Crystalline form of quinazoline derivative, preparation, composition and use thereof

Abstract

To provide a polymorphic form of a quinazoline compound exhibiting type I receptor tyrosine kinase inhibitory activity.SOLUTION: Provided is a crystalline form of Compound (I) represented by the following structural formula: wherein the crystalline form is a complex of the free base and a pharmaceutically acceptable acid, or the free base.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to International Patent Application No. PCT / CN2021 / 125016, filed October 20, 2021, the contents of which are incorporated herein by reference in their entirety.

[0002] FIELD OF THE INVENTION This application relates to crystalline forms of (R)—N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine, processes for their preparation, pharmaceutical compositions containing one or more crystalline forms as active ingredients, and uses of the crystalline forms in the treatment of hyperproliferative diseases. [Background technology]

[0003] Background of the Invention The type I tyrosine kinase receptor family consists of four structurally related receptors: EGFR (ErbB1 or HER1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4) (reviewed in Riese and Stern, Bioessays, 1998, 20:41-48; Olayioye et al., EMBO Journal, 2000, 19:3159-3167; and Schlessinger, Cell, 2002, 110:669-672). All four family members have nearly identical structures, consisting of an extracellular region or ectodomain or ligand-binding region, a single transmembrane region, and an intracellular cytoplasmic tyrosine kinase domain.

[0004] It has been demonstrated that ErbB2 plays a role in cancer development. ErbB2 overexpression occurs in 20-25% of breast cancer (BC) patients (Leyland-Jones B, J Clin Oncol., 2009, 5278-86). Approximately 1,700,000 new cases of BC are diagnosed each year (Cardoso F, et al., Breast, 2018, 131-138), and 80% of BC are invasive, requiring chemotherapy, radiation, or targeted therapy in addition to surgery (Dai X., et al., Am J Cancer Res., 2015, 2929-2943). Brain metastases frequently occur in patients with metastatic breast cancer. The overall survival of patients with breast cancer brain metastases (BCBM) ranges from 2 to 25.3 months (Leone JP Exp. Hematol. Oncol., 2015, 4, 33). Surgery, whole-brain radiation therapy (WBRT), and stereotactic radiosurgery (SRS) are the three main treatment options for BCBM. Surgery is used for solitary metastases or up to three brain metastases. SRS may be used for patients with four or fewer intracranial lesions. WBRT is used to manage multiple brain metastases but can result in significant neurocognitive decline (Venur VA et al., Int. J. Mol. Sci., 2016, 1543).

[0005] Compared with other types of breast cancer, ErbB2-positive tumors have a higher incidence of brain metastases, with up to 50% of patients with ErbB2-positive breast cancer developing intracranial metastases (Leyland-Jones B, J Clin Oncol., 2009, 5278-86). The high prevalence of BCBM in ErbB2-positive patients is thought to be due to the inherent tropism of ErbB2-positive breast cancer cells to the brain, the prolonged survival of patients treated with anti-ErbB2 therapy, and the limited intracranial activity of anti-ErbB2 therapy (Venur V.A. et al., Int. J. Mol. Sci., 2016, 17, 1543).

[0006] Several anti-ErbB2 agents have been developed for clinical use, including monoclonal antibodies such as trastuzumab, antibody-drug conjugates (ADCs) such as T-DM1, and tyrosine kinase inhibitors (TKIs) such as lapatinib, neratinib, afatinib, and tucatinib (Kabraji S. et al., Clinical Cancer Research, 2018, 3351; Askoxylakis V. et al., JNCI J Natl Cancer Inst, 2015, 763-763; Tanaka Y. et al., Scientific Reports, 2018, 343; Zhang, Shilong, et al., Acta Pharmacologica Sinica, 2017, 233-240; Dinkel V. et al., Cancer Research, 2012, 72). However, none of these antibodies, ADCs, or TKIs are considered to be central nervous system (CNS) permeable. Limited clinical efficacy has been observed when treating patients with BCBM with the non-brain-penetrating aforementioned antibodies, ADCs, and TKIs.

[0007] WO 2020 / 057511, the entirety of which is incorporated herein by reference, discloses quinazoline compounds that inhibit type I receptor tyrosine kinase, exhibit good brain penetrance in animals, and have a favorable toxicity profile (e.g., reduced activity against hERG), and are therefore particularly useful for the treatment of type I receptor tyrosine kinase-mediated diseases or conditions, particularly ErbB2-related diseases or conditions, including cancer (e.g., metastatic cancer, such as brain metastasis). A particular compound (also referred to herein as Compound (I)) identified as (R)—N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine TIFF2026027273000001.tif33170 is considered an efficient blood-brain barrier (BBB)-permeable ErbB2 (HER2) inhibitor that exhibits high selectivity over wild-type EGFR to minimize EGFR-mediated diarrhea and skin rash, and is therefore useful for treating ErbB2-positive BC patients with or without brain metastases (see Example 31 and biochemical assays in WO 2020 / 057511).

[0008] Polymorphism is the existence of different crystalline forms of a single compound and is a characteristic of some compounds and complexes. Thus, polymorphs are distinct solids that share the same molecular formula, but each polymorph may have distinct solid-state physical properties. A single compound can therefore produce various polymorphs, each with distinct solid-state physical properties such as a different solubility profile, melting point temperature, flowability, dissolution rate, and / or different X-ray diffraction peaks. These actual physical properties are influenced by the conformation and orientation of molecules within the unit cell that defines a particular polymorph of a substance. Due to the potential for variable solubility of each polymorph, identifying the existence of pharmaceutical polymorphs is essential to providing pharmaceuticals with predictable solubility profiles. It is desirable to investigate all solid forms of a drug, including all polymorphic forms, and determine the stability, dissolution, and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in the laboratory by X-ray diffraction spectroscopy, such as X-ray powder diffraction (XRPD), and other methods, such as infrared spectroscopy. Furthermore, polymorphic forms of the same drug substance or active pharmaceutical ingredient, which may be administered alone or formulated as a pharmaceutical composition, are well known in the pharmaceutical arts to affect, for example, the solubility, stability, flowability, handling, and compressibility of the drug substance, as well as the safety and efficacy of the formulation. For further details, see Hilfiker, Rolf (ed.), Polymorphism in the Pharmaceutical Industry, Weinheim, Germany: Wiley-VCH 2006.

[0009] The discovery of new polymorphs of pharmaceutically useful compounds provides new opportunities for improving the performance characteristics of pharmaceutical products. Therefore, there is a continuing need to investigate the polymorphic forms of the quinazoline compounds that exhibit type I receptor tyrosine kinase inhibitory activity. It has now been discovered that new polymorphs of compound (I) exist. Summary of the Invention

[0010] In one aspect, the present invention relates to a complex of the free base with a pharmaceutically acceptable acid, or a crystalline form of the free base (R)—N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine (Compound (I)). TIFF2026027273000002.tif35170

[0011] In some embodiments, the complex of the free base and a pharmaceutically acceptable acid, or the free base form, is a solvate or a non-solvate. In some embodiments, the complex of the free base and a pharmaceutically acceptable acid is a salt, or a co-crystal, or a co-crystal of a salt. In some embodiments, disclosed herein are crystalline forms of Compound (I) designated Fumarate Type A, Fumarate Type B, Fumarate Type C, Fumarate Type E, Free Base Type A, Free Base Type B, Free Base Type C, Free Base Type D, Free Base Type E, Free Base Type F, Free Base Type G, HCl Salt Type A, HCl Salt Type B, Mesylate Type A, Mesylate Type B, Phosphate Type A, L-Tartrate Type A, and Adipic Acid Type A.

[0012] In another aspect, the present invention relates to amorphous forms of Compound (I), which are pharmaceutically acceptable salts or free bases. In some embodiments, amorphous forms of Compound (I), designated as the amorphous fumarate salt and the amorphous free base, are disclosed herein.

[0013] In another aspect, the present invention relates to a method for preparing a crystalline form of Compound (I).

[0014] Also disclosed herein are methods for the preparation of amorphous forms of Compound (I).

[0015] In another aspect, the present invention relates to a pharmaceutical composition comprising a crystalline or amorphous form of Compound (I) and a pharmaceutically acceptable carrier or excipient.

[0016] In another aspect, the invention relates to a dosage form comprising a therapeutically effective amount of the crystalline form, amorphous form, or pharmaceutical composition described herein.

[0017] In another aspect, the present invention relates to a method of treating or ameliorating a hyperproliferative disease in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline or amorphous form of Compound (I).

[0018] In another aspect, the present invention relates to a crystalline or amorphous form of Compound (I) for use in the treatment or amelioration of a hyperproliferative disorder.

[0019] In another aspect, the present invention relates to the use of a crystalline or amorphous form of Compound (I) in the manufacture of a medicament for treating or ameliorating a hyperproliferative disease. [Brief explanation of the drawings]

[0020] The summary and the following detailed description will be better understood when read in conjunction with the accompanying drawings. For the purpose of illustrating the invention, there are shown in the drawings exemplary embodiments of the invention. However, the invention is not limited to the specific disclosure of the drawings. In the drawings, [Figure 1] FIG. 1 is a representative XRPD pattern of Fumarate Type A. [Figure 2] FIG. 2 is a representative TGA curve of fumarate type A. [Figure 3]FIG. 3 is a representative DSC curve of Fumarate Type A. [Figure 4] FIG. 4 is a representative 1H NMR spectrum of fumarate salt Type A. [Figure 5] Figure 5 shows a representative PLM image of fumarate type A. [Figure 6] FIG. 6 is a representative XRPD pattern of fumarate salt Type B. [Figure 7] FIG. 7 is a representative TGA curve of fumarate type B. [Figure 8] FIG. 8 is a representative DSC curve of fumarate type B. [Figure 9] FIG. 9 is a representative 1H NMR spectrum of fumarate type B. [Figure 10] FIG. 10 is a representative XRPD pattern of fumarate salt Type C. [Figure 11] FIG. 11 is a representative XRPD pattern of fumarate salt Type E. [Figure 12] FIG. 12 is a representative TGA curve of fumarate salt Type E. [Figure 13] FIG. 13 is a representative DSC curve for fumarate type E. [Figure 14] FIG. 14 is a representative XRPD pattern of free base Type B. [Figure 15] FIG. 15 is a representative TGA curve of free base Type B. [Figure 16] FIG. 16 is a representative DSC curve of free base Type B. [Figure 17] FIG. 17 is a representative 1H NMR spectrum of free base Type B. [Figure 18] FIG. 18 is a representative PLM image of free base Type B. [Figure 19] FIG. 19 is a representative XRPD pattern of free base Type C. [Figure 20] FIG. 20 is a representative TGA curve of free base Type C. [Figure 21]FIG. 21 is a representative DSC curve of free base Type C. [Figure 22] FIG. 22 is a representative 1H NMR spectrum of free base Type C. [Figure 23] FIG. 23 is a representative XRPD pattern of free base Type D. [Figure 24] FIG. 24 is a representative XRPD pattern of free base Type E. [Figure 25] FIG. 25 is a representative XRPD pattern of free base Type F. [Figure 26] FIG. 26 is a representative TGA curve of free base Type F. [Figure 27] FIG. 27 is a representative DSC curve of free base Type F. [Figure 28] FIG. 28 is a representative XRPD pattern of free base Type G. [Figure 29] FIG. 29 is a representative TGA curve of free base Type G. [Figure 30] FIG. 30 is a representative DSC curve of free base Type G. [Figure 31] FIG. 31 is a representative XRPD pattern of free base Type A. [Figure 32] FIG. 32 is a representative TGA curve of free base Type A. [Figure 33] Figure 33 is a representative DSC curve of free base Type A [Figure 34] FIG. 34 is a representative 1H NMR spectrum of free base Type A. [Figure 35] FIG. 35 is a representative XRPD pattern of HCl salt Type A. [Figure 36] FIG. 36 is a representative TGA curve of HCl salt Type A. [Figure 37] FIG. 37 is a representative DSC curve of HCl salt Type A. [Figure 38] FIG. 38 is a representative XRPD pattern of HCl salt Type B. [Figure 39]FIG. 39 is a representative TGA curve of HCl salt Type B. [Figure 40] FIG. 40 is a representative DSC curve of HCl salt Type B. [Figure 41] FIG. 41 is a representative XRPD pattern of mesylate Type A. [Figure 42] FIG. 42 is a representative TGA curve of mesylate Type A. [Figure 43] FIG. 43 is a representative DSC curve of mesylate Type A. [Figure 44] FIG. 44 is a representative XRPD pattern of mesylate Type B. [Figure 45] Figure 45 is a representative TGA curve of mesylate type B. [Figure 46] FIG. 46 is a representative DSC curve of mesylate type B. [Figure 47] FIG. 47 is a representative XRPD pattern of Phosphate Type A. [Figure 48] FIG. 48 is a representative TGA curve of Phosphate Type A. [Figure 49] FIG. 49 is a representative DSC curve for Phosphate Type A. [Figure 50] FIG. 50 is a representative XRPD pattern of L-tartrate salt Type A. [Figure 51] Figure 51 is a representative TGA curve of L-tartrate salt Type A. [Figure 52] Figure 52 is a representative DSC curve of L-tartrate salt Type A. [Figure 53] FIG. 53 is a representative XRPD pattern of adipate Type A. [Figure 54] Figure 54 is a representative TGA curve of adipate type A. [Figure 55] Figure 55 is a representative DSC curve of adipate type A. [Figure 56] Figure 56 is a representative XRPD pattern of the amorphous fumarate salt. [Figure 57]Figure 57 is a representative TGA curve for the amorphous fumarate salt. [Figure 58] Figure 58 is a representative mDSC curve of the amorphous fumarate salt. [Figure 59] Figure 59 is a representative XRPD pattern of the amorphous free base. [Figure 60] Figure 60 is a representative TGA curve of the amorphous free base. [Figure 61] Figure 61 is a representative mDSC curve of the amorphous free base. DETAILED DESCRIPTION OF THE INVENTION

[0021] Detailed Description of the Invention Reference will now be made in detail to certain embodiments, examples of which are set forth in the accompanying detailed description. While enumerated embodiments are described, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the present invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present invention as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described. In the event that one or more of the incorporated literature and similar materials differs or contradicts with this application, including, but not limited to, defined terms, term usage, described techniques, etc., this application controls.

[0022] It will be appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0023] definition Terms used in this specification have their ordinary meaning, and the meaning of such terms is independent at each occurrence. Nevertheless, unless otherwise stated, the following definitions apply throughout the specification and claims.

[0024] As used herein, the terms "comprise," "comprising," "include," and "including" are intended to specify the presence of stated features, integers, components, or steps, but do not exclude the presence or addition of one or more other features, integers, components, steps, or groups thereof.

[0025] As used herein, the term "about" means approximately, in the region of, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies that range by expanding the upper and lower limits of the stated numerical values. Generally, the term "about" is used herein to modify numerical values ​​above and below a given value by a variance of 20%, typically 10%, more typically 5%, even more typically 1%, and even more typically 0.1%. Sometimes, such ranges may be within the range of experimental error, the type of standard method used to measure and / or determine the given value or range. When the term "about" is used in reference to temperatures from a differential scanning calorimetry (DSC) curve (e.g., the onset of an endothermic transition, melting, etc.), each temperature value is understood to mean ±5°C, more typically ±2°C, of ​​the given value, unless otherwise specified.

[0026] As used herein, the term "substantially the same" with respect to X-ray powder diffraction means that variations in reflection positions and relative intensities of reflections are taken into account. For example, typical accuracy of two-theta (2θ) values ​​is within ±0.2° of a given value in 2θ, more typically within ±0.1° in 2θ. Thus, for example, under standard conditions, in most X-ray diffractometers, a reflection that typically appears at 6.9° in 2θ may appear between 6.7° and 7.1° in 2θ, more typically between 6.8° and 7.0° in 2θ. Furthermore, those skilled in the art will understand that relative reflection intensities exhibit instrument-to-instrument variability as well as variability due to crystallinity, preferred orientation, sample preparation, and other factors known to those skilled in the art, and should be interpreted only as a qualitative measure.

[0027] As used herein, when a polymorph is identified using one or more temperatures from a differential scanning calorimetry thermogram (DSC) curve (e.g., onset of an endothermic transition, melting, etc.), each of the temperature values ​​is understood to mean ±5°C, more typically ±2°C, of ​​the given value unless otherwise indicated.

[0028] Crystalline and amorphous forms In one aspect, provided herein are crystalline forms of Compound (I), particularly those designated Fumarate Type A, Fumarate Type B, Fumarate Type C, Fumarate Type E, Free Base Type A, Free Base Type B, Free Base Type C, Free Base Type D, Free Base Type E, Free Base Type F, Free Base Type G, HCl Salt Type A, HCl Salt Type B, Mesylate Type A, Mesylate Type B, Phosphate Type A, L-Tartrate Type A, and Adipate Type A. Also provided herein are amorphous forms of Compound (I), particularly those designated amorphous fumarate and amorphous free base. Methods for preparing the crystalline or amorphous forms, and pharmaceutical compositions comprising the crystalline or amorphous forms, are also provided.

[0029] The crystalline form of Compound (I) can be a complex of a free base and a pharmaceutically acceptable acid, or the free base. Such complexes include, but are not limited to, salts, cocrystals, or salt cocrystals. The amorphous form of Compound (I) can be a pharmaceutically acceptable salt or the free base.

[0030] As used herein, the term "crystalline form" refers to a crystalline structure in which a compound (or a salt or solvate thereof) can crystallize in various crystal packing arrangements, all of which have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density hardness, crystal shape, optical and electrical properties, stability, and solubility. Depending on the recrystallization solvent, crystallization rate, storage temperature, and other factors, one crystalline form may predominate. Crystalline polymorphs of a compound may be prepared by crystallization under different conditions.

[0031] As used herein, the term "polymorphic form" or "polymorphism" in the context of this specification refers to crystalline and amorphous forms as well as solvates and hydrate forms. Crystalline forms have various arrangements and / or conformations of molecules in a crystal lattice. Amorphous forms consist of irregular arrangements of molecules without a distinguishable crystal lattice. Solvates are crystalline forms that contain stoichiometric or non-stoichiometric amounts of solvent. When a drug substance exists in multiple forms, it is said to exhibit polymorphism.

[0032] As used herein, the term "complex" refers to a crystalline substance composed of two or more different molecules, one of which is an active pharmaceutical ingredient (API), in the same crystal lattice bound by ionic / non-ionic and ionic / non-covalent bonds. In the context of this specification, API may refer to Compound (I).

[0033] As used herein, the term "cocrystal" refers to a crystalline material composed of two or more different molecules (one of which is an API) within the same crystal lattice bound by non-ionic and non-covalent bonds.

[0034] As used herein, the term "salt" refers to any of a number of compounds resulting from substituting some or all of the acid hydrogens of an acid to form an ionic or ionically bonded compound.

[0035] As used herein, the term "salt co-crystal" refers to a crystalline form in which the chlorided API and coformer (or vice versa) are in the same crystal lattice bound by non-ionic and non-covalent bonds.

[0036] As used herein, the term "pharmaceutically acceptable" indicates that a substance or composition is chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the subject being treated therewith.

[0037] As used herein, the term " pharmaceutically acceptable acid " may refer to such an acid that contains pharmaceutically acceptable anion.Preferably, examples of pharmaceutically acceptable acids described herein include, but are not limited to, hydrochloride, methanesulfonic acid, phosphoric acid, tartaric acid, fumaric acid and adipic acid.More examples of suitable acids can be found, for example, in P.H. Stahl and C.G. Wermuth, eds., Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich: Wiley-VCH / VHCA, 2002.

[0038] As used herein, the term "pharmaceutically acceptable salts," unless otherwise indicated, includes salts that retain the biological effectiveness of the free base of the specified compound and are not biologically or otherwise undesirable. Contemplated pharmaceutically acceptable salt forms include, but are not limited to, mono-, bis-, tris-, tetrakis-, and the like. Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered. The preparation of such salts can facilitate pharmacological use by altering the physical properties of a compound without preventing the compound from exerting its physiological effect. Useful changes in physical properties include lowering the melting point to facilitate transmucosal administration and increasing solubility to facilitate the administration of higher drug concentrations.

[0039] Pharmaceutically acceptable salts may include acid addition salts such as sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate, and quinate. Illustrative examples of pharmaceutically acceptable salts described herein include hydrochloride, mesylate, phosphate, tartrate, fumarate, and adipate. The salts described herein may have an acid / base molar ratio of about 0.5:1 to about 3:1, typically about 0.5:1 to about 2.5:1, and more typically about 1:1 to about 1.5:1. For example, the salts described herein can have an acid / base molar ratio of about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, about 1:1, about 1.1:1, about 1.2:1, about 1.3:1, about 1.4:1, about 1.5:1, about 1.6:1, about 1.7:1, about 1.8:1, about 1.9:1, about 2:1, about 2.1:1, about 2.2:1, about 2.3:1, about 2.4:1 and about 2.5:1.

[0040] Pharmaceutically acceptable salts can be obtained from suitable acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, quinic acid, etc. Preferably, examples of suitable acids include hydrochloride, methanesulfonic acid, phosphoric acid, tartaric acid, fumaric acid, and adipic acid.

[0041] Pharmaceutically acceptable salts can be prepared by standard techniques.For example, the free base form of a compound can be isolated by dissolving it in a suitable solvent, such as an aqueous or aqueous alcoholic solution containing a suitable acid, and then evaporating the solution.Therefore, if a particular compound is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, such as treating the free base with an inorganic or organic acid.

[0042] It will be understood that the crystalline or amorphous compounds described herein may exist in unsolvated or solvated forms, and that the present invention is intended to encompass all such forms.

[0043] As used herein, the terms "solvate" and "solvated" refer to solvent addition forms that contain stoichiometric or non-stoichiometric amounts of solvent.Some compounds tend to capture a certain molar ratio of solvent molecules in crystalline solid state, thus forming solvates.For example, when the solvent is water, the solvate that forms is a hydrate; when the solvent is alcohol, the solvate that forms is an alcoholate; when the solvent is acetone, the solvate that forms is an acetone solvate.A hydrate is formed by combining one or more water molecules with one molecule of a substance, with water retaining its molecular state as H2O.Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, acetone, DMSO, ethyl acetate, acetic acid and ethanolamine.

[0044] As used herein, the terms "nonsolvate" and "non-solvated" indicate that the organic solvent is not incorporated into or accommodated by the solid structure, including both crystalline and amorphous structures. The nonsolvated form may still contain residual organic solvent that is not part of the solid structure but may be adsorbed to surfaces or absorbed into irregular regions of the solid structure. Typically, the nonsolvated form contains no more than 2.0 wt. %, typically no more than 1.0 wt. %, and more typically no more than 0.5 wt. % of organic solvent, based on the weight of the crystalline form. The organic solvent content may be determined by thermogravimetric analysis (TGA), e.g., by measuring weight loss in the range of 25°C to the melting point of the solid form at a heating rate of 10 K / min, and / or by gas chromatography.

[0045] Thus, in one aspect, a compound of the following structural formula: Provided herein is a crystalline form of Compound (I) represented by TIFF2026027273000003.tif33170, wherein the crystalline form is a complex of the free base with a pharmaceutically acceptable acid, or the free base.

[0046] In certain embodiments, the complex or free base is solvated or unsolvated.

[0047] In certain embodiments, the complex is a salt, or a co-crystal, or a co-crystal of a salt.

[0048] In certain embodiments, the complex has an acid / base molar ratio of about 3:1, preferably about 0.5:1 to about 2.5:1, and more preferably about 1:1 to about 1.5:1.

[0049] In certain embodiments, the pharmaceutically acceptable acid is selected from the group consisting of hydrochloride, methanesulfonic acid, phosphoric acid, tartaric acid, fumaric acid, and adipic acid.

[0050] In certain embodiments, the pharmaceutically acceptable acid is fumaric acid.

[0051] Fumarate Type A In certain embodiments, the compound is characterized by an X-ray powder diffraction pattern comprising peaks at least 6.9 and 11.5 2θ (±0.2°); typically, the compound is characterized by an X-ray powder diffraction pattern comprising peaks at least 5.8, 6.9, 11.5, 12.1, and 17.7 2θ (±0.2°); more typically, the compound is characterized by an X-ray powder diffraction pattern comprising peaks at least 5.8, 6.9, 11.5, 12.1, 17.7, 20.8, and 24.0 2θ (±0.2°). Provided herein is a crystalline form of Compound (I), Fumarate Type-A, characterized by an X-ray powder diffraction pattern comprising peaks at least 5.8, 6.9, 11.5, 12.1, 17.7, 18.9, 20.8, 23.1, 23.7, 24.0, and 28.8 2θ (±0.2°); more typically, an X-ray powder diffraction pattern comprising peaks at least 5.8, 6.9, 11.5, 12.1, 17.7, 18.9, 20.8, 23.1, 23.7, 24.0, and 28.8 2θ (±0.2°); and even more typically, an X-ray powder diffraction pattern substantially the same as Figure 1. In certain embodiments, provided herein is a crystalline form of Compound (I), Fumarate Type-A, characterized by a differential scanning calorimeter peak phase transition temperature of about 167.6°C.

[0052] Fumarate Type B In certain embodiments, provided herein is a crystalline form of Compound (I), fumarate Type-B, characterized by an X-ray powder diffraction pattern including peaks at at least 6.6 and 11.4; typically, an X-ray powder diffraction pattern including peaks at least 6.6, 10.7, 11.4, 12.9, 25.1, and 28.2 2θ (±0.2°); more typically, an X-ray powder diffraction pattern including peaks at at least 6.6, 10.7, 11.4, 12.9, 15.8, 17.9, 19.7, 25.1, and 28.2 2θ (±0.2°); and even more typically, an X-ray powder diffraction pattern substantially the same as Figure 6. In certain embodiments, provided herein is a crystalline form of Compound (I), fumarate Type-B, characterized by differential scanning calorimeter peak phase transition temperatures of about 91.3°C and about 166.3°C.

[0053] Fumarate Type C In certain embodiments, provided herein is a crystalline form of Compound (I), Fumarate Type C, characterized by an X-ray powder diffraction pattern comprising peaks at least 6.8 and 11.8 2θ (±0.2°); typically, characterized by an X-ray powder diffraction pattern comprising peaks at least 6.8, 11.2, 11.8, 13.6, and 18.4 2θ (±0.2°); more typically, characterized by an X-ray powder diffraction pattern comprising peaks at least 6.8, 11.2, 11.8, 13.6, 15.1, 16.0, 17.2, 18.4, and 24.5 2θ (±0.2°); and even more typically, characterized by an X-ray powder diffraction pattern substantially the same as in FIG. 10.

[0054] Fumarate Type E In certain embodiments, the compound is characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.7, 11.6, and 28.5 degrees 2θ (±0.2°); typically, the compound is characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.7, 10.9, 11.6, 16.9, 25.2, and 28.5 degrees 2θ (±0.2°); more typically, the compound is characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.7, 10.9, 11.6, 12.9, 15.3, 16.9, 19.9, 25.2, and 28.5 degrees 2θ (±0.2°). Provided herein is a crystalline form of Compound (I), fumarate Type-E, characterized by an X-ray powder diffraction pattern comprising peaks at 2θ (±0.2°); more typically, an X-ray powder diffraction pattern comprising peaks at least 5.5, 6.7, 10.9, 11.6, 12.9, 15.3, 16.9, 18.1, 19.9, 25.2, 27.5, and 28.5 (±0.2°) 2θ; and even more typically, an X-ray powder diffraction pattern substantially the same as Figure 11. In certain embodiments, provided herein is a crystalline form of Compound (I), fumarate Type-E, characterized by differential scanning calorimeter peak phase transition temperatures of about 134.5°C and about 166.0°C.

[0055] Free base type B In certain embodiments, the compound is characterized by an X-ray powder diffraction pattern comprising peaks at least at 8.0 and 11.5 2θ (±0.2°); typically, the compound is characterized by an X-ray powder diffraction pattern comprising peaks at least at 8.0, 11.5, 16.0, 17.2, 18.8, and 24.3 2θ (±0.2°); more typically, the compound is characterized by an X-ray powder diffraction pattern comprising peaks at least at 8.0, 11.5, 16.0, 17.2, 18.2, 18.8, 20.3, 21.9, and 24.3 2θ (±0.2°). Provided herein is a crystalline form of Compound (I), Free Base Type-B, characterized by an X-ray powder diffraction pattern comprising peaks at 8.0, 11.5, 13.1, 16.0, 17.2, 18.2, 18.8, 20.3, 21.2, 21.9, 24.3, and 27.7 2θ (±0.2°); more typically, by an X-ray powder diffraction pattern comprising peaks at 8.0, 11.5, 13.1, 16.0, 17.2, 18.2, 18.8, 20.3, 21.2, 21.9, 24.3, and 27.7 2θ (±0.2°); and even more typically, by an X-ray powder diffraction pattern substantially the same as Figure 14. In certain embodiments, provided herein is a crystalline form of Compound (I), Free Base Type-B, characterized by a differential scanning calorimeter peak phase transition temperature of about 169.4°C.

[0056] Free base type C In certain embodiments, the compound is characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.6 and 18.8 2θ (±0.2°); typically, it is characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.6, 12.7, 18.8, 20.7, and 24.4 2θ (±0.2°); more typically, it is characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.6, 12.7, 14.1, 18.1, 18.8, 20.7, 23.4, 24.4, and 26.7 2θ (±0.2°). Provided herein is a crystalline form of Compound (I), Free Base Type-C, characterized by an X-ray powder diffraction pattern comprising peaks at 6.6, 9.4, 12.7, 14.1, 14.9, 18.1, 18.8, 20.7, 22.9, 23.4, 24.4, and 26.7 2θ (±0.2°); more typically, an X-ray powder diffraction pattern comprising peaks at least 6.6, 9.4, 12.7, 14.1, 14.9, 18.1, 18.8, 20.7, 22.9, 23.4, 24.4, and 26.7 2θ (±0.2°); and even more typically, an X-ray powder diffraction pattern substantially the same as Figure 19. In certain embodiments, provided herein is a crystalline form of Compound (I), Free Base Type-C, characterized by differential scanning calorimeter peak phase transition temperatures of about 86.2°C and about 114.4°C.

[0057] Free base type D In certain embodiments, provided herein is a crystalline form of Compound (I), Free Base Type D, characterized by an X-ray powder diffraction pattern comprising peaks at least at 5.7, 5.8, and 18.8 2θ (±0.2°); typically, characterized by an X-ray powder diffraction pattern comprising peaks at least at 5.7, 5.8, 11.8, 12.6, 18.8, 20.6, and 24.3 2θ (±0.2°); more typically, characterized by an X-ray powder diffraction pattern comprising peaks at least at 5.7, 5.8, 11.8, 12.6, 18.8, 20.6, 22.8, 23.3, and 24.3 2θ (±0.2°); and even more typically, characterized by an X-ray powder diffraction pattern substantially the same as that of FIG. 23.

[0058] Free Base Type E In certain embodiments, the compound is characterized by an X-ray powder diffraction pattern comprising peaks at least at 7.2, 18.2, and 22.3 2θ (±0.2°); typically, the compound is characterized by an X-ray powder diffraction pattern comprising peaks at least at 7.2, 18.2, 19.2, 22.3, 23.0, and 24.0 2θ (±0.2°); more typically, the compound is characterized by an X-ray powder diffraction pattern comprising peaks at least at 7.2, 14.9, 16.7, 18.2, 19.2, 22.3, 23.0, 24.0, and 26.8 2θ (±0.2°). Provided herein is a crystalline form of Compound (I), free base Type E, characterized by an X-ray powder diffraction pattern comprising peaks at 7.2, 12.6, 14.9, 16.7, 18.2, 19.2, 19.7, 20.5, 22.3, 23.0, 24.0, and 26.8 2θ (±0.2°); more typically, by an X-ray powder diffraction pattern comprising peaks at least 7.2, 12.6, 14.9, 16.7, 18.2, 19.2, 19.7, 20.5, 22.3, 23.0, 24.0, and 26.8 2θ (±0.2°); and even more typically, by an X-ray powder diffraction pattern substantially the same as that in Figure 24.

[0059] Free Base Type F In certain embodiments, the compound is characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.2, 11.6, and 12.6 2θ (±0.2°); typically, the compound is characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.2, 11.6, 12.6, 14.8, 16.5, and 24.4 2θ (±0.2°); more typically, the compound is characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.2, 11.6, 12.6, 14.8, 16.5, 17.6, 19.3, 24.4, and 26.0 2θ (±0.2°). Provided herein is a crystalline form of Compound (I), Free Base Type-F, characterized by an X-ray powder diffraction pattern comprising peaks at 2θ (±0.2°); more typically, an X-ray powder diffraction pattern comprising peaks at least 6.2, 9.3, 11.6, 12.6, 14.8, 16.5, 17.6, 18.7, 19.3, 24.4, and 26.0 (±0.2°); and even more typically, an X-ray powder diffraction pattern substantially the same as Figure 25. In certain embodiments, provided herein is a crystalline form of Compound (I), Free Base Type-F, characterized by differential scanning calorimeter peak phase transition temperatures of about 55.4°C and about 109.5°C.

[0060] Free Base Type G In certain embodiments, the compound is characterized by an X-ray powder diffraction pattern comprising peaks at least at 5.7, 5.9, and 12.7 degrees 2θ (±0.2°); typically, the compound is characterized by an X-ray powder diffraction pattern comprising peaks at least at 5.7, 5.9, 11.9, 12.7, 14.5, and 26.2 degrees 2θ (±0.2°); more typically, the compound is characterized by an X-ray powder diffraction pattern comprising peaks at least at 5.7, 5.9, 11.9, 12.7, 14.5, 17.6, 19.7, 22.9, and 26.2 degrees 2θ (±0.2° 28. Provided herein is a crystalline form of Compound (I), Free Base Type-G, characterized by an X-ray powder diffraction pattern comprising peaks at 5.7, 5.9, 11.9, 12.7, 14.5, 17.2, 17.6, 19.7, 20.6, 22.9, 24.8, and 26.2 2θ (±0.2°); more typically, an X-ray powder diffraction pattern comprising peaks at least 5.7, 5.9, 11.9, 12.7, 14.5, 17.2, 17.6, 19.7, 20.6, 22.9, 24.8, and 26.2 2θ (±0.2°); and even more typically, an X-ray powder diffraction pattern substantially the same as Figure 28. In certain embodiments, provided herein is a crystalline form of Compound (I), Free Base Type-G, characterized by differential scanning calorimeter peak phase transition temperatures of about 32.9°C, about 59.2°C, and about 110.2°C.

[0061] Free Base Type A In certain embodiments, provided herein is a crystalline form of Compound (I), Free Base Type A, characterized by an X-ray powder diffraction pattern comprising peaks at least at 7.0, 9.0, and 23.3 2θ (±0.2°); typically characterized by an X-ray powder diffraction pattern comprising peaks at least at 7.0, 9.0, 11.6, 13.6, 15.4, 18.1, 19.6, and 23.3 2θ (±0.2°); more typically characterized by an X-ray powder diffraction pattern substantially the same as Figure 31. In certain embodiments, provided herein is a crystalline form of Compound (I), Free Base Type A, characterized by a differential scanning calorimeter peak phase transition temperature of about 71.3°C.

[0062] HCl Salt Type A In certain embodiments, provided herein is a crystalline form of Compound (I), HCl Salt Type A, characterized by an X-ray powder diffraction comprising a peak at least at 18.1 2θ (±0.2°); typically, characterized by an X-ray powder diffraction pattern substantially the same as the pattern depicted in Figure 35. In certain embodiments, provided herein is a crystalline form of Compound (I), HCl Salt Type A, characterized by a differential scanning calorimeter peak phase transition temperature of about 110.0°C.

[0063] HCl salt type B In certain embodiments, the compound is characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.9, 12.4, and 25.0 2θ (±0.2°); typically, the compound is characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.9, 11.9, 12.4, 17.0, 25.0, and 29.1 2θ (±0.2°); more typically, the compound is characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.9, 9.6, 11.9, 12.4, 17.0, 21.2, 22.7, 25.0, and 29.1 2θ (±0.2°). Provided herein is a crystalline form of Compound (I), HCl Salt Type B, characterized by an X-ray powder diffraction pattern including peaks at 6.9, 9.6, 11.9, 12.4, 17.0, 19.9, 21.2, 22.7, 25.0, 25.9, 27.2, and 29.1 2θ (±0.2°); typically, an X-ray powder diffraction pattern including peaks at least 6.9, 9.6, 11.9, 12.4, 17.0, 19.9, 21.2, 22.7, 25.0, 25.9, 27.2, and 29.1 2θ (±0.2°); and more typically, an X-ray powder diffraction pattern substantially the same as Figure 38. In certain embodiments, provided herein is a crystalline form of Compound (I), HCl Salt Type B, characterized by a differential scanning calorimeter peak phase transition temperature of about 241.7°C.

[0064] Mesylate Type A In certain embodiments, provided herein is a crystalline form of Compound (I), mesylate Type-A, characterized by an X-ray powder diffraction pattern comprising peaks at least 6.5, 19.6, and 21.0 2θ (±0.2°); typically, characterized by an X-ray powder diffraction pattern comprising peaks at least 5.3, 6.5, 7.8, 13.1, 15.7, 19.6, and 21.0 2θ (±0.2°); and more typically, characterized by an X-ray powder diffraction pattern substantially the same as Figure 41. In certain embodiments, provided herein is a crystalline form of Compound (I), mesylate Type-A, characterized by a differential scanning calorimeter peak phase transition temperature of about 65.1°C.

[0065] Mesylate Type B In certain embodiments, provided herein is a crystalline form of Compound (I), mesylate Type-B, characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.0, 16.3, and 18.3 2θ (±0.2°); typically, characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.0, 7.2, 12.4, 16.3, 18.3, 21.5, and 26.5 2θ (±0.2°); and more typically, characterized by an X-ray powder diffraction pattern substantially the same as Figure 44. In certain embodiments, provided herein is a crystalline form of Compound (I), mesylate Type-B, characterized by a differential scanning calorimeter peak phase transition temperature of about 63.4°C.

[0066] Phosphate Type A In certain embodiments, provided herein is a crystalline form of Compound (I), Phosphate Type A, characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.4, 14.0, and 22.9 2θ (±0.2°); typically, characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.4, 14.0, 14.9, 20.5, 22.9, and 24.5 2θ (±0.2°); more typically, characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.4, 14.0, 14.9, 16.3, 18.7, 20.5, 21.4, 22.9, and 24.5 2θ (±0.2°); and even more typically, characterized by an X-ray powder diffraction pattern substantially the same as that of FIG. 47. In certain embodiments, provided herein is a crystalline form of Compound (I), Phosphate Type A, characterized by differential scanning calorimeter peak phase transition temperatures of about 79.1°C and about 194.8°C.

[0067] L-tartrate type A In certain embodiments, provided herein is a crystalline form of Compound (I), L-tartrate Type-A, characterized by an X-ray powder diffraction pattern comprising peaks at least 6.5, 12.7, and 18.8 2θ (±0.2°); typically, characterized by an X-ray powder diffraction pattern comprising peaks at least 6.5, 9.4, 12.7, 18.8, 20.7, 22.7, 24.4, and 26.5 2θ (±0.2°); more typically, characterized by an X-ray powder diffraction pattern substantially the same as Figure 50. In certain embodiments, provided herein is a crystalline form of Compound (I), L-tartrate Type-A, characterized by differential scanning calorimeter peak phase transition temperatures of about 77.6°C and about 164.7°C.

[0068] Adipate Type A In certain embodiments, the compound is characterized by an X-ray powder diffraction comprising peaks at least at 7.4, 10.8, and 25.7 2θ (±0.2°); typically, the compound is characterized by an X-ray powder diffraction comprising peaks at least at 7.4, 10.8, 16.0, 17.7, 19.7, and 25.7 2θ (±0.2°); more typically, the compound is characterized by an X-ray powder diffraction comprising peaks at least at 7.4, 10.8, 12.6, 16.0, 17.7, 19.7, 20.9, 23.6, and 25.7 2θ (±0.2°). Provided herein is a crystalline form of Compound (I), Adipate Type-A, characterized by an X-ray powder diffraction pattern including peaks at 2θ (±0.2°) of at least 7.4, 8.5, 10.8, 12.6, 14.9, 15.5, 16.0, 16.9, 17.7, 19.0, 19.7, 20.9, 23.6, 25.7, and 32.3; and even more typically, characterized by an X-ray powder diffraction pattern substantially the same as Figure 53. In certain embodiments, provided herein is a crystalline form of Compound (I), Adipate Type-A, characterized by a differential scanning calorimeter peak phase transition temperature of about 106.7°C.

[0069] In another aspect, there is provided herein a compound of the following structural formula: An amorphous form of the compound of formula (I) represented by TIFF2026027273000004.tif35170 is provided, which amorphous form is a pharmaceutically acceptable salt or free base.

[0070] Amorphous Fumarate In certain embodiments, provided herein is an amorphous fumarate salt, which is an amorphous form of Compound (I), characterized by an X-ray powder diffraction pattern substantially the same as in Figure 56. In certain embodiments, provided herein is an amorphous fumarate salt, which is an amorphous form of Compound (I), characterized by a differential scanning calorimeter thermogram curve substantially the same as in Figure 58.

[0071] Amorphous Free Base In certain embodiments, provided herein is an amorphous free base, an amorphous form of Compound (I), characterized by an X-ray powder diffraction pattern substantially the same as in Figure 59. In certain embodiments, provided herein is an amorphous free base, an amorphous form of Compound (I), characterized by a differential scanning calorimeter thermogram curve substantially the same as in Figure 61.

[0072] In certain embodiments, the crystalline or amorphous form of compound (I) described herein can be provided in substantially pure form.Specifically, the crystalline forms of compound (I), particularly those referred to as fumarate type A, fumarate type B, fumarate type C, fumarate type E, free base type A, free base type B, free base type C, free base type D, free base type E, free base type F, free base type G, HCl salt type A, HCl salt type B, mesylate type A, mesylate type B, phosphate type A, L-tartrate type A and adipate type A, and the amorphous form of compound (I), particularly those referred to as amorphous fumarate and amorphous free base, can exist in substantially pure form.

[0073] As used herein, the term "substantially pure" means that the polymorph or amorphous material contains less than about 15% by weight of impurities, including other polymorphs. In certain embodiments, a substantially pure polymorph or amorphous material contains less than about 10% by weight of impurities, including other polymorphs. In certain embodiments, a substantially pure polymorph or amorphous material contains less than about 5% by weight of impurities, including other polymorphs. In certain embodiments, a substantially pure polymorph or amorphous material contains less than about 1% by weight of impurities, including other polymorphs. In certain embodiments, a substantially pure polymorph or amorphous material is free of impurities, including other polymorphs.

[0074] The present invention also includes crystalline and amorphous forms of (R)—N-(4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazolin-4-amine (Compound (I)) that are identical but have been replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that may be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, and oxygen, e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 17 O and 18 Polymorphs described herein that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, e.g. 3 H and 14 Incorporating radioactive isotopes such as C are useful in drug and / or substrate tissue distribution assays. 3 H and carbon-14, i.e., 14 The C isotope is particularly widely used as a result of its ease of preparation and detectability. 2 Substitution with heavier isotopes, such as H, may confer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and may therefore be utilized in certain circumstances. The isotopically labeled salts of the present invention may generally be prepared by carrying out the procedures disclosed in WO 2020 / 057511 by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent during preparation, or, if necessary, by using isotopically labeled sulfuric acid in the preparation of the salt.

[0075] Compound synthesis The compounds described herein can be synthesized by synthetic routes, including processes similar to those well known in the chemical field, especially in light of the description contained herein.Starting materials are generally available from commercial sources such as Sigma-Aldrich (St. Louis, Missouri), Alfa Aesar (Ward Hill, Massachusetts) or TCI (Portland, Oregon), or can be easily prepared using methods well known to those skilled in the art (for example, Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v.1-23, New York: Wiley 1967-2006 (also available via Wiley InterScience® website) or prepared by the methods generally described in Beilstein's Handbuch der organischen Chemie, 4, Aufl. (ed.), Springer-Verlag, Berlin (including supplements) (also available via Beilstein online database).

[0076] In general, compound (I) can be prepared by coupling 4-chloro-5-((3,3-difluoro-1-methylpiperidin-4-yl)oxy)-6-methoxyquinazoline with 4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-3-methylaniline. The coupling can be carried out, for example, in a solvent such as propan-2-ol at 100°C under the catalysis of toluenesulfonic acid TsOH·HO, followed by separation of the two isomers of the racemic product by chiral supercritical fluid chromatography (SFC). A more detailed description of the individual reaction steps can be found, for illustrative purposes, in the Examples section of WO 2020 / 057511, which is incorporated by reference in its entirety. Those skilled in the art will appreciate that other synthetic routes can be used to synthesize the compounds.

[0077] Polymorphs are determined by final crystallization or isolation, as further detailed in the Examples section herein.

[0078] Preparation of crystalline forms In one aspect, there is provided a process for the preparation of a crystalline form of Compound (I), comprising: If the crystalline form is a complex of the free base and a pharmaceutically acceptable acid, the method may further comprise: a) adding compound (I) and an acid in a solvent; and b) Slurrying at a temperature for a time sufficient to initiate precipitation of the complex. Includes; If the crystalline form is the free base, a) adding compound (I) in a solvent; and b) Slurrying at a temperature for a time sufficient to initiate precipitation of the free base. A method is provided herein, comprising:

[0079] In certain embodiments, the acid is selected from the group consisting of hydrochloride, methanesulfonic acid, phosphoric acid, tartaric acid, fumaric acid, and adipic acid.

[0080] In certain embodiments in which the crystalline form is a complex of the free base and a pharmaceutically acceptable acid, in step a), Compound (I) and the acid are added to a solvent at an acid / base molar ratio ranging from about 0.5:1 to about 3:1, preferably from about 0.5:1 to about 2.5:1, and more typically from about 1:1 to about 1.5:1. For example, the salts described herein may have an acid / base molar ratio of about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, about 1:1, about 1.1:1, about 1.2:1, about 1.3:1, about 1.4:1, about 1.5:1, about 1.6:1, about 1.7:1, about 1.8:1, about 1.9:1, about 2:1, about 2.1:1, about 2.2:1, about 2.3:1, about 2.4:1, and about 2.5:1.

[0081] In certain embodiments, the solvent is selected from the group consisting of HO, EtOH, EtOAc, n-heptane, ethyl formate, acetone, cyclohexane, isopropyl alcohol, methyl isobutyl ketone, tetrahydrofuran, acetonitrile, and methyl tert-butyl ether, and combinations thereof.

[0082] In certain embodiments, the methods described herein further comprise seeding the solvent with a crystalline form described herein.

[0083] In a particular embodiment, in step b), the temperature is about 5 to 50°C.

[0084] In a particular embodiment, in step b), the time is about 2 to 7.5 hours.

[0085] In certain embodiments, there is provided a process for the preparation of crystalline form of Fumarate Salt Type A of Compound (I) described herein, comprising: a) dissolving the free base of Compound (I) in an ester or alcohol to form a free base solution; b) dissolving fumaric acid in EtOH to form an acid solution; c) adding the acid solution dropwise to the free base solution while stirring; d) adding the alkane dropwise; and then optionally seeding the mixture with crystalline form of fumarate salt Type A of Compound (I); e) stirring at 0 to 10°C for 12 to 24 hours; and f) isolating the solid by filtration and then drying the solid under reduced pressure at 40-60°C. A method is provided herein, comprising:

[0086] In certain embodiments, the ester is selected from the group consisting of ethyl acetate, ethyl formate, methyl acetate, and isopropyl acetate.

[0087] In certain embodiments, the ester is ethyl acetate.

[0088] In certain embodiments, the alcohol is selected from the group consisting of methanol, ethanol, n-propanol, and isopropanol.

[0089] In certain embodiments, the alcohol is ethanol.

[0090] In certain embodiments, the alkane is selected from the group consisting of n-hexane, n-heptane, n-octane, and mixtures thereof.

[0091] In certain embodiments, the alkane is n-heptane.

[0092] In certain embodiments, there is provided a process for the preparation of crystalline form of Fumarate Salt Type-B of Compound (I) described herein, comprising: a) suspending the crystalline form of fumarate salt Type A of Compound (I) in HO; b) magnetic stirring at about room temperature at a speed of 1000 rpm for about 11 days; and c) isolating the solid by centrifugation and storing the solid open at ambient conditions for approximately 4 days. A method is provided herein, comprising:

[0093] In certain embodiments, there is provided a process for the preparation of crystalline form of Fumarate Salt Type C of Compound (I) described herein, comprising: a) suspending the crystalline form of fumarate salt Type A of Compound (I) in HO; b) magnetically stirring at about room temperature at a speed of about 1000 rpm for about 9 days; and c) Isolating the wet solid A method is provided herein, comprising:

[0094] In certain embodiments, there is provided a process for the preparation of the crystalline form of fumarate salt Type E of Compound (I) described herein, comprising: a) dissolving the fumarate-type crystalline form of Compound (I) in ethyl formate; b) evaporating the ethyl formate at about room temperature; c) isolating the solid A method is provided herein, comprising:

[0095] In certain embodiments, there is provided a process for the preparation of crystalline form of Fumarate Salt Type A of Compound (I) described herein, comprising: a) suspending the amorphous free base of Compound (I) in a solvent of acetone / n-heptane having a volume ratio of about 1:4; b) magnetically stirring at about room temperature at a speed of about 1000 rpm for about 3 days; and c) isolating the solid by centrifugation and drying the solid at ambient conditions for about 1 day; A method is provided herein, comprising:

[0096] In certain embodiments, there is provided a process for the preparation of the crystalline form of the free base Type B of Compound (I) described herein, comprising: a) suspending the amorphous free base of Compound (I) in a solvent of methyl isobutyl ketone / cyclohexane having a volume ratio of about 1:4; b) magnetically stirring at a speed of about 1000 rpm at about 5°C for about 7 days; and c) isolating the solid by centrifugation A method is provided herein, comprising:

[0097] In certain embodiments, there is provided a method for the preparation of the crystalline form of the free base Type C of Compound (I) described herein, comprising: a) suspending the amorphous free base of Compound (I) in a solvent of tetrahydrofuran / HO having a volume ratio of about 1:4; b) magnetically stirring at a speed of about 1000 rpm at about 5°C for about 7 days; and c) isolating the solid by centrifugation A method is provided herein, comprising:

[0098] In certain embodiments, there is provided a process for the preparation of the crystalline form of the free base Type D of Compound (I) described herein, comprising: a) suspending the amorphous free base of Compound (I) in a solvent of tetrahydrofuran / HO having a volume ratio of about 1:4; b) magnetically stirring at a speed of about 1000 rpm at about 5°C for about 3 days; and c) isolating the solid by centrifugation and drying the solid at ambient conditions for approximately 2 hours; A method is provided herein, comprising:

[0099] In certain embodiments, there is provided a process for the preparation of the crystalline form of the free base Type E of Compound (I) described herein, comprising: a) suspending the amorphous free base of Compound (I) in a solvent of tetrahydrofuran / HO having a volume ratio of about 1:4; b) magnetic stirring at a speed of about 1000 rpm at about 5°C for about 4 days; c) isolating the solid by centrifugation and drying the solid at ambient conditions for about 2 hours; and d) Sweeping the solid with N2 at about 30°C for about 20 minutes. A method is provided herein, comprising:

[0100] In certain embodiments, there is provided a process for the preparation of the crystalline form of the free base Type F of Compound (I) described herein, comprising: a) suspending the amorphous free base of Compound (I) in a solvent of acetonitrile / n-heptane; b) magnetic stirring at about room temperature at a speed of about 1000 rpm for about 2 days; c) isolating the solid A method is provided herein, comprising:

[0101] In certain embodiments, there is provided a process for the preparation of the crystalline form of the free base Type G of Compound (I) described herein, comprising: a) dissolving the amorphous free base of Compound (I) in EtOH; b) adding HO to obtain a suspension; and c) isolating the solid from the suspension A method is provided herein, comprising:

[0102] In certain embodiments, there is provided a process for the preparation of crystalline form of HCl salt Type A of Compound (I) described herein, comprising: a) adding an amorphous free base of Compound (I) and concentrated HCl in a solvent of EtOAc / n-heptane having a volume ratio of about 1:2 at an acid / base molar ratio of about 2:1; b) magnetically stirring at about room temperature at a speed of about 1000 rpm for about 3 days; and c) isolating the solid by centrifugation and drying the solid at ambient conditions for about 1 day; A method is provided herein, comprising:

[0103] In certain embodiments, there is provided a process for the preparation of the HCl salt Type B crystalline form of Compound (I) described herein, comprising: a) dissolving the amorphous free base of Compound (I) in EtOAc to form a free base solution; b) diluting an EtOAc solution of HCl in EtOH to form an acid solution; c) optionally adding seed crystals of HCl salt Type B of Compound (I) to the free base solution, where the seed crystals are not completely dissolved; d) adding the acid solution dropwise while stirring at a speed of about 1000 rpm; e) stirring at room temperature for about 8 hours, then at about 5° C. for about 13 hours; f) isolating the solid by filtration and then drying the solid under vacuum at about room temperature overnight; Methods are provided herein wherein the acid / base molar ratio is about 2:1.

[0104] In certain embodiments, there is provided a process for the preparation of mesylate salt Type A of Compound (I) described herein, comprising: a) suspending the amorphous free base of Compound (I) and methanesulfonic acid in a solvent of acetone / n-heptane having a volume ratio of about 1:4 at an acid / base molar ratio of about 2:1; b) magnetically stirring at about room temperature at a speed of about 1000 rpm for about 3 days; and c) isolating the solid by centrifugation and drying the solid at ambient conditions for about 1 day; A method is provided herein, comprising:

[0105] In certain embodiments, there is provided a process for the preparation of mesylate salt type B of compound (I) described herein, comprising: a) suspending the amorphous free base of Compound (I) and methanesulfonic acid in a solvent of isopropyl alcohol / cyclohexane having a volume ratio of about 1:4 at an acid / base input molar ratio of about 2:1; b) magnetically stirring at about room temperature at a speed of about 1000 rpm for about 3 days; and c) isolating the solid by centrifugation and drying the solid at ambient conditions for about 1 day; A method is provided herein, comprising:

[0106] In certain embodiments, there is provided a process for the preparation of phosphate salt Type A of Compound (I) described herein, comprising: a) suspending the amorphous free base of Compound (I) and concentrated HPO in a solvent of acetone / n-heptane having a volume ratio of about 1:4 at an acid / base molar ratio of about 1:1; b) magnetically stirring at a speed of about 1000 rpm at room temperature for about 3 days; and c) isolating the solid by centrifugation and drying the solid at ambient conditions for about 1 day; A method is provided herein, comprising:

[0107] In certain embodiments, there is provided a process for the preparation of L-tartrate salt Type A of Compound (I) described herein, comprising: a) suspending the amorphous free base of Compound (I) and L-tartaric acid in a solvent of EtOAc / n-heptane having a volume ratio of about 1:2 at an acid / base molar ratio of about 1:1; b) magnetically stirring at about room temperature at a speed of about 1000 rpm for about 3 days; and c) isolating the solid by centrifugation and drying the solid at ambient conditions for about 1 day; A method is provided herein, comprising:

[0108] In certain embodiments, there is provided a process for the preparation of Compound (I) adipate type A described herein, comprising: a) suspending the amorphous free base of Compound (I) and adipic acid in a solvent of EtOAc / n-heptane having a volume ratio of about 1:2 at an acid / base molar ratio of about 1:1; b) magnetically stirring at about room temperature at a speed of about 1000 rpm for about 3 days; and c) isolating the solid by centrifugation and drying the solid at ambient conditions for about 1 day; A method is provided herein, comprising:

[0109] Furthermore, in another aspect, there is provided a process for the preparation of an amorphous form of Compound (I) as described herein, comprising: a) dissolving compound (I) in a solvent; and b) Removing the solvent A method is provided herein, comprising:

[0110] In certain embodiments, the solvent is selected from the group consisting of HO, MeOH, EtOH, EtOAc, DCM, n-heptane, ethyl formate, acetone, cyclohexane, isopropyl alcohol, methyl isobutyl ketone, tetrahydrofuran, acetonitrile, methyl tert-butyl ether, and combinations thereof.

[0111] In certain embodiments, there is provided a process for the preparation of an amorphous fumarate salt of Compound (I) described herein, comprising: a) dissolving the fumarate salt Type A of Compound (I) in MeOH; and b) Removing the MeOH by rotary evaporation at about 60°C A method is provided herein, comprising:

[0112] In certain embodiments, there is provided a process for the preparation of amorphous free base of Compound (I) described herein, comprising: a) dissolving the free base type B of Compound (I) in DCM; and b) Removing the DCM by rotary evaporation at about 40°C A method is provided herein, comprising:

[0113] As used herein, the terms "seeding" or "seeding" refer to the addition of crystalline material to a solution or mixture to initiate crystallization or recrystallization.

[0114] Purpose The crystalline and amorphous forms of Compound (I) described herein may exhibit high inhibitory activity against type I receptor tyrosine kinases, particularly HER2.

[0115] As used herein, the term "inhibitory activity against type I receptor tyrosine kinase" refers to a decrease in the activity of type I receptor tyrosine kinase as a direct or indirect response to the presence of a crystalline or amorphous form of Compound (I), compared to the activity of type I receptor tyrosine kinase in the absence of the crystalline or amorphous form of Compound (I). Such a decrease in activity may be due to the direct interaction of the crystalline or amorphous form of Compound (I) with type I receptor tyrosine kinase, or may be due to the interaction of the crystalline or amorphous form of Compound (I) with one or more other factors that affect the activity of type I receptor tyrosine kinase. For example, the crystalline or amorphous form of Compound (I) described herein may decrease the activity of type I receptor tyrosine kinase by directly binding to type I receptor tyrosine kinase, by inducing (directly or indirectly) another factor to decrease the type I receptor tyrosine kinase activity, or by decreasing (directly or indirectly) the amount of type I receptor tyrosine kinase present in a cell or organism.

[0116] As a result of their inhibitory activity against type I receptor tyrosine kinases, crystalline and amorphous forms of Compound (I) are useful in therapy, for example, in the treatment of diseases or medical conditions mediated at least in part by one or more type I receptor tyrosine kinases, including cancer.

[0117] As used herein, the term "cancer" refers to or refers to a physiological condition in mammals that is typically characterized by abnormal or unregulated cell proliferation. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More specific examples of such cancer include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), small cell lung cancer, non-small cell lung cancer ("NSCLC"), lung cancer including adenocarcinoma of the lung and squamous carcinoma of the lung, peritoneal cancer, hepatocellular carcinoma, gastric cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatocellular carcinoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, brain cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney cancer or renal carcinoma, prostate cancer, vulvar cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, skin cancer including melanoma, and head and neck cancer. Typically, such cancers include breast cancer, gastric cancer, bile duct cancer, colorectal cancer, brain cancer, lung cancer, NSCLC, pancreatic cancer, head and neck cancer, ovarian cancer and uterine cancer.As used herein, the term "cancer" is intended to encompass both non-metastatic cancer and metastatic cancer.In this context, the treatment of cancer includes the treatment of both primary tumor and tumor metastasis.

[0118] As used herein, the term "mammal" means a warm-blooded animal that has or is at risk of developing a disease as described herein, including, but not limited to, guinea pigs, dogs, cats, rats, mice, hamsters, and primates, including humans.

[0119] As used herein, the term "treatment" is intended to have its ordinary meaning of addressing a disease to completely or partially alleviate one, some, or all of its symptoms, or to correct or compensate for the underlying pathology, thereby achieving a beneficial or desired clinical result. For purposes of the present invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, whether detectable or undetectable, reduction in the extent of the disease, stabilization (i.e., not worsening) of the disease pathology, delay or slowing of disease progression, remission or alleviation of the disease pathology, and remission (whether partial or complete). "Treatment" can also mean prolonging survival compared to expected survival in the absence of treatment. Those in need of treatment include those already with the condition or disorder, as well as those prone to have the condition or disorder, or those in whom the condition or disorder is to be prevented. The term "treatment" also encompasses prophylaxis, unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be interpreted accordingly.

[0120] As used herein, the term "prevention" is intended to have its ordinary meaning and includes primary prevention, to prevent the onset of a disease, and secondary prevention, where the disease has already developed and the patient is temporarily or permanently protected from progression or worsening of the disease or the development of new symptoms associated with the disease.

[0121] The term "treatment" is used synonymously with "therapy." Similarly, the term "treating" may be considered as "applying treatment," as "treatment" is defined herein.

[0122] In some embodiments, the compounds of the present invention have anti-cell proliferation properties that are believed to result from type I receptor tyrosine kinase inhibitory activity.Therefore, the compounds of the present invention are expected to be useful for treating the disease or condition that is mediated solely or partially by type I receptor tyrosine kinase, that is, the compounds can be used to produce the anti-proliferative effect that is mediated solely or partially by inhibiting type I receptor tyrosine kinase.In some embodiments, the disease or condition that is treated by providing anti-proliferative effect is type I receptor tyrosine kinase sensitive cancer, for example, but not limited to, breast cancer, lung cancer, colon cancer, rectal cancer, gastric cancer, prostate cancer, bladder cancer, pancreatic cancer and ovarian cancer, or other cell proliferation diseases such as psoriasis.

[0123] Thus, in one aspect, crystalline or amorphous forms of Compound (I) described herein are provided for use in therapy. In some embodiments, crystalline and amorphous forms of Compound (I) described herein are provided for use as pharmaceuticals. In some embodiments, the present invention provides crystalline and amorphous forms of Compound (I) described herein for use in treating diseases or conditions mediated solely or in part by type I receptor tyrosine kinases. In some embodiments, the present invention provides crystalline and amorphous forms of Compound (I) described herein for use in treating or ameliorating hyperproliferative diseases, typically cancer, more typically ErbB2-positive cancers.

[0124] In another aspect, provided is a crystalline or amorphous form of Compound (I) described herein for use in the manufacture of a medicament for treating a type I receptor tyrosine kinase-related disease or condition, preferably an ErbB2-related disease or condition. In some embodiments, provided is a crystalline or amorphous form of Compound (I) described herein for use in the manufacture of a medicament for treating or ameliorating a hyperproliferative disease, typically cancer, more typically ErbB2-positive cancer.

[0125] Pharmaceutical Compositions / Dosage Forms The crystalline and amorphous forms of Compound (I) described herein can be administered by any convenient route appropriate to the condition to be treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), ocular, vaginal, intraperitoneal, intrapulmonary and intranasal.

[0126] The crystalline and amorphous forms of Compound (I) described herein can be administered in any convenient dosage form, such as tablets, powders, capsules, liquids, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain conventional pharmaceutical ingredients, such as diluents, carriers, pH adjusters, sweeteners, fillers, and additional active agents. For example, if parenteral administration is desired, the composition is sterile and in the form of a solution or suspension suitable for injection or infusion.

[0127] Typical formulations are prepared by mixing the crystalline and amorphous forms of Compound (I) described herein with pharmaceutically acceptable carriers or excipients.

[0128] As used herein, the term "pharmaceutically acceptable carrier or excipient" refers to a carrier or excipient that is generally safe, non-toxic, and not biologically or otherwise undesirable and is useful in preparing pharmaceutical compositions, and includes carriers or excipients that are acceptable for veterinary use as well as human pharmaceutical use. As used in the specification and claims, "pharmaceutically acceptable carrier or excipient" includes both one and more than one such carrier or excipient. The particular excipient, carrier, or diluent used will depend on the means and purpose for which the compound of the invention is being applied. Suitable carriers and additives are well known to those skilled in the art and are described in detail, for example, in Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams and Wilkins, 2004; Gennaro, Alfonso R., et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents, diluents, and other known additives to provide an elegant presentation of the drug (i.e., crystalline and amorphous forms of Compound (I) or pharmaceutical compositions thereof described herein) or to aid in the manufacture of a pharmaceutical product (i.e., drug product).

[0129] Thus, in one aspect, there is provided a pharmaceutical composition comprising as an active ingredient a crystalline or amorphous form of Compound (I) as described herein. In certain embodiments, there is provided a pharmaceutical composition comprising a crystalline or amorphous form of Compound (I) as described herein, together with a pharmaceutically acceptable carrier or excipient.

[0130] The pharmaceutical compositions described herein may be formulated into dosage forms comprising a therapeutically effective amount of the crystalline forms, amorphous forms, or pharmaceutical compositions described herein.

[0131] As used herein, the term "therapeutically effective amount" refers to the amount of a pharmaceutical agent to treat, ameliorate, or prevent a specified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend on the subject's weight, size, and health; the nature and extent of the condition; the rate of administration; the therapeutic agent or combination of therapeutic agents selected for administration; and the discretion of the prescribing physician. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician.

[0132] In some embodiments, the pharmaceutical composition may be formulated to administer a dose of 0.001 to 500 mg / kg body weight / day, e.g., 0.01 to 400 mg / kg body weight / day, 0.01 to 300 mg / kg body weight / day, 0.1 to 200 mg / kg body weight / day, 0.1 to 150 mg / kg body weight / day, 0.1 to 100 mg / kg body weight / day, 0.5 to 100 mg / kg body weight / day, 0.5 to 80 mg / kg body weight / day, 0.5 to 60 mg / kg body weight / day, 0.5 to 50 mg / kg body weight / day, 1 to 50 mg / kg body weight / day, or 1 to 40 mg / kg body weight / day of a crystalline or amorphous form of Compound (I) described herein. In some cases, dosage levels below the lower limit of the aforementioned range may be more than sufficient, while in other cases, larger doses may be used without causing any adverse side effects, provided that such larger doses are first divided into several smaller doses for administration over the course of a day.For further information on routes of administration and dosage regimens, see Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of the Editorial Board), Pergamon Press 1990, which is expressly incorporated herein by reference.

[0133] Treatment method In a further aspect, there is provided a method of treating or ameliorating a hyperproliferative disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a crystalline or amorphous form described herein having type I receptor tyrosine kinase inhibitory activity and brain penetration ability of a compound of the invention.

[0134] As used herein, the term "subject in need of treatment or amelioration" refers to a subject having a type I receptor tyrosine kinase-associated disease or condition (e.g., cancer) or a subject at increased risk of developing a type I receptor tyrosine kinase-associated disease or condition (e.g., cancer) compared to the general population. In the case of cancer, the subject in need of treatment or amelioration may have a precancerous condition. The term "subject" includes warm-blooded animals. In some embodiments, the warm-blooded animal is a mammal. In some embodiments, the warm-blooded animal is a human.

[0135] In certain embodiments, the hyperproliferative disease is cancer.

[0136] In certain embodiments, the cancer is ErbB2 positive.

[0137] In certain embodiments, the cancer is selected from the group consisting of breast cancer, gastric cancer, bile duct cancer, colorectal cancer, brain cancer, lung cancer, NSCLC, pancreatic cancer, head and neck cancer, ovarian cancer and uterine cancer.

[0138] In certain embodiments, one or more additional compounds with anti-cancer properties are administered in combination.

[0139] Combination therapy The crystalline form, amorphous form and pharmaceutical composition described herein can be used alone or in combination with additional therapeutic agents for treatment.Useful additional therapeutic agents include, but are not limited to, antitumor agents, such as additional compounds with anticancer properties.The additional therapeutic agents of the combined pharmaceutical preparation or dosage regimen preferably have complementary activities to the compounds described herein so as not to adversely affect each other.Such molecules are suitably present in combination in an amount effective for the intended purpose.

[0140] As used herein, the term "combination" refers to simultaneous, separate, or sequential administration. In some embodiments, "combination" refers to simultaneous administration. In some embodiments, "combination" refers to separate administration. In some embodiments, "combination" refers to sequential administration. When administration is sequential or separate, the delay in administration of the second component should not be such that the beneficial effect of the combination is lost.

[0141] Examples of useful anti-tumor agents fall into the following categories: (i) Antiproliferative / antineoplastic drugs and combinations thereof such as TKIs; DNA alkylating agents; antimetabolites; antitumor antibiotics; antimitotic agents; and topoisomerase inhibitors; inhibitors of DNA repair mechanisms such as CHK kinase; DNA-dependent protein kinase inhibitors; inhibitors of poly(ADP-ribose) polymerase (PARP inhibitors); and Hsp90 inhibitors such as tanespimycin and retaspimycin, inhibitors of ATR kinase; and inhibitors of WEE1 kinase; (ii) Cytostatic agents such as antiestrogens; estrogen receptor downregulators; antiandrogens; LHRH antagonists or agonists; progestogens; aromatase inhibitors; inhibitors of 5α-reductase; and p38 inhibitors; (iii) drugs that inhibit cancer cell invasion; (iv) inhibitors of growth factor function such as growth factor antibodies, growth factor receptor antibodies, antibody drug conjugates, farnesyltransferase inhibitors, tyrosine kinase inhibitors and serine-threonine kinase inhibitors; inhibitors of the platelet-derived growth factor family; inhibitors of the hepatocyte growth factor family; and MEK inhibitors, and compounds such as those disclosed in U.S. Patent Application Publication No. 2004 / 0116710; (v) antiangiogenic agents, such as, but not limited to, those that inhibit the effects of vascular endothelial growth factor, such as the anti-vascular endothelial growth factor antibody bevacizumab, VEGF receptor tyrosine kinase inhibitors; compounds such as those disclosed in International Patent Applications WO 97 / 22596, WO 97 / 30035, WO 97 / 32856 and WO 98 / 13354; compounds that act by other mechanisms, or inhibitors of angiopoietin and its receptors (Tie-1 and Tie-2), inhibitors of PLGF, inhibitors of delta-like ligand (DLL-4); (vi) vascular damaging agents; (vii) antisense therapy; (viii) gene therapy approaches, including, for example, GVAX™, approaches to replace abnormal genes such as abnormal p53 or abnormal BRCA1 or BRCA2, GDEPT (gene-directed enzyme prodrug therapy) approaches, and approaches to increase a patient's resistance to chemotherapy or radiation therapy, such as multidrug resistance gene therapy; (ix) interferon; (x) Immunotherapeutic approaches, including, but not limited to, ex vivo and in vivo approaches to increase the immunogenicity of patient tumor cells; approaches that reduce T cell anergy or regulatory T cell function; approaches that enhance T cell responses to tumors; approaches that use transfected immune cells; approaches that use cytokine-transfected tumor cell lines, antibodies against tumor-associated antigens, and antibodies that deplete target cell types; approaches that use anti-idiotypic antibodies; approaches that enhance natural killer cell function; and approaches that utilize antibody-toxin conjugates; immunotoxins; agonists of toll-like receptor 7 or toll-like receptor 9; (xi) efficacy enhancers such as leucovorin can be selected from.

[0142] For illustrative purposes, more detailed examples of such combination therapies can be found in WO 2020 / 057511, which is incorporated by reference in its entirety.

[0143] In certain embodiments, the additional anti-tumor agent (additional compound with anti-cancer properties) is selected from the group consisting of TKIs (e.g., lapatinib, neratinib, and afatinib), anti-HER2 agents (e.g., monoclonal antibodies such as trastuzumab, ADCs such as T-DM1, T-DXd), and combinations thereof. In some embodiments, the additional anti-tumor agent includes capecitabine, anti-HER2 antibodies, T-DXd, and T-DM1. In some embodiments, one additional anti-tumor agent is present. In some embodiments, two additional anti-tumor agents are present. In some embodiments, three or more additional anti-tumor agents are present.

[0144] Salt screening and evaluation Using the amorphous free base or free base type B of Compound (I) as starting materials, salt screening experiments were conducted using various acids or coformers in various solvent systems. HCl, methanesulfonic acid, and p-toluenesulfonic acid were tested at two loading ratios. Seven crystalline salts were obtained: HCl salt type A, HCl salt type B, mesylate salt type A, mesylate salt type B, phosphate salt type A, L-tartrate salt type A, fumarate salt type A, and adipate salt type A. Additionally, one crystalline free base, free base type A, was observed in the screening.

[0145] Polymorphism Test Amorphous free base, free base type B, and free base type G were used as starting materials for polymorph screening of the free base of Compound (I). Polymorph screening experiments were set up using methods including, but not limited to, slow evaporation, slow cooling, slurry, solid vapor diffusion, liquid vapor diffusion, and antisolvent addition. A total of six crystalline forms of the free base were observed during the screening and identification process, and these were designated free base types B, C, D, E, F, and G. Most forms were characterized by XRPD, TGA, DSC, and NMR. 1Characterization by H NMR revealed that free base types B and E are anhydrates, free base types C, D, F, and G are hydrates, and free base type A is an acetone solvate.

[0146] To test the interconversion relationship between free base type B and free base type C, a slurry competition experiment was conducted. Results showed that free base type B was obtained after slurrying in solvent systems with water activities (Aw) of approximately 0.4, 0.6, and 0.8 at 24 ± 3 °C, and free base type C was obtained after slurrying in HO with a water activity of approximately 1, indicating that the critical water activity between free base types B and C is in the range of 0.8–1. The interconversion relationship between anhydrous free base type B and hydrate types C / F / G was further investigated under different water activities at room temperature. Saturated solutions of free base type B were obtained via slurrying free base type B in the corresponding solvent systems overnight at room temperature. A mixture of free base types B+C+F+G was added to the corresponding saturated solution of free base type B to form a suspension. After stirring at 750 rpm for 4 days at room temperature, the suspension was sampled for XRPD. Free base type B was observed in EtOH and EtOH / H2O (aw = 0.2, 0.4, 0.6, 0.8) systems, whereas free base type G was obtained in pure H2O systems. [Example]

[0147] The following examples are included for illustrative purposes. However, it should be understood that these examples do not limit the invention and are meant only to suggest methods of practicing the invention. Those skilled in the art will recognize that the chemical reactions described can be readily adapted to prepare the crystalline or amorphous forms described herein, and alternative methods for preparing the crystalline or amorphous forms are considered to be within the scope of the present invention. For example, the preparation of the crystalline or amorphous forms described herein can be successfully carried out with modifications apparent to those skilled in the art, such as by utilizing other suitable reagents known in the art other than those described and / or by making routine modifications to the reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing the crystalline or amorphous forms described herein. Those skilled in the art will also recognize that the described crystalline and amorphous forms can be readily adapted to prepare other crystalline and amorphous forms, and other methods for preparing the crystalline and amorphous forms are within the scope of the present invention.

[0148] In the examples described below, all temperatures are in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI and used without further purification unless otherwise indicated.

[0149] The crystalline or amorphous forms of Compound (I) were characterized by X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). 1 H solution nuclear magnetic resonance ( 1 H NMR) or high performance liquid chromatography (HPLC) coupled with ion chromatography (IC).

[0150] Abbreviation Most of the abbreviations used in this invention are listed in Table 1.

[0151] [Table 1] TIFF2026027273000006.tif156170

[0152] Analysis conditions X-ray powder diffraction (XRPD) XRPD analysis was performed using a PANalytical Empyrean or X'Pert3 X-ray powder diffractometer. Typical XRPD parameters used in salt screening and evaluation and polymorph testing are listed in Table 2. [Table 2]

[0153] Thermogravimetric analysis and differential scanning calorimetry (TGA and DSC) For salt screening and evaluation and polymorphism testing, TGA was performed using a TA Instruments TA Q500, TA Q5000, or Discovery 5500 TGA. DSC or mDSC was performed using a TA Instruments TA Q200 / Q2000 or Discovery 2500 DSC. Typical parameters are listed in Tables 3 and 4. [Table 3] [Table 4]

[0154] Dynamic Vapor Sorption (DVS) DVS is measured via the DVS Intrinsic of an SMS (Surface Measurement Systems). Relative humidity at 25°C is calibrated against the deliquescence points of LiCl, Mg(NO3)2, and KCl. Typical parameters for a DVS test are listed in Table 5. [Table 5]

[0155] 1H-nuclear magnetic resonance spectroscopy ( 1 H-NMR) 1 H solution NMR was collected on a Bruker 400M NMR spectrometer using DMSO-d6 as the solvent.

[0156] Polarized Light Microscope (PLM) PLM images were captured on a Carl Zeiss Axio Scope. A1 microscope at room temperature.

[0157] High-performance liquid chromatography (HPLC) An Agilent 1260 HPLC instrument was utilized and the detailed chromatographic conditions for purity and solubility analysis are listed in Table 6. [Table 6] *: Data presented in this report correspond to a UV wavelength of 214 nm.

[0158] Ion chromatograph (IC) Thermo Fisher ICS-1100 was used, and the detailed parameters are listed in Table 7. [Table 7]

[0159] Example 1 Fumarate Type A of Compound (I) Compound (I) fumarate salt type A was prepared according to the following process: a) dissolving 500 mg of Compound (I) free base in approximately 10 mL of EtOAc to form a free base solution; b) Dissolve 158.6 mg of fumaric acid (charge molar ratio 1.5:1, acid / free base) in approximately 5 mL of EtOH to form an acid solution; c) Add the acid solution dropwise to the free base solution while stirring; d) adding about 13 mL of n-heptane dropwise; and then optionally seeding the mixture with crystalline form of fumarate salt Type A of Compound (I); e) stirring at about 5° C. for about 16 hours; and f) Isolating the solid by filtration and then drying the solid under vacuum at about 50°C.

[0160] The fumarate salt type A of Compound (I) is anhydrous, slightly hygroscopic rod-like crystals (as shown by PLM in Figure 5) with an acid / base stoichiometry of approximately 1.5:1, as determined by XRPD, TGA, DSC, and 1 The compound was characterized by H NMR. The XRPD pattern and data are shown in Figure 1 and Table 8, respectively. The TGA / DSC results in Figures 2 and 3 showed a weight loss of 1.9% up to 150°C, with a sharp endothermic peak at 167.6°C. 1 1 H NMR results indicated an acid / base molar ratio of 1.5:1. [Table 8] TIFF2026027273000014.tif59170

[0161] Example 2 Fumarate Type B of Compound (I) Approximately 15 mg of Compound (I) fumarate type A was suspended in 0.5 mL of HO in an HPLC vial. The suspension was magnetically stirred at a speed of approximately 1000 rpm at room temperature for 11 days. The solid was isolated by centrifugation and stored open at ambient conditions for 4 days to obtain Compound (I) fumarate type B. The XRPD results are shown in Figure 6 and Table 9. The TGA and DSC results are shown in Figures 7 and 8. The TGA curve showed a 4.9% weight loss up to 150°C. The DSC curve showed a broad endothermic peak at 91.3°C and a sharp endothermic peak at 166.3°C, which may be caused by the removal of water or solvent. 1H NMR results revealed that the molar ratio of fumaric acid to free base was 1:1. Compound (I) fumarate type B was heated to 140 °C and cooled to room temperature to obtain Compound (I) fumarate type A. Therefore, Compound (I) fumarate type B was a hydrate, which converted to the anhydrate after losing water of crystallization by heating. [Table 9]

[0162] Example 3 Fumarate Type C of Compound (I) Approximately 15 mg of Compound (I) fumarate type A was suspended in 0.5 mL of HO in an HPLC vial. The suspension was magnetically stirred at approximately 1000 rpm for 9 days at room temperature. The wet solid was isolated to obtain Compound (I) fumarate type C (the wet sample was analyzed). Since a transformation between Compound (I) fumarate type C and fumarate type B was observed during storage at ambient conditions, further characterization was not performed. Compound (I) fumarate type C had an acid / base stoichiometry of 1:1. The XRPD pattern and data are shown in Figure 10 and Table 10, respectively. [Table 10]

[0163] Example 4 Fumarate Type E of Compound (I) Approximately 30 mg of Compound (I) fumarate Type A was dissolved in 1 mL of ethyl formate in a glass vial. The solution was kept at room temperature for evaporation to obtain Compound (I) fumarate Type E. The XRPD pattern and data are shown in Figure 11 and Table 11, respectively. The TGA and DSC results in Figures 12 and 13 showed a 9.4% weight loss at a maximum of 150°C, with endothermic peaks at 134.5°C and 166.0°C. The molar ratio of formic acid to free base was 1.5:1. [Table 11]

[0164] Example 5 Free base type B of compound (I) Approximately 15 mg of the amorphous free base of Compound (I) was suspended in 0.5 mL of MIBK / cyclohexane (1:4, v / v) in an HPLC vial. The suspension was magnetically stirred at a speed of approximately 1000 rpm at 5°C for 7 days. The solid was isolated by centrifugation to obtain Form B of Compound (I). The XRPD pattern and data are shown in Figure 14 and Table 12, respectively. The TGA and DSC results in Figures 15 and 16 showed a weight loss of 3.5% up to 150°C and a sharp endothermic peak at 169.4°C. The results in Figure 17 showed a 3.5% weight loss up to 150°C and a sharp endothermic peak at 169.4°C. 1 H NMR results revealed a residual solvent cyclohexane / free base molar ratio of 0.1:1 (corresponding to a TGA weight loss of 0.2%). PLM in Figure 18 showed that Compound (I) free base Type B was anhydrous, slightly hygroscopic, irregular particles with aggregates. [Table 12]

[0165] Example 6 Free base type C of compound (I) Approximately 15 mg of the amorphous free base of Compound (I) was suspended in 0.5 mL of THF / HO (1:4, v / v) in an HPLC vial. The suspension was magnetically stirred at a speed of approximately 1000 rpm at 5°C for 7 days. The solid was isolated via centrifugation to obtain the free base Type C of Compound (I). The XRPD results are shown in Figure 19 and Table 13. The TGA and DSC results are shown in Figures 20 and 21. In the TGA / DSC curve, a weight loss of 1.5% was observed up to 150°C, and two endotherms (peaks) at 86.2°C and 114.4°C were observed. 1 The results of H NMR showed that the solvent THF was not detected. Combined with the characterization results of the free base type D of compound (I) (see Example 7), it was speculated that the free base type C of compound (I) was a hydrate. [Table 13]

[0166] Example 7 Compound (I) free base type D Approximately 60 mg of the amorphous free base of Compound (I) was suspended in 2 mL of THF / HO (1:4, v / v) in an HPLC vial. The suspension was magnetically stirred at approximately 1000 rpm for 3 days at 5° C. The solid was isolated and dried at ambient conditions for approximately 2 hours to obtain Compound (I) free base Type D. The XRPD results are shown in FIG. 23 and Table 14. Compound (I) free base Type D is a hydrate and can be obtained by placing Compound (I) free base Type C at ambient conditions. [Table 14]

[0167] Example 8 Compound (I) free base type E Approximately 60 mg of the amorphous free base of Compound (I) was suspended in 2 mL of THF / HO (1:4, v / v) in an HPLC vial. The suspension was magnetically stirred at approximately 1000 rpm at 5° C. for 4 days. The solid was isolated by centrifugation and dried at ambient conditions for approximately 2 hours. After sweeping the solid with N at 30° C. for 20 minutes, Compound (I) free base Type E was obtained. The XRPD pattern and XRPD data are shown in FIG. 24 and Table 15. Free base Type E was assumed to be anhydrous and converted to Compound (I) free base Type C after exposure to ambient conditions for 30 minutes. [Table 15]

[0168] Example 9 Free base type F of compound (I) Approximately 15 mg of the amorphous free base of Compound (I) was suspended in 0.5 mL of ACN / n-heptane (1:9, v / v) in an HPLC vial. The suspension was magnetically stirred at a speed of approximately 1000 rpm at room temperature for 2 days. The solid was isolated by centrifugation. Free base Type F was a hydrate. The XRPD pattern and data are shown in Figure 25 and Table 16. The TGA curve in Figure 26 showed a weight loss of 5.7% up to 70°C. The DSC curve in Figure 27 showed endothermic peaks at 55.4 and 109.5°C. [Table 16]

[0169] Example 10 Free base type G of compound (I) Approximately 15 mg of amorphous free base of Compound (I) was dissolved in 0.5 mL of EtOH in a glass vial. An anti-solvent of HO was then added to the EtOH solution to obtain a suspension. The solid was isolated by centrifugation. Free base Type G was a hydrate. The XRPD pattern and data are shown in Figure 28 and Table 17. The TGA curve in Figure 29 showed a weight loss of 7.3% up to 70°C. The DSC curve in Figure 30 showed endothermic peaks at 32.9, 59.2, and 110.2°C. [Table 17]

[0170] Example 11 Free base type A of compound (I) Approximately 15 mg of the amorphous free base of Compound (I) was suspended in 0.5 mL of acetone / n-heptane (1:4, v:v) in an HPLC vial. The suspension was magnetically stirred at a speed of approximately 1000 rpm at room temperature for 3 days. The solid was isolated by centrifugation and dried at ambient conditions for 1 day. Compound (I) free base Type A was an acetone solvate obtained via slurrying the amorphous free base in acetone / n-heptane (1:4) at room temperature for 3 days. The XRPD pattern and data are shown in Figure 31 and Table 18, respectively. The TGA and DSC curves in Figures 32 and 33 showed a 9.9% weight loss up to 140°C and an endotherm at 71.3°C (peak temperature). As shown in Figure 34 1 HNMR results indicated that the molar ratio of acetone:free base was 0.7:1 (6.9 wt %). [Table 18]

[0171] Example 12 HCl salt type A of compound (I) Approximately 15 mg of amorphous free base of Compound (I) and 4.6 μL of concentrated HCl (charge molar ratio 2:1, acid / free base) were suspended in 0.5 mL of EtOAc / n-heptane (1:2, v:v) in an HPLC vial. The suspension was magnetically stirred at a speed of approximately 1000 rpm at room temperature for 3 days. The solid was isolated by centrifugation and dried at ambient conditions for 1 day to obtain Compound (I) HCl salt Type A. The XRPD pattern and data are shown in Figure 35 and Table 19, respectively. The TGA and DSC curves in Figures 36 and 37 showed an 8.8% weight loss up to 150°C and an endotherm at 110.0°C (peak temperature). The molar ratio of HCl:free base was 2.5:1. [Table 19]

[0172] Example 13 HCl salt type B of compound (I) Approximately 500 mg of amorphous free base of Compound (I) was dissolved in approximately 10 mL of EtOAc. 935 μL of HCl (charge molar ratio 2:1, acid / free base) in EtOAc was diluted with 15 mL of EtOH. Compound (I) HCl salt type B was optionally added as seed crystals to the free base solution, but did not completely dissolve. The acid solution was then added dropwise while stirring at approximately 1000 rpm. After the mixture became cloudy, it was stirred at room temperature for 8 hours and then at 5°C for an additional 13 hours. The precipitated solid was isolated by filtration and dried under reduced pressure at room temperature overnight to obtain Compound (I) HCl salt type B. The XRPD pattern and data are shown in Figure 38 and Table 20, respectively. The TGA and DSC curves in Figures 39 and 40 show a 2.3% weight loss up to 150°C and an endotherm at 241.7°C (peak temperature). The molar ratio of HCl:free base was 2.2:1. [Table 20]

[0173] Example 14 Mesylate Type A of Compound (I) Approximately 15 mg of amorphous free base of Compound (I) and 5.5 mg of methanesulfonic acid (charge molar ratio 2:1, acid / free base) were suspended in 0.5 mL of acetone / n-heptane (1:4, v:v) in an HPLC vial. The suspension was magnetically stirred at a speed of approximately 1000 rpm at room temperature for 3 days. The solid was isolated by centrifugation and dried at ambient conditions for 1 day to obtain Compound (I) mesylate Type A. The XRPD pattern and data are shown in Figure 41 and Table 21, respectively. The TGA and DSC curves in Figures 42 and 43 showed a 10.2% weight loss up to 150°C and an endotherm at 65.1°C (peak temperature). The molar ratio of acid to free base was 2.0:1. [Table 21]

[0174] Example 15 Mesylate Type B of Compound (I) Approximately 15 mg of amorphous free base of Compound (I) and 5.4 mg of methanesulfonic acid (charge molar ratio 2:1, acid / free base) were suspended in 0.5 mL of IPA / cyclohexane (1:4, v:v) in an HPLC vial. The suspension was magnetically stirred at a speed of approximately 1000 rpm at room temperature for 3 days. The solid was isolated by centrifugation and dried at ambient conditions for 1 day to obtain Compound (I) mesylate Type B. The XRPD pattern and data are shown in Figure 44 and Table 22, respectively. The TGA and DSC curves in Figures 45 and 46 showed a 7.6% weight loss up to 150°C and an endotherm at 63.4°C (peak temperature). The molar ratio of acid to free base was 1.7:1. [Table 22]

[0175] Example 16 Phosphate Type A of Compound (I) Approximately 15 mg of amorphous free base of Compound (I) and 1.9 μL of concentrated HPO (charge molar ratio 1:1, acid / free base) were suspended in 0.5 mL of acetone / n-heptane (1:4, v:v) in an HPLC vial. The suspension was magnetically stirred at approximately 1000 rpm for 3 days at room temperature. The solid was isolated by centrifugation and dried at ambient conditions for 1 day to obtain Compound (I) phosphate salt Type A. The XRPD pattern and data are shown in Figure 47 and Table 23, respectively. The TGA and DSC curves in Figures 48 and 49 showed a 9.5% weight loss up to 150 °C and endotherms at 79.1 °C and 194.8 °C (peak temperatures). The molar ratio of acid to free base was 1.1:1. [Table 23]

[0176] Example 17 L-tartrate salt type A of compound (I) Approximately 15 mg of amorphous free base of Compound (I) and 4.3 mg of L-tartaric acid (charge molar ratio 1:1, acid / free base) were suspended in 0.5 mL of EtOAc / n-heptane (1:2, v:v) in an HPLC vial. The suspension was magnetically stirred at a speed of approximately 1000 rpm at room temperature for 3 days. The solid was isolated by centrifugation and dried at ambient conditions for 1 day to obtain Compound (I) L-tartrate salt Type A. The XRPD pattern and data are shown in Figure 50 and Table 24, respectively. The TGA and DSC curves in Figures 51 and 52 showed a weight loss of 3.7% up to 150°C and endothermic peaks at 77.6 and 164.7°C. The molar ratio of L-tartaric acid to free base was 0.5:1. [Table 24]

[0177] Example 18 Compound (I) adipate type A Approximately 15 mg of amorphous free base of Compound (I) and 4.3 mg of adipic acid (charge molar ratio 1:1, acid / free base) were suspended in 0.5 mL of EtOAc / n-heptane (1:2, v:v) in an HPLC vial. The suspension was magnetically stirred at a speed of approximately 1000 rpm at room temperature for 3 days. The solid was isolated by centrifugation and dried at ambient conditions for 1 day to obtain Compound (I) adipate salt Type A. The XRPD pattern and data are shown in Figure 53 and Table 25, respectively. The TGA and DSC curves in Figures 54 and 55 showed a 3.0% weight loss up to 150°C and an endotherm at 106.7°C (peak temperature). The molar ratio of adipic acid to free base was 1.3:1. [Table 25]

[0178] Example 19 Amorphous fumarate of compound (I) Approximately 3 g of Compound (I) fumarate Type A was dissolved in approximately 50 mL of MeOH in a glass vial. The solution was transferred to a rotary evaporator, and the solvent was removed by rotary evaporation at 60°C to obtain amorphous Compound (I) fumarate. The XRPD pattern is shown in Figure 56. The TGA curve in Figure 57 showed a weight loss of 3.6% up to 150°C. The mDSC curve in Figure 58 showed a thermogravimetry (TG) midpoint temperature of 79.9 and 107.5°C. The molar ratio of formic acid to free base was 1.5:1.

[0179] Example 20 Amorphous free base of compound (I) Approximately 2 g of Compound (I) free base type B was dissolved in approximately 40 mL of DCM in a glass vial. The solution was transferred to a rotary evaporator, and the solvent was removed by rotary evaporation at 40°C to obtain amorphous Compound (I) free base. The XRPD pattern is shown in Figure 59. The TGA curve in Figure 60 showed a weight loss of 1.9% up to 150°C. The mDSC curve in Figure 61 showed a thermogravimetry (TG) midpoint temperature of 58.7°C.

[0180] Example 21: Comparison of the solubility of amorphous free base, fumarate type B, and fumarate type E in FaSSIF Kinetic solubility of amorphous free base and fumarate salt types B and E was measured in FaSSIF to assess solubility. All solubility samples (5-10 mg / mL initial solid loading) were rotated on a rotating incubator and sampled at 1, 4, and 24 hours at 37 °C. After centrifugation, the supernatant was collected for HPLC testing.

[0181] The results are summarized in Table 26. Compared to the amorphous free base seen in the prior art, Fumarate Type B and Fumarate Type E showed higher solubility in FaSSIF. [Table 26]

[0182] Example 22 Solubility Comparison of Amorphous Free Base and Fumarate Types A / B / E in HO The equilibrium solubility of the amorphous free base and fumarate salt types A, B, and E was evaluated in HO at 37°C. Approximately 5-10 mg of the solid was suspended in HO to obtain a mixture. The suspension was stirred for 24 hours, followed by centrifugation and filtration to obtain the supernatant for HPLC testing.

[0183] The results are summarized in Table 27. Compared to the amorphous free base seen in the prior art, Fumarate Type A, Fumarate Type B, and Fumarate Type E showed much better solubility in HO. [Table 27]

[0184] Example 23 Comparison of Solubility of Amorphous Free Base, Free Base Type B, and Fumarate Types A / B / E in pH 4.5 Buffer The equilibrium solubility of the amorphous free base, free base type B, and fumarate salt types A, B, and E was evaluated in a pH 4.5 buffer solution at 37°C. Approximately 5-10 mg of the solid was suspended in a pH 4.5 buffer solution to obtain a mixture. The suspension was stirred for 24 hours, then centrifuged and filtered to obtain the supernatant for HPLC analysis.

[0185] The results are summarized in Table 28. Compared to the amorphous free base seen in the prior art, free base Type B, fumarate Type A, fumarate Type B, and fumarate Type E showed better solubility in pH 4.5 buffer. [Table 28]

[0186] Example 24 Comparison of Solubility of Amorphous Free Base and Fumarate Salt Types B / E in pH 6.8 Buffer The equilibrium solubility of the amorphous free base and fumarate salt types B and E was evaluated in pH 6.8 buffer at 37°C. Approximately 5-10 mg of the solid was suspended in pH 6.8 buffer to obtain a mixture. The suspension was stirred for 24 hours, then centrifuged and filtered to obtain the supernatant for HPLC testing.

[0187] The results are summarized in Table 29. Compared to the amorphous free base seen in the prior art, Fumarate Type B and Fumarate Type E had improved solubility in pH 6.8 buffer. [Table 29]

[0188] Example 25: Flowability and Compressibility Bulk density was determined by adding an appropriate amount (m) of material to a 5 mL graduated cylinder and recording its apparent volume (v). Bulk density was obtained by dividing the amount of material by the apparent volume of unsettled material (ρ = m / v). For tapped density, the cylinder was then tapped 200 times. Tapped density was then calculated by dividing the amount of material by its final tapped volume (ρ = m / v). Carr index = (ρ - ρ) / ρ.

[0189] A repose angle is formed on a fixed base with a retaining lip to hold the powder layer on the base. A symmetrical powder cone is carefully constructed. The height (h) and base radius (r) of the powder cone are measured and calculated using the following equation: α = tan -1 The angle of repose is determined by calculating the angle of repose α from (h / r).

[0190] The flow and compressibility results for amorphous free base, free base Type F, fumarate Type B, and fumarate Type E are summarized in Table 30. In general, powders with a lower Carr index exhibit better compressibility and flowability. Also, powders with a lower angle of repose exhibit better flowability.

[0191] The results showed that it exhibited relatively good flow and compressibility compared to amorphous free base, free base Type F, fumarate Type B and fumarate Type E. [Table 30]

[0192] Example 26: Contact angle The wettability of the solid forms was evaluated by contact angle with water. The results, summarized in Table 31, showed that all samples of the selected solid forms were wettable with water. Compared to the amorphous free base samples, the contact angles of Fumarate Type A and Fumarate Type B were relatively small, suggesting that Fumarate Type A and Fumarate Type B could be more easily wetted by water. [Table 31]

[0193] Example 27: Crystal Habit PLM was used to observe the crystal habits of the particles (amorphous free base and fumarate type A). Results showed that the amorphous free base sample consisted of irregularly shaped particles without clear boundaries. Fumarate type A had rod-like particles with a regular shape. Compared to the amorphous free base, fumarate type A showed better crystallinity, which makes it more suitable for further development.

[0194] Example 28: Hygroscopicity DVS isotherm plots were collected at 25°C to investigate the stability of selected solid forms as a function of humidity. The results are summarized in Table 32. Compared to the amorphous free base, free base Type B, fumarate Type A, fumarate Type B, and fumarate Type E were less hygroscopic below 80% RH / 25°C. [Table 32]

[0195] Example 29: Mechanical Stability The mechanical stability of the solid forms was evaluated by monitoring XRPD morphology changes after milling (about 5 minutes) and tableting (about 234 MPa). The XRPD results showed that no morphology changes were observed for Free Base Type-B, Fumarate Type-A, and Fumarate Type-E after milling or tableting (Table 33), confirming that Free Base Type-B, Fumarate Type-A, and Fumarate Type-E exhibit good mechanical stability. [Table 33]

[0196] Example 30: Solid-state stability To evaluate the solid-state stability of selected forms (amorphous free base, free base Type F, fumarate Type A, and fumarate Type B), samples were stored at 40°C / 75% RH / open for one month. Samples for stability were characterized by XRPD to check for any solid-state form changes and by HPLC to check for purity changes. All results are summarized in Table 34.

[0197] The results showed that: (1) Free Base Type F, Fumarate Type A, and Fumarate Type B exhibited good physical stability, as evidenced by the lack of morphological change under all conditions; (2) Free Base Type F, Fumarate Type A, and Fumarate Type B exhibited better chemical stability with less purity change compared to the purity change of the amorphous free base after 1 month of storage at 40°C / 75% RH. [Table 34]

[0198] Characterization results The results of characterization of the fumarate, free base, and crystalline salt forms of Compound (I) are summarized in Tables 35-37. [Table 35] --Fumarate Type C was not characterized and identified due to the transformation between fumarate types B and C. *: Intermediate temperature of thermogravimetry [Table 36] --Free base Type D could not be characterized TGA / DSC due to limited amount of material and morphology change to free base Type E after N2 purging. Free base Type E, which converted to Type D after exposure to ambient conditions, could not be characterized by TGA / DSC. *:Tg, medium temperature. [Table 37]

[0199] The foregoing description is considered merely as illustrative of the principles of this invention. Moreover, since numerous modifications and changes will be readily apparent to those skilled in the art, it is not desired to limit the invention to the exact structures and processes shown above. Accordingly, all suitable modifications and equivalents may be considered to fall within the scope of the present invention as defined by the claims that follow.

Claims

1. The following structural formula: A crystalline form of compound (I) represented by A crystalline form that is a complex of the free base with a pharmaceutically acceptable acid, or the free base.

2. 2. The crystalline form of claim 1, wherein the complex or free base is a solvate or a non-solvate.

3. 3. The crystalline form of claim 1 or 2, wherein the complex is a salt, or a co-crystal, or a co-crystal of a salt.

4. 4. The crystalline form of any one of claims 1 to 3, wherein the complex has an acid / base molar ratio of from 0.5:1 to 3:1, preferably from 0.5:1 to 2.5:1, more preferably from 1:1 to 1.5:

1.

5. 5. The crystalline form of any one of claims 1 to 4, wherein the pharmaceutically acceptable acid is selected from the group consisting of hydrochloride, methanesulfonic acid, phosphoric acid, tartaric acid, fumaric acid and adipic acid.

6. 6. The crystalline form of any one of claims 1 to 5, wherein the pharmaceutically acceptable acid is fumaric acid.

7. 7. The crystalline form of claim 6, wherein the crystalline form is Fumarate Type A characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.9 and 11.5 2θ (±0.2°).

8. 8. The crystalline form of claim 7, wherein the crystalline form is Fumarate Type A characterized by an X-ray powder diffraction pattern comprising peaks at at least 5.8, 6.9, 11.5, 12.1, and 17.7 2θ (±0.2°).

9. 9. The crystalline form of claim 8, wherein the crystalline form is Fumarate Type A characterized by an X-ray powder diffraction pattern comprising peaks at least at 5.8, 6.9, 11.5, 12.1, 17.7, 20.8, and 24.0 2θ (±0.2°).

10. 10. The crystalline form of claim 9, wherein the crystalline form is Fumarate Type A characterized by an X-ray powder diffraction pattern comprising peaks at least at 5.8, 6.9, 11.5, 12.1, 17.7, 18.9, 20.8, 23.1, 23.7, 24.0, and 28.8 2θ (±0.2°).

11. 11. The crystalline form of claim 10, wherein the crystalline form is Fumarate Type A, characterized by an X-ray powder diffraction pattern substantially the same as that in FIG.

12. 12. The crystalline form of any one of claims 7 to 11, characterized by a differential scanning calorimeter peak phase transition temperature of about 167.6°C.

13. 7. The crystalline form of claim 6, wherein the crystalline form is Fumarate Type B characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.6 and 11.4 2θ (±0.2°).

14. 14. The crystalline form of claim 13, wherein the crystalline form is Fumarate Type B characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.6, 10.7, 11.4, 12.9, 25.1, and 28.2 2θ (±0.2°).

15. 15. The crystalline form of claim 14, wherein the crystalline form is Fumarate Type B characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.6, 10.7, 11.4, 12.9, 15.8, 17.9, 19.7, 25.1, and 28.2 2θ (±0.2°).

16. 16. The crystalline form of claim 15, wherein the crystalline form is Fumarate Type B, characterized by an X-ray powder diffraction pattern substantially the same as that of Figure 6.

17. 17. The crystalline form of any one of claims 13 to 16, characterized by differential scanning calorimeter peak phase transition temperatures of about 91.3°C and about 166.3°C.

18. 7. The crystalline form of claim 6, wherein the crystalline form is Fumarate Type C characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.8 and 11.8 2θ (±0.2°).

19. 19. The crystalline form of claim 18, wherein the crystalline form is Fumarate Type C characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.8, 11.2, 11.8, 13.6, and 18.4 2θ (±0.2°).

20. 20. The crystalline form of claim 19, wherein the crystalline form is Fumarate Type C characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.8, 11.2, 11.8, 13.6, 15.1, 16.0, 17.2, 18.4, and 24.5 2θ (±0.2°).

21. 21. The crystalline form of claim 20, wherein the crystalline form is Fumarate Type C, with an X-ray powder diffraction pattern substantially the same as Figure 10.

22. 7. The crystalline form of claim 6, wherein the crystalline form is Fumarate Type E characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.7, 11.6, and 28.5 2θ (±0.2°).

23. 23. The crystalline form of claim 22, wherein the crystalline form is Fumarate Type E characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.7, 10.9, 11.6, 16.9, 25.2, and 28.5 2θ (±0.2°).

24. 24. The crystalline form of claim 23, wherein the crystalline form is Fumarate Type E characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.7, 10.9, 11.6, 12.9, 15.3, 16.9, 19.9, 25.2, and 28.5 2θ (±0.2°).

25. 25. The crystalline form of claim 24, wherein the crystalline form is Fumarate Type E characterized by an X-ray powder diffraction pattern comprising peaks at least at 5.5, 6.7, 10.9, 11.6, 12.9, 15.3, 16.9, 18.1, 19.9, 25.2, 27.5, and 28.5 2θ (±0.2°).

26. 26. The crystalline form of claim 25, wherein the crystalline form is Fumarate Type E, with an X-ray powder diffraction pattern substantially the same as Figure 11.

27. 27. The crystalline form of any one of claims 22 to 26, characterized by differential scanning calorimeter peak phase transition temperatures of about 134.5°C and about 166.0°C.

28. 3. The crystalline form of claim 1 or 2, wherein the crystalline form is free base Type B, characterized by an X-ray powder diffraction pattern containing peaks at least at 8.0 and 11.5 2θ (±0.2°).

29. 29. The crystalline form of claim 28, wherein the crystalline form is free base Type B characterized by an X-ray powder diffraction pattern comprising peaks at at least 8.0, 11.5, 16.0, 17.2, 18.8, and 24.3 2θ (±0.2°).

30. 30. The crystalline form of claim 29, wherein the crystalline form is free base Type B characterized by an X-ray powder diffraction pattern comprising peaks at least at 8.0, 11.5, 16.0, 17.2, 18.2, 18.8, 20.3, 21.9, and 24.3 2θ (±0.2°).

31. 31. The crystalline form of claim 30, wherein the crystalline form is free base Type B characterized by an X-ray powder diffraction pattern comprising peaks at least at 8.0, 11.5, 13.1, 16.0, 17.2, 18.2, 18.8, 20.3, 21.2, 21.9, 24.3, and 27.7 2θ (±0.2°).

32. 32. The crystalline form of claim 31 , wherein the crystalline form is free base Type B, characterized by an X-ray powder diffraction pattern substantially the same as that of FIG.

14.

33. 33. The crystalline form of any one of claims 28 to 32, characterized by a differential scanning calorimeter peak phase transition temperature of about 169.4°C.

34. 3. The crystalline form of claim 1 or 2, wherein the crystalline form is free base Type C characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.6 and 18.8 2θ (±0.2°).

35. 35. The crystalline form of claim 34, wherein the crystalline form is free base Type C characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.6, 12.7, 18.8, 20.7, and 24.4 2θ (±0.2°).

36. 36. The crystalline form of claim 35, wherein the crystalline form is free base Type C characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.6, 12.7, 14.1, 18.1, 18.8, 20.7, 23.4, 24.4, and 26.7 2θ (±0.2°).

37. 37. The crystalline form of claim 36, wherein the crystalline form is free base Type C characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.6, 9.4, 12.7, 14.1, 14.9, 18.1, 18.8, 20.7, 22.9, 23.4, 24.4, and 26.7 2θ (±0.2°).

38. 38. The crystalline form of claim 37, wherein the crystalline form is free base Type C, characterized by an X-ray powder diffraction pattern substantially the same as the pattern of Figure 19.

39. 39. The crystalline form of any one of claims 34 to 38, characterized by differential scanning calorimeter peak phase transition temperatures of about 86.2°C and about 114.4°C.

40. 3. The crystalline form of claim 1 or 2, which is free base Type D, characterized by an X-ray powder diffraction pattern containing peaks at least at 5.7, 5.8, and 18.8 2θ (±0.2°).

41. 41. The crystalline form of claim 40, wherein the crystalline form is free base Type D characterized by an X-ray powder diffraction pattern comprising peaks at least at 5.7, 5.8, 11.8, 12.6, 18.8, 20.6, and 24.3 2θ (±0.2°).

42. 42. The crystalline form of claim 41, wherein the crystalline form is free base Type D characterized by an X-ray powder diffraction pattern comprising peaks at least at 5.7, 5.8, 11.8, 12.6, 18.8, 20.6, 22.8, 23.3, and 24.3 2θ (±0.2°).

43. 43. The crystalline form of claim 42, wherein the crystalline form is free base Type D, characterized by an X-ray powder diffraction pattern substantially the same as the pattern of Figure 23.

44. 3. The crystalline form of claim 1 or 2, wherein the crystalline form is free base Type E, characterized by an X-ray powder diffraction pattern containing peaks at least at 7.2, 18.2, and 22.3 2θ (±0.2°).

45. 45. The crystalline form of claim 44, wherein the crystalline form is free base Type E characterized by an X-ray powder diffraction pattern comprising peaks at least at 7.2, 18.2, 19.2, 22.3, 23.0, and 24.0 2θ (±0.2°).

46. 46. ​​The crystalline form of claim 45, wherein the crystalline form is free base Type E characterized by an X-ray powder diffraction pattern comprising peaks at least at 7.2, 14.9, 16.7, 18.2, 19.2, 22.3, 23.0, 24.0, and 26.8 2θ (±0.2°).

47. 47. The crystalline form of claim 46, wherein the crystalline form is free base Type E characterized by an X-ray powder diffraction pattern comprising peaks at least at 7.2, 12.6, 14.9, 16.7, 18.2, 19.2, 19.7, 20.5, 22.3, 23.0, 24.0, and 26.8 2θ (±0.2°).

48. 48. The crystalline form of claim 47, wherein the crystalline form is free base Type E, characterized by an X-ray powder diffraction pattern substantially the same as the pattern of Figure 24.

49. 3. The crystalline form of claim 1 or 2, wherein the crystalline form is free base type F, characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.2, 11.6, and 12.6 2θ (±0.2°).

50. 50. The crystalline form of claim 49, wherein the crystalline form is free base Type F characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.2, 11.6, 12.6, 14.8, 16.5, and 24.4 2θ (±0.2°).

51. 51. The crystalline form of claim 50, wherein the crystalline form is free base Type F characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.2, 11.6, 12.6, 14.8, 16.5, 17.6, 19.3, 24.4, and 26.0 2θ (±0.2°).

52. 52. The crystalline form of claim 51, wherein the crystalline form is free base Type F characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.2, 9.3, 11.6, 12.6, 14.8, 16.5, 17.6, 18.7, 19.3, 24.4, and 26.0 2θ (±0.2°).

53. 53. The crystalline form of claim 52, wherein the crystalline form is free base Type F, with an X-ray powder diffraction pattern substantially the same as Figure 25.

54. 54. The crystalline form of any one of claims 49 to 53, characterized by differential scanning calorimeter peak phase transition temperatures of about 55.4°C and about 109.5°C.

55. 3. The crystalline form of claim 1 or 2, wherein the crystalline form is free base type G, characterized by an X-ray powder diffraction pattern comprising peaks at least at 5.7, 5.9, and 12.7 2θ (±0.2°).

56. 56. The crystalline form of claim 55, wherein the crystalline form is free base Type G, characterized by an X-ray powder diffraction pattern comprising peaks at least at 5.7, 5.9, 11.9, 12.7, 14.5, and 26.2 2θ (±0.2°).

57. 57. The crystalline form of claim 56, wherein the crystalline form is free base Type G characterized by an X-ray powder diffraction pattern comprising peaks at least at 5.7, 5.9, 11.9, 12.7, 14.5, 17.6, 19.7, 22.9, and 26.2 2θ (±0.2°).

58. 58. The crystalline form of claim 57, wherein the crystalline form is free base Type G characterized by an X-ray powder diffraction pattern comprising peaks at least at 5.7, 5.9, 11.9, 12.7, 14.5, 17.2, 17.6, 19.7, 20.6, 22.9, 24.8, and 26.2 2θ (±0.2°).

59. 59. The crystalline form of claim 58, wherein the crystalline form is free base Type G, with an X-ray powder diffraction pattern substantially the same as Figure 28.

60. 60. The crystalline form of any one of claims 55-59, characterized by differential scanning calorimeter peak phase transition temperatures of about 32.9°C, about 59.2°C, and about 110.2°C.

61. 3. The crystalline form of claim 1 or 2, wherein the crystalline form is an acetone solvate, free base type A, characterized by an X-ray powder diffraction pattern comprising peaks at least at 7.0, 9.0, and 23.3 2θ (±0.2°).

62. 62. The crystalline form of claim 61, wherein the crystalline form is an acetone solvate, free base Type A, characterized by an X-ray powder diffraction comprising peaks at at least 7.0, 9.0, 11.6, 13.6, 15.4, 18.1, 19.6, and 23.3 2θ (±0.2°).

63. 63. The crystalline form of claim 62, wherein the crystalline form is an acetone solvate, free base Type A, characterized by an X-ray powder diffraction pattern substantially the same as that of Figure 31.

64. 64. The crystalline form of any one of claims 61 to 63, characterized by a differential scanning calorimeter peak phase transition temperature of about 71.3°C.

65. 6. The crystalline form of any one of claims 1 to 5, wherein the salt is HCl salt Type A, characterized by an X-ray powder diffraction peak at least at 18.1 2θ (±0.2°).

66. 66. The crystalline form of claim 65, wherein the salt is HCl salt Type A, characterized by an X-ray powder diffraction pattern substantially the same as the pattern of Figure 35.

67. 67. The crystalline form of claim 65 or 66, characterized by a differential scanning calorimeter peak phase transition temperature of about 110.0°C.

68. 6. The crystalline form of any one of claims 1 to 5, wherein the salt is HCl salt Type B, characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.9, 12.4, and 25.0 2θ (±0.2°).

69. 69. The crystalline form of claim 68, wherein the salt is HCl salt Type B, characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.9, 11.9, 12.4, 17.0, 25.0, and 29.1 2θ (±0.2°).

70. 70. The crystalline form of claim 69, wherein the salt is HCl salt Type B, characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.9, 9.6, 11.9, 12.4, 17.0, 21.2, 22.7, 25.0, and 29.1 2θ (±0.2°).

71. 71. The crystalline form of claim 70, wherein the salt is HCl salt Type B, characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.9, 9.6, 11.9, 12.4, 17.0, 19.9, 21.2, 22.7, 25.0, 25.9, 27.2, and 29.1 2θ (±0.2°).

72. 72. The crystalline form of claim 71, wherein the salt is HCl salt Type B, characterized by an X-ray powder diffraction pattern substantially the same as the pattern of Figure 38.

73. 73. The crystalline form of any one of claims 68-72, characterized by a differential scanning calorimeter peak phase transition temperature of about 241.7°C.

74. 6. The crystalline form of any one of claims 1 to 5, wherein the salt is mesylate type A, characterized by an X-ray powder diffraction comprising peaks at least at 6.5, 19.6 and 21.0 2θ (±0.2°).

75. 75. The crystalline form of claim 74, wherein the salt is mesylate Type A characterized by an X-ray powder diffraction comprising peaks at least at 5.3, 6.5, 7.8, 13.1, 15.7, 19.6, and 21.0 2θ (±0.2°).

76. 76. The crystalline form of claim 75, wherein the salt is mesylate Type A, characterized by an X-ray powder diffraction pattern substantially the same as the pattern of Figure 41.

77. 77. The crystalline form of any one of claims 74 to 76, characterized by a differential scanning calorimeter peak phase transition temperature of about 65.1°C.

78. 6. The crystalline form of any one of claims 1 to 5, wherein the salt is mesylate type B characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.0, 16.3 and 18.3 2θ (±0.2°).

79. 79. The crystalline form of claim 78, wherein the salt is mesylate type B characterized by an X-ray powder diffraction pattern comprising peaks at at least 6.0, 7.2, 12.4, 16.3, 18.3, 21.5, and 26.5 2θ (±0.2°).

80. 80. The crystalline form of claim 79, wherein the salt is mesylate Type B characterized by an X-ray powder diffraction pattern substantially the same as the pattern of Figure 44.

81. 81. The crystalline form of any one of claims 78-80, characterized by a differential scanning calorimeter peak phase transition temperature of about 63.4°C.

82. 6. The crystalline form of any one of claims 1 to 5, wherein the salt is Phosphate Type A characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.4, 14.0 and 22.9 2θ (±0.2°).

83. 83. The crystalline form of claim 82, wherein the salt is Phosphate Type A characterized by an X-ray powder diffraction comprising peaks at at least 6.4, 14.0, 14.9, 20.5, 22.9, and 24.5 2θ (±0.2°).

84. 84. The crystalline form of claim 83, wherein the salt is Phosphate Type A characterized by an X-ray powder diffraction comprising peaks at at least 6.4, 14.0, 14.9, 16.3, 18.7, 20.5, 21.4, 22.9, and 24.5 2θ (±0.2°).

85. 85. The crystalline form of claim 84, wherein the salt is Phosphate Type A characterized by an X-ray powder diffraction pattern substantially the same as the pattern of Figure 47.

86. 86. The crystalline form of any one of claims 82-85, characterized by differential scanning calorimeter peak phase transition temperatures of about 79.1°C and about 194.8°C.

87. 6. The crystalline form of any one of claims 1 to 5, wherein the salt is L-tartrate Type A characterized by an X-ray powder diffraction pattern comprising peaks at least at 6.5, 12.7, and 18.8 2θ (±0.2°).

88. 88. The crystalline form of claim 87, wherein the salt is L-tartrate Type A characterized by an X-ray powder diffraction pattern comprising peaks at at least 6.5, 9.4, 12.7, 18.8, 20.7, 22.7, 24.4, and 26.5 2θ (±0.2°).

89. 89. The crystalline form of claim 88, wherein the salt is L-tartrate salt Type A characterized by an X-ray powder diffraction pattern substantially the same as the pattern in FIG.

50.

90. 90. The crystalline form of any one of claims 87-89, characterized by differential scanning calorimeter peak phase transition temperatures of about 77.6°C and about 164.7°C.

91. 6. The crystalline form of any one of claims 1 to 5, wherein the salt is adipate type A, characterized by an X-ray powder diffraction pattern comprising peaks at at least 7.4, 10.8, and 25.7 2θ (±0.2°).

92. 92. The crystalline form of claim 91, wherein the salt is adipate type A characterized by an X-ray powder diffraction comprising peaks at least at 7.4, 10.8, 16.0, 17.7, 19.7, and 25.7 2θ (±0.2°).

93. 93. The crystalline form of claim 92, wherein the salt is adipate type A characterized by an X-ray powder diffraction comprising peaks at least at 7.4, 10.8, 12.6, 16.0, 17.7, 19.7, 20.9, 23.6, and 25.7 2θ (±0.2°).

94. 94. The crystalline form of claim 93, wherein the salt is adipate type A characterized by an X-ray powder diffraction comprising peaks at least at 7.4, 8.5, 10.8, 12.6, 14.9, 15.5, 16.0, 16.9, 17.7, 19.0, 19.7, 20.9, 23.6, 25.7, and 32.3 2θ (±0.2°).

95. 95. The crystalline form of claim 94, wherein the salt is adipate Type A, characterized by an X-ray powder diffraction pattern substantially the same as the pattern of Figure 53.

96. 96. The crystalline form of any one of claims 91 to 95, characterized by a differential scanning calorimeter peak phase transition temperature of about 106.7°C.

97. The following structural formula: An amorphous form of compound (I) represented by Amorphous forms that are pharmaceutically acceptable salts or free bases.

98. 98. The amorphous form of claim 97, wherein the amorphous form is an amorphous fumarate salt characterized by an X-ray powder diffraction pattern substantially the same as Figure 56.

99. 99. The amorphous form of claim 98, characterized by a modulated differential scanning calorimeter thermogram curve substantially the same as Figure 58.

100. 98. The amorphous form of claim 97, wherein the amorphous form is an amorphous free base characterized by an X-ray powder diffraction pattern substantially the same as Figure 59.

101. 101. The amorphous form of claim 100, characterized by a modulated differential scanning calorimeter thermogram curve substantially the same as Figure 61.

102. A process for the preparation of the crystalline form of any one of claims 1 to 96, comprising the steps of: When the crystalline form is a complex of a free base and a pharmaceutically acceptable acid, the method comprises: a) adding compound (I) and the acid in a solvent; and b) slurrying at a temperature for a time sufficient to initiate precipitation of said complex; Including; When the crystalline form is a free base, the method comprises: a) adding compound (I) in a solvent; and b) slurrying at a temperature for a time sufficient to initiate precipitation of the free base. A method comprising:

103. 103. The method of claim 102, wherein the acid is selected from the group consisting of hydrochloride, methanesulfonic acid, phosphoric acid, tartaric acid, fumaric acid, and adipic acid.

104. 104. The method according to claim 102 or 103, wherein in step a), the crystalline form is a complex of a free base and a pharmaceutically acceptable acid, and the compound (I) and the acid are added to the solvent in an acid / base molar ratio ranging from 0.5:1 to 3:1, preferably from 0.5:1 to 2.5:1; more preferably from 1:1 to 1.5:

1.

105. The solvent is H ２ 105. The method of any one of claims 102-104, wherein the solvent is selected from the group consisting of 0, EtOH, EtOAc, n-heptane, ethyl formate, acetone, cyclohexane, isopropyl alcohol, methyl isobutyl ketone, tetrahydrofuran, acetonitrile methyl tert-butyl ether, and combinations thereof.

106. 106. The method of any one of claims 102 to 105, further comprising seeding the solvent with the crystalline form of any one of claims 1 to 96.

107. 107. The method of any one of claims 102 to 106, wherein the temperature is about 5 to 50°C.

108. 108. The method of any one of claims 102 to 107, wherein the period of time is about 2 to 7.5 hours.

109. A process for the preparation of the crystalline form of fumarate type A of compound (I) according to any one of claims 7 to 12, comprising: a) dissolving the free base of Compound (I) in an ester or alcohol to form a free base solution; b) dissolving fumaric acid in EtOH to form an acid solution; c) adding the acid solution dropwise to the free base solution with stirring; d) adding alkane dropwise; and then optionally seeding the mixture with crystalline form of fumarate salt Type A of Compound (I); e) stirring at 0-10°C for 12-24 hours; and f) isolating the solid by filtration and then drying the solid under reduced pressure at 40-60°C. A method comprising:

110. 110. The method of claim 109, wherein the ester is selected from the group consisting of ethyl acetate, ethyl formate, methyl acetate, and isopropyl acetate.

111. 111. The method of claim 110, wherein the ester is ethyl acetate.

112. 110. The method of claim 109, wherein the alcohol is selected from the group consisting of methanol, ethanol, n-propanol, and isopropanol.

113. 113. The method of claim 112, wherein the alcohol is ethanol.

114. 110. The method of claim 109, wherein the alkane is selected from the group consisting of n-hexane, n-heptane, n-octane, and mixtures thereof.

115. 115. The method of claim 114, wherein the alkane is n-heptane.

116. A process for the preparation of the crystalline form of fumarate type B of compound (I) according to any one of claims 13 to 17, comprising: a) The crystalline form of fumarate type A of compound (I) was ２ suspending in O; b) magnetically stirring at a speed of about 1000 rpm at about room temperature for about 11 days; and c) isolating the solids by centrifugation and storing said solids open at ambient conditions for about 4 days. A method comprising:

117. A process for the preparation of the crystalline form of fumarate type C of compound (I) according to any one of claims 18 to 21, comprising: a) The crystalline form of fumarate type A of compound (I) was ２ suspending in O; b) magnetically stirring at a speed of about 1000 rpm at about room temperature for about 9 days; and c) Isolating the wet solid A method comprising:

118. A process for the preparation of the crystalline form of fumarate type E of compound (I) according to any one of claims 22 to 27, comprising: a) dissolving the fumarate-type crystalline form of Compound (I) in ethyl formate; b) evaporating the ethyl formate at about room temperature; c) isolating the solid A method comprising:

119. A process for the preparation of the crystalline form of free base Type A of compound (I) according to any one of claims 61 to 64, comprising: a) suspending the amorphous free base of Compound (I) in a solvent of acetone / n-heptane having a volume ratio of about 1:4; b) magnetically stirring at about room temperature at a speed of about 1000 rpm for about 3 days; and c) isolating the solid by centrifugation and drying the solid at ambient conditions for about 1 day. A method comprising:

120. A process for the preparation of the crystalline form of free base type B of compound (I) according to any one of claims 28 to 33, comprising: a) suspending the amorphous free base of Compound (I) in a solvent of methyl isobutyl ketone / cyclohexane having a volume ratio of about 1:4; b) magnetically stirring at a speed of about 1000 rpm at about 5° C. for about 7 days; and c) isolating the solids by centrifugation A method comprising:

121. A process for the preparation of the crystalline form of the free base type C of compound (I) according to any one of claims 34 to 39, comprising: a) tetrahydrofuran / H2O having a volume ratio of about 1:4 ２ suspending the amorphous free base of Compound (I) in a solvent of O; b) magnetically stirring at a speed of about 1000 rpm at about 5° C. for about 7 days; and c) isolating the solids by centrifugation A method comprising:

122. A process for the preparation of the crystalline form of free base type D of compound (I) according to any one of claims 40 to 43, comprising: a) tetrahydrofuran / H2O having a volume ratio of about 1:4 ２ suspending the amorphous free base of Compound (I) in a solvent of O; b) magnetically stirring at a speed of about 1000 rpm at about 5° C. for about 3 days; and c) isolating the solid by centrifugation and drying the solid at ambient conditions for about 2 hours. A method comprising:

123. A process for the preparation of the crystalline form of free base Type E of compound (I) according to any one of claims 44 to 48, comprising: a) tetrahydrofuran / H2O having a volume ratio of about 1:4 ２ suspending the amorphous free base of Compound (I) in a solvent of O; b) magnetically stirring at a speed of about 1000 rpm at about 5°C for about 4 days; c) isolating the solid by centrifugation and drying the solid at ambient conditions for about 2 hours; and d) N at about 30°C for about 20 minutes ２ sweeping the solid by A method comprising:

124. A process for the preparation of the crystalline form of the free base type F of compound (I) according to any one of claims 49 to 54, comprising: a) suspending the amorphous free base of Compound (I) in a solvent of acetonitrile / n-heptane; b) magnetically stirring at about room temperature at a speed of about 1000 rpm for about 2 days; c) isolating the solid A method comprising:

125. A process for the preparation of the crystalline form of the free base type G of compound (I) according to any one of claims 55 to 60, comprising: a) dissolving the amorphous free base of Compound (I) in EtOH; b) H ２ Add O to obtain a suspension; c) isolating the solid from said suspension. A method comprising:

126. A process for the preparation of HCl salt type A of compound (I) according to any one of claims 65 to 67, comprising: a) adding the amorphous free base of Compound (I) and concentrated HCl in a solvent of EtOAc / n-heptane having a volume ratio of about 1:2 at an acid / base molar ratio of about 2:1; b) magnetically stirring at about room temperature at a speed of about 1000 rpm for about 3 days; and c) isolating the solid by centrifugation and drying the solid at ambient conditions for about 1 day. A method comprising:

127. A process for the preparation of HCl salt type B of compound (I) according to any one of claims 68 to 73, comprising: a) dissolving the amorphous free base of Compound (I) in EtOAc to form a free base solution; b) diluting a solution of HCl in EtOAc in EtOH to form an acid solution; c) optionally adding seed crystals of HCl salt Type B of Compound (I) to the free base solution, wherein the seed crystals are not completely dissolved; d) adding the acid solution dropwise while stirring at a speed of about 1000 rpm; e) further stirring at room temperature for about 8 hours, then at about 5° C. for about 13 hours; f) isolating the solid by filtration and then drying said solid under vacuum at about room temperature overnight. Including, The method wherein the acid / base molar ratio is about 2:

1.

128. A process for the preparation of mesylate type A of compound (I) according to any one of claims 74 to 77, comprising: a) suspending the amorphous free base of Compound (I) and methanesulfonic acid in a solvent of acetone / n-heptane having a volume ratio of about 1:4 at an acid / base molar ratio of about 2:1; b) magnetically stirring at about room temperature at a speed of about 1000 rpm for about 3 days; and c) isolating the solid by centrifugation and drying the solid at ambient conditions for about 1 day. A method comprising:

129. A process for the preparation of mesylate type B of compound (I) according to any one of claims 78 to 81, comprising: a) suspending the amorphous free base of Compound (I) and methanesulfonic acid in a solvent of isopropyl alcohol / cyclohexane having a volume ratio of about 1:4, with an acid / base input molar ratio of about 2:1; b) magnetically stirring at about room temperature at a speed of about 1000 rpm for about 3 days; and c) isolating the solid by centrifugation and drying the solid at ambient conditions for about 1 day. A method comprising:

130. A process for the preparation of phosphate type A of compound (I) according to any one of claims 82 to 86, comprising the steps of: a) Amorphous free base of Compound (I) and concentrated H ３ P.O. ４ in a solvent of acetone / n-heptane having a volume ratio of about 1:4, with an acid / base molar ratio of about 1:1; b) magnetically stirring at a speed of about 1000 rpm at room temperature for about 3 days; and c) isolating the solid by centrifugation and drying the solid at ambient conditions for about 1 day. A method comprising:

131. A process for the preparation of L-tartrate salt type A of compound (I) according to any one of claims 87 to 90, comprising: a) suspending the amorphous free base of Compound (I) and L-tartaric acid in a solvent of EtOAc / n-heptane having a volume ratio of about 1:2 at an acid / base molar ratio of about 1:1; b) magnetically stirring at about room temperature at a speed of about 1000 rpm for about 3 days; and c) isolating the solid by centrifugation and drying the solid at ambient conditions for about 1 day. A method comprising:

132. A process for the preparation of compound (I) adipate type A according to any one of claims 91 to 96, comprising the steps of: a) suspending the amorphous free base of Compound (I) and adipic acid in a solvent of EtOAc / n-heptane having a volume ratio of about 1:2 at an acid / base molar ratio of about 1:1; b) magnetically stirring at about room temperature at a speed of about 1000 rpm for about 3 days; and c) isolating the solid by centrifugation and drying the solid at ambient conditions for about 1 day. A method comprising:

133. A process for the preparation of an amorphous form of compound (I) according to any one of claims 97 to 101, comprising: a) dissolving compound (I) in a solvent; and b) removing the solvent A method comprising:

134. The solvent is H ２ 134. The method of claim 133, wherein the solvent is selected from the group consisting of O, EtOH, EtOAc, n-heptane, ethyl formate, acetone, cyclohexane, isopropyl alcohol, methyl isobutyl ketone, tetrahydrofuran, acetonitrile, methyl tert-butyl ether, and combinations thereof.

135. 100. A process for the preparation of an amorphous fumarate salt of compound (I) according to claim 98 or 99, comprising: a) dissolving Compound (I) fumarate salt Type A in MeOH; and b) removing the MeOH by rotary evaporation at about 60° C. A method comprising:

136. 102. A process for the preparation of the amorphous free base of compound (I) according to claim 100 or 101, comprising: a) dissolving the free base type B of compound (I) in DCM; and b) removing the DCM by rotary evaporation at about 40° C. A method comprising:

137. 102. A pharmaceutical composition comprising the crystalline form of any one of claims 1 to 96 or the amorphous form of any one of claims 97 to 101 and a pharmaceutically acceptable carrier or excipient.

138. 138. A dosage form comprising a therapeutically effective amount of the crystalline form of any one of claims 1-96, the amorphous form of any one of claims 97-101, or the pharmaceutical composition of claim 137.

139. 102. A method of treating or ameliorating a hyperproliferative disease in a subject, comprising administering to said subject in need thereof a therapeutically effective amount of the crystalline form of any one of claims 1-96 or the amorphous form of any one of claims 97-101.

140. 140. The method of claim 139, wherein the hyperproliferative disease is cancer.

141. 141. The method of claim 140, wherein the cancer is ErbB2 positive.

142. 142. The method of claim 140 or 141, wherein the cancer is selected from the group consisting of breast cancer, gastric cancer, bile duct cancer, colorectal cancer, brain cancer, lung cancer, NSCLC, pancreatic cancer, head and neck cancer, ovarian cancer and uterine cancer.

143. 143. The method of any one of claims 139 to 142, wherein one or more additional compounds having anti-cancer properties are administered in combination.

144. 102. The crystalline form of any one of claims 1 to 96 or the amorphous form of any one of claims 97 to 101 for use in treating or ameliorating a hyperproliferative disease.

145. 145. The crystalline or amorphous form of claim 144, wherein the hyperproliferative disease is cancer.

146. 146. The crystalline or amorphous form of claim 145, wherein the cancer is ErbB2 positive.

147. 147. The crystalline or amorphous form of claim 145 or 146, wherein the cancer is selected from the group consisting of breast cancer, gastric cancer, bile duct cancer, colorectal cancer, brain cancer, lung cancer, NSCLC, pancreatic cancer, head and neck cancer, ovarian cancer and uterine cancer.

148. 148. The crystalline or amorphous form of any one of claims 144 to 147, administered in combination with one or more additional compounds having anti-cancer properties.

149. 102. Use of the crystalline form of any one of claims 1 to 96 or the amorphous form of any one of claims 97 to 101 in the manufacture of a medicament for treating or ameliorating a hyperproliferative disease.

150. 150. The use of claim 149, wherein the hyperproliferative disease is cancer.

151. 151. The use of claim 150, wherein the cancer is ErbB2 positive.

152. 152. The use of claim 150 or 151, wherein the cancer is selected from the group consisting of breast cancer, gastric cancer, bile duct cancer, colorectal cancer, brain cancer, lung cancer, NSCLC, pancreatic cancer, head and neck cancer, ovarian cancer and uterine cancer.

153. 153. The use according to any one of claims 149 to 152, wherein one or more anti-tumour agents are administered in combination.

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