Salts and polymorphic forms of 6-chloro-7-(4-(4-chlorobenzyl)piperazin-1-yl)-2-(1,3-dimethyl-1h-pyrazol-4-yl)-3h-imidazo[4,5-b]pyridine

Abstract

To provide forms of Compound A, which is a potent Aurora A, B, and C, and FLT3 kinase inhibitor, that are stable and have a certain degree of inherent water solubility.SOLUTION: Provided are a fumarate salt and polymorphic forms of Compound A (6-chloro-7-(4-(4-chlorobenzyl)piperazin-1-yl)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine). The present invention also provides processes for preparation of salts and polymorphic forms of Compound A, pharmaceutical compositions comprising them, and their use in treatment of proliferative disorders such as cancer, and other diseases or conditions in which Aurora kinase and / or FLT3 activity is implicated.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to salts and polymorphs of pharmaceutically active compounds. More specifically, the present invention relates to salts and physical forms of compounds that are inhibitors of Aurora kinase enzymatic activity. The compounds of the present invention are also inhibitors of FMS-like tyrosine kinase 3 (FLT3) activity. The present invention also relates to methods for preparing the salts and crystalline forms of the compounds, pharmaceutical compositions containing them, and their use in the treatment of proliferative disorders, such as cancer, and other diseases or conditions in which Aurora kinase and / or FLT3 activity is implicated. [Background technology]

[0002] Proliferative diseases such as cancer are characterized by uncontrolled and unregulated cell proliferation, and exactly what causes cells to proliferate in an uncontrolled and unregulated manner has been the focus of intensive research over the past few decades.

[0003] Aurora kinases are a family of three serine-threonine kinases, designated A, B, and C, that play important and distinct roles in various stages of mitosis. During the early stages of mitosis, Aurora-A forms a complex with Xklp2 (TPX2) as a target protein, regulating centrosome maturation and spindle assembly. Aurora-B forms a complex with inner centromere protein (INCENP), survivin, and borealin, thereby regulating chromosome condensation, chromosome alignment, the mitotic checkpoint, and cytokinesis. Overexpression of Aurora-A and Aurora-B has been reported in various human malignancies, including breast, colorectal, ovarian, glioma, thyroid cancer, and seminoma. The function of Aurora-C during mitosis is less clear. However, high expression of Aurora-C has been reported in the testis.

[0004] FLT3 is a transmembrane kinase belonging to the class III receptor tyrosine kinase (RTK) family. Binding of FLT3 ligand (FL) to its receptor leads to dimerization, autophosphorylation, and subsequent activation of downstream signaling pathways. High levels of FLT3 expression have been found in acute myeloid leukemia (AML) blasts, and two major classes of mutations have been identified in AML patients: internal tandem duplications (ITDs) and point mutations in the tyrosine kinase domain (TKDs). Internal tandem duplications are detected in 20–25% of AML patients, and point mutations in the tyrosine kinase domain are detected in 5–10% of AML patients.

[0005] Thus, there is a further need for compounds that have the dual function of inhibiting both Aurora kinases and FLT3, which would be useful in the treatment of diseases and / or conditions in which Aurora and / or FLT3 are implicated, such as AML.

[0006] Compound A described herein is one such dual inhibitor compound that has high activity against Aurora A, B, and C, and FLT3 kinase, and has a favorable therapeutic window resulting from minimal interaction with cytochrome P450 activity and hERG. The preparation and biological testing of Compound A are described in WO2013 / 190319. Other promising dual Aurora / FLT3 kinase inhibitors are also described in WO2013 / 190319.

[0007] To prepare active pharmaceutical ingredients (APIs) for clinical use, commercially viable manufacturing processes are required. The API must possess certain physical properties that enable its processing. Therefore, the physical and chemical stability of the API is an important factor. For example, the API and formulations containing it must be able to be effectively stored for a reasonable period of time without exhibiting changes in their physicochemical properties. Furthermore, because APIs often need to come into contact with solvents during the manufacturing process, it is desirable for the API to be stable in commonly used organic solvents.

[0008] Furthermore, compounds ideally possess some inherent water solubility so that they can be formulated in a manner that provides acceptable bioavailability, e.g., via gastrointestinal absorption. Obtaining a therapeutically promising form of an API that meets these complex and often conflicting requirements is a significant obstacle in pharmaceutical development.

[0009] It is therefore an object of the present invention to provide new forms of API Compound A that possess one or more of the above advantageous properties. Summary of the Invention

[0010] The present invention relates to salts and polymorphs of Compound A. Compound A (6-chloro-7-(4-(4-chlorobenzyl)piperazin-1-yl)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine) is: [ka] It has the following structure.

[0011] Compound A is a potent Aurora A, B, C, and FLT3 kinase inhibitor with a large therapeutic index due to minimal interaction with the hERG channel and cytochrome P450 enzymes. The inventors have discovered multiple salts and polymorphs of Compound A.

[0012] Salt of Compound A The present invention provides salts of Compound A. For example, the present invention provides Compound A fumarate, Compound A mesylate, Compound A hydrochloride, Compound A malate, Compound A sulfate, and Compound A tartrate. More specifically, the present invention provides Compound A hemifumarate, Compound A monofumarate, Compound A monomesylate, Compound A dimesylate, Compound A monohydrochloride, and Compound A dihydrochloride.

[0013] The inventors discovered that many of these salts provided desirable improvements in the aqueous solubility of Compound A. For example, the mesylate and hydrochloride salts provided unexpectedly large increases in solubility compared to the free base of Compound A and were considered for further development. However, considering a broader range of factors, including hygroscopicity, Compound A fumarate was developed as a more advantageous salt form.

[0014] A preferred salt of Compound A is the fumarate salt, especially the monofumarate salt.

[0015] Polymorphs of Compound A The present invention provides polymorphs of the dual Aurora kinase / FLT3 inhibitor Compound A. The present invention provides crystalline forms of Compound A, such as crystalline Compound A free base and crystalline Compound A fumarate. The present invention provides amorphous Compound A, such as amorphous Compound A free base and amorphous Compound A fumarate. The present invention provides Form 1 of Compound A. The present invention provides Form 2 of Compound A. The present invention provides Form 3 of Compound A. The present invention provides Form 4 of Compound A. The present invention provides Form 5 of Compound A. The present invention provides Form 6 of Compound A. The present invention provides Form 7 of Compound A. The present invention provides Form 8 of Compound A. The inventors have discovered that Form 1 of Compound A is particularly advantageous.

[0016] Form 1 In one aspect, the present invention relates to Form 1 of Compound A. Form 1 is characterized by one or more of the following properties: a) Form 1 exhibits an XRPD pattern having at least the following XRPD peaks (CuK°2θ) at about (±0.1): 12.9, 20.5, 21.2, 22.9, and 23.4; b) Form 1 exhibits an XRPD pattern substantially the same as that shown in Figure 1; c) Form 1 exhibits substantially the following unit cell parameters at 298K: [Table 1] d) Form 1 exhibits a DTA-TGA thermogram containing a major endotherm with an onset temperature of approximately (±0.5) 238°C; e) Form 1 exhibits a DTA-TGA thermogram substantially identical to that shown in Figure 11; f) Form 1 contains a 1:1 molar ratio of fumarate to Compound A (Form 1 is a stoichiometric fumarate); g) Form 1 is a non-solvated crystalline form; and / or h) Form 1 can be obtained from 1-butanol, 1-propanol, 2-ethoxyethanol, acetone, acetonitrile, methyl ethyl ketone (MEK), tetrahydrofuran (THF), 1,1-dimethoxymethane, or dimethyl sulfoxide (DMSO).

[0017] Form 1 is preferably characterized by at least a), b), and / or c) above. Form 1 possesses an advantageous balance of unexpected properties of a single physical form, including stability over a wide range of conditions; solubility; absence of solvates; lack of hygroscopicity; and a useful particulate morphology.

[0018] Form 2 In another aspect, the present invention relates to Form 2 of Compound A. Form 2 is characterized by one or more of the following properties: a) Form 2 exhibits an XRPD pattern having at least the following XRPD peaks (CuK 2θ) at about (±0.1): 15.4, 15.8, 16.3, and 24.5. b) Form 2 exhibits an XRPD pattern substantially the same as that shown in FIG. c) Form 2 exhibits substantially the following unit cell parameters at 298K: [Table 2] d) Form 2 exhibits a DTA-TGA thermogram containing a major endotherm with an onset temperature of approximately (±0.5) 231°C; e) Form 2 exhibits a DTA-TGA thermogram substantially identical to that shown in Figure 12; f) Form 2 contains a 1:1 molar ratio of fumarate to Compound A (Form 2 is a stoichiometric fumarate); g) Form 2 is a non-solvated crystalline form; and / or h) Form 2 is obtained from 1,4-dioxane

[0019] Form 2 is preferably characterized by at least a), b), and / or c) above. Form 2 exhibits unexpected stability in 1,4-dioxane and under lyophilization conditions.

[0020] Form 3 In another aspect, the present invention relates to Form 3 of Compound A. Form 3 is characterized by one or more of the following properties: a) Form 3 exhibits an XRPD pattern having at least the following XRPD peaks (CuK 2θ) at about (±0.1): 8.8, 17.4, 17.7, and 18.2. b) Form 3 exhibits an XRPD pattern substantially the same as that shown in Figure 3; c) Form 3 exhibits substantially the following unit cell parameters at 298K: [Table 3] d) Form 3 exhibits a DTA-TGA thermogram containing a major endotherm with an onset temperature of approximately (±0.5) 184°C; e) Form 3 exhibits a DTA-TGA thermogram substantially identical to that shown in Figure 13; f) Form 3 contains a 1:2 molar ratio of fumarate to Compound A (Form 3 is the hemifumarate salt); g) Form 3 is a monohydrate (1:1 molar ratio of water to Compound A); and / or h) Form 3 can be obtained from dimethoxymethane, 2-MeTHF, water:methanol (0:100, 40:60, 80:20, 95:5, 100:0), EtOAc IPA, MEK, MIBK, THF, acetone, acetonitrile.

[0021] Form 3 is preferably characterized by at least a), b), and / or c) above. Form 3 has the advantage of being stable to organic solvents such as dimethoxymethane, 2-MeTHF, water:methanol (0:100, 40:60, 80:20, 95:5, 100:0), EtOAc, IPA, MEK, MIBK, THF, acetone, and acetonitrile. Form 3 has good stability under stressful ambient conditions. Form 3 is slightly hygroscopic.

[0022] Form 4 In another aspect, the present invention relates to Form 4 of Compound A. Form 4 is characterized by one or more of the following properties: a) Form 4 exhibits an XRPD pattern having at least the following XRPD peaks (CuK 2θ) at about (±0.1): 16.3, 18.7, 22.8, 23.1, and 25.7; b) Form 4 exhibits an XRPD pattern substantially the same as that shown in Figure 4; c) Form 4 exhibits a DTA-TGA thermogram containing a major endotherm with an onset temperature of approximately (±0.5) 142°C; d) Form 4 exhibits a DTA-TGA thermogram substantially identical to that shown in Figure 14; e) Form 4 contains a 1:1 molar ratio of fumarate to Compound A (Form 4 is a stoichiometric fumarate); and / or f) Form 4 is a 1,4-dioxane solvate;

[0023] Form 4 is preferably characterized by at least a) and / or b). Form 4 is stable in organic solvents such as 1,4-dioxane. Form 4 converts to Form 2 upon drying.

[0024] Form 5 In another aspect, the present invention relates to Form 5 of Compound A. Form 5 is characterized by one or more of the following properties: a) Form 5 exhibits an XRPD pattern having at least the following XRPD peaks (CuK 2θ) at about (±0.1): 21.5, 24.5, and 27.3. b) Form 5 exhibits an XRPD pattern substantially the same as that shown in Figure 5; c) Form 5 exhibits substantially the following unit cell parameters at 298K: [Table 4] d) Form 5 exhibits a DTA thermogram containing a major endotherm with an onset temperature of approximately (±0.5) 229°C; e) Form 5 exhibits a DTA thermogram substantially identical to that shown in Figure 15; f) Form 5 contains a 1:2 molar ratio of fumarate to Compound A (Form 5 is the hemifumarate salt); g) Form 5 is a benzyl alcohol solvate; and / or h) Form 5 can be obtained from benzyl alcohol.

[0025] Form 5 is preferably characterized by at least a), b), and / or c) above. Form 5 is stable in organic solvents such as benzyl alcohol.

[0026] form 6 In another aspect, the present invention relates to Form 6 of Compound A. Form 6 is characterized by one or more of the following properties: a) Form 6 has at least the following XRPD peaks (CuK 2θ) at about (±0.1): Showing an XRPD pattern of: 9.1, 9.4, 9.8, 16.0, and 26.4; b) Form 6 exhibits an XRPD pattern substantially the same as that shown in Figure 6; c) Form 6 exhibits substantially the following unit cell parameters at 298K: [Table 5] d) Form 6 is the free base of Compound A; e) Form 6 is a DMSO solvate; and / or f) Form 6 can be obtained from DMSO.

[0027] Form 6 is preferably characterized by at least a), b), and / or c) above. Form 6 is stable in organic solvents such as DMSO.

[0028] Form 7 In another aspect, the present invention relates to Form 7 of Compound A. Form 7 is characterized by one or more of the following properties: a) Form 7 exhibits an XRPD pattern having at least the following XRPD peaks (CuK 2θ) at about (±0.1): 7.5, 7.9, 25.6, and 26.2; b) Form 7 exhibits an XRPD pattern substantially the same as that shown in Figure 7; c) Form 7 exhibits substantially the following unit cell parameters at 298K: [Table 6] d) Form 7 exhibits a DTA thermogram containing a major endotherm with an onset temperature of approximately (±0.5) 240°C; e) Form 7 exhibits a DTA thermogram substantially identical to that shown in Figure 16; f) Form 7 is unsolvated. g) Form 7 is the free base of Compound A; and / or h) Form 7 can be obtained by drying Form 6 or from methanol.

[0029] Form 7 is preferably characterized by at least a), b), and / or c) above. Form 7 is stable in organic solvents such as methanol.

[0030] Form 8 In another aspect, the present invention relates to Form 8 of Compound A. Form 8 is characterized by one or more of the following properties: a) Form 8 exhibits an XRPD pattern having at least the following XRPD peaks (CuK 2θ) at about (±0.1): 10.4, 10.7, 11.1, 24.2, and 24.5; b) Form 8 exhibits an XRPD pattern substantially the same as that shown in Figure 8; c) Form 8 exhibits substantially the following unit cell parameters at 298K: [Table 7] d) Form 8 exhibits a DTA thermogram containing a major endotherm with an onset temperature of approximately (±0.5) 232°C; e) Form 8 exhibits a DTA thermogram substantially identical to that shown in Figure 17; f) Form 8 is a benzyl alcohol solvate; g) Form 8 contains a 1:1 molar ratio of fumarate to Compound A (Form 8 is a stoichiometric fumarate); and / or h) Form 8 can be obtained from benzyl alcohol.

[0031] Form 8 is preferably characterized by at least a), b), and / or c) above. Form 8 is stable in organic solvents such as benzyl alcohol.

[0032] The present invention also provides processes for preparing crystalline forms of Compound A. Thus, the present invention provides Forms 1, 2, 3, 4, 5, 6, 7, and 8, as well as processes for preparing any of these forms, including crystallization of those forms from Compound A. In a preferred embodiment, the forms are prepared by lyophilization of Compound A.

[0033] Uses and Applications of the Invention Each of the salts and polymorphs of the present invention described above has many useful applications. The salts and / or polymorphs can be used together or individually. For example, embodiments described herein can include combinations of two forms, e.g., forms 1 and 2, 1 and 3, 1 and 4, 1 and 5, 1 and 6, 1 and 7, 1 and 8, 2 and 3, 2 and 4, 2 and 5, 2 and 6, 2 and 7, 2 and 8, 3 and 4, 3 and 5, 3 and 6, 3 and 7, 3 and 8, 4 and 5, 4 and 6, 4 and 7, 4 and 8, 5 and 6, 5 and 7, 5 and 8, 6 and 7, 6 and 8, or 7 and 8. Embodiments described herein can include combinations of 3, 4, 5, 6, 7, or 8 forms.

[0034] The present invention also provides pharmaceutical compositions comprising one or more salts and / or polymorphs of Compound A. The present invention also provides processes for formulating pharmaceutical compositions comprising Compound A.

[0035] The present invention also provides one or more salts and / or polymorphs of Compound A, or pharmaceutical compositions as defined herein, for use in therapy. [Brief explanation of the drawings]

[0036] [Figure 1] 1 shows the XRPD spectrum of Form 1. [Figure 2] 1 shows the XRPD spectrum of Form 2. [Figure 3] 1 shows the XRPD spectrum of Form 3. [Figure 4] 1 shows the XRPD spectrum of Form 4. [Figure 5] 1 shows the XRPD spectrum of Form 5. [Figure 6] 1 shows the XRPD spectrum of Form 6. [Figure 7] 1 shows the XRPD spectrum of Form 7. [Figure 8] 1 shows the XRPD spectrum of Form 8. [Figure 9] 1 shows the XRPD spectra of Form 1 after 1, 3, and 6 months of storage (Example 5). [Figure 10]1 shows an XRPD spectrum of lyophilized Compound A fumarate salt. [Figure 11] 1 shows the DTA-TGA thermogram of Form 1. [Figure 12] 1 shows the DTA-TGA thermogram of Form 2. [Figure 13] 1 shows the DTA-TGA thermogram of Form 3. [Figure 14] 1 shows the DTA-TGA thermogram of Form 4. [Figure 15] 1 shows the DTA-TGA thermogram of Form 5. [Figure 16] 1 shows the DTA-TGA thermogram of Form 7. [Figure 17] 1 shows the DTA-TGA thermogram of Form 8. [Figure 18] 1 shows a DSC thermogram of Form 1. [Figure 19] 1 shows a DSC thermogram of Form 3. [Figure 20] 1 shows a DSC thermogram of Form 7. [Figure 21a] 1 shows an unpolarized PLM image of Form 1. [Figure 21b] Polarized PLM image of Form 1 is shown. [Figure 22a] 1 shows a non-polarized PLM image of Form 2. [Figure 22b] Polarized PLM image of Form 2 is shown. [Figure 23a] 1 shows a non-polarized PLM image of Form 3. [Figure 23b] Polarized PLM image of Form 3 is shown. [Figure 24a] 1 shows an unpolarized PLM image of Form 4. [Figure 24b] Polarized PLM image of Form 4 is shown. [Figure 25a] 1 shows a non-polarized PLM image of Form 5. [Figure 25b] Polarized PLM image of Form 5 is shown. [Figure 26a] A non-polarized PLM image of Form 7 is shown. [Figure 26b] Polarized PLM image of Form 7 is shown. [Figure 27a] 10 shows an unpolarized PLM image of Form 8. [Figure 27b] Polarized PLM image of Form 8 is shown. [Figure 28-1] 1H NMR of Form 1 is shown. [Figure 28-2] 1H NMR of Form 1 is shown. [Figure 29-1] 1H NMR of Form 2 is shown. [Figure 29-2] 1H NMR of Form 2 is shown. [Figure 30-1] 1H NMR of Form 3 is shown. [Figure 30-2] 1H NMR of Form 3 is shown. [Figure 31-1] 1H NMR of Form 4 is shown. [Figure 31-2] 1H NMR of Form 4 is shown. [Figure 32-1] 1H NMR of Form 5 is shown. [Figure 32-2] 1H NMR of Form 5 is shown. [Figure 33-1] 1H NMR of Form 7 is shown. [Figure 33-2] 1H NMR of Form 7 is shown. [Figure 34-1] 1H NMR of Form 8 is shown. [Figure 34-2] 1H NMR of Form 8 is shown. [Figure 35] 1 shows a DVS isotherm plot of Form 1. [Figure 36] 1 shows the DVS kinetic plot of Form 1. [Figure 37] 1 shows a DVS isotherm plot of Form 3. [Figure 38] 1 shows the DVS kinetic plot of Form 3. [Figure 39] 1 shows the results of a salt evaluation experiment (Example 4). [Figure 40-1] 1 shows the change in impurity levels over a 24 month period for Form 1 (Example 5). [Figure 40-2] 1 shows the change in impurity levels over a 24 month period for Form 1 (Example 5). DETAILED DESCRIPTION OF THE INVENTION

[0037] Salt of Compound A The present invention provides a salt of Compound A. The present invention provides a fumarate salt of Compound A. The present invention provides Compound A mesylate. The present invention provides Compound A hydrochloride. The present invention provides Compound A maleate. The present invention provides Compound A sulfate. The present invention provides Compound A L-tartrate. More specifically, the present invention provides Compound A hemifumarate. The present invention provides Compound A monofumarate. The present invention provides Compound A monomesylate. The present invention provides Compound A dimesylate. The present invention provides Compound A monohydrochloride. The present invention provides Compound A dihydrochloride.

[0038] The inventors have discovered that many of these salts provide desirable improvements in the aqueous solubility of Compound A. For example, the mesylate and hydrochloride salts unexpectedly provided large increases in solubility compared to the free base of Compound A and were considered for further development. However, when a broader range of factors were considered, Compound A fumarate was found to have the most balanced properties.

[0039] Based on its advantageous properties, the mono-fumarate salt of Compound A was selected for further development. The fumarate salt of Compound A is only slightly hygroscopic. The fumarate salt of Compound A has an aqueous solubility of 0.05-4 mg / ml.

[0040] Polymorphism of Compound A Form 1 In one aspect, the present invention relates to Form 1 of Compound A. Form 1 is characterized by one or more of the following properties: a) Form 1 exhibits an XRPD pattern having at least the following XRPD peaks (CuK°2θ) at about (±0.1): 12.9, 20.5, 21.2, 22.9, and 23.4; b) Form 1 exhibits an XRPD pattern substantially the same as that shown in Figure 1; c) Form 1 exhibits substantially the following unit cell parameters at 298K: [Table 8] d) Form 1 exhibits a DTA-TGA thermogram containing a major endotherm with an onset temperature of approximately (±0.5) 238°C; e) Form 1 exhibits a DTA-TGA thermogram substantially identical to that shown in Figure 11; f) Form 1 contains a 1:1 molar ratio of fumarate to Compound A (Form 1 is a stoichiometric fumarate); g) Form 1 is a non-solvated crystalline form; and / or h) Form 1 can be obtained from 1-butanol, 1-propanol, 2-ethoxyethanol, acetone, acetonitrile, MEK, THF, 1,1-dimethoxymethane, or DMSO.

[0041] Form 1 may be characterized by at least a). Form 1 may be characterized by at least b). Form 1 may be characterized by at least c). Form 1 may be characterized by at least d). Form 1 may be characterized by at least e). Form 1 may be characterized by at least f). Form 1 may be characterized by at least g). Form 1 may be characterized by at least h). .

[0042] Form 1 may be characterized by at least two of the above properties. Form 1 may be characterized by at least a) and b). Form 1 may be characterized by at least a) and c). Form 1 may be characterized by at least a) and d). Form 1 may be characterized by at least a) and e). Form 1 may be characterized by at least a) and f). Form 1 may be characterized by at least a) and g). Form 1 may be characterized by at least a) and h). Form 1 may be characterized by at least b) and c). Form 1 may be characterized by at least b) and d). Form 1 may be characterized by at least b) and e). Form 1 may be characterized by at least b) and f). Form 1 may be characterized by at least b) and g). Form 1 may be characterized by at least b) and h). Form 1 may be characterized by at least c) and d). Form 1 may be characterized by at least c) and e). Form 1 may be characterized by at least c) and f). Form 1 may be characterized by at least c) and g). Form 1 may be characterized by at least c) and h).

[0043] Form 1 may be characterized by at least three of the above properties. Form 1 may be characterized by at least four of the above properties. Form 1 may be characterized by at least five of the above properties. Form 1 may be characterized by at least six of the above properties. Form 1 may be characterized by at least seven of the above properties. Form 1 may be characterized by all of the above properties.

[0044] Preferably, Form 1 is characterized by at least one of a), b), and c). Form 1 may be characterized by at least one of a), b), c), and d). Form 1 may be characterized by at least one of a), b), c), and e). Form 1 may be characterized by at least one of a), b), c), and f). Form 1 may be characterized by at least one of a), b), c), and g). Form 1 may be characterized by at least one of a), b), c), and h).

[0045] Preparation of Form 1 The present invention provides a process for making or preparing Form 1. Form 1 can be prepared from a range of solvents. For example, Form 1 can be prepared from 1-butanol, 1-propanol, 2-ethoxyethanol, acetone, or acetonitrile, 1,1-dimethoxymethane, or dimethyl sulfoxide (DMSO).

[0046] Form 1 can be prepared by temperature cycling, evaporation, or solvent drop-out and trituration. In one embodiment, Form 1 can be prepared from 1-butanol, 1-propanol, 2-ethoxyethanol, acetone, or acetonitrile by temperature cycling. In another embodiment, Form 1 can be prepared from 1,1-dimethoxymethane or DMSO by solvent drop-out and trituration.

[0047] Characterization of Form 1 Form 1 is crystalline by XRPD with characteristic peaks (CuK°2θ) at about (±0.1): 12.9, 20.5, 21.2, 22.9, and 23.4. For example, Form 1 may have characteristic peaks at about (±0.1): 12.9, 17.5, 20.5, 21.2, 22.9, 23.4, 26.8, and 27.1. For example, Form 1 may have characteristic peaks at about (±0.1): 5.9, 12.9, 17.5, 18.3, 19.6, 20.5, 21.2, 22.9, 23.4, 26.8, and 27.1. It may have characteristic peaks at 0.4, 26.8, and 27.1.

[0048] Form 1 particles, as shown in Figure 21 and determined by PLM, are weakly birefringent and consist of fragmented plates. The consistent, rounded shape of Form 1 particles is advantageous because it allows for easier physical manipulation than other crystalline shapes. This is particularly important in pharmaceutical processing. In this regard, rounded, consistent particles are preferable to, for example, long, thin, or inconsistently shaped particles.

[0049] Form 1 1 1 H NMR was consistent with the structure of Compound A and showed the expected connectivity. 1 H One equivalent of fumaric acid was observed by NMR.

[0050] The DTA / TG thermogram of Form 1 is shown in Figure 11. Form 1 has an unsolvated crystalline structure, as evidenced by the lack of significant weight loss at low temperatures in thermogravimetric experiments. Unsolvated crystalline forms are easier to handle than solvated forms, as the presence of solvent molecules in the lattice can introduce variability into analytical assays and complicate their use as active pharmaceutical ingredients. Furthermore, the reproducible absence of solvates avoids potential administration and toxicity complications.

[0051] DT analysis shows that Form 1 exhibits a small melt with an onset of approximately 227°C associated with the loss of fumarate, followed by melting of Compound A free base with an onset of approximately 237°C (peak at 242°C). The high melting temperature of the Form 1 lattice supports its beneficial thermodynamic stability.

[0052] Form 1 is slightly hygroscopic, absorbing 0.7 wt % (0.07 equivalents of water) at 90% RH by DVS. When the recovered solid was characterized by XRPD, no evidence of form change due to hydration or recrystallization was observed. See Figures 35 and 36.

[0053] A high purity of 99.7% (by area %) was observed by HPLC.

[0054] Stability studies performed on Form 1 showed no significant changes in form over 6 months or chemical composition over 24 months at ambient and accelerated conditions. Accordingly, Form 1 exhibits substantially the same characteristic peaks as described above after storage at 40°C / 75% RH. Form 1 exhibits substantially the same XRPD as shown in Figure 1 after storage at 40°C / 75% RH.

[0055] Furthermore, Form 1 is stable in a variety of organic solvents, demonstrating that exposure to 1-butanol, 1-propanol, 2-ethoxyethanol, acetone, acetonitrile, MEK, THF, 1,1-dimethoxymethane, or DMSO does not alter its morphology (as assessed by XRPD based on the characteristic peaks described above and shown in Figure 1 , as shown in the unit cell above). The chemical and physical stability, including resistance to morphological changes in a variety of environments, indicates that Form 1 is particularly advantageous.

[0056] Form 2 In another aspect, the present invention relates to Form 2 of Compound A. Form 2 is characterized by one or more of the following properties: a) Form 2 exhibits an XRPD pattern having at least the following XRPD peaks (CuK 2θ) at about (±0.1): 15.4, 15.8, 16.3, and 24.5. b) Form 2 exhibits an XRPD pattern substantially the same as that shown in Figure 2; c) Form 2 exhibits substantially the following unit cell parameters at 298K: [Table 9] d) Form 2 exhibits a DTA-TGA thermogram containing a major endotherm with an onset temperature of approximately (±0.5) 231°C; e) Form 2 exhibits a DTA-TGA thermogram substantially identical to that shown in Figure 12; f) Form 2 contains a 1:1 molar ratio of fumarate to Compound A (Form 2 is a stoichiometric fumarate); g) Form 2 is a non-solvated crystalline form; and / or h) Form 2 can be obtained from 1,4-dioxane.

[0057] Form 2 may be characterized by at least a). Form 2 may be characterized by at least b). Form 2 may be characterized by at least c). Form 2 may be characterized by at least d). Form 2 may be characterized by at least e). Form 2 may be characterized by at least f). Form 2 may be characterized by at least g). Form 2 may be characterized by at least h).

[0058] Form 2 may be characterized by at least two of the above properties. Form 2 may be characterized by at least a) and b). Form 2 may be characterized by at least a) and c). Form 2 may be characterized by at least a) and d). Form 2 may be characterized by at least a) and e). Form 2 may be characterized by at least a) and f). Form 2 may be characterized by at least a) and g). Form 2 may be characterized by at least a) and h). Form 2 may be characterized by at least b) and c). Form 2 may be characterized by at least b) and d). Form 2 may be characterized by at least b) and e). Form 2 may be characterized by at least b) and f). Form 2 may be characterized by at least b) and g). Form 2 may be characterized by at least b) and h). Form 2 may be characterized by at least c) and d). Form 2 may be characterized by at least c) and e). Form 2 may be characterized by at least c) and f). Form 2 may be characterized by at least c) and g). Form 2 may be characterized by at least c) and h).

[0059] Form 2 may be characterized by at least three of the above properties. Form 2 may be characterized by at least four of the above properties. Form 2 may be characterized by at least five of the above properties. Form 2 may be characterized by at least six of the above properties. Form 2 may be characterized by at least seven of the above properties. Form 2 may be characterized by all of the above properties.

[0060] Preferably, Form 2 is characterized by at least one of a), b), and c). Form 2 may be characterized by at least one of a), b), c), and d). Form 2 may be characterized by at least one of a), b), c), and e). Form 2 may be characterized by at least one of a), b), c), and f). Form 2 may be characterized by at least one of a), b), and c), and g). Form 2 may be characterized by at least one of a), b), and c), and h).

[0061] Preparation of Form 2 The present invention provides a process for making or preparing Form 2. For example, Form 2 can be prepared from 1,4-dioxane. In one embodiment, Form 2 can be prepared by drying Form 4 in 1,4-dioxane. Form 2 can also be prepared by lyophilization of Compound A fumarate (see Figure 10).

[0062] Characterization of Form 2 Form 2 is crystalline by XRPD with characteristic peaks (CuK 2θ) at about (±0.1):15.4, 15.8, 16.3, and 24.5. For example, Form 2 may have characteristic peaks at about (±0.1):13.5, 15.4, 15.8, 16.3, 17.8, 24.5, 25.7, and 27.3. For example, Form 2 may have characteristic peaks at about (±0.1):7.2, 9.3, 10.7, 13.5, 15.4, 15.8, 16.3, 17.8, 18.9, 24.5, 25.7, and 27.3.

[0063] Form 2 particles are highly birefringent and do not have a defined morphology, as shown in Figure 22 and as determined by PLM.

[0064] Form 2 1 1 H NMR analysis was consistent with the structure of Compound A and showed the expected connectivity. 1 One equivalent of fumaric acid was observed by 1 H NMR.

[0065] The DTA / TG thermogram of Form 2 is shown in Figure 12. Form 2 has a nonsolvated crystalline structure, as evidenced by the lack of significant mass loss until above approximately 120°C. Above 120°C, a continuous weight loss was observed, associated with the potential loss of fumaric acid and the onset of decomposition. Form 2 has a complex thermal profile from approximately 120°C to 230°C. A large melting endotherm was observed with an onset of approximately 232°C (peaking at 239°C).

[0066] Form 2 exhibits unexpected stability in 1,4-dioxane and under lyophilization conditions (ie, Form 2 exhibits no changes in the characteristic XRPD peaks, spectra, or unit cell described above under these conditions).

[0067] Form 3 In another aspect, the present invention relates to Form 3 of Compound A. Form 3 is characterized by one or more of the following properties: a) Form 3 exhibits an XRPD pattern having at least the following XRPD peaks (CuK 2θ) at about (±0.1): 8.8, 17.4, 17.7, and 18.2. b) Form 3 exhibits an XRPD pattern substantially the same as that shown in Figure 3; c) Form 3 exhibits substantially the following unit cell parameters at 298K: [Table 10] d) Form 3 exhibits a DTA-TGA thermogram containing a major endotherm with an onset temperature of approximately (±0.5) 184°C; e) Form 3 exhibits a DTA-TGA thermogram substantially identical to that shown in Figure 13; f) Form 3 contains a 1:2 molar ratio of fumarate to Compound A (Form 3 is the hemifumarate salt); g) Form 3 is a monohydrate (1:1 molar ratio of water to Compound A); and / or h) Form 3 can be obtained from dimethoxymethane, 2-MeTHF, water:methanol (0:100, 40:60, 80:20, 95:5, 100:0), EtOAc IPA, MEK, MIBK, THF, acetone, acetonitrile.

[0068] Form 3 may be characterized by at least a). Form 3 may be characterized by at least b). Form 3 may be characterized by at least c). Form 3 may be characterized by at least d). Form 3 may be characterized by at least e). Form 3 may be characterized by at least f). Form 3 may be characterized by at least g). Form 3 may be characterized by at least h).

[0069] Form 3 may be characterized by at least two of the above properties. Form 3 may be characterized by at least a) and b). Form 3 may be characterized by at least a) and c). Form 3 may be characterized by at least a) and d). Form 3 may be characterized by at least a) and e). Form 3 may be characterized by at least a) and f). Form 3 may be characterized by at least a) and g). Form 3 may be characterized by at least a) and h). Form 3 may be characterized by at least b) and c). Form 3 may be characterized by at least b) and d). Form 3 may be characterized by at least b) and e). Form 3 may be characterized by at least b) and f). Form 3 may be characterized by at least b) and g). Form 3 may be characterized by at least b) and h). Form 3 may be characterized by at least c) and d). Form 3 may be characterized by at least c) and e). Form 3 may be characterized by at least c) and f). Form 3 may be characterized by at least c) and g). Form 3 may be characterized by at least c) and h).

[0070] Form 3 may be characterized by at least three of the above properties. Form 3 may be characterized by at least four of the above properties. Form 3 may be characterized by at least five of the above properties. Form 3 may be characterized by at least six of the above properties. Form 3 may be characterized by at least seven of the above properties. Form 3 may be characterized by all of the above properties.

[0071] Preferably, Form 3 is characterized by at least one of a), b), and c). Form 3 may be characterized by at least one of a), b), c), and d). Form 3 may be characterized by at least one of a), b), c), and e). Form 3 may be characterized by at least one of a), b), c), and f). Form 3 may be characterized by at least one of a), b), c), and g). Form 3 may be characterized by at least one of a), b), c), and h).

[0072] Preparation of Form 3 The present invention provides a process for making or preparing Form 3. Form 3 can be prepared from a variety of solvents. For example, Form 3 can be prepared from dimethoxymethane; 2-MeTHF; water:MeOH (0:100, 40:60, 80:20, 95:5, 100:0); EtO It can be prepared from Ac; IPA; MEK; MIBK; THF; acetone; or acetonitrile.

[0073] Form 3 can be prepared by temperature cycling, evaporation, or anti-solvent addition. In one embodiment, Form 3 can be prepared by temperature cycling from dimethoxymethane; 2-MeTHF; water:MeOH (0:100, 40:60, 80:20, 95:5, 100:0); IPA; In another embodiment, Form 3 can be prepared from water:MeOH (0:100, 40:60, 80:20, 95:5, 100:0); EtOAc; MEK; acetone; or acetonitrile by evaporation. In another embodiment, Form 3 can be prepared from THF and TMBE by anti-solvent addition.

[0074] Characterization of Form 3 Form 3 is crystalline by XRPD with characteristic (CuK°2θ) peaks at about (±0.1): 8.8, 17.4, 17.7, and 18.2. For example, Form 3 may have characteristic peaks at about (±0.1): 8.8, 15.6, 17.4, 17.7, 18.2, and 22.5. For example, Form 3 may have characteristic peaks at about (±0.1): 3.7, 7.4, 8.8, 15.6, 17.4, 17.7, 18.2, 22.5, 26.8, and 27.0.

[0075] Morphology 3 particles are shown in Figure 23 and are rod-shaped agglomerated particles as determined by PLM.

[0076] Form 3 1 H NMR analysis showed the expected connectivity consistent with the structure of Compound A. Approximately 0.5 equivalents of fumaric acid were observed, indicating that the material was a hemifumarate salt.

[0077] The DTA / TG thermogram of Form 3 is shown in Figure 13. Form 3 is a monohydrate, as indicated by a mass loss of approximately 3.3% (1.1 equivalents of water) from 80 to 110°C and the associated endotherm with an onset at approximately 65°C (peak at 110°C). A further mass loss of approximately 10.3% and a sharp endothermic event are observed with an onset at approximately 184°C (peak at 188°C), which may be associated with the loss or onset of decomposition of fumaric acid. From approximately 231°C, Form 3 has a complex temperature profile.

[0078] Form 3 is only slightly hygroscopic, as shown by DVS, with a weight gain of approximately 0.5 wt % at 90% RH. No evidence of hydration or dehydration was observed.

[0079] Form 3 is stable under ambient and stress conditions (40°C / 75% RH (open vial) and 80°C (closed vial)) with no change in appearance, purity, or XRPD pattern after 1 week at these conditions. Form 3 can be treated in organic solvents such as dimethoxymethane; 2-MeTHF; water:MeOH (0:100, 40:60, 80:20, 95:5, 100:0); EtOAc; IPA; MEK; MIBK; THF; acetone; or acetonitrile without altering the form (i.e., no change in the characteristic XRPD peaks, spectrum, or unit cell described above).

[0080] Form 4 In another aspect, the present invention relates to Form 4 of Compound A. Form 4 is characterized by one or more of the following properties: a) Form 4 exhibits an XRPD pattern having at least the following XRPD peaks (CuK 2θ) at about (±0.1): 16.3, 18.7, 22.8, 23.1, and 25.7; b) Form 4 exhibits an XRPD pattern substantially the same as that shown in Figure 4; c) Form 4 has a DTA-T with a major endotherm with an onset temperature of approximately (±0.5) 142°C. Showing GA thermogram; d) Form 4 exhibits a DTA-TGA thermogram substantially identical to that shown in Figure 14; e) Form 4 contains a 1:1 molar ratio of fumarate to Compound A (Form 4 is a stoichiometric fumarate); and / or f) Form 4 is a 1,4-dioxane solvate;

[0081] Form 4 may be characterized by at least a). Form 4 may be characterized by at least b). Form 4 may be characterized by at least c). Form 4 may be characterized by at least d). Form 4 may be characterized by at least e). Form 4 may be characterized by at least f).

[0082] Form 4 may be characterized by at least two of the above properties. Form 4 may be characterized by at least a) and b). Form 4 may be characterized by at least a) and c). Form 4 may be characterized by at least a) and d). Form 4 may be characterized by at least a) and e). Form 4 may be characterized by at least a) and f). Form 4 may be characterized by at least b) and c). Form 4 may be characterized by at least b) and d). Form 4 may be characterized by at least b) and e). Form 4 may be characterized by at least b) and f). Form 4 may be characterized by at least c) and d). Form 4 may be characterized by at least c) and e). Form 4 may be characterized by at least c) and f). Form 4 may be characterized by at least d) and e). Form 4 may be characterized by at least e) and f).

[0083] Form 4 may be characterized by at least three of the above properties. Form 4 may be characterized by at least four of the above properties. Form 4 may be characterized by at least five of the above properties. Form 4 may be characterized by all of the above properties.

[0084] Preferably, Form 4 is characterized by at least one of a) and b). Form 3 may be characterized by at least one of a), b), and c). Form 4 may be characterized by at least one of a), b), and d). Form 4 may be characterized by at least one of a), b), and e). Form 4 may be characterized by at least one of a), b), and f).

[0085] Form 4 is preferably characterized by at least a) and / or b): Form 4 is stable (i.e., shows no changes in the XRPD characteristic peaks or spectra described above) in organic solvents such as 1,4-dioxane.

[0086] Form 5 In another aspect, the present invention relates to Form 5 of Compound A. Form 5 is characterized by one or more of the following properties: a) Form 5 exhibits an XRPD pattern having at least the following XRPD peaks (CuK 2θ) at about (±0.1): 21.5, 24.5, and 27.3. b) Form 5 exhibits an XRPD pattern substantially the same as that shown in Figure 5; c) Form 5 exhibits substantially the following unit cell parameters at 298K: [Table 11] d) Form 5 exhibits a DTA thermogram containing a major endotherm with an onset temperature of approximately (±0.5) 229°C; e) Form 5 exhibits a DTA thermogram substantially identical to that shown in Figure 15; f) Form 5 contains a 1:2 molar ratio of fumarate to Compound A (Form 5 is the hemifumarate salt); g) Form 5 is a benzyl alcohol solvate; and / or h) Form 5 can be obtained from benzyl alcohol.

[0087] Form 5 may be characterized by at least a). Form 5 may be characterized by at least b). Form 5 may be characterized by at least c). Form 5 may be characterized by at least d). Form 5 may be characterized by at least e). Form 5 may be characterized by at least f). Form 5 may be characterized by at least g). Form 5 may be characterized by at least h).

[0088] Form 5 may be characterized by at least two of the above properties. Form 5 may be characterized by at least a) and b). Form 5 may be characterized by at least a) and c). Form 5 may be characterized by at least a) and d). Form 5 may be characterized by at least a) and e). Form 5 may be characterized by at least a) and f). Form 5 may be characterized by at least a) and g). Form 5 may be characterized by at least a) and h). Form 5 may be characterized by at least b) and c). Form 5 may be characterized by at least b) and d). Form 5 may be characterized by at least b) and e). Form 5 may be characterized by at least b) and f). Form 5 may be characterized by at least b) and g). Form 5 may be characterized by at least b) and h). Form 5 may be characterized by at least c) and d). Form 5 may be characterized by at least c) and e). Form 5 may be characterized by at least c) and f). Form 5 may be characterized by at least c) and g). Form 5 may be characterized by at least c) and h).

[0089] Form 5 may be characterized by at least three of the above properties. Form 5 may be characterized by at least four of the above properties. Form 5 may be characterized by at least five of the above properties. Form 5 may be characterized by at least six of the above properties. Form 5 may be characterized by at least seven of the above properties. Form 5 may be characterized by all of the above properties.

[0090] Preferably, Form 5 is characterized by at least one of a), b), and c). Form 5 may be characterized by at least one of a), b), c), and d). Form 5 may be characterized by at least one of a), b), c), and e). Form 5 may be characterized by at least one of a), b), c), and f). Form 5 may be characterized by at least one of a), b), c), and g). Form 5 may be characterized by at least one of a), b), c), and h). ) may be characterized by at least one of

[0091] Preparation of Form 5 The present invention provides a process for making or preparing Form 5. Form 5 can be prepared from benzyl alcohol. Form 5 can be prepared by temperature cycling or solvent addition followed by grinding. In one embodiment, Form 5 can be prepared from benzyl alcohol by temperature cycling. In another embodiment, Form 5 can be prepared from benzyl alcohol by solvent addition followed by grinding.

[0092] Characterization of Form 5 Form 5 has characteristic peaks (CuK) at approximately (±0.1):21.5, 24.5, and 27.3. Form 5 is crystalline by XRPD with a 2θ (angle). For example, Form 5 may have characteristic peaks at about (±0.1): 21.5, 22.2, 22.4, 23.2, 24.5, and 27.3. For example, Form 5 may have characteristic peaks at about (±0.1): 15.7, 15.9, 16.6, 21.5, 22.2, 22.4, 23.2, 24.5, and 27.3.

[0093] Form 5 particles are shown in Figure 25 and are rod-shaped aggregate particles that are highly birefringent as determined by PLM.

[0094] Form 5 1H NMR analysis was consistent with the structure of Compound A and showed the expected connectivity. Approximately 0.5 equivalents of fumaric acid were observed, indicating that the material is a hemifumarate salt. 1 1 H NMR showed the characteristic peaks of benzyl alcohol.

[0095] The DTA / TG thermogram of Form 5 is shown in Figure 15. Form 5 is a benzyl alcohol solvate, as indicated by a weight loss of 41.7% (3.8 equivalents of benzyl alcohol) from the onset of heating up to about 135°C and a broad endothermic event (peak at 136°C) from an onset of about 120°C. Form 5 exhibits a sharp melting endotherm (peak at 236°C) from an onset of about 229°C.

[0096] Form 5 can be handled in organic solvents such as benzyl alcohol without change in form (i.e., Form 5 does not exhibit changes in the above-mentioned characteristic XRPD peaks, spectra, or unit cell under these conditions).

[0097] form 6 In another aspect, the present invention relates to Form 6 of Compound A. Form 6 is characterized by one or more of the following properties: a) Form 6 exhibits an XRPD pattern having at least the following XRPD peaks (CuK 2θ) at about (±0.1): 9.1, 9.4, 9.8, 16.0, and 26.4; b) Form 6 exhibits an XRPD pattern substantially the same as that shown in Figure 6; c) Form 6 exhibits substantially the following unit cell parameters at 298K: [Table 12] d) Form 6 is the free base of Compound A; e) Form 6 is a DMSO solvate; and / or f) Form 6 can be obtained from DMSO.

[0098] Form 6 may be characterized by at least a). Form 6 may be characterized by at least b). Form 6 may be characterized by at least c). Form 6 may be characterized by at least d). Form 6 may be characterized by at least e). Form 6 may be characterized by at least f).

[0099] Form 6 may be characterized by at least two of the above properties. Form 6 may be characterized by at least a) and b). Form 6 may be characterized by at least a) and c). Form 6 may be characterized by at least a) and d). Form 6 may be characterized by at least a) and e). Form 6 may be characterized by at least a) and f). Form 6 may be characterized by at least b) and c). Form 6 may be characterized by at least b) and d). Form 6 may be characterized by at least b) and e). Form 6 may be characterized by at least b) and f). Form 6 may be characterized by at least c) and d). Form 6 may be characterized by at least c) and e). Form 6 may be characterized by at least c) and f). Form 6 may be characterized by at least d) and e). Form 6 may be characterized by at least d) and f). Form 6 can be characterized by at least e) and f).

[0100] Form 6 may be characterized by at least three of the above properties. Form 6 may be characterized by at least four of the above properties. Form 6 may be characterized by all of the above properties.

[0101] Preferably, Form 6 is characterized by at least one of a), b), and c). Form 6 may be characterized by at least one of a), b), c), and d). Form 6 may be characterized by at least one of a), b), c), and e). Form 6 may be characterized by at least one of a), b), c), and f).

[0102] Preparation of Form 6 The present invention provides a process for making or preparing Form 6. For example, Form 6 can be prepared from DMSO. In one embodiment, Form 6 can be prepared from DMSO by temperature cycling.

[0103] Characterization of Form 6 Form 6 is crystalline by XRPD with characteristic peaks (CuK°2θ) at about (±0.1): 9.1, 9.4, 9.8, 16.0, and 26.4. For example, Form 6 may have characteristic peaks at about (±0.1): 9.1, 9.4, 9.8, 12.7, 16.0, 20.4, 21.0, and 26.4. For example, Form 6 may have characteristic peaks at about (±0.1): 9.1, 9.4, 9.8, 12.7, 16.0, 20.4, 21.0, 24.5, 25.2, and 26.4.

[0104] Form 6 1 H NMR analysis was consistent with the structure of Compound A and showed the expected connectivity. 1 1 H NMR showed characteristic peaks of DMSO.

[0105] Form 6 can be handled in DMSO without altering its morphology (ie, Form 6 does not exhibit changes in the above characteristic XRPD peaks, spectra, or unit cell under these conditions).

[0106] Form 7 In another aspect, the present invention relates to Form 7 of Compound A. Form 7 is characterized by one or more of the following properties: a) Form 7 exhibits an XRPD pattern having at least the following XRPD peaks (CuK 2θ) at about (±0.1): 7.5, 7.9, 25.6, and 26.2; b) Form 7 exhibits an XRPD pattern substantially the same as that shown in Figure 7; c) Form 7 exhibits substantially the following unit cell parameters at 298K: [Table 13] d) Form 7 exhibits a DTA thermogram containing a major endotherm with an onset temperature of approximately (±0.5) 240°C; e) Form 7 exhibits a DTA thermogram substantially identical to that shown in Figure 16; f) Form 7 is unsolvated. g) Form 7 is the free base of Compound A; and / or h) Form 7 can be obtained by drying Form 6 or from methanol.

[0107] Form 7 may be characterized by at least a). Form 7 may be characterized by at least b). Form 7 may be characterized by at least c). Form 7 may be characterized by at least d). Form 7 may be characterized by at least e). Form 7 may be characterized by at least f). Form 7 may be characterized by at least g). Form 7 may be characterized by at least h).

[0108] Form 7 may be characterized by at least two of the above properties. Form 7 may be characterized by at least a) and b). Form 7 may be characterized by at least a) and c). Form 7 may be characterized by at least a) and d). Form 7 may be characterized by at least a) and e). Form 7 may be characterized by at least a) and f). Form 7 may be characterized by at least a) and g). Form 7 may be characterized by at least a) and h). Form 7 may be characterized by at least b) and c). Form 7 may be characterized by at least b) and d). Form 7 may be characterized by at least b) and e). Form 7 may be characterized by at least b) and f). Form 7 may be characterized by at least b) and g). Form 7 may be characterized by at least b) and h). Form 7 may be characterized by at least c) and d). Form 7 may be characterized by at least c) and e). Form 7 may be characterized by at least c) and f). Form 7 may be characterized by at least c) and g). Form 7 may be characterized by at least c) and h).

[0109] Form 7 may be characterized by at least three of the above properties. Form 7 may be characterized by at least four of the above properties. Form 7 may be characterized by at least five of the above properties. Form 7 may be characterized by at least six of the above properties. Form 7 may be characterized by at least seven of the above properties. Form 7 may be characterized by all of the above properties.

[0110] Preferably, Form 7 is characterized by at least one of a), b), and c). Form 7 may be characterized by at least one of a), b), c), and d). Form 7 may be characterized by at least one of a), b), c), and e). Form 7 may be characterized by at least one of a), b), c), and f). Form 7 may be characterized by at least one of a), b), c), and g). Form 7 may be characterized by at least one of a), b), c), and h).

[0111] Preparation of Form 7 The present invention provides a process for making or preparing Form 7. Form 7 can be prepared by drying Form 6. Form 7 can be prepared by slurrying Form 6 in TBME. Alternatively, Form 7 can be prepared from methanol. In one embodiment, Form 7 can be prepared from methanol by temperature cycling.

[0112] Characterization of Form 7 Form 7 is crystalline by XRPD with characteristic peaks (CuK 2θ) at about (±0.1): 7.5, 7.9, 25.6, and 26.2. For example, Form 7 may have characteristic peaks at about (±0.1): 4.3, 6.4, 7.5, 7.9, 14.4, 19.9, 25.6, and 26.2. For example, Form 7 may have characteristic peaks at about (±0.1): 4.3, 6.4, 7.5, 7.9, 14.4, 15.7, 16.2, 18.5, 19.9, 22.2, 25.6, and 26.2.

[0113] Form 7 particles are shown in Figure 26 and are rod-shaped aggregate particles that are highly birefringent as determined by PLM.

[0114] Form 7 1H NMR analysis was consistent with the structure of Compound A and showed the expected connectivity. Form 7 did not exhibit a fumaric acid peak by NMR, indicating that the material is the free base of Compound A. This provides a higher activity content than other forms. In some embodiments, low levels of fumarate may be detected as an impurity in Form 7 material.

[0115] The DTA / TG thermogram of Form 7 is shown in Figure 16. Form 7 exhibits a sharp melting endotherm with an onset of approximately 241°C (peaking at 244°C), indicating a thermodynamically favored lattice. Weight loss at low temperatures associated with removal of surface moisture and solvent.

[0116] Form 7 can be handled in organic solvents such as methanol and TBME without change in morphology (i.e., Form 7 does not exhibit changes in the XRPD characteristic peaks, spectra, or unit cell described above under these conditions.) Form 7 is slightly hygroscopic and is stable under long-term storage conditions.

[0117] Form 8 In another aspect, the present invention relates to Form 8 of Compound A. Form 8 is characterized by one or more of the following properties: a) Form 8 exhibits an XRPD pattern having at least the following XRPD peaks (CuK 2θ) at about (±0.1): 10.4, 10.7, 11.1, 24.2, and 24.5; b) Form 8 exhibits an XRPD pattern substantially the same as that shown in Figure 8; c) Form 8 exhibits substantially the following unit cell parameters at 298K: [Table 14] d) Form 8 exhibits a DTA thermogram containing a major endotherm with an onset temperature of approximately (±0.5) 232°C; e) Form 8 exhibits a DTA thermogram substantially identical to that shown in FIG. f) Form 8 is a benzyl alcohol solvate; g) Form 8 contains a 1:1 molar ratio of fumarate to Compound A (Form 8 is a stoichiometric fumarate); and / or h) Form 8 can be obtained from benzyl alcohol.

[0118] Form 8 may be characterized by at least a). Form 8 may be characterized by at least b). Form 8 may be characterized by at least c). Form 8 may be characterized by at least d). Form 8 may be characterized by at least e). Form 8 may be characterized by at least f). Form 8 may be characterized by at least g). Form 8 may be characterized by at least h).

[0119] Form 8 may be characterized by at least two of the above properties. Form 8 may be characterized by at least a) and b). Form 8 may be characterized by at least a) and c). Form 8 may be characterized by at least a) and d). Form 8 may be characterized by at least a) and e). Form 8 may be characterized by at least a) and f). Form 8 may be characterized by at least a) and g). Form 8 may be characterized by at least a) and h). Form 8 may be characterized by at least b) and c). Form 8 may be characterized by at least b) and d). Form 8 may be characterized by at least b) and e). Form 8 may be characterized by at least b) and f). Form 8 may be characterized by at least b) and g). Form 8 may be characterized by at least b) and h). Form 8 may be characterized by at least c) and d). Form 8 may be characterized by at least c) and e). Form 8 may be characterized by at least c) and f). Form 8 may be characterized by at least c) and g). Form 8 may be characterized by at least c) and h).

[0120] Form 8 may be characterized by at least three of the above properties. Form 8 may be characterized by at least four of the above properties. Form 8 may be characterized by at least five of the above properties. Form 8 may be characterized by at least six of the above properties. Form 8 may be characterized by at least seven of the above properties. Form 8 may be characterized by all of the above properties.

[0121] Preferably, Form 8 is characterized by at least one of a), b), and c). Form 8 may be characterized by at least one of a), b), c), and d). Form 8 may be characterized by at least one of a), b), c), and e). Form 8 may be characterized by at least one of a), b), c), and f). Form 8 may be characterized by at least one of a), b), c), and g). Form 8 may be characterized by at least one of a), b), c), and h). ) may be characterized by at least one of

[0122] Preparation of Form 8 The present invention provides a process for making or preparing Form 8. Form 8 can be prepared from benzyl alcohol. In one aspect, Form 8 can be prepared from benzyl alcohol by solvent trituration. Optionally, excess benzyl alcohol can be removed by slurrying with tert-butyl methyl ether.

[0123] Characterization of Form 8 Form 8 is crystalline by XRPD with characteristic peaks (CuK 2θ) at about (±0.1): 10.4, 10.7, 11.1, 24.2, and 24.5. For example, Form 8 may have characteristic peaks at about (±0.1): 5.2, 5.5, 10.4, 10.7, 11.1, 15.5, 16.5, 24.2, and 24.5. For example, Form 8 may have characteristic peaks at about (±0.1): 5.2, 5.5, 8.2, 10.4, 10.7, 11.1, 15.5, 16.5, 21.4, 23.3, 24.2, and 24.5.

[0124] Form 8 particles, as shown in Figure 27 and as determined by PLM, are highly birefringent aggregates with no defined morphology.

[0125] Form 8 1 H NMR analysis was consistent with the structure of Compound A and showed the expected connectivity. Approximately 1 equivalent of fumaric acid was observed. 1 1 H NMR shows the characteristic peaks of benzyl alcohol.

[0126] The DTA / TG thermogram of Form 8 is shown in Figure 17. Form 8 exhibits a loss of mass up to about 120°C (corresponding to the removal of benzyl alcohol). Form 8 exhibits a sharp melting endotherm (peaking at 240°C) with an onset of about 232°C. The weight loss at low temperatures is associated with the removal of surface moisture and solvent.

[0127] definition "Compound A" refers to the compound having the chemical name: 6-chloro-7-(4-(4-chlorobenzyl)piperazin-1-yl)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine. This compound has CAS number 1402709-93-6. For the avoidance of doubt, unless otherwise stated, references to Compound A or "the Compound" are references to this compound having the above structure, optionally in the form of a pharmaceutically acceptable salt and / or solvate.

[0128] A salt of Compound A refers to the product of forming an ion pair between Compound A and an acidic or basic compound. Without wishing to be bound by any theory, compounds of formula (I) can form acid salts due to the presence of nitrogen-containing groups that can accept one or more protons from the acidic moiety.

[0129] Compound A can form salts in various molar ratios, e.g., a 1:1 or 1:2 molar ratio of acidic salt-forming moiety:Compound A. In this context, "Compound A" encompasses, for example, ionic species formed from protonation of Compound A. For example, a 1:1 molar ratio of fumarate:Compound A would result from the reaction of a 1:1 ratio of fumaric acid with Compound A.

[0130] Preferably, the pharmaceutically acceptable salt of Compound A is a fumarate, such as a stoichiometric fumarate or hemifumarate, preferably a stoichiometric fumarate (1:1 molar ratio of Compound A:fumarate).

[0131] The crystalline form of the present invention can exist in both non-solvated and solvated forms.The term "solvate" is used herein to describe a molecular complex comprising an API such as Compound A and an amount of one or more pharmaceutically acceptable solvents.When the solvent is water, the term "hydrate" is used.In the case of crystalline form, the solvent can be dispersed throughout the lattice by intermolecular interactions.

[0132] As used herein, the term "pharmaceutically acceptable excipient" refers to a substance, such as a carrier, diluent, stabilizer, dispersant, suspending agent, thickener, or the like, that allows an active pharmaceutical ingredient (API) to be processed into a form suitable for administration to a mammal, such as a human. A pharmaceutically acceptable excipient refers to a substance that does not substantially neutralize the desired biological activity or desired properties of the compound (i.e., API) and is relatively non-toxic. That is, the substance may be administered to an individual without causing undesired biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0133] "Active pharmaceutical ingredient" or API refers to a compound having a desired biological activity or desired property. In the present invention, the API is Compound A. In some embodiments, the API has a purity of greater than 90%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 98%, or greater than 99%.

[0134] The term "pharmaceutical composition" refers to a mixture of Compound A, or a pharmaceutically acceptable salt and / or solvate thereof, with other chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, excipients, etc. Pharmaceutical compositions facilitate administration of a compound to a mammal.

[0135] As used herein, the term "acceptable" with respect to a formulation, composition, or ingredient means that it does not have a lasting adverse effect on the overall health of the subject being treated.

[0136] As used herein, the term "effective amount" or "therapeutically effective amount" refers to that amount of an agent administered sufficient to relieve to some extent one or more of the symptoms of the disease or condition being treated. That result can be a reduction and / or alleviation of the signs, symptoms, or pathogenesis of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound as disclosed herein required to produce a clinically significant reduction in a symptom of the disease. The term "therapeutically effective amount" includes, for example, a prophylactically effective amount. An effective amount will be selected based on the particular patient and disease level. It is understood that the "effective amount" or "therapeutically effective amount" will vary from subject to subject, due to variations in drug metabolism, the subject's age, weight, general condition, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician. In one embodiment, an appropriate "effective" amount in any individual case is determined using techniques such as a dose escalation study.

[0137] Terms such as "substantially," "nearly," "about," and the like, as applied to the terms herein, should be understood to account for the natural degree of variation in a given parameter. For example, a person skilled in the art of XRPD comparing two spectra that are said to be "substantially the same" would focus on the major characteristic peaks and would not expect the two spectra to be identical. In other words, "substantially" is consistent with the degree of variation inherent in spectroscopic techniques such as XRPD. Unit cell parameters determined from diffraction data are similarly subject to variation. For example, terms such as "substantially," "approximately," "about," and the like can be understood to refer to variation within the reported significance. By way of example, a value of substantially, approximately, or about 60 encompasses at least 55 to less than 65, and a value of substantially, approximately, or about 60.0 encompasses at least 59.5 to less than 60.5.

[0138] The term "subject" or "patient" includes mammals. In a preferred embodiment, The mammal is a human. In another aspect, the mammal is a non-human primate, such as a chimpanzee, as well as other ape and monkey species. In one aspect, the mammal is a livestock animal, such as a cow, horse, sheep, goat, or pig. In one aspect, the mammal is a domestic animal, such as a rabbit, dog, or cat. In one aspect, the mammal is a laboratory animal, including rodents, such as rats, mice, and guinea pigs.

[0139] The terms "treat," "treating," or "treatment" as used herein include alleviating, attenuating, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting a disease or condition, e.g., preventing the onset of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating symptoms caused by a disease or condition, or arresting the symptoms of a disease or condition prophylactically and / or therapeutically.

[0140] Pharmaceutical Compositions / Formulations According to a further aspect of the present invention there is provided a pharmaceutical composition comprising a salt and / or polymorph of Compound A as defined herein. The pharmaceutical composition may further comprise a pharmaceutically acceptable diluent or carrier.

[0141] The compositions of the present invention may also be in a form suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups, or elixirs), topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g., as a finely divided powder or liquid aerosol), administration by insufflation (e.g., as a finely divided powder), or parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal, or intramuscular administration, or as a suppository for rectal administration). Preferably, the dosage form is a hard or soft capsule.

[0142] The compositions of the present invention can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. For example, compositions intended for oral use can contain, for example, one or more coloring agents, sweeteners, flavoring agents, and / or preservatives. Suitable techniques, carriers, and excipients are described, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference in their entireties.

[0143] An effective amount of Compound A for use in treating a proliferative disorder is an amount sufficient to symptomatically alleviate the symptoms of the infection in a warm-blooded animal, particularly a human, slow the progression of the infection, or reduce the risk of deterioration in a patient with symptoms of the infection.

[0144] The amount of active ingredient that can be combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. Formulations intended for oral administration to humans will generally contain, for example, 0.5 mg to 0.5 g of active agent, e.g., 10 to 150 mg, e.g., 20, 50, or 100 mg of Compound A (by weight of the free base), compounded with an appropriate and convenient amount of excipient, which may vary from about 5 to about 98 weight percent of the total composition.

[0145] The size of a therapeutic or prophylactic dose of Compound A will naturally vary according to well-known principles of medicine depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration. Contemplated pharmaceutical compositions provide a therapeutically effective amount of Compound A that allows for administration, for example, once daily, twice daily, three times daily, etc.

[0146] Therapeutic Uses and Applications The salts and / or polymorphs of Compound A of the present invention are inhibitors of Aurora kinase and FLT3 activity.

[0147] Accordingly, the present invention also provides one or more salts and / or polymorphs of Compound A as defined herein, or pharmaceutical compositions, for use in the treatment of a disease or condition in which Aurora kinase and / or FLT3 activity is implicated.

[0148] The present invention also provides the use of one or more salts and / or polymorphs of Compound A as defined herein in the manufacture of a medicament for use in the treatment of a disease or condition in which Aurora kinase and / or FLT3 activity is implicated.

[0149] The present invention also provides methods for treating diseases or conditions in which Aurora kinase and / or FLT3 activity is implicated, said methods comprising administering to a subject in need of such treatment a therapeutically effective amount of one or more salts and / or polymorphs of Compound A, or pharmaceutical compositions as defined herein.

[0150] The present invention also provides one or more salts and / or polymorphs of Compound A for use in the treatment of a proliferative disease, such as cancer. In certain embodiments, the cancer is a human cancer.

[0151] The present invention also provides the use of one or more salts and / or polymorphs of Compound A in the manufacture of a medicament for use in the treatment of a proliferative disease, such as cancer. In certain embodiments, the cancer is a human cancer.

[0152] The present invention also provides methods of treating a proliferative disorder, such as cancer, comprising administering to a subject in need of such treatment a therapeutically effective amount of one or more salts and / or polymorphs of Compound A, or pharmaceutical compositions as defined herein. In certain embodiments, the cancer is a human cancer.

[0153] The present invention also provides one or more salts and / or polymorphs of Compound A for use in producing an inhibitory effect of Aurora kinase and / or FLT3.

[0154] The invention provides the use of a compound, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for use in producing an Aurora kinase and / or FLT3 inhibitory effect.

[0155] The present invention also provides a method for producing an inhibitory effect of Aurora kinase and / or FLT3 in vitro or in vivo, said method comprising administering an effective amount of one or more salts and / or polymorphs of Compound A.

[0156] The present invention also provides a method of inhibiting cell proliferation in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound defined herein, or a pharmaceutically acceptable salt or solvate thereof.

[0157] Processes and methods related to the claimed invention The present invention also provides processes for preparing crystalline forms of Compound A. Accordingly, the present invention provides processes for preparing Forms 1, 2, 3, 4, 5, 6, 7, and 8, as well as any of these forms, including crystallization thereof from Compound A. In a preferred embodiment, the process comprises lyophilizing Compound A fumarate and, optionally, exposing the lyophilizate to one or more solvents.

[0158] The process may further include crystallizing a form of Compound A using one of the crystallization techniques described herein. For example, the process may include crystallizing a form of Compound A by temperature cycling, anti-solvent addition, crash cooling, evaporation, and / or solvent trituration. In one embodiment, the crystallization technique is temperature cycling. In one embodiment, the crystallization technique is anti-solvent addition. In one embodiment, the crystallization technique is crash cooling. In one embodiment, the crystallization technique is evaporation. In one embodiment, the crystallization technique is solvent trituration.

[0159] Due to their advantageous properties, the claimed salts and / or polymorphs are useful in processes for the manufacture of Compound A and pharmaceutical formulations thereof. Accordingly, the present invention also provides a process for formulating a pharmaceutical composition comprising Compound A, the process comprising one or more salts and / or polymorphs of Compound A described herein. The process may include: a) synthesizing salts and / or polymorphs of Compound A; b) storing salts and / or polymorphs of Compound A, for example, before or after preparation of the final pharmaceutical form or composition; c) analyzing the salts and / or polymorphs of Compound A by one of the techniques described herein, such as, for example, XRPD, NMR, DSC, DTA, TG, and / or DVS; and / or d) formulating the salt and / or polymorph of Compound A into a pharmaceutical composition, optionally wherein the pharmaceutical composition is selected from the group consisting of a tablet, a lozenge, a hard or soft capsule, a solid dispersion, an aqueous or oily suspension, an emulsion, a dispersible powder or granules, a syrup or elixir, a cream, an ointment, a gel, or an aqueous or oily solution or suspension, a liquid aerosol, a sterile aqueous or oily solution, or a suppository.

[0160] The process may include any or all of steps a) through d) above. For example, the process may include steps a) and b); steps a) and c); steps a) and d); steps b) and c); steps b) and d); steps c) and d); steps a), b), and c); steps a), b), and d); steps a), c), and d); steps b), c), and d); or steps a), b), c), and d).

[0161] Formulation can be by any means known in the art, such as tableting, compression, granulation (wet or dry), micronization, capsule filling, dissolving, dispersing, emulsifying spray drying, melt extrusion, and / or lyophilization. The final composition can comprise any form of Compound A described herein, such as Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7, Form 8, or amorphous Compound A.

[0162] The present invention also provides compositions made by these processes. [Example]

[0163] Analysis method X-ray powder diffraction (XRPD). XRPD analysis was performed on a PANalytical X'pert Pro equipped with a PIXcel detector (128 channels), scanning samples from 3 to 35° 2θ. Materials were gently ground to release any aggregates and loaded into multiwell plates with Kapton or Mylar polymer films to support the samples. The multiwell plates were then placed in a diffractometer and analyzed using Cu K radiation (αλ = 1.54060 Å; α = 1.54443 Å; β = 1.39225 Å; α:α ratio = 0.5) operating in transmission mode (step size 0.0130° 2θ, step time 18.87 s) using a 40 kV / 40 mA generator setting). Data were visualized and images were generated using the HighScore Plus 4.7 desktop application (PANalytical, 2017).

[0164] Polarized Light Microscope (PLM) The presence of crystallinity (birefringence) was determined using an Olympus BX53 microscope equipped with cross-polarized lenses and a Motic camera. Images were captured using Motic Images Plus 2.0. Unless otherwise stated, all images were recorded using a 20x objective.

[0165] Thermogravimetric / differential thermal analysis (TG / DTA) Approximately 5 mg of material was weighed into an open aluminum pan and loaded into a simultaneous thermogravimetric / differential thermal analyzer (TG / DTA) and held at room temperature. The sample was then heated from 20 to 300°C at a rate of 10°C / min, during which the change in sample weight was recorded along with the differential thermal event (DTA). Nitrogen was used as the purge gas at a flow rate of 300 cm. 3 / min.

[0166] Thermogravimetric analysis / differential scanning calorimetry (TGA / DSC) Approximately 5–10 mg of material was added to a pre-tared, open aluminum pan and loaded into a TA Instruments Discovery SDT 650 Auto-Simultaneous DSC. The pan was held at room temperature. The sample was then heated at a rate of 10°C / min from 30°C to 300°C, during which the change in sample weight was recorded along with the heat flow response (DSC). Nitrogen was used as the purge gas at a flow rate of 200 cm. 3 / min.

[0167] Differential scanning calorimetry (DSC) Approximately 1-5 mg of material was weighed into an aluminum DSC pan and non-hermetically sealed with an aluminum lid. The sample pan was then placed in a TA Instruments DSC chamber equipped with an RC90 condenser. The samples were loaded into a Discovery DSC 2500 differential scanning calorimeter. The samples and standards were heated to 240°C at a scan rate of 10°C / min and the resulting heat flow response was monitored. The samples were recooled to 20°C and then reheated to 240°C, all at 10°C / min. Nitrogen was used as the purge gas at a flow rate of 50 cm. 3 / min.

[0168] nuclear magnetic resonance (NMR) NMR experiments were performed on a Bruker AVIIIHD spectrometer equipped with a DCH cryoprobe operating at 500.12 MHz for protons. Experiments were performed in deuterated dimethyl sulfoxide, and each sample was prepared to a concentration of approximately 10 mM.

[0169] Dynamic Vapor Sorption (DVS) Approximately 10 mg of sample was placed in a mesh vapor sorption pan and loaded onto a DVS Intrinsic Dynamic Vapor Sorption Balance by Surface Measurement Systems. The samples were subjected to a ramp profile from 40% to 90% relative humidity (RH) in 10% increments (dm / dt 0.004%, minimum step length 30 min, maximum step length 500 min), maintaining the sample at each step until a stable weight was achieved at 25 °C. After the sorption cycle was completed, the sample was dried to 0% RH using the same procedure and then returned to 40% RH for a second sorption cycle. Two cycles were performed. The weight change during the sorption / desorption cycle was plotted, allowing the hygroscopicity of the sample to be measured. XRPD analysis was then performed on the retained solid.

[0170] High-performance liquid chromatography with ultraviolet detection (HPLC-UV) HPLC experiments were performed using the following parameters: [Table 15]

[0171] HPLC was performed with the following gradient program: [Table 16]

[0172] The solution preparation can be varied depending on the working concentration.

[0173] Standard / Sample Preparation: (Duplicate) Weigh 10 mg into a 10 mL volumetric flask. Dissolve substance in 5 mL of diluent and make to volume with diluent. Standards A+B. Working concentration: 1 mg / mL

[0174] Sensitivity Solution: Pipette 50 μL of Standard A into a 100 mL volumetric flask. Make up the volume of the flask and mix. Concentration of the sensitivity solution: 0.0005 mg / mL, which corresponds to 0.05%.

[0175] Calculation: Detailed calculations required for Chromeleon: bracketing standards, calibration curve through origin.

[0176] System compatibility: Accuracy: ≤0~2%RSD. Standard verification 98~102%. Sensitivity solution requirements. mass spectrometry

[0177] Mass spectrometry experiments were performed using the following parameters: [Table 17] [Table 18]

[0178] Both +ve and -ve ESI are used. [Table 19]

[0179] Example 1: Synthesis of Compound A Means for preparing the physical forms of the present invention are described below, however, alternative methods (e.g., alternative synthetic routes or sample preparation methods) can be used to provide materials with the same properties as the present invention.

[0180] The preparation of Compound A is a two-step process starting from the starting materials 5-chloro-4-[4-(4-chlorobenzyl)piperazin-1-yl]-3-nitropyridin-2-amine (CR8B) and 1,3-dimethyl-1H-pyrazole-4-carbaldehyde. A typical batch size of Compound A is approximately 1 kg, but this can be adjusted depending on development and clinical needs. The synthetic route used to produce Compound A is outlined below. [ka]

[0181] Step 1—Crude Compound A Dissolve CR8B and 1,3-dimethyl-1H-pyrazole-4-carbaldehyde in dimethyl sulfoxide and gently heat the mixture to approximately 35°C. Add a slurry of sodium hydrosulfite in water in small portions, allowing the temperature to exotherm (maximum temperature approximately 72°C). After the addition, allow the reaction to stabilize at 80°C ± 5°C and maintain this temperature until the reaction is complete. Cool the reaction to <15°C, then add an aqueous solution of potassium hydroxide dropwise to a pH of 9-10, maintaining the temperature at <20°C. Stir the slurry at this temperature for approximately 15-30 minutes.

[0182] The slurry is filtered and the crude product is washed with water. The crude solid is slurried in water with stirring at about 40°C, then cooled and the solid is isolated by filtration. The solid is slurry washed on the filter with water, followed by 2-propanol / water, then vacuum dried at <60°C.

[0183] Step 2 - Purify Compound A Crude Compound A is slurried in 2-propanol (IPA) under nitrogen. Water is added and the mixture is heated to gentle reflux and stirred at this temperature for approximately 30 minutes. The mixture is then stirred and Cool to 2-8°C. Isolate the product by filtration and dry in vacuo at <60°C.

[0184] Salt preparation Compound A monofumarate Purified compound A (1 equivalent) and excess fumaric acid (1.15 equivalents) are dissolved in warm n-propanol (26 relative volumes). The mixture is heated to reflux and stirred for approximately 60 minutes.

[0185] The solution is clarified by hot filtration and the solution is concentrated by about 25% by vacuum distillation at about 60°C.

[0186] The mixture is again heated to reflux, then cooled to approximately 3°C and the product isolated by filtration. The product is washed with ethyl acetate (2 x 1 vol), sucked dry and dried in vacuo at <50°C.

[0187] Compound A hemifumarate Purified compound A (approximately 25 mg) was dissolved in 100-300 μl of dichloromethane or acetone:water (10%) and mixed with 0.5 equivalents of fumaric acid. The mixture was then subjected to temperature cycling (4-hour cycles from ambient to 40 °C at a cooling / heating rate of 1 °C / min for 3 days), and the solid was isolated and dried. If no solid formed, ethyl acetate can be added to promote precipitation.

[0188] Compound A mesylate Purified compound A (approximately 25 mg) was dissolved in 100-300 μL of dichloromethane, ethyl acetate, 2-propanol, tetrahydrofuran, or acetone:water (10%) and mixed with 1 or 2 equivalents of methanesulfonic acid. The mixture was then subjected to temperature cycling (4-hour cycles from ambient to 40 °C at a cooling / heating rate of 1 °C / min for 3 days), and the solid was isolated and dried. If no solid formed, ethyl acetate can be added to promote precipitation.

[0189] Compound A hydrochloride (monohydrochloride or dihydrochloride) Purified compound A (approximately 25 mg) was dissolved in 100–300 μL of dichloromethane, ethyl acetate, 2-propanol, N-methyl-2-pyrrolidone, tetrahydrofuran, or acetone:water (10%) and mixed with 1 or 2 equivalents of hydrochloric acid. The mixture was then subjected to temperature cycling (4-hour cycles from ambient to 40°C at a cooling / heating rate of 1°C / min for 3 days), and the solid was isolated and dried. If no solid formed, ethyl acetate can be added to promote precipitation.

[0190] Compound A maleate (monomaleate or dimaleate) Purified compound A (approximately 25 mg) was dissolved in 100-300 μl of acetone:water (10%) and mixed with 1 or 2 equivalents of malic acid. The mixture was then subjected to temperature cycling (4-hour cycles from ambient temperature to 40 °C at a cooling / heating rate of 1 °C / min for 3 days), and the solid was isolated and dried. If no solid formed, ethyl acetate can be added to promote precipitation.

[0191] Compound A sulfate (monosulfate or disulfate) Purified compound A (approximately 25 mg) was dissolved in 100–300 μL of ethyl acetate, 2-propanol, N-methyl-2-pyrrolidone, tetrahydrofuran, or acetone:water (10%) and mixed with 1 or 2 equivalents of sulfuric acid. The mixture was then subjected to temperature cycling (4-hour cycles from ambient to 40 °C at a cooling / heating rate of 1 °C / min for 3 days), and the solid was isolated and dried. If no solid formed, ethyl acetate can be added to promote precipitation.

[0192] Compound A L-tartrate Purified compound A (approximately 25 mg) was dissolved in 100-300 μl of tetrahydrofuran and mixed with 1 or 2 equivalents of L-tartaric acid. The mixture was then subjected to temperature cycling (4-hour cycles from ambient temperature to 40 °C at a cooling / heating rate of 1 °C / min for 3 days), and the solid was isolated and dried. If no solid formed, ethyl acetate can be added to promote precipitation.

[0193] Preparation of Crystalline Forms - General Techniques Freeze drying The preparation of physical forms of Compound A uses lyophilized Compound A fumarate as the starting material. Lyophilized Compound A fumarate ("lyophilizate") can be prepared as described below.

[0194] 1.2 g of Compound A monofumarate salt prepared above was weighed into a beaker and dissolved in 84 ml of 1,4-dioxane. Gentle heating was applied until dissolution was observed. The solution was then divided into 24 x 2 ml vials (50 mg / ml per vial), and the solution was frozen and lyophilized using a Lablyo mini freeze dryer. Samples were frozen at -50°C, then held at 19-22°C, and the solvent was removed under a 0.09 mbar vacuum. After lyophilization, an aliquot was analyzed by XRPD and found to be a mixture of Form 2.

[0195] Crystallization Technology Temperature cycling Compound A fumarate lyophilizate slurries are prepared by adding aliquots of solvent to the lyophilizate until a fluid slurry is observed. The solvents and volumes are listed in Table 1 below. The slurry is temperature cycled between ambient temperature (approximately 25°C) and 40°C with stirring in 4-hour cycles over a period of 72 hours. After temperature cycling, the samples are filtered by centrifugation. The isolated solid can be analyzed by XRPD.

[0196] The saturated solution (mother liquor) from the temperature cycling experiment can be used for further experiments. The mother liquor can be filtered through a 0.22 μm syringe filter to remove potential seed material and divided between vials for use in preparing additional crystalline forms.

[0197] Antisolvent addition The selected antisolvent can be added to the mother liquor of Compound A fumarate salt obtained from the temperature cycling experiment. The antisolvent can be added in 100 μL aliquots until precipitation is observed or until 1 mL has been added. To facilitate precipitation, the sample can be capped and stored at 5 °C for 3 days. The resulting solid is analyzed by XRPD. Details of the selected antisolvents and volumes are listed in Table 1.

[0198] Crash Cooling The saturated solution of Compound A fumarate (mother liquor) produced from the temperature cycling experiment was placed in a refrigerator at approximately 4°C. After 24 hours, an observation was made. Samples that showed a clear solution were placed in a freezer at approximately -18°C for 7 days.

[0199] evaporation The saturated solutions of Compound A fumarate salt (mother liquor) produced from the temperature cycling experiments can be transferred to 2 mL vials. These vials are uncapped and allowed to evaporate under ambient conditions. Observations are made after 3 days, and any solids produced are analyzed by XRPD.

[0200] Solvent dropping grinding 10 μL of the saturated solution of Compound A fumarate produced from the temperature cycling experiment can be added to 20 mg of lyophilized material in a bead mill vial. 2 x 2.4 mm aluminum balls are placed in each vial. Milling of Compound A is completed in a Precellys® Evolution SUPER homogenizer using the following procedure: o Speed: 4500RPM; o Cycle time: 30 seconds; o Cycle repetition: 3; o Pause time between each cycle: 10 seconds.

[0201] The solid is analyzed by XRPD. [Table 20-1] [Table 20-2] [Table 20-3]

[0202] Preparation of Form 1 Form 1 was prepared by taking approximately 175 mg of the lyophilized Compound A fumarate salt prepared above and adding 1-butanol, 1-propanol, 2-ethoxyethanol, acetone, or acetonitrile in the amounts listed in the "Temperature Cycle" column of Table 1 above to form a flowable slurry. Temperature cycling was performed using the conditions described above (4 hour cycles between ambient temperature (approximately 25°C) and 40°C, with stirring for 72 hours). Following temperature cycling, the solid crystalline material was filtered by centrifugation and characterized by XRPD as Form 1.

[0203] Form 1 was also prepared from 10 μL of saturated Compound A fumarate solution in 1,1-dimethyloxymethane or DMSO, added to 20 mg of lyophilized Compound A in a bead mill vial, and subjected to the solvent drop-grinding process described above. The solid was isolated and characterized by XRPD as Form 1.

[0204] Form 1 was also prepared by dissolving purified Compound A (1 equivalent) and excess fumaric acid (1.15 equivalents) in warm n-propanol (26 relative volumes), heating the mixture to reflux, and stirring for approximately 60 minutes. The solution is clarified by hot filtration, and the solution is concentrated by approximately 25% by vacuum distillation at approximately 60°C. The mixture is again heated to reflux, then cooled to approximately 3°C, and the product is isolated by filtration. The product is washed with ethyl acetate (2 x 1 volume), sucked dry, and vacuum dried at <50°C. The solid was isolated and characterized by XRPD as Form 1.

[0205] [Table 21]

[0206] Preparation of Form 2 Form 2 was prepared by dissolving approximately 330 mg of Compound A monofumarate salt, as prepared above, in 33 mL of 1,4-dioxane in a 20 mL glass vial. Gentle heating was applied until dissolution was observed. The solution was then divided equally into 33 x 1.5 mL vials (approximately 10 mg per vial), and the solution was frozen and lyophilized using a Lablyo mini freeze dryer. The solid material was analyzed by XPRD and found to be Form 2.

[0207] Form 2 was also prepared by taking approximately 175 mg of the lyophilized Compound A fumarate salt prepared above and adding 400 μL of 1,4-dioxane to form a flowable slurry. Temperature cycling was performed using the conditions described above (4-hour cycles between ambient temperature and 40°C, with stirring for 72 hours). After temperature cycling, the material was dried at 40°C under ambient pressure and characterized by XRPD as Form 2 (Figure 10).

[0208] [Table 22]

[0209] Preparation of Form 3 Form 3 was prepared by taking approximately 175 mg of the lyophilized Compound A fumarate salt prepared above and adding the amounts of dimethoxymethane; 2-MeTHF; water:MeOH (0:100, 40:60, 80:20, 95:5, 100:0); or IPA listed in Table 1 above to form a fluid slurry. Using the conditions described above, temperature cycling was performed (4-hour cycles between ambient temperature and 40°C, with stirring for 72 hours). Following temperature cycling, the solid crystalline material was filtered by centrifugation and characterized by XRPD as Form 3.

[0210] Form 3 was also prepared by placing 10 mg of the lyophilized Compound A fumarate salt prepared above in a glass vial and adding 100 μL aliquots of water:MeOH (0:100, 40:60, 80:20, 95:5, 100:0); EtOAc; MEK; acetone; or acetonitrile, heating and stirring at 40° C. until dissolved or until a 2 mL volume was added. The vials were uncapped and allowed to evaporate under ambient conditions. The solid was isolated and characterized by XRPD as Form 3.

[0211] Form 3 was also prepared by taking 1600 μL of a saturated solution of Compound A fumarate, filtering it through a 0.22 μL syringe filter, and adding 1000 μL of TMBE antisolvent in 100 μL aliquots, followed by storage at 5° C. for 3 days. was isolated and characterized by XRPD as Form 3.

[0212] [Table 23]

[0213] Preparation of Form 4 Form 4 was prepared by taking approximately 175 mg of the lyophilized Compound A fumarate salt prepared above and adding 400 μL of 1,4-dioxane to form a fluid slurry. Temperature cycling was performed using the conditions described above (4 hour cycles between ambient temperature and 40°C, with stirring for 72 hours). Following temperature cycling, the solid crystalline material was filtered by centrifugation and characterized by XRPD as Form 4.

[0214] [Table 24]

[0215] Preparation of Form 5 Form 5 was prepared by taking approximately 175 mg of the lyophilized Compound A fumarate salt prepared above and adding 800 μL of benzyl alcohol to form a fluid slurry. Temperature cycling was performed using the conditions described above (4 hour cycles between ambient temperature and 40°C, with stirring for 72 hours). Following temperature cycling, the solid crystalline material was filtered by centrifugation and characterized by XRPD as Form 5.

[0216] [Table 25]

[0217] Preparation of Form 6 Form 6 was prepared by taking approximately 175 mg of the lyophilized Compound A fumarate salt prepared above and adding 700 μL of DMSO to form a fluid slurry. Temperature cycling was performed using the conditions described above (4 hour cycles between ambient temperature and 40° C., with stirring for 72 hours). Following temperature cycling, the solid crystalline material was filtered by centrifugation and characterized by XRPD as Form 6.

[0218] [Table 26]

[0219] Preparation of Form 7 Form 7 was prepared by taking approximately 175 mg of the lyophilized Compound A fumarate salt prepared above and adding 4000 μL of methanol to form a fluid slurry. Temperature cycling was performed using the conditions described above (4 hour cycles between ambient temperature and 40°C, with stirring for 72 hours). Following temperature cycling, the solid crystalline material was filtered by centrifugation and characterized by XRPD as Form 7.

[0220] Form 7 was also prepared by taking approximately 400 mg of Form 6 material and slurrying it in 0.5 ml of TBME at ambient temperature for 24 hours. The solid was then isolated by centrifugation and dried under ambient conditions. TG / DTA analysis revealed a lower DMSO content than Form 6, so the sample was reslurried in 2 ml of TBME at ambient temperature for 72 hours. The solid isolated by centrifugation was characterized by XRPD as Form 7.

[0221] [Table 27]

[0222] Preparation of Form 8 Form 8 was also prepared from 10 μL of saturated Compound A fumarate solution in benzyl alcohol, which was added to 20 mg of lyophilized Compound A in a bead mill vial, which was subjected to the solvent drop-grinding process described above. Because the sample showed a large amount of benzyl alcohol by DT analysis, the sample was slurried with TBME. The solid was isolated and characterized by XRPD as Form 8.

[0223] [Table 28]

[0224] Example 4: Evaluation of Compound A Salts The monomesylate, dimesylate, monohydrochloride, dihydrochloride, and fumarate salts of Compound A were evaluated for suitability for the following properties identified by the inventors as relevant to pharmaceutical suitability: [Table 29]

[0225] Aqueous solubility was determined by weighing approximately 3 mg of the salt form into a clean HPLC vial, adding HPLC-grade water, and mixing by shaking, vortexing, and / or sonication, as needed, to facilitate dissolution. Upon complete dissolution (clear solution), the solubility was calculated based on the amount of water added. HPLC purity and DVS can be determined using methods described herein or known in the art. Processability is based on the solubility of the salt form in a particular excipient. Automated elemental analysis can be performed on 10 mg of Compound A salt using caffeine as a reference substance. The stoichiometry of the salt relative to CHNX and Compound A is determined. Dissolution was determined by compressing 5-10 mg of Compound A salt into tablet discs over four pH values ​​(2.0, 3.8, 5.3, and 7.2) using a Sirius T3 module, SOPs 2070 and 2071.

[0226] The results are shown in Figure 39. It can be seen that the fumarate salt has the best overall balance of properties, especially its unexpectedly low hygroscopicity, which is comparable to that of the free base.

[0227] Example 5: Stability of Form 1 The stability of Form 1 was tested for compliance with the following stability acceptance criteria. [Table 30]

[0228] Form 1 was prepared as described above in Example X. The following amounts of Form 1 were weighed into 30 ml HDPE Nalgene containers: [Table 31]

[0229] Each container was placed in a small grip seal bag and incubated under the conditions described above.

[0230] Visual appearance and purity by HPLC were assessed periodically (0, 1, 3, 6, 9, 12, and 24 months). Water content was assessed by Karl Fischer titration and TGA at 0, 1, 6, and 12 months. XRPD spectra were acquired at 0, 1, 3, and 6 months.

[0231] As shown in Figure 40, the impurity levels were very low (≤0.6%) and did not increase over time. There was negligible change in mass, and the water content was below the limit of quantitation after 12 months. No change in XRPD was observed at any time, as shown in Figure 9. Collectively, these observations support the utility of Form 1 in the production and development of Compound A.

[0232] Example 6: One-week stability study of Form 3 The stability of Compound A fumarate Form 3 was evaluated under ambient and stress conditions. The following procedure was performed: Approximately 20 mg of material was added to 3 x 1.5 mL glass vials. The vials were then stored under the following conditions: Ambient light and temperature (sealed vials) o 40℃ / 75%RH (with vial open) o 80℃ (sealed vial)

[0233] After one week, samples were collected and analyzed by XRPD and HPLC.

[0234] The following observations and results were made during a one-week stability study of Compound A fumarate Form 3: No visual changes were observed in the samples after one week. All samples appeared as pale yellow, free-flowing solids. Compound A fumarate Form 3 was observed in all samples by XRPD. No change in purity was observed in the samples. [Table 32]

[0235] Example 7: Thermodynamic solubility evaluation The thermodynamic solubilities of Compound A free base, Compound A fumarate Form 1, and Compound A hemifumarate Form 3 were evaluated in three biological media: fasted-state simulated intestinal fluid (FaSSIF); fed-state simulated intestinal fluid (FeSSIF), and fasted-state simulated gastric fluid (FaSSGF).

[0236] The following procedure was carried out: Approximately 10 mg of material was weighed into 3 x 1.5 mL glass vials. A 0.02 mL aliquot of the appropriate buffer was added to each vial until a final concentration of 10 mg / mL was achieved. The samples were then filtered by centrifugation and the mother liquor was analyzed by HPLC.

[0237] The following observations and results were obtained during the thermodynamic solubility evaluation: Compound A fumarate Form 1 was found to be insoluble in FaSSIF. A low solubility of 0.3 mg / mL was observed in FeSSIF. A high solubility of 3.4 mg / mL was observed in FaSSGF. Compound A fumarate Form 3 was found to have low solubility (<0.1 mg / mL) in FaSSIF and FeSSIF. A high solubility of 2.0 mg / mL was observed in FaSSGF. Compound A free base was found to have low solubility (<0.1 mg / mL) in FaSSIF and FeSSIF. A high solubility of 1.5 mg / mL was observed in FaSSGF. [Table 33]

Claims

1. Fumarate salt of Compound A: 【Chemistry 1】 。

2. 2. The fumarate salt of claim 1, wherein the molar ratio of compound A to fumarate is 1:

1.

3. 2. The fumarate salt of claim 1, wherein the molar ratio of compound A to fumarate is 2:

1.

4. 10. The fumarate salt according to any of the preceding claims, wherein the salt is crystalline.

5. Crystalline Form 1 of Compound A fumarate, 【Chemistry 2】 Crystalline Form 1 of Compound A fumarate salt, characterized by one or more of the following properties: a) an XRPD pattern having at least the following XRPD peaks (CuK°2θ) at about (±0.1): 12.9, 20.5, 21.2, 22.9, and 23.4; b) an XRPD pattern substantially the same as that shown in Figure 1; c) at 298K substantially the following unit cell parameters: Table 1 d) DTA-TGA thermogram with a major endotherm with an onset temperature of approximately (±0.5) 238°C; e) A DTA-TGA thermogram substantially the same as that shown in Figure 11; f) 1:1 molar ratio of fumarate to Compound A; g) unsolvated crystalline structure; and / or h) Can be obtained from 1-butanol, 1-propanol, 2-ethoxyethanol, acetone, acetonitrile, MEK, THF, 1,1-dimethoxymethane, or DMSO.

6. 6. The crystalline form of claim 5, wherein Form 1 is characterized by at least one of a), b), and c).

7. Crystalline Form 2 of Compound A fumarate, 【Transformation 3】 Crystalline Form 2 of Compound A fumarate salt, characterized by one or more of the following properties: a) an XRPD pattern having at least the following XRPD peaks (CuK 2θ) at about (±0.1): 15.4, 15.8, 16.3, and 24.5; b) An XRPD pattern substantially the same as that shown in Figure 2; c) at 298K substantially the following unit cell parameters: Table 2 d) DTA-TGA thermogram with a major endotherm with an onset temperature of approximately (±0.5) 231°C; e) A DTA-TGA thermogram substantially the same as that shown in Figure 12; f) 1:1 molar ratio of fumarate to Compound A; g) unsolvated crystalline structure; and / or h) Can be obtained from 1,4-dioxane.

8. 8. The crystalline form of claim 7, characterized by at least one of a), b), and c).

9. Crystalline Form 3 of Compound A fumarate, 【Chemistry 4】 Crystalline Form 3 of Compound A fumarate salt, characterized by one or more of the following properties: a) an XRPD pattern having at least the following XRPD peaks (CuK 2θ) at about (±0.1): 8.8, 17.4, 17.7, and 18.2; b) An XRPD pattern substantially the same as that shown in Figure 3; c) at 298K substantially the following unit cell parameters: Table 3 d) DTA-TGA thermogram with a major endotherm with an onset temperature of approximately (±0.5) 184°C; e) A DTA-TGA thermogram substantially the same as that shown in Figure 13; f) a molar ratio of fumarate to Compound A of 1:2; g) a monohydrate crystal structure; and / or h) Can be obtained from dimethoxymethane, 2-MeTHF, water:methanol (0:100, 40:60, 80:20, 95:5, 100:0), EtOAc, IPA, MEK, MIBK, THF, acetone, acetonitrile.

10. 10. The crystalline form of claim 9, characterized by at least one of a), b), and c).

11. Crystalline Form 4 of Compound A fumarate, 【Transformation 5】 A crystalline form of Compound A fumarate characterized by one or more of the following properties: ４： a) an XRPD pattern having at least the following XRPD peaks (CuK 2θ) at about (±0.1): 16.3, 18.7, 22.8, 23.1, 25.7; b) An XRPD pattern substantially the same as that shown in Figure 4; c) DTA-TGA thermogram with a major endotherm with an onset temperature of approximately (±0.5) 142°C; d) A DTA-TGA thermogram substantially the same as that shown in Figure 14; e) a 1:1 molar ratio of fumarate to Compound A (Form 4 is the stoichiometric fumarate); and / or f) 1,4-dioxane solvated crystal structure.

12. 12. The crystalline form of claim 11, characterized by at least one of a) and b).

13. Crystalline Form 5 of Compound A fumarate, 【Transformation 6】 Crystalline Form 5 of Compound A fumarate salt, characterized by one or more of the following properties: a) an XRPD pattern having at least the following XRPD peaks (CuK 2θ) at about (±0.1): 21.5, 24.5, and 27.3; b) An XRPD pattern substantially the same as that shown in Figure 5; c) at 298K substantially the following unit cell parameters: Table 4 d) a DTA thermogram containing a major endotherm with an onset temperature of about (±0.5) 229°C; e) a DTA thermogram substantially the same as that shown in Figure 15; f) a molar ratio of fumarate to Compound A of 1:2; g) benzyl alcohol solvate crystal structure; and / or h) Can be obtained from benzyl alcohol.

14. 14. The crystalline form of claim 13, characterized by at least one of a), b), and c).

15. Crystalline Form 8 of Compound A fumarate, 【Transformation 7】 Crystalline Form 8 of Compound A fumarate salt, characterized by one or more of the following properties: a) an XRPD pattern having at least the following XRPD peaks (CuK 2θ) at about (±0.1): 10.4, 10.7, 11.1, 24.2, and 24.5; b) An XRPD pattern substantially the same as that shown in Figure 8; c) at 298K substantially the following unit cell parameters: Table 5 d) a DTA thermogram containing a major endotherm with an onset temperature of about (±0.5) 232°C; e) a DTA thermogram substantially the same as that shown in Figure 17; f) benzyl alcohol solvate crystal structure; g) a 1:1 molar ratio of fumarate to Compound A (Form 8 is the stoichiometric fumarate); and / or h) Can be obtained from benzyl alcohol.

16. 16. The crystalline form of claim 15, characterized by at least one of a), b), and c).

17. A process for preparing crystalline Compound A fumarate, comprising: lyophilizing Compound A fumarate; and crystallizing the resulting lyophilized product, for example, by temperature cycling, antisolvent addition, crash cooling, evaporation, and / or solvent trituration.

18. 18. A crystalline form of Compound A fumarate salt preparable according to the process of claim 17.

19. A process for preparing a pharmaceutical composition comprising Compound A fumarate salt according to any one of claims 1 to 16 and 18.

20. 20. The process of claim 19, comprising: a) synthesizing a compound A fumarate salt according to any one of claims 1 to 16 and 18; b) storing Compound A fumarate according to any one of claims 1 to 16 and 18, for example before or after preparation of the final pharmaceutical form or composition; c) for example, by XRPD, NMR, DSC, DTA, TG, and / or DVS; Analysing the compound A fumarate salt according to any one of claims 1 to 16 and 18; and / or d 20.) Formulating Compound A fumarate according to any one of claims 1 to 16 and 18 into a pharmaceutical composition, for example by tabletting, compression, granulation (wet or dry), micronization, capsule filling, dissolving, dispersing, emulsifying spray drying, melt extrusion, and / or lyophilization.

21. 21. A pharmaceutical composition prepareable according to the process of claim 19 or 20.

22. A pharmaceutical composition comprising compound A according to any one of claims 1 to 16 and 18.

23. Compound A fumarate salt according to any one of claims 1 to 16 and 18, or a pharmaceutical composition according to claim 21 or 22, for use in therapy.

24. Compound A fumarate salt according to any one of claims 1 to 16 and 18, or a pharmaceutical composition according to claim 21 or 22, for use in the treatment of a disease or condition associated with Aurora kinase activity and / or FLT3 activity.

25. 21. A method of treating a proliferative disorder in a human or animal subject, said method comprising administering to said subject a therapeutically acceptable amount of compound A fumarate according to any one of claims 1 to 16 and 18, or the pharmaceutical composition according to claim 21 or 22, wherein, for example, said proliferative disorder is cancer, such as acute myeloid leukemia (AML).

26. Use of compound A fumarate salt according to any one of claims 1 to 16 and 18 in the manufacture of a medicament comprising the pharmaceutical composition according to claim 21 or 22.

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