconds.

[0263] 1 H nuclear magnetic resonance spectroscopy (NMR) NMR analyses were carried out on a Bruker 400 MHz or 500 MHz instrument in d-DMSO or CDCl3, and the instrumental parameters are listed on the relevant spectrograms.

[0264] Polarizing microscope Microscopic analysis was performed on an Olympus BX51 instrument. Photomicrographs of compound 1 were obtained using a polarized light source and a 10x objective magnification.

[0265] HPLC The HPLC method used to determine the aqueous equilibrium solubility is outlined in Table 32. The retention time of compound 1 was typically 19.1±0.2 minutes, and no new peaks were detected during the analysis of the experimental samples. [Table 32-1] [Table 32-2]

[0266] FT-IR spectroscopy Thermonicolet Avatar with Golden Gate ATR FT-IR spectroscopy was performed on a 370 FT-IR spectrometer. Spectra were processed using GRAMS AI v8.0 software.

[0267] Materials and Reagents The acids and co-crystal formers used in the salt / co-crystal screen include mineral acids, sulfonic acids, and carboxylic acids. Isethionic acid was supplied as the sodium salt and then liberated to the free acid form by ion exchange chromatography.

[0268] Experimental Example The synthesis of Compound 1 and its various polymorphic forms is disclosed in US patent application Ser. No. 15 / 118,738, the entire contents of which are incorporated herein by reference.

[0269] Example 1: Preparation of isethionic acid from the corresponding sodium salt Isethionic acid was prepared from its sodium salt by ion exchange chromatography. A solution of isethionic acid sodium salt (105.5 mg) in water (5 mL) was added to the washed resin (2.5 g) and the mixture was stirred at ambient temperature for 4 days. The mixture was filtered and the resin was washed with water (approximately 4 mL). The filtrate was added to a 10 mL volumetric flask and filled to the mark with water. This gave an approximately 0.07M isethionic acid solution.

[0270] Example 2: Screening methods Screening experiments were performed at approximately 40 mg scale at 1:1 and 0.5:1 stoichiometries (API:acid). A wide range of salt formation methods were performed including precipitation, slurry, sonication, and evaporation.

[0271] Example 3: Preparation of stock solution Compound 1 (1.28 g) was added to a 50 mL volumetric flask and THF / water (80:20) was added up to the mark to form a 0.052 M solution. This was sonicated in a water bath to ensure dissolution. Separately, compound 1 (1.5 g) was added to a 150 mL volumetric flask and acetone was added up to the mark to form a 0.02 M solution.

[0272] Acid solutions were prepared as described in Table 33. Sulfonic acid solutions were added directly due to concerns about the sulfonic acid reacting with MeOH (Table 34). [Table 33-1] [Table 33-2] [Table 34]

[0273] Example 4: Precipitation experiments in THF / water (80:20) To each HPLC vial was added the acid solution (1.05 equiv.) and evaporated to dryness. In the case of sulfonic acids and liquid coformers, these were added directly to the vials. A THF / water solution of compound 1 (1.6 mL, 1 equiv.) was added to each vial and the solutions were stirred at ambient temperature for 16 hours. Any solids that precipitated were separated by centrifugation, the solvent was decanted, and the solids were dried on filter paper prior to XRPD analysis. Samples that remained as solutions were evaporated uncapped and the solids were analyzed by XRPD.

[0274] Solids that gave disturbed XRPD patterns were slurried in THF (50° C.), EtOH (60° C.), or a mixture of THF / EtOH (50° C.) (see Table 35). These slurries were first performed at elevated temperature (1 h), then slowly cooled to ambient temperature and slurried at ambient temperature for 16 h.

[0275] Example 5: Precipitation experiments in acetone / THF (97:3) Acid / coformer (1.05 equiv), THF (100 μL), and a solution of compound 1 (1 equiv) in acetone (0.02 M, 4 mL) were added to each HPLC vial and the mixtures were stirred for approximately 1 hour and heated at 50° C. They were allowed to cool and stirred at ambient temperature for 16-18 hours. If a precipitate formed, the solid was separated by centrifugation, the solvent was decanted, and the solid was dried on filter paper prior to XRPD analysis. Reaction mixtures that formed solutions were allowed to evaporate uncapped to approximately 1.5 mL. The solids were analyzed by XRPD. Solids were isolated as described above (see Table 36). Any samples that remained as solutions were allowed to evaporate uncapped, and any solids were analyzed by XRPD.

[0276] Example 6: Precipitation experiments in acetone / THF (97:3) Acid / coformer (1.05 equiv), THF (100 μL), and a solution of compound 1 (1 equiv) in acetone (0.02 M, 4 mL) were added to each HPLC vial and the mixtures were stirred for approximately 1 hour and heated at 50° C. They were allowed to cool and stirred at ambient temperature for 16-18 hours. If a precipitate formed, the solid was separated by centrifugation, the solvent was decanted, and the solid was dried on filter paper prior to XRPD analysis. Reaction mixtures that formed solutions were allowed to evaporate uncapped to approximately 1.5 mL. The solids were analyzed by XRPD. Solids were isolated as described above (see Table 36). Any samples that remained as solutions were allowed to evaporate uncapped, and any solids were analyzed by XRPD.

[0277] Example 7: Slurry experiment with 0.5 equivalents of acid The acid (0.5 equiv.) was placed in a vial and 100 μL of THF was added. A suspension of compound 1 in acetone (4 mL, 10 mg / mL) was added and the suspension was stirred. The flask was left open and the solvent was allowed to evaporate to about half its volume to increase the yield of the product. The suspensions were stirred at ambient temperature for 5 days, then they were centrifuged and the solvent was decanted. The solids were dried on a strip of filter paper and then analyzed by XRPD.

[0278] Example 8: Experiments carried out with liquid acid Compound 1 (approximately 40 mg) was placed in an HPLC vial, acid (1 molar equivalent) and acetonitrile (100-200 μL) were added, and the slurries were stirred at ambient temperature for 16 hours. The slurries were sampled, and the solids were analyzed by XRPD.

[0279] Example 9: Sonication of Paste The acid solution (1 equiv.) was added to the vial and evaporated to dryness. The sulfonic acid, liquid coformer, and 4-hydroxybenzoic acid were added directly to the vial. Compound 1 (approximately 40 mg, 1 equiv.) and 200 μL of solvent (acetonitrile or acetonitrile / H2O (87:13)) were added and sonicated (3×30 sec.) at 30% intensity using a Cole-Parmer 130W sonicator. All solids recovered from these experiments were analyzed by XRPD.

[0280] Example 10: Humidity stress experiment The salts of Compound 1 were weighed out into individual vials. The vials were placed unsealed in vials of saturated sodium chloride solution at 40° C. (75% relative humidity). The salts were stored for 5-7 days and then visually inspected for deliquescence. The vials were reweighed to assess weight gain / loss and the solids were analyzed by XRPD.

[0281] Example 11: Desolvation Experiments The experiments were carried out on the TG / DTA by heating the material to just above the desolvation temperature and holding the material at that temperature for 15 minutes until desolvation was complete. The samples were analyzed by XRPD.

[0282] Example 12: Determination of solubility by HPLC Approximately 5 mg of each salt was added to a vial with distilled water (1 mL). These were stirred at ambient temperature (approximately 25° C.) for 24 hours. The solution was filtered through a 0.2 μm PTFE filter and analyzed for concentration by HPLC. The pH of the solution was confirmed by pH paper.

[0283] Example 13: Preparation of Compound 1 Pyruvate (Form 14) With seeding Compound 1 (1000 mg) and acetone (80 mL) were added to a flask and stirred at 35° C. to form a thin white suspension (almost all of compound 1 was dissolved). A solution of pyruvic acid (184 mg, 1.05 eq.) in THF (10 mL) was added. This was washed with an additional 5 mL of THF. A clear solution formed, which was stirred at ambient temperature. This was seeded with Form 14 material and stirred for 18 hours. The resulting suspension was evaporated to approximately 40 mL and stirred for an additional 18 hours to maximize the yield. The solid was collected by filtration and dried on a sinter for approximately 30 minutes to give the product as a white solid (671 mg, 57% yield).

[0284] No seeding Compound 1 (100 mg), acetone / THF (97:3, 2 mL), and pyruvic acid (23.4 μL) were stirred at ambient temperature for about 96 hours. The solids were collected by centrifugal filtration and analyzed by XRPD.

[0285] XRPD analysis showed that the salt was crystalline (Figure 53A). Polarized light microscopy confirmed the crystallinity with some aggregation or agglomeration. Ta.

[0286] DSC thermograms of compound 1 pyruvate were recorded at 10°C / min. A thermal event with a peak temperature of 183°C was most likely due to melting of the salt (Figure 53B). The material appeared to decompose immediately after melting. Thermal analysis (TG / DTA) (Figure 53C) showed a slight weight loss of about 1.7% between 30 and 140°C, likely due to residual moisture / solvent, suggesting that compound 1 pyruvate is in the anhydrous form. A broad endotherm was observed with an onset temperature of 157°C, accompanied by a weight loss of about 11.4%, which corresponds to about 0.85 moles of pyruvic acid. It is believed that pyruvic acid is lost as the material melts, leading to the decomposition of the material.

[0287] The hygroscopic and adsorption properties of Compound 1 pyruvate were measured using dynamic vapor sorption (DVS). The sample was dried at 0% RH before performing adsorption and desorption cycles. The isotherm (Figure 53D) revealed that the total weight gain observed between 0% RH and 80% RH was 0.10% w / w, indicating that the sample is non-hygroscopic according to the European Pharmacopoeia classification and is less hygroscopic than both forms of Compound 1 (S)-malate (approximately 0.4% w / w). No significant hysteresis was observed between the adsorption and desorption curves. XRPD analysis of the sample after DVS (Figure 53E) revealed that the material remained unchanged.

[0288] The FT-IR spectrum obtained for this material is shown in Figure 53F and was found to be consistent with the structure of the material with all expected functional groups present. 1 The H NMR spectrum was consistent with the structure and confirmed a 1:1 ratio of API to acid peaks (Figure 53G).

[0289] The 1:1 compound 1 pyruvate was a highly crystalline, non-hygroscopic, anhydrous material with a melting peak temperature of 183°C and an aqueous solubility of approximately 0.133mg / mL (pH approximately 3). This compound 1 pyruvate has a lower molecular weight (potentially resulting in higher drug loading compared to compound 1 malate), higher solubility, and a lower aspect ratio compared to compound 1 malate, and is the only physical morphology observed to date. This improved particle morphology / aspect ratio may translate into improved filterability and flow properties compared to compound 1 malate. As a natural human metabolite, pyruvate is well tolerated in vivo.

[0290] Example 14: Preparation of Compound 1 Glutarate Salt (Form 20) With seeding Compound 1 (1000 mg), acetonitrile (10 mL), and glutaric acid (275 mg, 1.05 equiv.) were added to a glass vial and heated to 50° C. The mixture was seeded with compound 1 glutarate and stirred at 50° C. for 30 min. The mixture was very viscous, so an additional 3 mL of acetonitrile was added, stirred for 3 h, cooled to ambient temperature, and stirred for an additional 16-20 h. A sample was withdrawn from the mixture and the solid was isolated by centrifugal filtration to confirm completion of the reaction. The solid was analyzed by XRPD analysis.

[0291] The remaining portion of this material was isolated by filtration and washed with acetonitrile (1 mL). The solid was air-dried in the filter funnel. (Yield=1.145 g, 91%)

[0292] No seeding Compound 1 (100 mg), acetonitrile (1.5 mL), and glutaric acid (27.62 mg) were placed in a vial and heated to 50° C. for 1 h. The mixture was cooled to ambient temperature and stirred for 96 h. The experimental mixture remained in suspension throughout. The solid was removed by centrifugation. and analyzed by XRPD.

[0293] XRPD analysis (Figure 54A) showed that the salt was highly crystalline. Optical microscopy confirmed the crystalline nature of the salt and revealed birefringent irregular particles.

[0294] The DSC thermogram obtained for compound 1 glutarate is shown in Figure 54B. The thermogram showed one endotherm with an onset temperature of approximately 176 °C, which was attributed to melting. Thermal analysis by TG / DTA (Figure 54C) showed a small amount of weight loss (0.5%) between 30 and 160 °C, which could be attributed to residual moisture / solvent, suggesting that compound 1 glutarate is in anhydrous form. An endotherm with an onset temperature of 175 °C was observed with an associated weight loss of 0.5%.

[0295] The hygroscopic and adsorption properties of Compound 1 glutarate were measured using dynamic vapor sorption (DVS). The sample was dried at 0% RH before performing the adsorption and desorption cycles. The isotherm (Figure 54D) revealed that the total weight gain observed between 0% RH and 80% RH was 0.08% w / w, indicating that the sample is non-hygroscopic according to the European Pharmacopoeia classification and is less hygroscopic than both forms of Compound 1 (S)-malate (approximately 0.4% w / w). This lower weight gain was reflected in the slightly noisy data. No significant hysteresis was observed between the adsorption and desorption curves. XRPD analysis of the sample after DVS (Figure 54E) revealed that the material remained unchanged.

[0296] The FT-IR spectrum obtained for the above material (Figure 54F) was found to be consistent with the structure of the material with all expected functional groups present. 1 1 H NMR spectroscopic analysis (Figure 54G) revealed that the material conformed to the structure (API:acid 1:1).

[0297] The 1:1 compound 1 glutarate was a highly crystalline, non-hygroscopic, anhydrous material with a peak melting temperature of 178°C. The glutarate had an aqueous solubility of about 0.016 mg / mL (pH 3). The compound 1 glutarate is less hygroscopic and has a lower aspect ratio than the compound 1 malate, and is the only physical morphology observed to date. This improved particle morphology / aspect ratio may lead to improved filterability and flow properties compared to the compound 1 malate. The glutarate is well tolerated in vivo, being a natural human metabolite.

[0298] Example 15: Preparation of Compound 1 Isethionate Monohydrate (Form 27) A 0.07 M aqueous solution of isethionic acid (8.5 mL, 1.2 molar equivalents) was added to a glass vial and the water was evaporated under a stream of N2. Compound 1 (250 mg) and 2.5 mL of acetone / THF (97:3) were added. The suspension was heated at 50° C. for approximately 30 minutes. The experimental mixture was slowly cooled to ambient temperature and stirred for approximately 96 hours. A sample was drawn from the mixture and the solid was isolated by centrifugal filtration and analyzed by XRPD analysis. XRPD analysis confirmed the presence of pure Form 27 material. The remaining portion of the material was isolated by filtration, washed with acetone / THF (97:3) (approximately 1 mL), and the solid was air-dried in the filter funnel for 30 minutes (yield approximately 215 mg, 68%).

[0299] XRPD analysis (Figure 55A) showed that the salt was crystalline. Optical microscopy confirmed this, revealing birefringent, needle-like particles that readily aggregated.

[0300] The DSC thermogram obtained for Compound 1 isethionate salt is shown in Figure 55B. The thermogram shows two endothermic events, the first with a peak temperature of about 80° C. and the second with a peak temperature of about 203° C. The TG / DTA curve (Figure 55C) The compound also exhibits two endotherms, the first occurring with an onset temperature of about 49° C. and having an associated weight loss of 3%, corresponding to one molar equivalent of water. The second endothermic event with an onset temperature of about 199° C. is attributed to the melting of the material.

[0301] The hygroscopic and adsorption properties of Compound 1 isethionate monohydrate were measured using dynamic vapor sorption (DVS). The sample was dried at 0% RH before adsorption and desorption cycles were performed. The isotherm (Figure 55D) showed a plateau of moisture content of about 3.0±0.1% w / w (1 molar equivalent) between 10 and 50% RH. Above 50% RH, an increase in hygroscopicity was observed. The total weight gain observed between 20% RH and 80% RH was about 2.4% w / w, implying that this hydrate form is hygroscopic. No significant hysteresis was observed between the adsorption and desorption curves. XRPD analysis of the sample after DVS (Figure 55E) revealed that the material remained unchanged.

[0302] The FT-IR spectrum obtained for this material is shown in Figure 55F and was found to be consistent with the structure of the material with all expected functional groups present. 1 The H NMR spectrum was consistent with the structure and confirmed a 1:1 ratio of API to acid peaks (Figure 55G).

[0303] The 1:1 Compound 1 isethionate monohydrate was a crystalline material with a peak melting temperature of the anhydrous form of 203° C. The solubility of the salt monohydrate in water was about 0.195 mg / mL at a pH of about 2. The solubility of Compound 1 isethionate monohydrate is significantly higher than that of Compound 1 malate.

[0304] Example 16: (Crystal habit experiment) Temperature cycling in acetone / water (97:3, v / v) The salt of compound 1 (approximately 30 mg) was weighed into an HPLC vial and 1 mL of acetone / water (97:3, v / v) was added. The suspension was stirred at 400 rpm and subjected to 15 cycles of the following: 1) heating from 23° C. to 53° C. at 0.5° C. / min, and 2) cooling from 53° C. to 23° C. at 0.2° C. / min. The samples were centrifuged, the solvent was decanted, and the solids were dried on a strip of filter paper prior to XRPD analysis and optical microscopy.

[0305] Example 17: (Crystal Habit Experiment) Vapor Diffusion Acetone / THF (50:50) was added to the compound 1 salt in 100 μL aliquots until nearly dissolved. The suspension was filtered through a 0.2 μm filter into an HPLC vial, which was then placed in a glass vial containing heptane. For compound 1 glutarate, glutarate seeds were added to the solution. The solution was allowed to stand at ambient temperature until sufficient solids were observed (3-6 days). The samples were centrifuged, the solvent was decanted, and the solids were dried on a filter paper strip before XRPD analysis and optical microscopy. Compound 1 salt (approximately 20 mg) was added to an HPLC vial, and the solids were dissolved in 200 μL of THF / H2O (80:20). The vial was placed uncapped in a glass vial containing acetone. The solids were collected by decanting the solvent and drying the solids on a filter paper strip. XRPD analysis and optical microscopy were performed on the solids.

[0306] Example 18: (Crystal Habit Experiment) Slow Evaporation from Acetone / THF The salt of compound 1 (approximately 20 mg) was dissolved in 1 mL of acetone / THF (50:50). The vial was covered with perforated aluminum foil and left to evaporate at ambient temperature. The solid was analyzed by XRPD and optical microscopy.

[0307] Example 19: (Crystal Habit Experiment) Slurry in Chloroform Compound 1 pyruvate or glutarate (approximately 20 mg) was slurried in CDCl3 (200-500 μL) at 50° C. for 24 hours. For the isethionate salt, no solids were present and the solution was cooled to ambient temperature and stirred for 6 days. Solids were collected by centrifugation and decantation of the solvent, and the solids were dried on filter paper strips. XRPD analysis and optical microscopy were performed on the solids.

[0308] Example 20: (Crystal Habit Experiment) Slurry in EtOH Compound 1 pyruvate or isethionate (approximately 20 mg) was slurried in EtOH (500 μL) at 50° C. for 24 hours, and the solids were collected by centrifugation and decantation of the solvent. The solids were dried on a strip of filter paper. XRPD analysis and optical microscopy were performed on the solids. Compound 1 glutarate (approximately 20 mg) and EtOH (1 mL) were added to a vial. Dissolution was observed. The vial was covered with perforated aluminum foil, and the solvent was allowed to evaporate. XRPD analysis and optical microscopy were performed on the solids.

[0309] Example 21: Salt / Co-crystal Screening Part A: Solvent Screening Techniques Solvent experiments were performed on a 40 mg scale in glass vials. Methods used are described in detail herein. Evaporation, precipitation, sonication, and slurry (ambient and elevated temperatures) are methods of choice for salt formation and were used in this screen.

[0310] Part B: Sedimentation / slurry experiments Precipitation experiments were performed by mixing the API and acid in THF / HO (80:20) or THF / acetone (97:3) and isolating any precipitated solids. Any experimental mixtures that remained in solution were evaporated and any solids produced were analyzed by XRPD. Solids that displayed novel XRPD patterns were 1 Further analysis was performed by H NMR spectroscopy and TG / DTA to confirm stoichiometry and solvent content. Table 35 shows the results of precipitation / slurry experiments performed in THF / H2O (80:20). Five of the experimental mixtures from THF / H2O (80:20) gave precipitates with unique crystalline XRPD patterns (Forms 1-5). The remaining portions of the experimental mixtures were evaporated and any solids isolated were analyzed by XRPD. In an attempt to generate more crystalline material, these solids were reslurried in THF, THF / EtOH, or EtOH as described herein to give Forms 15 and 16. [Table 35-1] [Table 35-2]

[0311] Table 36 shows the results of a precipitation / slurry experiment carried out in THF / acetone (97:3). The solids were collected by centrifugation, decanting the solvent, and drying on filter paper and then analyzed by XRPD. The experimental mixture contained no solids after 16 hours of evaporation. The solids were analyzed by XRPD. Forms 1, 6-14, and 27 were isolated from these experimental mixtures. [Table 36-1] [Table 36-2]

[0312] Part C: Salt formation using 0.5 molar equivalents of coformer Salt formation was carried out as detailed herein using 2:1 equivalents of API:acid / coformer. Forms 11 and 12 were isolated from these experimental mixtures. 1 1 H NMR spectroscopy confirmed a 2:1 ratio of API to acid. [Table 37]

[0313] Part D: Salt formation with liquid acids and compound 1 Reaction of compound 1 in liquid acid in the absence of a solvent did not produce any salts, therefore acetonitrile was added and the mixture was slurried for an additional 16 hours. Forms 5, 25, and 26 (sulfate, mesylate, and gluconate) were isolated from these reaction mixtures. [Table 38-1] [Table 38-2]

[0314] Part E: Sonication Table 39 shows the results of salt formation by sonication. Forms 6, 9, 10, 12, 14, 17, 18, 19, 20, 21, 22, and 26 were all isolated from these experimental mixtures. [Table 39-1] [Table 39-2]

[0315] Example 22: Humidity stress experiment Salts of Compound 1 were stressed at 40°C / 75% relative humidity for approximately 7 days and analyzed by XRPD to determine their physical stability at increasing relative humidity. Weight changes were also recorded (see Table 40). Forms 1, 2, 6, 9-14, 16, 19, 21, 22, 24, and 27 showed small weight changes and no change in morphology by XRPD analysis, indicating that these salts are relatively stable to high relative humidity. Forms 5, 7, 15, 17 , 18, 25, and 26 showed greater weight changes and / or changes in physical morphology after humidity stress. Compound 1 oxalate (Form 3) had a weight loss of 43.17% but no change in morphology by XRPD analysis, suggesting that this salt contained a large amount of surface solvent and / or water. [Table 40]

[0316] Example 23: Examination of crystal habits of selected salts of compound 1 Crystal habit studies were carried out for each of the selected salts using a variety of experiments including temperature cycling experiments, vapor diffusion experiments, slow evaporation experiments, and slurry experiments.

[0317] Part A: Crystal habit experiments of Compound 1 pyruvate (Form 14) Compound 1 pyruvate formed from precipitation of compound 1 and pyruvic acid in THF / acetone. The acid salt (Form 14) consisted of small amorphous particles. Attempts were made to increase the particle size by temperature cycling, vapor diffusion, slurrying, and slow evaporation. The solids were analyzed by XRPD analysis upon recovery. Slurrying in ethanol gave Compound 1 (Form III), and vapor diffusion with heptane in acetone / THF gave a solid with a weak / amorphous XRPD diffractogram. Temperature cycling in acetone / water increased the particle size. Vapor diffusion with THF / water (80:20) as solvent and acetone as antisolvent gave very large crystals. Slurrying in chloroform and slow evaporation from acetone / THF did not produce a significant change in crystal habit.

[0318] Part B: Crystal habit experiments of compound 1 glutarate salt (form 20) Compound 1 glutarate (Form 20), formed from a slurry of Compound 1 and glutaric acid in acetonitrile, consisted of small amorphous particles. Attempts were made to increase the particle size by temperature cycling, vapor diffusion, slurrying, and slow evaporation. These solids maintained Form 20, except for the solids isolated from slurrying in ethanol, which gave Form III material. Temperature cycling in acetone / water (97:3% v / v) significantly increased the particle size, with large blocky particles (30-50 μm) observed. Vapor diffusion using acetone / THF (50:50) as solvent and heptane as antisolvent gave larger ellipsoidal particles, which may improve filterability. Slurrying in chloroform, slow evaporation from acetone / THF, and vapor diffusion using THF / H2O (80:20) as solvent and acetone as antisolvent did not show any significant change in crystal habit.

[0319] Part C: Crystal habit experiments of compound 1 isethionate monohydrate (form 27) Compound 1 isethionate (Form 27) isolated from a slurry of Compound 1 and isethionic acid in acetone / THF consisted of needle-like particles. Attempts to increase particle size were made by temperature cycling, vapor diffusion, slurrying, and slow evaporation. The solids were analyzed by XRPD analysis upon recovery. Form 27 material was only recovered from two experiments: temperature cycling in acetone / water and vapor diffusion with acetone in THF / water. Temperature cycling caused a slight increase in the size of the needle-like particles and also produced some large blocky particles. Vapor diffusion from THF / water (80:20) solvent with acetone as the antisolvent gave longer needle-like particles that may cause difficulties in filtration. A novel pattern was observed from slurrying in EtOH, 1 H NMR suggests that the pattern is an ethanol solvate of the salt. Vapor diffusion using acetone / THF (50:50) as the solvent and heptane as the antisolvent produced a solid with a novel XRPD pattern. 1 H NMR spectroscopic analysis revealed that this material was related to the free base. Slow evaporation from acetone / THF (50:50) afforded Form III solid.

[0320] Other embodiments The foregoing disclosure has been described in some detail by way of illustration and example, for purposes of clarity and understanding. The present invention has been described with reference to various specific and preferred embodiments and techniques. It should be understood, however, that many variations and modifications can be made while remaining within the spirit and scope of the present invention. It will be apparent to those skilled in the art that changes and modifications can be practiced within the scope of the appended claims. It is therefore to be understood that the above description is illustrative and not limiting. The scope of the present invention should therefore be determined not with reference to the above description, but with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled.

[0321] According to a preferred embodiment of the present invention, for example, the following is provided: (Section 1) A crystalline solid salt of N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1), the salt being N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (compound 1) pyruvate; N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (compound 1) glutarate, N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (compound 1) isethionate monohydrate and The crystalline solid salt is selected from the group consisting of: (Section 2) Item 1, a crystalline solid N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1) pyruvate according to item 1, characterized as Form 14, wherein the crystalline solid comprises Compound 1 and pyruvate in a 1:1 molar ratio. (Section 3) 3. The crystalline solid Compound 1 pyruvate according to claim 2, characterized as Form 14, wherein said Form 14 is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 7.84, 8.81, 11.58, 15.67, 16.30, 16.55, 17.67, 17.92, 18.00, 18.20, 18.62, 19.66, 20.54, 20.75, 23.84, 26.35, and 26.42 degrees on the 2θ scale. (Section 4) Item 2 or 3, wherein the crystalline solid Compound 1 pyruvate is characterized as Form 14, wherein the pyruvate is characterized by peaks in a powder X-ray diffraction spectrum at 8.81, 11.58, 17.67, 18.00, 23.84, and 26.35 degrees on the 2θ scale. (Section 5) Item 5. The crystalline solid Compound 1 pyruvate according to any one of items 2 to 4, characterized as Form 14, wherein said Form 14 is characterized by the XRPD pattern of FIG. (Section 6) Item 2, wherein the crystalline solid Compound 1 pyruvate is characterized as Form 14, wherein said Form 14 is characterized by a thermal event having a peak temperature of about 183° C. in a differential scanning calorimetry (DSC) thermogram recorded at 10° C. / min. (Section 7) Item 2, wherein the crystalline solid Compound 1 pyruvate is characterized as Form 14, wherein said Form 14 is characterized by a broad endotherm with an onset temperature of about 157° C., as measured by thermogravimetry / differential thermal analysis (TG / DTA), accompanied by an associated weight loss of about 11.4%. (Section 8) Item 3. The crystalline solid Compound 1 pyruvate according to item 2, characterized as Form 14, wherein said Form 14 has a water content of about 0.10% as measured by dynamic vapor sorption (DVS). The pyruvate salt is characterized by a total weight gain, w / w, between 0% relative humidity and 80% relative humidity. (Section 9) 2. The crystalline solid N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1) glutarate salt according to claim 1, characterized as Form 20, wherein the glutarate salt comprises Compound 1 and glutarate in a 1:1 molar ratio. (Section 10) 10. The crystalline solid Compound 1 glutarate salt according to claim 9, characterized as Form 20, wherein said Form 20 salt is characterized by one or more peaks in an XRPD pattern selected from the group consisting of 8.06, 11.77, 19.97, 20.21, 22.27, 23.11, 23.17, 25.81, 25.87, 26.00, and 26.06 degrees on the 2θ scale. (Section 11) Item 9 or Item 10, wherein the crystalline solid Compound 1 glutarate is characterized as Form 20, wherein the glutarate is characterized by peaks in a powder X-ray diffraction spectrum at 8.06, 11.77, 20.21, 22.27, 23.11, 25.81, 25.87, and 26.00 degrees on the 2θ scale. (Section 12) 12. The crystalline solid Compound 1 glutarate according to any one of the above items 9 to 11, characterized as Form 20, wherein said Form 20 is characterized by the XRPD pattern of FIG. (Section 13) Item 9, wherein the crystalline solid Compound 1 glutarate is characterized as Form 20, wherein said Form 20 is characterized by a thermal event having a peak temperature of about 176°C in a differential scanning calorimetry (DSC) thermogram recorded at 10°C / min. (Section 14) Item 9, the crystalline solid Compound 1 glutarate salt as described above, characterized as Form 20, wherein said Form 20 is characterized by an endotherm with an onset temperature of about 175° C., as measured by thermogravimetry / differential thermal analysis (TG / DTA), associated with an associated weight loss of about 0.5%. (Section 15) 10. The crystalline solid Compound 1 glutarate salt according to claim 9, characterized as Form 20, wherein said Form 20 has a water content of about 0.08% as measured by dynamic vapor sorption (DVS). The glutarate salt is characterized by a total weight gain, w / w, between 0% relative humidity and 80% relative humidity. (Section 16) 2. The crystalline solid N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1) isethionate monohydrate according to claim 1, characterized as Form 27, wherein the crystalline solid comprises Compound 1 and isethionate in a 1:1 molar ratio. (Section 17) 17. The crystalline solid Compound 1 isethionate monohydrate of claim 16, characterized as Form 27, wherein said Form 27 is characterized by one or more peaks in a powder X-ray diffraction spectrum selected from the group consisting of 6.56, 12.39, 12.59, 13.14, 16.57, 17.55, 21.68, 23.66, 24.33, 26.09, 26.53, 26.69, and 27.40 degrees on the 2θ scale. (Section 18) Item 16 or Item 17, a crystalline solid compound characterized as Form 27. 1 isethionate monohydrate, wherein said Form 27 is characterized by peaks in a powder X-ray diffraction spectrum at 12.39, 12.59, 17.55, 21.68, 23.66, 24.33, and 26.09 degrees on the 2θ scale. (Section 19) 19. The crystalline solid Compound 1 isethionate monohydrate according to any one of items 16 to 18, characterized as Form 27, wherein said Form 27 is characterized by the XRPD pattern of FIG. 9. (Section 20) 17. The crystalline solid Compound 1 isethionate monohydrate of claim 16, characterized as Form 27, wherein said Form 27 is characterized by a first thermal event having a peak temperature of about 80° C. and a second thermal event having a peak temperature of about 203° C. in a differential scanning calorimetry (DSC) thermogram recorded at 10° C. / min. (Section 21) 17. The crystalline solid Compound 1 isethionate monohydrate of claim 16, characterized as Form 27, wherein said Form 27 is characterized by a first endotherm with an onset temperature of about 49° C. with an associated weight loss of about 3% and a second endotherm with an onset temperature of about 196° C. with no associated weight loss, as measured by thermogravimetric / differential thermal analysis (TG / DTA). (Section 22) 17. The crystalline solid Compound 1 isethionate monohydrate of claim 16, characterized as Form 27, wherein said Form 27 is characterized by a total weight gain between 20% relative humidity and 80% relative humidity of about 2.4% w / w as measured by dynamic vapor sorption (DVS). (Section 23) A pharmaceutical composition comprising a therapeutically effective amount of a substantially pure crystalline solid form of a salt of compound 1 as described by any one of paragraphs 1 to 22 above, and a pharma- ceutically acceptable carrier. (Section 24) A pharmaceutical composition comprising a therapeutically effective amount of a mixture of crystalline solid forms of a salt of compound 1 as described by any one of paragraphs 1 to 22 above, and a pharma- ceutically acceptable carrier. (Section 25) A method for treating cancer, comprising administering to a subject a therapeutically effective amount of a crystalline solid form of a salt of compound 1 as described in any one of paragraphs 1 to 22 above. (Section 26) A method for treating cancer, comprising administering to a subject the pharmaceutical composition according to item 23 or 24. (Section 27) 27. The method according to claim 25 or 26, wherein the cancer is selected from thyroid cancer, gastric cancer, esophageal cancer, kidney cancer, liver cancer, ovarian cancer, cervical cancer, bladder cancer, colon cancer, small intestine cancer, brain cancer, lung cancer, bone cancer, prostate cancer, pancreatic cancer, skin cancer, bone cancer, lymphoma, solid tumor, Hodgkin's disease, or non-Hodgkin's lymphoma. (Section 28) 28. The method according to item 27, wherein the thyroid cancer is medullary thyroid cancer. (Section 29) 28. The method according to item 27, wherein the kidney cancer is renal cell carcinoma. (Section 30) 28. The method according to item 27 above, wherein the liver cancer is hepatocellular carcinoma. (Section 31) 28. The method according to item 27, wherein the brain cancer is an astrocytic tumor. (Section 32) 32. The method according to claim 31, wherein the astrocytic tumor is selected from glioblastoma, giant cell glioblastoma, and gliosarcoma. (Section 33) 33. The method of claim 32, wherein the glioblastoma has an oligodendrocyte component. (Section 34) 28. The method according to item 27, wherein the lung cancer is non-small cell lung cancer. (Section 35) 28. The method according to item 27, wherein the prostate cancer is castration-resistant prostate cancer. (Section 36) A method for treating a disease or disorder associated with uncontrolled, abnormal and / or unwanted cellular activity resulting from overexpression of cMET or RET, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one solid form of compound 1 as described in any one of paragraphs 1 to 22 above. (Section 37) A method for treating a disease or disorder associated with uncontrolled, abnormal, and / or unwanted cellular activity resulting from overexpression of cMET or RET, comprising administering a therapeutically effective amount of the pharmaceutical composition described in any one of items 1 to 22 above to a subject in need of such treatment.

Claims

1. A crystalline solid salt of N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1), wherein the salt is N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1) isethionate monohydrate.

2. The crystalline solid N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1) isethionate monohydrate of claim 1, characterized as Form 27, wherein the crystalline solid comprises Compound 1 and isethionate in a 1:1 molar ratio.

3. Crystalline solid Compound 1 isethionate monohydrate as described in claim 2, characterized as Form 27, wherein said Form 27 is characterized by one or more peaks in a powder X-ray diffraction spectrum selected from 6.56, 12.39, 12.59, 13.14, 16.57, 17.55, 21.68, 23.66, 24.33, 26.09, 26.53, 26.69, and 27.40 degrees on the 2θ scale.

4. Crystalline solid Compound 1 isethionate monohydrate as described in claim 2 or claim 3, characterized as Form 27, wherein said Form 27 is characterized by peaks in a powder X-ray diffraction spectrum at 12.39, 12.59, 17.55, 21.68, 23.66, 24.33, and 26.09 degrees on the 2θ scale.

5. Crystalline solid Compound 1 isethionate monohydrate as described in claim 2, characterized as Form 27, wherein said Form 27 is characterized by a first thermal event having a peak temperature of 80°C and a second thermal event having a peak temperature of 203°C in a differential scanning calorimetry (DSC) thermogram recorded at 10°C / min.

6. Crystalline solid Compound 1 isethionate monohydrate as described in claim 2, characterized as Form 27, wherein said Form 27 is characterized by a first endotherm with an onset temperature of 49°C with an associated weight loss of 3% and a second endotherm with an onset temperature of 196°C with no associated weight loss as measured by thermogravimetric / differential thermal analysis (TG / DTA).

7. The crystalline solid Compound 1 isethionate monohydrate of claim 2, characterized as Form 27, wherein said Form 27 is characterized by a total weight gain between 20% relative humidity and 80% relative humidity of 2.4% w / w as measured by dynamic vapor sorption (DVS).

8. A pharmaceutical composition comprising a therapeutically effective amount of a substantially pure crystalline solid form of a salt of Compound 1, as described by any one of claims 1 to 7, and a pharma- ceutically acceptable carrier, wherein the substantially pure crystalline solid form of the salt of Compound 1 contains at least 90 percent by weight of the crystalline solid form of the salt of Compound 1, based on the weight of the substantially pure crystalline solid form of the salt of Compound 1.

9. A composition for treating cancer comprising a crystalline solid form of a salt of compound 1 described in any one of claims 1 to 7.

10. The pharmaceutical composition of claim 8 for treating cancer.

11. The composition or pharmaceutical composition described in claim 9 or 10, wherein the cancer is selected from thyroid cancer, gastric cancer, esophageal cancer, renal cancer, liver cancer, ovarian cancer, cervical cancer, bladder cancer, colon cancer, small intestine cancer, brain cancer, lung cancer, bone cancer, prostate cancer, pancreatic cancer, skin cancer, bone cancer, lymphoma, solid tumors, Hodgkin's disease, or non-Hodgkin's lymphoma.

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