Crystalline forms of quinazoline derivatives, their preparation, compositions and uses

Abstract

The invention relates to a preparation method of (R)-N-(4-([1, 2, 4] triazolo [1, 5-c] pyrimidin-7-yloxy)-3-methylphenyl)-5-((3, 4, 5-triazolo [1, 5-c] pyrimidin-7-yloxy)-3-methylphenyl The present invention relates to crystalline forms of 2, 3-difluoro-1-methylpiperidin-4-yl) oxy)-6-methoxyquinazolin-4-amine, to processes for their preparation, to pharmaceutical compositions comprising one or more of the crystalline forms as an active ingredient and to the use of said crystalline forms in the treatment of hyperproliferative diseases.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the priority benefit of international patent application No. PCT / CN2021 / 125016 filed on October 20, 2021, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0003] The present application relates to a crystalline form 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, a method for preparing the same, a pharmaceutical composition comprising one or more of the crystalline forms as an active ingredient, and the use of the crystalline form in the treatment of hyperproliferative diseases. Background Art

[0004] 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 almost identical structures, consisting of an extracellular region or ectodomain or ligand binding region, a single transmembrane region, and an intracellular cytoplasmic tyrosine kinase domain.

[0005] It has been demonstrated that ErbB2 plays a role in the development of cancer. ErbB2 overexpression occurs in 20% to 25% of breast cancer (BC) patients (Leyland-Jones B, J Clin Oncol. , 2009, 5278-86). Approximately 1.7 million new cases of BC are diagnosed each year (Cardoso F et al., Breast , 2018, 131-138), and 80% of BC are invasive, requiring chemotherapy, radiotherapy, 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 months 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 to treat a single or up to three brain metastases. SRS can be used for patients with four or fewer intracranial lesions. WBRT is used to manage multiple brain metastases but may result in significant neurocognitive decline (Venur VA et al., Int.J.Mol.Sci. ,2016,1543).

[0006] 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. The high incidence of BCBM in ErbB2-positive patients has been attributed to the intrinsic 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 VA et al., Int.J.Mol.Sci. ,2016,17,1543).

[0007] 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,Shirong et al., Acta Pharmacologica Sinica ,2017,233-240; Dinkel V et al., Cancer Research , 2012, 72). However, it is believed that none of these antibodies, ADCs, and TKIs have central nervous system (CNS) penetration. When non-brain penetrating antibodies, ADCs, and TKIs are used to treat BCBM patients, limited clinical efficacy is observed.

[0008] International Patent Publication No. WO 2020 / 057511 A1 (which is incorporated herein by reference in its entirety) discloses quinazoline compounds that inhibit type I receptor tyrosine kinases, exhibit good brain penetration in animals, and have favorable toxicity characteristics (e.g., reduced activity on hERG), and are therefore particularly useful for treating 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 specific compound, 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-methoxyquinazoline-4-amine (also referred to herein as compound (I)),

[0009]

[0010] It has been considered as a highly effective blood-brain barrier (BBB) ​​penetrating ErbB2 (HER2) inhibitor that exhibits high selectivity for wild-type EGFR and can minimize EGFR-mediated diarrhea and 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 A1).

[0011] Polymorphism is the phenomenon that different crystalline forms occur in a single compound, and it is a characteristic of some compounds and complexes. Therefore, polymorphs are different solids with the same molecular formula, but each polymorph may have different solid-state physical properties. Therefore, a single compound can produce a variety of polymorphic forms, wherein each form has different and unique solid-state physical properties, such as different solubility characteristics, melting point temperatures, fluidity, dissolution rate and / or different X-ray diffraction peaks. These actual physical properties are affected by the conformation and orientation of the molecules in the unit cell, which define the specific polymorphic form of the material. Due to the possibility of variable solubility of each polymorph, it is essential to identify the presence of drug polymorphs for providing predictable solubility characteristics for drugs. It is desirable to study all solid forms of drugs, including all polymorphic forms, and determine the stability, dissolution and flow characteristics of each polymorphic form. The polymorphic forms of compounds can be distinguished in the laboratory by X-ray diffraction spectrometry (such as X-ray powder diffraction ("XRPD")) and by other methods (such as infrared spectroscopy). In addition, polymorphic forms of the same drug substance or active pharmaceutical ingredient may be administered alone or formulated as a pharmaceutical composition and are well known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, ease of handling and compressibility of the drug substance and the safety and efficacy of the drug product. For more information, see Hilfiker, Rolf (ed.), Polymorphism in the Pharmaceutical Industry ,Weinheim, Germany: Wiley-VCH 2006.

[0012] The discovery of new polymorphic forms of pharmaceutically useful compounds provides new opportunities for improving the performance characteristics of drug products. Therefore, there is a continuing need to study the polymorphic forms of the above-mentioned quinazoline compounds that exhibit type I receptor tyrosine kinase inhibitory activity. It has now been found that there are new polymorphic forms of compound (I). Summary of the invention

[0013] In one aspect, the present invention relates to a crystalline form 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)), which is a complex of the free base and a pharmaceutically acceptable acid, or the free base.

[0014]

[0015] In some embodiments, the free base and the pharmaceutical acid complex or free base is a solvate or an unsolvate. In some embodiments, the free base and the pharmaceutical acid complex is a salt or a cocrystal or a cocrystal of a salt. In some embodiments, disclosed herein is a crystalline form of compound (I), which is designated as A-type fumarate, B-type fumarate, C-type fumarate, E-type fumarate, A-type free base, B-type free base, C-type free base, D-type free base, E-type free base, F-type free base, G-type free base, A-type hydrochloride, B-type hydrochloride, A-type mesylate, B-type mesylate, A-type phosphate, A-type L-tartrate and A-type adipate.

[0016] In another aspect, the present invention relates to an amorphous form of Compound (I), which is a pharmaceutically acceptable salt or free base. In some embodiments, disclosed herein is an amorphous form of Compound (I), which is designated as an amorphous fumarate salt and an amorphous free base.

[0017] In another aspect, the present invention relates to a process for preparing a crystalline form of Compound (I).

[0018] Additionally disclosed herein is a process for preparing an amorphous form of Compound (I).

[0019] In another aspect, the present invention relates to a pharmaceutical composition comprising a crystalline form or an amorphous form of Compound (I) and a pharmaceutically acceptable carrier or excipient.

[0020] In another aspect, the invention relates to a dosage form comprising a therapeutically effective amount of a crystalline form, an amorphous form, or a pharmaceutical composition as described herein.

[0021] In another aspect, the present invention relates to a method for treating or ameliorating a hyperproliferative disease in a subject, the method comprising administering to the subject in need thereof a therapeutically effective amount of a crystalline form or an amorphous form of Compound (I).

[0022] In another aspect, the present invention relates to a crystalline form or an amorphous form of Compound (I) for use in the treatment or amelioration of a hyperproliferative disease.

[0023] In another aspect, the present invention relates to the use of a crystalline form or an amorphous form of Compound (I) in the manufacture of a medicament for treating or ameliorating a hyperproliferative disease. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] The summary of the invention and the following detailed description may be further understood when read in conjunction with the accompanying drawings. For the purpose of illustrating the invention, exemplary embodiments of the invention are shown in the accompanying drawings; however, the invention is not limited to the specific disclosure of the accompanying drawings. In the accompanying drawings:

[0025] Figure 1 A representative XRPD pattern of the fumarate salt Form A.

[0026] Figure 2 The representative TGA curve of the A-type fumarate.

[0027] Figure 3 The representative DSC curve of the A-type fumarate.

[0028] Figure 4 Representative of Type A fumarate 1 H NMR spectrum.

[0029] Figure 5 Representative PLM images of fumarate form A.

[0030] Figure 6 A representative XRPD pattern of the Form B fumarate salt is shown.

[0031] Figure 7 The representative TGA curve of Form B fumarate.

[0032] Figure 8 The representative DSC curve of Form B fumarate.

[0033] Fig. 9 Representative of Type B fumarate 1 H NMR spectrum.

[0034] Fig.10The representative XRPD pattern of Form C fumarate.

[0035] Fig.11 The representative XRPD pattern of the E-fumarate salt is shown in FIG.

[0036] Fig.12 The representative TGA curve of E-fumarate.

[0037] Fig.13 The representative DSC curve of E-type fumarate.

[0038] Fig.14 A representative XRPD pattern of the free base Form B is shown.

[0039] Fig.15 This is a representative TGA curve of the free base type B.

[0040] Fig.16 The representative DSC curve of the free base type B is shown in FIG.

[0041] Fig.17 Representative of Type B free base 1 H NMR spectrum.

[0042] Fig.18 Representative PLM images of free base form B.

[0043] Fig.19 A representative XRPD pattern of Form C free base is shown.

[0044] Fig. 20 This is a representative TGA curve of the free base type C.

[0045] Fig.21 The representative DSC curve of the free base type C is shown in FIG.

[0046] Fig. 22 Representative of C-type free base 1 H NMR spectrum.

[0047] Fig.23 The representative XRPD pattern of the D-type free base is shown in FIG.

[0048] Fig.24 is a representative XRPD pattern of the free base Form E.

[0049] Fig.25 A representative XRPD pattern of Form F free base is shown.

[0050] Fig.26 This is a representative TGA curve of the free base of Form F.

[0051] Fig. 27 The representative DSC curve of Form F free base is shown in FIG.

[0052] Fig.28 is a representative XRPD pattern of Form G free base.

[0053] Fig.29 This is a representative TGA curve of the G-type free base.

[0054] Fig.30 The representative DSC curve of the free base of type G.

[0055] Fig.31 A representative XRPD pattern of the free base Form A.

[0056] Fig.32 This is a representative TGA curve of the free base type A.

[0057] Fig.33 The representative DSC curve of the free base type A.

[0058] Fig.34 A representative free base 1 H NMR spectrum.

[0059] Fig.35 A representative XRPD pattern of the hydrochloride salt form.

[0060] Fig.36 The representative TGA curve of the hydrochloride type A.

[0061] Fig.37 The representative DSC curve of Type A hydrochloride is shown in FIG.

[0062] Fig.38 The representative XRPD pattern of Form B hydrochloride is shown in FIG.

[0063] Fig.39 The representative TGA curve of Form B hydrochloride.

[0064] Fig.40 The representative DSC curve of Form B hydrochloride is shown in FIG.

[0065] Fig.41 A representative XRPD pattern of the mesylate salt Form A.

[0066] Fig.42 The representative TGA curve of the mesylate type A.

[0067] Fig.43 A representative DSC curve of the mesylate salt type.

[0068] Fig.44 A representative XRPD pattern of Form B mesylate salt is shown.

[0069] Fig.45 The representative TGA curve of Form B mesylate.

[0070] Fig.46 The representative DSC curve of Form B mesylate is shown.

[0071] Fig.47 A representative XRPD pattern of phosphate type A.

[0072] Fig.48 The representative TGA curve of type A phosphate.

[0073] Fig.49 The representative DSC curve of type A phosphate.

[0074] Fig.50 A representative XRPD pattern of L-tartrate salt Form A.

[0075] Fig.51 The representative TGA curve of Form A L-tartrate.

[0076] Fig.52 The representative DSC curve of Form A L-tartrate.

[0077] Fig.53 A representative XRPD pattern of the adipate salt Form A.

[0078] Fig.54 The representative TGA curve of type A adipate.

[0079] Fig.55 The representative DSC curve of type A adipate salt is shown in FIG.

[0080] Fig.56 A representative XRPD pattern of the amorphous fumarate salt is shown in FIG.

[0081] Fig.57 A representative TGA curve of the amorphous fumarate salt is shown in FIG.

[0082] Fig.58 Representative mDSC curve of amorphous fumarate salt.

[0083] Fig.59 is a representative XRPD pattern of the amorphous free base.

[0084] Fig.60 A representative TGA curve of the amorphous free base.

[0085] Fig.61 Representative mDSC curve of the amorphous free base. DETAILED DESCRIPTION

[0086] Reference will now be made in detail to certain embodiments, examples of which are shown in the attached detailed description. Although the enumerated embodiments will be described, it should be understood that they are not intended to limit the present invention to those embodiments. On the contrary, the present invention is intended to cover all substitutions, modifications and equivalents that may be included within the scope of the present invention as defined in the claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to the methods and materials described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described. If one or more of the incorporated documents and similar materials differ or conflict with the present application, including but not limited to defined terms, term usage, described technology or the like, the present application shall prevail.

[0087] It should be understood that, for the sake of clarity, certain features of the present invention described in the context of independent embodiments may also be provided in combination in a single embodiment. Conversely, for the sake of brevity, various features of the present invention described in the context of a single embodiment may also be provided separately or in any suitable sub-combination.

[0088] definition

[0089] The terms used herein have their ordinary meanings, and the meaning of such terms is independent at each occurrence thereof. However, unless otherwise stated, the following definitions apply throughout the specification and claims.

[0090] As used herein, the terms "comprise", "comprising", "include" and "including" are intended to specify the presence of stated features, integers, components or steps, but they do not exclude the presence or addition of one or more other features, integers, components, steps or groups thereof.

[0091] As used herein, the term "about" means approximately, roughly, roughly or about. When the term "about" is used in conjunction with a numerical range, it modifies the range by extending the boundaries above and below the numerical value. Generally speaking, the term "about" is used herein to modify the numerical value of the variance of 20%, typically 10%, more typically 5%, even more typically 1% and even more typically 0.1% above and below a given value. Sometimes, such a range may be within the scope of experimental error (a standard method type for measuring and / or determining a given value or range). When the term "about" is used with reference to the temperature (e.g., the beginning of endothermic transition, melting, etc.) from a differential scanning calorimetry thermogram (DSC) curve, unless otherwise stated, each temperature value should be understood to mean a given value ± 5 ° C, more typically ± 2 ° C.

[0092] As used herein, the term "substantially the same" with reference to X-ray powder diffraction means that variations in the positions of reflections and the relative intensities of the reflections are taken into account. For example, the typical accuracy of 2-Theta (2θ) values ​​is within ±0.2° of a given value in 2θ, more typically within ±0.1° of a given value in 2θ. Thus, for example, on most X-ray diffractometers under standard conditions, a reflection that normally appears at 2θ6.9° may appear between 2θ6.7° and 7.1°, more typically between 2θ6.8° and 7.0°. In addition, those skilled in the art will recognize that relative reflection intensities will show inter-device 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 considered only as a qualitative measure.

[0093] As used herein, when one or more temperatures from a differential scanning calorimetry thermogram (DSC) curve (e.g., onset of an endothermic transition, melting, etc.) are used to identify a polymorphic form, unless otherwise indicated, each temperature value should be understood to mean the given value ±5°C, more typically ±2°C.

[0094] Crystalline and amorphous forms

[0095] In one aspect, the present invention provides a crystalline form of compound (I), particularly those designated as: A-type fumarate, B-type fumarate, C-type fumarate, E-type fumarate, A-type free alkali, B-type free alkali, C-type free alkali, D-type free alkali, E-type free alkali, F-type free alkali, G-type free alkali, A-type hydrochloride, B-type hydrochloride, A-type mesylate, B-type mesylate, A-type phosphate, A-type L-tartrate and A-type adipate. In addition, the present invention provides an amorphous form of compound (I), particularly those designated as amorphous fumarate and amorphous free alkali. Also provided are methods for preparing crystalline forms or amorphous forms, and pharmaceutical compositions comprising crystalline forms or amorphous forms.

[0096] The crystalline form of compound (I) may be a complex of the free base and a pharmaceutically acceptable acid, or the free base. Such complexes contemplated include, but are not limited to, salts or cocrystals or cocrystals of salts. The amorphous form of compound (I) may be a pharmaceutically acceptable salt or the free base.

[0097] As used herein, the term "crystalline form" means a crystal structure in which a compound (or a salt or solvate thereof) can crystallize in different 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, densities, hardnesses, crystal shapes, optical and electrical properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors may lead to one crystalline form being dominant. Crystal polymorphs of a compound can be prepared by crystallization under different conditions.

[0098] As used herein, the term "polymorphic form" or "polymorph" refers in the context of this specification to crystalline and amorphous forms as well as solvate and hydrate forms. Crystalline forms have different molecular arrangements and / or conformations in the crystal lattice. Amorphous forms consist of disordered arrangements of molecules that do not have a distinguishable crystal lattice. Solvates are crystalline forms that contain stoichiometric or non-stoichiometric amounts of solvent. When a drug substance exists in multiple crystalline forms, it is said to exhibit polymorphism.

[0099] As used herein, the term "complex" refers to a crystalline material composed of two or more different molecules associated in the same crystal lattice by ionic / non-ionic bonds and electrovalent / non-covalent bonds, one of which is an active pharmaceutical ingredient (API). In the context of this specification, API may refer to compound (I).

[0100] As used herein, the term "cocrystal" refers to a crystalline material composed of two or more different molecules associated in the same crystal lattice by non-ionic and non-covalent bonds, one of which is the API.

[0101] As used herein, the term "salt" refers to any of a number of compounds resulting from replacement of part or all of the acid hydrogens of an acid to form an ionic or electrovalent compound.

[0102] As used herein, the term "co-crystal of salt" refers to a crystalline form in which the salified API and the coformer (or vice versa) are associated in the same crystal lattice by non-ionic and non-covalent bonds.

[0103] As used herein, the term "pharmaceutically acceptable" means that a substance or composition is chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the subject to be treated.

[0104] As used herein, the term "pharmaceutically acceptable acid" may be such an acid containing a pharmaceutically acceptable anion. Preferably, illustrative examples of pharmaceutically acceptable acids described herein include, but are not limited to, hydrochloric acid, 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 / Zürich: Wiley-VCH / VHCA, 2002.

[0105] Unless otherwise indicated, the term "pharmaceutically acceptable salt" as used herein includes salts that retain the biological effectiveness of the free base of the specified compound and are not biologically or otherwise undesirable. Contemplated pharmaceutical salt forms include, but are not limited to, monosalts, disalts, trisalts, tetrasalts, and the like. Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations in which they are administered. The preparation of such salts can facilitate pharmacological use by changing the physical properties of the compound without preventing it from exerting its physiological effects. Useful changes in physical properties include lowering the melting point to facilitate transmucosal administration and increasing solubility to facilitate administration of higher concentrations of the drug.

[0106] Pharmaceutically acceptable salts may include acid addition salts, such as those containing sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclamates and quinates. Preferably, illustrative examples of pharmaceutically acceptable salts described herein include hydrochloride, methanesulfonate, phosphate, tartrate, fumarate and adipate. 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, 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.

[0107] 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, cyclohexylaminosulfonic acid, fumaric acid and quinic acid. Preferably, illustrative examples of suitable acids can include hydrochloric acid, methanesulfonic acid, phosphoric acid, tartaric acid, fumaric acid and adipic acid.

[0108] Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free base form of the compound can be dissolved in a suitable solvent (such as an aqueous or water-alcohol solution containing an appropriate acid) and then isolated by evaporating the solution. Thus, when the particular compound is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art (e.g., treating the free base with an inorganic acid or with an organic acid).

[0109] It should be understood that the crystalline or amorphous compounds described herein may exist in unsolvated as well as solvated forms, and the present invention is intended to encompass all such forms.

[0110] As used herein, the terms "solvate" and "solvated" refer to solvent addition forms containing either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap fixed molar ratios of solvent molecules in the crystalline solid state, thereby forming solvates. For example, if the solvent is water, the solvate formed is a hydrate; if the solvent is an alcohol, the solvate formed is an alcoholate; if the solvent is acetone, the solvate formed is an acetone solvate. Hydrates are formed by the combination of one or more water molecules with one molecule of a substance, wherein the water remains in its molecular state, 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.

[0111] As used herein, the terms "non-solvate" and "non-solvated" mean that there is no organic solvent coordinated or contained by the solid structure, including both crystalline and amorphous structures. The non-solvated form may still contain residual organic solvent, which is not part of the solid structure, but may be adsorbed on the surface of the solid structure or adsorbed in disordered regions of the solid structure. Typically, the non-solvated form does not contain more than 2.0% by weight, typically no more than 1.0% by weight, more typically no more than 0.5% by weight of organic solvent based on the weight of the crystalline form. The organic solvent content can be determined by thermogravimetric analysis (TGA), for example, by determining the weight loss in the range of 25°C to the melting point of the solid form at a heating rate of 10K / min and / or by gas chromatography.

[0112] Therefore, in one aspect, there is provided herein a crystalline form of Compound (I) represented by the following structural formula:

[0113]

[0114] The crystalline form is a complex of free base and pharmaceutical acid, or free base.

[0115] In certain embodiments, the complex or free base is a solvate or an unsolvate.

[0116] In certain embodiments, the complex is a salt or a co-crystal or a co-crystal of a salt.

[0117] 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, more preferably about 1:1 to about 1.5:1.

[0118] In certain embodiments, the pharmaceutically acceptable acid is selected from the group consisting of hydrochloric acid, methanesulfonic acid, phosphoric acid, tartaric acid, fumaric acid, and adipic acid.

[0119] In certain embodiments, the pharmaceutically acceptable acid is fumaric acid.

[0120] Fumarate Type A

[0121] In certain embodiments, provided herein is a crystalline form of Compound (I) which is a fumarate salt Form A, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 6.9 and 11.5; typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 5.8, 6.9, 11.5, 12.1, and 17.7; more typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 5.8, 6.9, 11.5, 12.1, 17.7, 20.8, and 24.0; more typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 5.8, 6.9, 11.5, 12.1, 17.7, 18.9, 20.8, 23.1, 23.7, 24.0, and 28.8; even more typically, characterized by Figure 1 Substantially identical X-ray powder diffraction patterns. In certain embodiments, provided herein is a crystalline form of Compound (I) which is a fumarate salt Form A characterized by a differential scanning calorimeter peak phase transition temperature of about 167.6°C.

[0122] Fumarate Type B

[0123] In certain embodiments, provided herein is a crystalline form of Compound (I) which is a Form B fumarate salt characterized by an X-ray powder diffraction pattern comprising at least peaks at 6.6 and 11.4; typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 6.6, 10.7, 11.4, 12.9, 25.1, and 28.2; more typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 6.6, 10.7, 11.4, 12.9, 15.8, 17.9, 19.7, 25.1, and 28.2; even more typically, characterized by Figure 6 Substantially identical X-ray powder diffraction patterns. In certain embodiments, provided herein is a crystalline form of Compound (I) that is a fumarate salt Form B characterized by differential scanning calorimeter peak phase transition temperatures of about 91.3°C and about 166.3°C.

[0124] Fumarate Type C

[0125] In certain embodiments, provided herein is a crystalline form of Compound (I) which is a Form C fumarate salt characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 6.8 and 11.8; typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 6.8, 11.2, 11.8, 13.6, and 18.4; more typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 6.8, 11.2, 11.8, 13.6, 15.1, 16.0, 17.2, 18.4, and 24.5; even more typically, characterized by Fig.10 Essentially the same X-ray powder diffraction pattern.

[0126] E-fumarate

[0127] In certain embodiments, provided herein is a crystalline form of Compound (I) which is a fumarate salt Form E, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 6.7, 11.6, and 28.5; typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 6.7, 10.9, 11.6, 16.9, 25.2, and 28.5; more typically, characterized by at least peaks at 2θ (± 0.2°) 6.7, 10.9, 11.6, 16.9, 25.2, and 28.5. 2θ (±0.2°) 5.5, 6.7, 10.9, 11.6, 12.9, 15.3, 16.9, 19.9, 25.2, and 28.5; more typically, an X-ray powder diffraction pattern characterized by at least peaks at 2θ (±0.2°) 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; even more typically, an X-ray powder diffraction pattern characterized by at least peaks at 2θ (±0.2°) 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 Fig.11 Substantially identical X-ray powder diffraction patterns. In certain embodiments, provided herein is a crystalline form of Compound (I) that is a fumarate salt Form E characterized by differential scanning calorimeter peak phase transition temperatures of about 134.5°C and about 166.0°C.

[0128] B-type free base

[0129] In certain embodiments, provided herein is a crystalline form of Compound (I) which is a Form B free base characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 8.0 and 11.5; typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 8.0, 11.5, 16.0, 17.2, 18.8 and 24.3; more typically, characterized by at least peaks at 2θ (± 0.2°) 8. .0, 11.5, 16.0, 17.2, 18.2, 18.8, 20.3, 21.9 and 24.3; more typically, an X-ray powder diffraction pattern characterized by at least peaks at 2θ (±0.2°) 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; even more typically, an X-ray powder diffraction pattern characterized by peaks at 2θ (±0.2°) 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 Fig.14 Substantially identical X-ray powder diffraction patterns. In certain embodiments, provided herein is a crystalline form of Compound (I) which is a free base Form B characterized by a differential scanning calorimeter peak phase transition temperature of about 169.4°C.

[0130] C-type free base

[0131] In certain embodiments, provided herein is a crystalline form of Compound (I) which is a Form C free base characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 6.6 and 18.8; typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 6.6, 12.7, 18.8, 20.7 and 24.4; more typically, characterized by at least peaks at 2θ (± 0.2°) 6.6. , 12.7, 14.1, 18.1, 18.8, 20.7, 23.4, 24.4 and 26.7; more typically, an X-ray powder diffraction pattern characterized by at least peaks at 2θ (±0.2°) 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; even more typically, an X-ray powder diffraction pattern characterized by at least peaks at 2θ (±0.2°) 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; Fig.19 Substantially identical X-ray powder diffraction patterns. In certain embodiments, provided herein is a crystalline form of Compound (I) which is a free base Form C characterized by differential scanning calorimeter peak phase transition temperatures of about 86.2°C and about 114.4°C.

[0132] D-free base

[0133] In certain embodiments, provided herein is a crystalline form of Compound (I) which is a D-type free base, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 5.7, 5.8, and 18.8; typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 5.7, 5.8, 11.8, 12.6, 18.8, 20.6, and 24.3; more typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 5.7, 5.8, 11.8, 12.6, 18.8, 20.6, 22.8, 23.3, and 24.3; even more typically, characterized by Fig.23 Essentially the same X-ray powder diffraction pattern.

[0134] E-type free base

[0135] In certain embodiments, provided herein is a crystalline form of Compound (I) which is a free base Form E, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 7.2, 18.2, and 22.3; typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 7.2, 18.2, 19.2, 22.3, 23.0, and 24.0; more typically, characterized by at least peaks at 2θ (± 0.2°) 7.2, 18.2, 19.2, 22.3, 23.0, and 24.0. ) 7.2, 14.9, 16.7, 18.2, 19.2, 22.3, 23.0, 24.0 and 26.8; more typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 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; even more typically, characterized by an X-ray powder diffraction pattern with peaks at 2θ (± 0.2°) 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; Fig.24 Essentially the same X-ray powder diffraction pattern.

[0136] F-type free base

[0137] In certain embodiments, provided herein is a crystalline form of Compound (I) which is a Form F free base characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 6.2, 11.6, and 12.6; typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 6.2, 11.6, 12.6, 14.8, 16.5, and 24.4; more typically, characterized by at least peaks at 2θ (± 0.2°) 6.2, 11.6, 12.6, 14.8, 16.5, and 24.4. .2°) 6.2, 11.6, 12.6, 14.8, 16.5, 17.6, 19.3, 24.4 and 26.0; more typically, an X-ray powder diffraction pattern characterized by at least peaks at 2θ (±0.2°) 6.2, 9.3, 11.6, 12.6, 14.8, 16.5, 17.6, 18.7, 19.3, 24.4 and 26.0; even more typically, an X-ray powder diffraction pattern characterized by peaks at 2θ (±0.2°) 6.2, 9.3, 11.6, 12.6, 14.8, 16.5, 17.6, 18.7, 19.3, 24.4 and 26.0; Fig.25 Substantially identical X-ray powder diffraction patterns. In certain embodiments, provided herein is a crystalline form of Compound (I) which is a free base Form F characterized by differential scanning calorimeter peak phase transition temperatures of about 55.4°C and about 109.5°C.

[0138] G-type free base

[0139] In certain embodiments, provided herein is a crystalline form of Compound (I) which is a free base Form G, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 5.7, 5.9, and 12.7; typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 5.7, 5.9, 11.9, 12.7, 14.5, and 26.2; more typically, characterized by at least peaks at 2θ (± 0.2°) 5.7, 5.9, 11.9, 12.7, 14.5, and 26.2. ) 5.7, 5.9, 11.9, 12.7, 14.5, 17.6, 19.7, 22.9 and 26.2; more typically, an X-ray powder diffraction pattern characterized by at least peaks at 2θ (±0.2°) 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; even more typically, an X-ray powder diffraction pattern characterized by at least peaks at 2θ (±0.2°) 5.7, 5.9, 11.9, 12.7, 14.5, 17.2, 19.7, 20.6, 22.9, 24.8 and 26.2 Fig.28 Substantially identical X-ray powder diffraction patterns. In certain embodiments, provided herein is a crystalline form of Compound (I) which is a free base Form G characterized by differential scanning calorimeter peak phase transition temperatures of about 32.9°C, about 59.2°C, and about 110.2°C.

[0140] A-type free base

[0141] In certain embodiments, provided herein is a crystalline form of Compound (I) which is a free base Form A, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 7.0, 9.0, and 23.3; typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 7.0, 9.0, 11.6, 13.6, 15.4, 18.1, 19.6, and 23.3; more typically, characterized by a peak at 2θ (± 0.2°) 7.0, 9.0, 11.6, 13.6, 15.4, 18.1, 19.6, and 23.3; Fig.31 Substantially identical X-ray powder diffraction patterns. In certain embodiments, provided herein is a crystalline form of Compound (I) which is a free base Form A characterized by a differential scanning calorimeter peak phase transition temperature of about 71.3°C.

[0142] Hydrochloride Form A

[0143] In certain embodiments, provided herein is a crystalline form of Compound (I) which is a hydrochloride salt Form A characterized by an X-ray powder diffraction pattern comprising at least a peak at 2θ (±0.2°) 18.1; typically, characterized by Fig.35 In certain embodiments, provided herein is a crystalline form of Compound (I) which is a hydrochloride salt Form A characterized by a differential scanning calorimeter peak phase transition temperature of about 110.0°C.

[0144] B hydrochloride

[0145] In certain embodiments, provided herein is a crystalline form of Compound (I) which is a Form B hydrochloride salt characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 6.9, 12.4, and 25.0; typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 6.9, 11.9, 12.4, 17.0, 25.0, and 29.1; more typically, characterized by at least peaks at 2θ (± 0.2°) 6.9, 11.9, 12.4, 17.0, 25.0, and 29.1. 2θ (±0.2°) 6.9, 9.6, 11.9, 12.4, 17.0, 21.2, 22.7, 25.0, 29.1; more typically, an X-ray powder diffraction pattern characterized by at least peaks at 2θ (±0.2°) 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; even more typically, an X-ray powder diffraction pattern characterized by at least peaks at 2θ (±0.2°) 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 Fig.38 Substantially identical X-ray powder diffraction patterns. In certain embodiments, provided herein is a crystalline form of Compound (I) which is a hydrochloride salt Form B characterized by a differential scanning calorimeter peak phase transition temperature of about 241.7°C.

[0146] Methanesulfonate Form A

[0147] In certain embodiments, provided herein is a crystalline form of Compound (I) which is a mesylate salt Form A, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 6.5, 19.6, and 21.0; typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 5.3, 6.5, 7.8, 13.1, 15.7, 19.6, and 21.0; more typically, characterized by a peak ... Fig.41 In certain embodiments, provided herein is a crystalline form of Compound (I) which is a mesylate salt Form A characterized by a differential scanning calorimeter peak phase transition temperature of about 65.1°C.

[0148] Methanesulfonate type B

[0149] In certain embodiments, provided herein is a crystalline form of Compound (I) which is a mesylate salt Form B, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 6.0, 16.3, and 18.3; typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 6.0, 7.2, 12.4, 16.3, 18.3, 21.5, and 26.5; more typically, characterized by a peak at 2θ (± 0.2°) 6.0, 7.2, 12.4, 16.3, 18.3, 21.5, and 26.5; Fig.44 In certain embodiments, provided herein is a crystalline form of Compound (I) which is a mesylate salt Form B characterized by a differential scanning calorimeter peak phase transition temperature of about 63.4°C.

[0150] Phosphate A

[0151] In certain embodiments, provided herein is a crystalline form of Compound (I) which is a phosphate salt Form A, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 6.4, 14.0, and 22.9; typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 6.4, 14.0, 14.9, 20.5, 22.9, and 24.5; more typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 6.4, 14.0, 14.9, 16.3, 18.7, 20.5, 21.4, 22.9, and 24.5; even more typically, characterized by Fig.47 In certain embodiments, provided herein is a crystalline form of Compound (I) which is a phosphate salt Form A characterized by differential scanning calorimeter peak phase transition temperatures of 79.1°C and about 194.8°C.

[0152] L-Tartrate Form A

[0153] In certain embodiments, provided herein is a crystalline form of Compound (I) which is a Form A L-tartrate salt characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 6.5, 12.7, and 18.8; typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 6.5, 9.4, 12.7, 18.8, 20.7, 22.7, 24.4, and 26.5; more typically, characterized by a peak at 2θ (± 0.2°) 6.5, 9.4, 12.7, 18.8, 20.7, 22.7, 24.4, and 26.5; Fig.50 In certain embodiments, provided herein is a crystalline form of Compound (I) which is a Form A L-tartrate salt characterized by differential scanning calorimeter peak phase transition temperatures of 77.6°C and about 164.7°C.

[0154] Adipic acid salt

[0155] In certain embodiments, provided herein is a crystalline form of Compound (I) which is an adipate salt Form A, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 7.4, 10.8, and 25.7; typically, characterized by an X-ray powder diffraction pattern comprising at least peaks at 2θ (± 0.2°) 7.4, 10.8, 16.0, 17.7, 19.7, and 25.7; more typically, characterized by at least peaks at 2θ (± 0.2°) 7.4, 10.8, 16.0, 17.7, 19.7, and 25.7. 2θ (±0.2°) 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; even more typically, characterized by an X-ray powder diffraction pattern comprising peaks at 2θ (±0.2°) 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; even more typically, characterized by an X-ray powder diffraction pattern comprising peaks at 2θ (±0.2°) 7.4, 8.5, 10.8, 12.6, 14.9, Fig.53 In certain embodiments, provided herein is a crystalline form of Compound (I) which is an adipate salt Form A characterized by a differential scanning calorimeter peak phase transition temperature of about 106.7°C.

[0156] In another aspect, provided herein is an amorphous form of Compound (I) represented by the following structural formula:

[0157]

[0158] The amorphous form is a pharmaceutically acceptable salt or free base.

[0159] Amorphous fumarate

[0160] In certain embodiments, provided herein is an amorphous form of Compound (I), which is an amorphous fumarate salt characterized by Fig.56 In certain embodiments, provided herein is an amorphous form of Compound (I), which is an amorphous fumarate salt characterized by being Fig.58 Essentially identical differential scanning calorimeter thermogram curves.

[0161] Amorphous free base

[0162] In certain embodiments, provided herein is an amorphous form of Compound (I), which is an amorphous free base characterized by being Fig.59 In certain embodiments, provided herein is an amorphous form of Compound (I), which is an amorphous free base characterized by being Fig.61 Essentially identical differential scanning calorimeter thermogram curves.

[0163] In certain embodiments, the crystalline form or amorphous form of compound (I) described herein can be provided in substantially pure form. Specifically, the crystalline form of compound (I), particularly those designated as: A-type fumarate, B-type fumarate, C-type fumarate, E-type fumarate, A-type free alkali, B-type free alkali, C-type free alkali, D-type free alkali, E-type free alkali, F-type free alkali, G-type free alkali, A-type hydrochloride, B-type hydrochloride, A-type mesylate, B-type mesylate, A-type phosphate, A-type L-tartrate and A-type adipate, and the amorphous form of compound (I), particularly those designated as amorphous fumarate and amorphous free alkali, can exist in substantially pure form.

[0164] As used herein, the term "substantially pure" means that the polymorphic form or amorphous material includes less than about 15% by weight of impurities (including other polymorphic forms). In certain embodiments, the substantially pure polymorphic form or amorphous material includes less than about 10% by weight of impurities (including other polymorphic forms). In certain embodiments, the substantially pure polymorphic form or amorphous material includes less than about 5% by weight of impurities (including other polymorphic forms). In certain embodiments, the substantially pure polymorphic form or amorphous material includes less than about 1% by weight of impurities (including other polymorphic forms). In certain embodiments, the substantially pure polymorphic form or amorphous material does not include impurities (including other polymorphic forms).

[0165] The present invention also includes crystalline and amorphous forms of isotopically labeled (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)) which are identical but for the fact that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen and oxygen, such as 2 H. 3 H. 13 C. 14 C. 15 N. 17 O and 18 O. Polymorphs containing the above-mentioned isotopes and / or other isotopes of other atoms described herein are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, for example, those into which a radioactive isotope (such as 3 H and 14 C) can be used for drug and / or substrate tissue distribution assays. In particular, tritiated (i.e. 3 H) and carbon-14 (i.e. 14 C) isotopes because they are easy to prepare and detect. Further, heavier isotopes such as deuterium (i.e., 2 H) substitution may provide certain therapeutic advantages due to greater metabolic stability (e.g., increased half-life in vivo or reduced dosage requirements) and may therefore be used in some specific situations. The isotopically labeled salts of the present invention can generally be prepared by performing the procedures disclosed in WO 2020 / 057511A1 by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent during preparation, or, if desired, using isotopically labeled sulfuric acid in the preparation of the salt.

[0166] Synthesis of compounds

[0167] The compounds described herein can be synthesized by the following synthetic routes, which include, particularly in view of the description contained herein, methods that are analogous to those well known in the chemical arts. Starting materials are generally available from commercial sources such as Sigma-Aldrich (St. Louis, MO), Alfa Aesar (Ward Hill, MA), or TCI (Portland, OR), or are readily prepared using methods well known to those skilled in the art (e.g., by the following generally used methods: Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, vols. 1-23, New York: Wiley 1967-2006 (also available through Wiley Website); or Beilsteins Handbuch The organic chemistry ,4,Aufl. ed., Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database)).

[0168] 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 (e.g., propan-2-ol) at 100 ° C. under the catalysis of toluenesulfonic acid TsOH · H2O, followed by separation of the two isomers of the racemic product by chiral supercritical fluid chromatography (SFC). For illustrative purposes, a more detailed description of the various reaction steps can be found in the Examples section of WO 2020 / 057511 A1, which is incorporated herein by reference in its entirety. Those skilled in the art will recognize that other synthetic routes can be used to synthesize the compounds.

[0169] The final crystallization or separation will determine the polymorphic form, which is further detailed in the Examples section herein.

[0170] Preparation of crystalline forms

[0171] In one aspect, provided herein is a method for preparing a crystalline form of Compound (I), the method comprising:

[0172] In the case where the crystalline form is a complex of the free base and a pharmaceutically acceptable acid,

[0173] a) adding compound (I) and an acid into a solvent, and

[0174] b) slurrying at a temperature and for a time sufficient to initiate precipitation of the composite;

[0175] In the case where the crystalline form is the free base,

[0176] a) adding compound (I) into a solvent; and

[0177] b) slurrying at a temperature and for a time sufficient to initiate precipitation of the free base.

[0178] In certain embodiments, the acid is selected from the group consisting of hydrochloric acid, methanesulfonic acid, phosphoric acid, tartaric acid, fumaric acid, and adipic acid.

[0179] In certain embodiments, in step a), where the crystalline form is a complex of a free base and a pharmaceutically acceptable acid, Compound (I) and an acid are added to a solvent at an acid / base molar ratio in the range of about 0.5: 1 to 3: 1, preferably about 0.5: 1 to about 2.5: 1, more preferably 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.

[0180] In certain embodiments, the solvent is selected from the group consisting of H2O, EtOH, EtOAc, n-heptane, ethyl formate, acetone, cyclohexane, isopropanol, methyl isobutyl ketone, tetrahydrofuran, acetonitrile, and methyl tert-butyl ether, and combinations thereof.

[0181] In certain embodiments, the methods described herein further comprise seeding the solvent with a crystalline form described herein.

[0182] In certain embodiments, in step b), the temperature is about 5°C to 50°C.

[0183] In certain embodiments, in step b), the time is about 2 hours to 7.5 hours.

[0184] In certain embodiments, provided herein is a method for preparing a crystalline form of a fumarate salt of Compound (I) described herein, the method comprising:

[0185] a) dissolving a free base of compound (I) in an ester or an alcohol to form a free base solution;

[0186] b) dissolving fumaric acid in EtOH to form an acid solution;

[0187] c) adding the acid solution dropwise to the free base solution while stirring;

[0188] d) adding an alkane dropwise; and then optionally seeding the mixture with a crystalline form of the fumarate salt Form A of Compound (I);

[0189] e) stirring at 0°C to 10°C for 12 to 24 hours; and

[0190] f) The solid was isolated via filtration and then dried under vacuum at 40 to 60 °C.

[0191] In certain embodiments, the ester is selected from the group consisting of ethyl acetate, ethyl formate, methyl acetate, and isopropyl acetate.

[0192] In certain embodiments, the ester is ethyl acetate.

[0193] In certain embodiments, the alcohol is selected from the group consisting of methanol, ethanol, n-propanol, and isopropanol.

[0194] In certain embodiments, the alcohol is ethanol.

[0195] In certain embodiments, the alkane is selected from the group consisting of n-hexane, n-heptane, n-octane, and mixtures thereof.

[0196] In certain embodiments, the alkane is n-heptane.

[0197] In certain embodiments, provided herein is a method for preparing a Type B fumarate crystalline form of Compound (I) described herein, the method comprising:

[0198] a) suspending the crystalline form of the fumarate salt of compound (I) Form A in H2O;

[0199] b) magnetically stirring at about 1000 rpm at about room temperature for about 11 days; and

[0200] c) The solids were separated via centrifugation and stored open at ambient conditions for about 4 days.

[0201] In certain embodiments, provided herein is a method for preparing a Type C fumarate crystalline form of Compound (I) described herein, the method comprising:

[0202] a) suspending the crystalline form of the fumarate salt of compound (I) Form A in H2O;

[0203] b) magnetically stirring at about 1000 rpm at about room temperature for about 9 days; and

[0204] c) Separation of wet solids.

[0205] In certain embodiments, provided herein is a method for preparing a crystalline form of the E-type fumarate salt of compound (I) described herein, the method comprising:

[0206] a) dissolving the fumarate crystalline form of compound (I) in ethyl formate;

[0207] b) evaporating ethyl formate at about room temperature;

[0208] c) separating the solid.

[0209] In certain embodiments, provided herein is a method for preparing a Type A free base crystalline form of Compound (I) described herein, the method comprising:

[0210] a) suspending the amorphous free base of compound (I) in an acetone / n-heptane solvent having a volume ratio of about 1:4;

[0211] b) magnetically stirring at about 1000 rpm at about room temperature for about 3 days; and

[0212] c) Isolate the solid via centrifugation and dry the solid at ambient conditions for about 1 day.

[0213] In certain embodiments, provided herein is a method for preparing a Type B free base crystalline form of Compound (I) described herein, the method comprising:

[0214] a) suspending an amorphous free base of compound (I) in a methyl isobutyl ketone / cyclohexane solvent having a volume ratio of about 1:4;

[0215] b) magnetically stirring at about 1000 rpm at about 5° C. for about 7 days; and

[0216] c) Separating the solids via centrifugation.

[0217] In certain embodiments, provided herein is a method for preparing a Type C free base crystalline form of Compound (I) described herein, the method comprising:

[0218] a) suspending the amorphous free base of compound (I) in a tetrahydrofuran / H2O solvent having a volume ratio of about 1:4;

[0219] b) magnetically stirring at about 1000 rpm at about 5° C. for about 7 days; and

[0220] c) Separating the solids via centrifugation.

[0221] In certain embodiments, provided herein is a method for preparing a Type D free base crystalline form of Compound (I) described herein, the method comprising:

[0222] a) suspending the amorphous free base of compound (I) in a tetrahydrofuran / H2O solvent having a volume ratio of about 1:4;

[0223] b) magnetically stirring at about 1000 rpm at about 5° C. for about 3 days; and

[0224] c) The solid was isolated via centrifugation and dried at ambient conditions for about 2 hours.

[0225] In certain embodiments, provided herein is a method for preparing a crystalline form of the free base of compound (I) described herein, the method comprising:

[0226] a) suspending the amorphous free base of compound (I) in a tetrahydrofuran / H2O solvent having a volume ratio of about 1:4;

[0227] b) stirring magnetically at about 1000 rpm at about 5° C. for about 4 days;

[0228] c) isolating the solid via centrifugation and drying the solid at ambient conditions for about 2 hours; and

[0229] d) Purge the solid with N2 at about 30°C for about 20 min.

[0230] In certain embodiments, provided herein is a method for preparing a Type F free base crystalline form of Compound (I) described herein, the method comprising:

[0231] a) suspending the amorphous free base of compound (I) in acetonitrile / n-heptane solvent;

[0232] b) stirring magnetically at about 1000 rpm at about room temperature for about 2 days;

[0233] c) separating the solid.

[0234] In certain embodiments, provided herein is a method for preparing a Type G free base crystalline form of Compound (I) described herein, the method comprising:

[0235] a) dissolving the amorphous free base of compound (I) in EtOH;

[0236] b) adding H2O and obtaining a suspension;

[0237] c) separating the solid from the suspension.

[0238] In certain embodiments, provided herein is a method for preparing the hydrochloride type A of compound (I) described herein, the method comprising:

[0239] a) adding an amorphous free base of compound (I) and concentrated hydrochloric acid at an acid / base molar ratio of about 2:1 to an EtOAc / n-heptane solvent having a volume ratio of about 1:2;

[0240] b) magnetically stirring at about 1000 rpm at about room temperature for about 3 days; and

[0241] c) Isolate the solid via centrifugation and dry the solid at ambient conditions for about 1 day.

[0242] In certain embodiments, provided herein is a method for preparing the Form B hydrochloride salt of Compound (I) described herein, the method comprising:

[0243] a) dissolving an amorphous free base of compound (I) in EtOAc to form a free base solution;

[0244] b) diluting a solution of hydrochloric acid in EtOAc in EtOH to form an acid solution;

[0245] c) optionally adding seed crystals of the hydrochloride form B of compound (I) to the free base solution, wherein the seed crystals are not completely dissolved;

[0246] d) adding the acid solution dropwise while stirring at a speed of about 1000 rpm;

[0247] e) further stirring at room temperature for about 8 hours, and then stirring at about 5° C. for about 13 hours;

[0248] f) isolating the solid by filtration and then drying the solid under vacuum at about room temperature overnight;

[0249] The molar ratio of acid to base is about 2:1.

[0250] In certain embodiments, provided herein is a method for preparing a mesylate salt of Compound (I) Form A described herein, the method comprising:

[0251] a) suspending an amorphous free base of compound (I) and methanesulfonic acid in an acid / base molar ratio of about 2:1 in an acetone / n-heptane solvent having a volume ratio of about 1:4;

[0252] b) magnetically stirring at about 1000 rpm at about room temperature for about 3 days; and

[0253] c) Isolate the solid via centrifugation and dry the solid at ambient conditions for about 1 day.

[0254] In certain embodiments, provided herein is a method for preparing a mesylate salt of Compound (I) Form B described herein, the method comprising:

[0255] a) suspending the amorphous free base of compound (I) and methanesulfonic acid in an isopropanol / cyclohexane solvent having a volume ratio of about 1:4 at an acid / base feed molar ratio of about 2:1;

[0256] b) magnetically stirring at about 1000 rpm at about room temperature for about 3 days; and

[0257] c) Isolate the solid via centrifugation and dry the solid at ambient conditions for about 1 day.

[0258] In certain embodiments, provided herein is a method for preparing a phosphate type A salt of compound (I) described herein, the method comprising:

[0259] a) suspending the amorphous free base of compound (I) and concentrated H3PO4 in an acetone / n-heptane solvent having a volume ratio of about 1:4 at an acid / base molar ratio of about 1:1;

[0260] b) stirring magnetically at about 1000 rpm at room temperature for about 3 days; and

[0261] c) Isolate the solid via centrifugation and dry the solid at ambient conditions for about 1 day.

[0262] In certain embodiments, provided herein is a method for preparing a Form A L-tartrate salt of Compound (I) described herein, the method comprising:

[0263] a) suspending the amorphous free base of compound (I) and L-tartaric acid in an acid / base molar ratio of about 1:1 in an EtOAc / n-heptane solvent having a volume ratio of about 1:2;

[0264] b) magnetically stirring at about 1000 rpm at about room temperature for about 3 days; and

[0265] c) Isolate the solid via centrifugation and dry the solid at ambient conditions for about 1 day.

[0266] In certain embodiments, provided herein is a method for preparing a Type A adipate salt of Compound (I) described herein, the method comprising:

[0267] a) suspending the amorphous free base of compound (I) and adipic acid in an acid / base molar ratio of about 1:1 in an EtOAc / n-heptane solvent having a volume ratio of about 1:2;

[0268] b) magnetically stirring at about 1000 rpm at about room temperature for about 3 days; and

[0269] c) Isolate the solid via centrifugation and dry the solid at ambient conditions for about 1 day.

[0270] In addition, in another aspect, provided herein is a method for preparing an amorphous form of compound (I) described herein, the method comprising:

[0271] a) dissolving compound (I) in a solvent; and

[0272] b) removing the solvent.

[0273] In certain embodiments, the solvent is selected from the group consisting of H2O, MeOH, EtOH, EtOAc, DCM, n-heptane, ethyl formate, acetone, cyclohexane, isopropanol, methyl isobutyl ketone, tetrahydrofuran, acetonitrile, methyl tert-butyl ether, and combinations thereof.

[0274] In certain embodiments, provided herein is a method for preparing an amorphous fumarate salt of compound (I) described herein, the method comprising:

[0275] a) dissolving the fumarate form A of compound (I) in MeOH; and

[0276] b) MeOH was removed by rotary evaporation at about 60 °C.

[0277] In certain embodiments, provided herein is a method for preparing an amorphous free base of Compound (I) described herein, the method comprising:

[0278] a) dissolving the free base Form B of compound (I) in DCM; and

[0279] b) DCM was removed by rotary evaporation at about 40 °C.

[0280] As used herein, the term "seeding" or "seeding" refers to the addition of a crystalline material to a solution or mixture to initiate crystallization or recrystallization.

[0281] use

[0282] The crystalline form and amorphous form of Compound (I) described herein may exhibit high inhibitory activity against type I receptor tyrosine kinases, particularly HER2.

[0283] As used herein, the term "inhibitory activity against type I receptor tyrosine kinase" means that, as a direct or indirect response to the presence of a crystalline form or an amorphous form of Compound (I), the activity of a type I receptor tyrosine kinase is reduced relative to the activity of a type I receptor tyrosine kinase in the absence of a crystalline form or an amorphous form of Compound (I). Such reduction in activity may be due to a direct interaction of a crystalline form or an amorphous form of Compound (I) with a type I receptor tyrosine kinase, or due to an interaction of a crystalline form or an amorphous form of Compound (I) with one or more other factors that in turn affect the activity of a type I receptor tyrosine kinase. For example, a crystalline form or an amorphous form of Compound (I) described herein may reduce the activity of a type I receptor tyrosine kinase by directly binding to a type I receptor tyrosine kinase, by causing (directly or indirectly) another factor to reduce the activity of a type I receptor tyrosine kinase, or by (directly or indirectly) reducing the amount of a type I receptor tyrosine kinase present in a cell or organism.

[0284] Due to their inhibitory activity against type I receptor tyrosine kinases, crystalline and amorphous forms of Compound (I) are useful in therapy, for example for treating diseases or medical conditions (including cancer) mediated at least in part by one or more type I receptor tyrosine kinases.

[0285] As used herein, the term "cancer" refers to or describes a physiological condition in mammals that is typically characterized by abnormal or uncontrolled cell growth. Examples of cancer include, but are not limited to, carcinomas, lymphomas, blastomas, sarcomas, and leukemias or lymphoid malignancies. More specific examples of such cancers include squamous cell carcinomas (e.g., epithelial squamous cell carcinomas), lung cancers (including small cell lung cancers, non-small cell lung cancers ("NSCLC")), lung adenocarcinomas and lung squamous cell carcinomas, peritoneal cancer, hepatocellular carcinomas, gastric cancers (including gastrointestinal cancers), pancreatic cancers, glioblastomas, cervical cancers, ovarian cancers, liver cancers (liver cancers), bladder cancers, hepatomas, breast cancers, colon cancers, rectal cancers, colorectal cancers, brain cancers, endometrial cancers or uterine cancers, salivary gland cancers, kidney or renal cancers, prostate cancers, vulvar cancers, thyroid cancers, hepatic carcinomas, anal cancers, penile cancers, skin cancers (including melanomas), and head and neck cancers. 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 cancers and metastatic cancers. In this context, treating cancer involves the treatment of both primary tumors and tumor metastases.

[0286] As used herein, the term "mammal" means a warm-blooded animal suffering from or at risk of developing a disease described herein, and includes, but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters, and primates (including humans).

[0287] As used herein, the term "therapy" is intended to have its usual meaning, which processes a disease so as to completely or partially alleviate one, part or all of its symptoms, or correct or compensate for potential pathology, so as to achieve a useful or desired clinical outcome. For the purposes of the present invention, useful or desired clinical outcomes include but are not limited to detectable or undetectable symptom relief, reduced disease extent, stable disease state (i.e., no deterioration), delay or slowing of disease progression, improvement or alleviation of disease state and alleviation (whether in part or in whole). "Therapy" may also mean that survival is extended compared to the expected survival of not receiving the therapy. Individuals requiring therapy include individuals who have already suffered from a disease or illness and individuals who are prone to a disease or illness or individuals whose disease or illness is to be prevented. Unless there is a specific indication to the contrary, the term "therapy" also encompasses prevention. The terms "treatment" and "therapeutically" should be interpreted in a corresponding manner.

[0288] As used herein, the term "prevention" is intended to have its ordinary meaning and includes primary prevention, which prevents the development of a disease, and secondary prevention, where a disease has already developed and temporarily or permanently protects the patient from worsening or aggravating the disease or developing new symptoms associated with the disease.

[0289] The term "treat" is used synonymously with "therapy." Similarly, the term "treatment" can be viewed as "applying a therapy," where "therapy" is as defined herein.

[0290] In some embodiments, the compounds of the present invention have anti-cell proliferation properties, which are believed to be derived from their type I receptor tyrosine kinase inhibitory activity. Therefore, it is expected that the compounds of the present invention can be used to treat diseases or conditions mediated alone or in part by type I receptor tyrosine kinase, that is, the compounds can be used to produce anti-proliferative effects mediated alone or in part by inhibiting type I receptor tyrosine kinase. In some embodiments, such diseases or conditions treated by providing an anti-proliferative effect are type I receptor tyrosine kinase-sensitive cancers, including 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 proliferative diseases (such as psoriasis).

[0291] Therefore, in one aspect, provided herein is a crystalline form or an amorphous form of a compound (I) as described herein for use in therapy. In some embodiments, provided herein is a crystalline form and an amorphous form of a compound (I) as described herein for use as a medicament. In some embodiments, the present invention provides a crystalline form and an amorphous form of a compound (I) as described herein for use in treating a disease or condition mediated alone or in part by a type I receptor tyrosine kinase. In some embodiments, the present invention provides a crystalline form and an amorphous form of a compound (I) as described herein for use in treating or ameliorating a hyperproliferative disease (typically cancer, more typically ErbB2-positive cancer).

[0292] On the other hand, provided herein is a crystalline form or an amorphous form of compound (I) as 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 herein is a crystalline form or an amorphous form of compound (I) as described herein, for use in the manufacture of a medicament for treating or ameliorating a hyperproliferative disease (typically cancer, more typically an ErbB2-positive cancer).

[0293] Pharmaceutical composition / dosage form

[0294] The crystalline and amorphous forms of Compound (I) described herein can be administered by any convenient route suitable for 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.

[0295] The crystalline and amorphous forms of Compound (I) described herein can be administered in any convenient form of administration, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain conventional components in pharmaceutical preparations, for example, diluents, carriers, pH adjusters, sweeteners, fillers and other active agents. For example, if parenteral administration is desired, the composition will be sterile and in the form of a solution or suspension suitable for injection or infusion.

[0296] A typical formulation is prepared by mixing the crystalline and amorphous forms of Compound (I) described herein with a pharmaceutically acceptable carrier or excipient.

[0297] As used herein, the term "pharmaceutically acceptable carrier or excipient" means a carrier or excipient that can be used to prepare a pharmaceutical composition, which is generally safe and non-toxic, neither biologically undesirable nor otherwise undesirable, and includes carriers or excipients that are acceptable for veterinary use as well as human pharmaceutical use. "Pharmaceutically acceptable carrier or excipient" as used in this specification and claims includes one and more than one such carrier or excipient. The specific excipient, carrier or diluent used will depend on the manner and purpose of application of the compound of the present invention. Suitable carriers and excipients are well known to those skilled in the art and are described in, for example, Ansel, Howard C et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems .Philadelphia: Lippincott, Williams & 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, opacifiers, glidants, processing aids, colorants, sweeteners, flavoring agents, flavoring agents, diluents and other known additives to provide an aesthetically pleasing drug (i.e., the crystalline form or amorphous form of Compound (I) described herein or a pharmaceutical composition thereof) display or to facilitate the manufacture of a drug product (i.e., a drug).

[0298] Therefore, in one aspect, provided herein is a pharmaceutical composition comprising a crystalline form or amorphous form of compound (I) as described herein as an active ingredient. In certain embodiments, provided herein is a pharmaceutical composition comprising a crystalline form or amorphous form of compound (I) as described herein and a pharmaceutically acceptable carrier or excipient.

[0299] The pharmaceutical compositions described herein can be formulated into a dosage form comprising a therapeutically effective amount of a crystalline form, an amorphous form, or a pharmaceutical composition described herein.

[0300] As used herein, the term "therapeutically effective amount" refers to an amount of a pharmaceutical agent that treats, ameliorates or prevents an identified disease or condition, or exhibits 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.

[0301] In some embodiments, the pharmaceutical composition can be formulated so that a dosage of 0.001 to 500 mg / kg body weight / day (e.g., 0.01 mg / kg body weight / day to 400 mg / kg body weight / day, 0.01 mg / kg body weight / day to 300 mg / kg body weight / day, 0.1 mg / kg body weight / day to 200 mg / kg body weight / day, 0.1 mg / kg body weight / day to 150 mg / kg body weight / day, 0.1 mg / kg body weight / day to 100 mg / kg body weight / day) can be administered. The present invention relates to a crystalline or amorphous form of a compound (I) as described herein (i) in an amount of 0.5 mg / kg body weight / day to 100 mg / kg body weight / day, 0.5 mg / kg body weight / day to 80 mg / kg body weight / day, 0.5 mg / kg body weight / day to 60 mg / kg body weight / day, 0.5 mg / kg body weight / day to 50 mg / kg body weight / day, 1 mg / kg body weight / day to 50 mg / kg body weight / day, 1 mg / kg body weight / day to 40 mg / kg body weight / day). In some cases, dosage levels below the lower limit of the above range may be more than sufficient, while in other cases, larger doses may be used without causing any harmful side effects, provided that such larger doses are first divided into several small doses for administration throughout the day. For further information on routes of administration and dosing regimens, see Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990 Vol. 5 Chapter 25.3, which is specifically incorporated herein by reference.

[0302] Treatment

[0303] In another aspect, provided herein is a method for 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 form or an amorphous form described herein, which is attributed to the type I receptor tyrosine kinase inhibitory activity and brain penetrating ability of the compounds of the present invention.

[0304] As used herein, the term "subject in need thereof" is a subject suffering from a type I receptor tyrosine kinase-related disease or disorder (e.g., cancer), or a subject with an increased risk of developing a type I receptor tyrosine kinase-related disease relative to the general population. In the case of cancer, a subject in need thereof may suffer from 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.

[0305] In certain embodiments, the hyperproliferative disease is cancer.

[0306] In certain embodiments, the cancer is ErbB2 positive.

[0307] 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.

[0308] In certain embodiments, one or more additional compounds having anti-cancer properties are administered in combination.

[0309] Combination therapy

[0310] The crystalline forms, amorphous forms and pharmaceutical compositions 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, anti-tumor agents, such as additional compounds with anti-cancer properties. The additional therapeutic agents of the pharmaceutical combination formulation or dosing regimen preferably have complementary activities to the compounds described herein so that they do not adversely affect each other. Such molecules are suitably present in combination in amounts effective for the intended purpose.

[0311] 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 administered sequentially or separately, a delay in administering the second component should not result in a loss of the beneficial effects of the combination.

[0312] Illustrative examples of useful anti-tumor agents can be selected from the following classes:

[0313] (i) antiproliferative / antineoplastic drugs and combinations thereof, such as TKIs; DNA alkylating agents; antimetabolites; antineoplastic antibiotics; antimitotic agents; and topoisomerase inhibitors; inhibitors of DNA repair mechanisms such as CHK kinases; DNA-dependent protein kinase inhibitors; inhibitors of poly (ADP-ribose) polymerase (PARP inhibitors); and Hsp90 inhibitors, e.g., tanespimycin and retaspimycin, inhibitors of ATR kinase; and inhibitors of WEE 1 kinase;

[0314] (ii) cytostatic agents, such as antiestrogens; estrogen receptor down-regulators; antiandrogens; LHRH antagonists or LHRH agonists; progestins; aromatase inhibitors; inhibitors of 5α-reductase; and p38 inhibitors;

[0315] (iii) agents that inhibit cancer cell invasion;

[0316] (iv) inhibitors of growth factor function, such as growth factor antibodies, growth factor receptor antibodies, antibody drug conjugates, farnesyl transferase 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 Publication No. 2004 / 0116710;

[0317] (v) anti-angiogenic agents, such as those that inhibit the action of vascular endothelial growth factor, such as, but not limited to, 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; and compounds that act by other mechanisms, or inhibitors of angiogenin and its receptors (Tie-1 and Tie-2), inhibitors of PLGF, inhibitors of delta-like ligand (DLL-4);

[0318] (vi) vascular damaging agents;

[0319] (vii) antisense therapy;

[0320] (viii) Gene therapy approaches, including, for example, GVAX TM , methods of replacing abnormal genes such as abnormal p53 or abnormal BRCA1 or BRCA2, GDEPT (gene-directed enzyme prodrug therapy) methods, and methods of increasing a patient's tolerance to chemotherapy or radiation therapy (such as multidrug resistance gene therapy);

[0321] (ix) interferon;

[0322] (x) immunotherapy methods, including but not limited to ex vivo and in vivo methods for increasing the immunogenicity of a patient's tumor cells; methods for reducing T cell anergy or regulatory T cell function; methods for enhancing T cell responses to tumors; methods using transfected immune cells; methods using cytokine-transfected tumor cell lines, methods using antibodies directed against tumor-associated antigens, and antibodies that deplete target cell types; methods using anti-idiotypic antibodies; methods for enhancing natural killer cell function; and methods utilizing antibody-toxin conjugates; immunotoxins; agonists of Toll-like receptor 7 or Toll-like receptor 9;

[0323] (xi) Effectiveness enhancers, such as folinic acid.

[0324] For illustrative purposes, more detailed examples of such combination therapies can be found in WO 2020 / 057511A1, which is incorporated by reference in its entirety.

[0325] In certain embodiments, the additional anti-tumor agent (another compound with anti-cancer properties) is selected from the group consisting of TKI (such as 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, there is one additional anti-tumor agent. In some embodiments, there are two additional anti-tumor agents. In some embodiments, there are three or more additional anti-tumor agents.

[0326] Salt Screening and Evaluation

[0327] Using the amorphous free base or the B-type free base of compound (I) as the starting material, salt screening experiments were performed using different acids or coformers in different solvent systems. HCl, methanesulfonic acid and p-toluenesulfonic acid were tested at 2 feed ratios. Seven crystalline salts were obtained: A-type hydrochloride, B-type hydrochloride, A-type methanesulfonate, B-type methanesulfonate, A-type phosphate, A-type L-tartrate, A-type fumarate and A-type adipate. In addition, a crystalline free base, i.e., A-type free base, was also observed in the screening.

[0328] Polymorph studies

[0329] Amorphous free base, B-type free base and G-type free base were used as starting materials for polymorph screening of the free base of compound (I). Polymorph screening experiments were established using methods including, but not limited to, slow evaporation, slow cooling, slurrying, solid-vapor diffusion, liquid-vapor diffusion and anti-solvent addition. Six crystalline forms of the free base were observed during the screening and identification process, which were designated as B-type, C-type, D-type, E-type, F-type and G-type free base, respectively. Most forms were identified by XRPD, TGA, DSC and 1 The results of H NMR characterization showed that free base types B and E were anhydrous, free base types C, D, F and G were hydrates, and free base type A was an acetone solvate.

[0330] Slurry competition experiments were conducted to study the interconversion relationship between Type B free alkali and Type C free alkali. The results showed that Type B free alkali was obtained after slurrying in solvent systems with water activities (Aw) of about 0.4, 0.6 and 0.8 at 24°C ± 3°C. Type C free alkali was obtained after slurrying in H2O with a water activity of about 1, indicating that the critical water activity between Type B and Type C free alkali was in the range of 0.8 to 1. The interconversion relationship between Type B anhydrous free alkali and Type C / F / G hydrate was further studied at different water activities at RT. The saturated solution of Type B free alkali was obtained by slurrying Type B free alkali in the corresponding solvent system overnight at RT. A mixture of Type B+C+F+G free alkali was added to the corresponding saturated solution of Type B free alkali to form a suspension. After stirring at a speed of 750rpm for four days at RT, the suspension was sampled for XRPD. Type B free base was observed in EtOH and EtOH / H2O (aw = 0.2, 0.4, 0.6, 0.8) systems, whereas type G free base was obtained in pure H2O system.

[0331] Examples

[0332] For illustrative purposes, the following examples are included. However, it should be understood that these examples do not limit the present invention, but are intended only to suggest methods for implementing the present invention. Those skilled in the art will recognize that the chemical reaction can be easily adjusted to prepare crystalline forms or amorphous forms as described herein, and alternative methods for preparing crystalline forms or amorphous forms are considered to be within the scope of the present invention. For example, by modifications apparent to those skilled in the art, for example, by utilizing other suitable reagents known in the art except the reagents and / or by conventional modifications to reaction conditions, the preparation of crystalline forms or amorphous forms as described herein can be successfully carried out. Alternatively, other reactions disclosed herein or known in the art will be considered to be suitable for preparing crystalline or amorphous forms as described herein. Those skilled in the art will also recognize that the crystalline forms and amorphous forms can be easily adjusted to prepare other crystalline forms and amorphous forms, and alternative methods for preparing crystalline forms and amorphous forms are within the scope of the present invention.

[0333] In the examples described below, all temperatures are in degrees Celsius unless otherwise stated. Reagents were purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar or TCI and were used without further purification unless otherwise stated.

[0334] The crystalline form or amorphous form of Compound (I) was characterized by X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). 1 H solution NMR ( 1 H NMR) or high performance liquid chromatography (HPLC) coupled with ion chromatography (IC) to determine the stoichiometry.

[0335] abbreviation

[0336] Most of the abbreviations used in the present invention are listed in Table 1.

[0337] Table 1 Abbreviations

[0338]

[0339]

[0340]

[0341] Analysis conditions

[0342] X-ray powder diffraction (XRPD)

[0343] XRPD analysis was performed using a PANalytical Empyrean or X'Pert3 X-ray powder diffractometer. Table 2 lists typical XRPD parameters used for salt screening and evaluation and polymorph studies.

[0344] Table 2 Typical XRPD parameters

[0345]

[0346] Thermogravimetric analysis and differential scanning calorimetry (TGA and DSC)

[0347] In salt screening and evaluation and polymorph studies, TGA was performed using a TA Q500, TAQ5000 or Discovery 5500 TGA from TA Instruments. DSC or mDSC was performed using a TA Q200 / Q2000 or Discovery 2500DSC from TA Instruments. Typical parameters are listed in Tables 3 and 4.

[0348] Table 3 Parameters of TGA and DSC tests used for salt screening and evaluation and polymorph studies

[0349]

[0350] Table 4 Parameters used for mDSC testing in salt screening and evaluation and polymorph studies

[0351]

[0352] Dynamic Vapor Sorption (DVS)

[0353] DVS was measured via SMS (Surface Measurement Systems) DVS Intrinsic. The relative humidity at 25°C was calibrated based on the deliquescent points of LiCl, Mg(NO3)2, and KCl. Typical parameters for DVS testing are listed in Table 5.

[0354] Table 5 Parameters used for DVS testing

[0355]

[0356] 1 H-NMR spectroscopy ( 1 H-NMR)

[0357] The spectra were collected on a Bruker 400M NMR spectrometer using DMSO-d6 as solvent. 1 H solution NMR.

[0358] Polarized Light Microscopy (PLM)

[0359] PLM images were taken at RT using a Carl Zeiss Axio Scope.A1 microscope.

[0360] High performance liquid chromatography (HPLC)

[0361] An Agilent 1260 HPLC instrument was utilized and the detailed chromatographic conditions for purity and solubility analysis are listed in Table 6.

[0362] Table 6 Chromatographic conditions and parameters

[0363]

[0364] *: The data stated in this report corresponds to a UV wavelength of 214nm.

[0365] Ion Chromatography (IC)

[0366] Thermo Fisher ICS-1100 was used and the detailed parameters are listed in Table 7.

[0367] Table 7 Ion chromatograph conditions and parameters

[0368]

[0369]

[0370] Example 1

[0371] Fumarate type A of compound (I)

[0372] The A-type fumarate of compound (I) was prepared according to the following method:

[0373] a) dissolving 500 mg of the free base of Compound (I) in about 10 mL of EtOAc to form a free base solution;

[0374] b) 158.6 mg of fumaric acid (charge molar ratio 1.5:1, acid / free base) was dissolved in about 5 mL of EtOH to form an acid solution;

[0375] c) adding the acid solution dropwise to the free base solution while stirring;

[0376] d) adding about 13 mL of n-heptane dropwise; then optionally seeding the mixture with a crystalline form of the fumarate salt of compound (I) Form A;

[0377] e) stirring at about 5° C. for about 16 hours; and

[0378] f) The solid was isolated via filtration and then dried under vacuum at about 50°C.

[0379] The A-type fumarate of compound (I) is an anhydrous substance and a slightly hygroscopic rod-shaped crystal (shown by PLM at Figure 5 ), with an acid / base stoichiometry of about 1.5:1, which was confirmed by XRPD, TGA, DSC and 1 H NMR characterization. XRPD patterns and data are shown in Figure 1 and as shown in Table 8. Figure 2 and Figure 3 The TGA / DSC results in show that the weight loss is 1.9% up to 150 °C and there is a sharp endothermic peak at 167.6 °C. Figure 4 In 1 H NMR results showed that the acid / base molar ratio was 1.5:1.

[0380] Table 8 XRPD data of the A-type fumarate salt of compound (I)

[0381]

[0382]

[0383]

[0384] Example 2

[0385] Fumarate type B of compound (I)

[0386] About 15 mg of the A-type fumarate of compound (I) was suspended in 0.5 mL of H2O in a HPLC vial. The suspension was magnetically stirred at RT at a speed of about 1000 rpm for 11 days. The solid was separated by centrifugation and left open to the air for 4 days under ambient conditions to obtain the B-type fumarate of compound (I). The XRPD results are shown in Table 1. Figure 6 and are shown in Table 9. TGA and DSC results are Figure 7 and Figure 8 The TGA curve shows that the weight loss is 4.9% up to 150°C. The DSC curve shows that there is a broad endothermic peak at 91.3°C, which may be caused by the removal of water or solvent, and a sharp endothermic peak at 166.3°C. Fig. 9 In 1 H NMR results showed that the molar ratio of fumaric acid / free base was 1: 1. After the B-type fumarate of compound (I) was heated to 140°C and cooled to room temperature, the A-type fumarate of compound (I) was obtained. Therefore, the B-type fumarate of compound (I) is a hydrate, which is converted into an anhydrate after losing crystal water by heating.

[0387] Table 9 XRPD data of Form B fumarate of compound (I)

[0388]

[0389] Example 3

[0390] Fumarate of compound (I) type C

[0391] About 15 mg of the A-type fumarate of compound (I) was suspended in 0.5 mL of H2O in an HPLC vial. The suspension was magnetically stirred at RT at a speed of about 1000 rpm for 9 days. The wet solid was separated to obtain the C-type fumarate of compound (I) (wet sample for analysis). During storage under ambient conditions, a form conversion between the C-type fumarate of compound (I) and the B-type fumarate was observed, so no further characterization was performed. The C-type fumarate of compound (I) has an acid / base stoichiometric ratio of 1:1. The XRPD pattern and data are shown in Figure 2. Fig.10 As shown in Table 10.

[0392] Table 10 XRPD data of Form C fumarate of compound (I)

[0393]

[0394] Example 4

[0395] E-type fumarate of compound (I)

[0396] About 30 mg of the A-type fumarate of compound (I) was dissolved in 1 mL of ethyl formate in a glass vial. The solution was kept at room temperature for evaporation to obtain the E-type fumarate of compound (I). The XRPD pattern and data are shown in Table 1. Fig.11 As shown in Table 11. Fig.12 and Fig.13 The TGA and DSC results in show a weight loss of 9.4% up to 150° C., and endothermic peaks at 134.5° C. and 166.0° C. The molar ratio of formic acid:free base is 1.5:1.

[0397] Table 11 XRPD data of E-type fumarate of compound (I)

[0398]

[0399]

[0400] Example 5

[0401] B-type free base of compound (I)

[0402] About 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 5°C at a speed of about 1000 rpm for 7 days. The solid was separated by centrifugation to obtain the B-type free base of compound (I). The XRPD pattern and data are shown as follows: Fig.14 and as shown in Table 12. Fig.15 and Fig.16 The TGA and DSC results in show a weight loss of 3.5% up to 150 °C and a sharp endothermic peak at 169.4 °C (peak). Fig.17 In 1 H NMR results showed that the molar ratio of residual solvent cyclohexane / free base was 0.1:1 (corresponding to a TGA weight loss of 0.2%). Fig.18 The PLM in showed that the free base Form B of Compound (I) was anhydrous and slightly hygroscopic irregular particles with aggregation.

[0403] Table 12 XRPD data of free base type B of compound (I)

[0404]

[0405] Example 6

[0406] Free base type C of compound (I)

[0407] About 15 mg of the amorphous free base of compound (I) was suspended in 0.5 mL of THF / H2O (1:4, v / v) in an HPLC vial. The suspension was magnetically stirred at 5°C at a speed of about 1000 rpm for 7 days. The solid was separated by centrifugation to obtain the free base of compound (I) Form C. The XRPD results were Fig.19 and are shown in Table 13. TGA and DSC results are Fig. 20 and Fig.21 It is shown in FIG. 1. It was observed on the TGA / DSC curve that up to 150° C., a weight loss of 1.5% and the presence of two endothermic peaks at 86.2° C. and 114.4° C. (peaks). Fig. 22 In 1 The H NMR results showed that no solvent THF was detected. Combined with the characterization results of the D-type free base of compound (I) (see Example 7), it was speculated that the C-type free base of compound (I) was a hydrate.

[0408] Table 13 XRPD data of free base type C of compound (I)

[0409]

[0410]

[0411] Example 7

[0412] D-type free base of compound (I)

[0413] About 60 mg of the amorphous free base of compound (I) was suspended in 2 mL of THF / H2O (1:4, v / v) in an HPLC vial. The suspension was magnetically stirred at 5°C at a speed of about 1000 rpm for 3 days. The solid was separated and dried under ambient conditions for about 2 hours to obtain the D-type free base of compound (I). XRPD results were obtained at Fig.23 and are shown in Table 14. The free base Form D of Compound (I) is a hydrate and can be obtained by subjecting the free base Form C of Compound (I) to ambient conditions.

[0414] Table 14 XRPD data of D-type free base of compound (I)

[0415]

[0416] Example 8

[0417] E-type free base of compound (I)

[0418] About 60 mg of the amorphous free base of compound (I) was suspended in 2 mL of THF / H2O (1:4, v / v) in an HPLC vial. The suspension was magnetically stirred at 5°C at a speed of about 1000 rpm for 4 days. The solid was separated by centrifugation and dried under ambient conditions for about 2 hours. After the solid was purged with N2 at 30°C for 20 min. The E-type free base of compound (I) was obtained. The XRPD pattern and XRPD data are at Fig.24 and are shown in Table 15. It is presumed that the free base Form E is an anhydrate which is converted to the free base Form C of Compound (I) after exposure to ambient conditions for 30 min.

[0419] Table 15 XRPD data of free base type E of compound (I)

[0420]

[0421]

[0422] Example 9

[0423] Compound (I) Form F free base

[0424] About 15 mg of the amorphous free base of compound (I) was suspended in 0.5 mL ACN / n-heptane (1:9, v / v) in an HPLC vial. The suspension was magnetically stirred at about 1000 rpm at RT for 2 days. The solid was separated by centrifugation. The free base of Form F is a hydrate. The XRPD pattern and data are shown in Table 1. Fig.25 and as shown in Table 16. Fig.26 The TGA curve in shows a weight loss of 5.7% up to 70 °C. Fig. 27 The DSC curve in shows that there are endothermic peaks at 55.4 °C and 109.5 °C.

[0425] Table 16 XRPD data of Form F free base of compound (I)

[0426]

[0427] Example 10

[0428] G-type free base of compound (I)

[0429] About 15 mg of the amorphous free base of compound (I) was dissolved in 0.5 mL of EtOH in a glass vial. Then an antisolvent of H2O was added to the EtOH solution, and a suspension was obtained. The solid was separated by centrifugation. The G-type free base is a hydrate. The XRPD pattern and data are shown in Fig.28 and as shown in Table 17. Fig.29 The TGA curve in shows a weight loss of 7.3% up to 70 °C. Fig.30 The DSC curve in shows that there are endothermic peaks at 32.9°C, 59.2°C and 110.2°C.

[0430] Table 17 XRPD data of free base type G of compound (I)

[0431]

[0432] Example 11

[0433] A-type free base of compound (I)

[0434] About 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 about 1000 rpm for 3 days at RT. The solid was separated by centrifugation and dried at ambient conditions for 1 day. The A-type free base of compound (I) is an acetone solvate, which was obtained by slurrying the amorphous free base in acetone / n-heptane (1:4) at RT for 3 days. The XRPD pattern and data are respectively at Fig.31 and as shown in Table 18. Fig.32 and Fig.33 The TGA and DSC curves in show a weight loss of 9.9% up to 140°C and an endotherm at 71.3°C (peak temperature). Fig.34 As shown in 1 H NMR results showed that the molar ratio of acetone:free base was 0.7:1 (6.9 wt %).

[0435] Table 18 XRPD data of free base type A of compound (I)

[0436]

[0437] Example 12

[0438] Compound (I) Type A hydrochloride

[0439] About 15 mg of amorphous free base of compound (I) and 4.6 μL concentrated hydrochloric acid (feed molar ratio of 2:1, acid / free base) were suspended in 0.5 mL EtOAc / n-heptane (1:2, v:v) in an HPLC vial. The suspension was magnetically stirred at RT at a speed of about 1000 rpm for 3 days. The solid was separated by centrifugation and dried at ambient conditions for 1 day to obtain the hydrochloride type A of compound (I). XRPD patterns and data are respectively at Fig.35 and shown in Table 19. Fig.36 and Fig.37 The TGA and DSC curves in show a weight loss of 8.8% up to 150° C. and an endotherm at 110.0° C. (peak temperature). The molar ratio of hydrochloric acid:free base was 2.5:1.

[0440] Table 19 XRPD data of Type A hydrochloride of Compound (I)

[0441]

[0442] Example 13

[0443] Compound (I) Type B hydrochloride

[0444] About 500 mg of the amorphous free base of compound (I) was dissolved in about 10 mL of EtOAc. 935 μL of an EtOAc solution of hydrochloric acid (at a molar ratio of 2:1, acid / free base) was diluted into 15 mL of EtOH. Optionally, the Type B hydrochloride of compound (I) was added as a seed to the free base solution and it was not completely dissolved. The acid solution was then added dropwise while stirring at a speed of about 1000 rpm. After the mixture became turbid, it was stirred at RT for 8 hours and then further stirred at 5 ° C for 13 hours. The precipitated solid was separated by filtration and dried in vacuo at RT overnight to obtain the Type B hydrochloride of compound (I). The XRPD pattern and data are respectively at Fig.38 and are shown in Table 20. Fig.39 and Fig.40 The TGA and DSC curves in show a weight loss of 2.3% up to 150° C. and an endotherm at 241.7° C. (peak temperature). The molar ratio of hydrochloric acid:free base was 2.2:1.

[0445] Table 20 XRPD data of Type B hydrochloride of compound (I)

[0446]

[0447] Example 14

[0448] Compound (I) Type A methanesulfonate

[0449] About 15 mg of amorphous free base of compound (I) and 5.5 mg of methanesulfonic acid (feed molar ratio of 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 about 1000 rpm for 3 days at RT. The solid was separated by centrifugation and dried at ambient conditions for 1 day to obtain the A-type mesylate salt of compound (I). The XRPD pattern and data are respectively at Fig.41 and as shown in Table 21. Fig.42 and Fig.43 The TGA and DSC curves in show a weight loss of 10.2% up to 150° C. and an endotherm at 65.1° C. (peak temperature). The molar ratio of acid:free base was 2.0:1.

[0450] Table 21 XRPD data of type A methanesulfonate of compound (I)

[0451]

[0452]

[0453] Example 15

[0454] Compound (I) Type B mesylate

[0455] About 15 mg of amorphous free base of compound (I) and 5.4 mg of methanesulfonic acid (feed molar ratio of 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 RT at a speed of about 1000 rpm for 3 days. The solid was separated by centrifugation and dried at ambient conditions for 1 day to obtain the B-type mesylate of compound (I). The XRPD pattern and data are respectively at Fig.44 and as shown in Table 22. Fig.45 and Fig.46 The TGA and DSC curves in show a weight loss of 7.6% up to 150° C. and an endotherm at 63.4° C. (peak temperature). The molar ratio of acid:free base is 1.7:1.

[0456] Table 22 XRPD data of Type B mesylate of Compound (I)

[0457]

[0458] Example 16

[0459] Phosphate type A of compound (I)

[0460] About 15 mg of amorphous free base of compound (I) and 1.9 μL concentrated H3PO4 (addition molar ratio of 1:1, acid / free base) were suspended in 0.5 mL acetone / n-heptane (1:4, v:v) in an HPLC vial. The suspension was magnetically stirred at about 1000 rpm for 3 days at RT. The solid was separated by centrifugation and dried at ambient conditions for 1 day to obtain the A-type phosphate salt of compound (I). The XRPD pattern and data are respectively at Fig.47 and as shown in Table 23. Fig.48 and Fig.49 The TGA and DSC curves in show a weight loss of 9.5% up to 150° C., and endotherms at 79.1° C. and 194.8° C. (peak temperatures). The molar ratio of acid:free base is 1.1:1.

[0461] Table 23 XRPD data of type A phosphate of compound (I)

[0462]

[0463] Example 17

[0464] A-type L-tartrate of compound (I)

[0465] About 15 mg of amorphous free base of compound (I) and 4.3 mg of L-tartaric acid (feed molar ratio of 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 RT at a speed of about 1000 rpm for 3 days. The solid was separated by centrifugation and dried at ambient conditions for 1 day to obtain the A-type L-tartrate of compound (I). The XRPD patterns and data are respectively at Fig.50 and as shown in Table 24. Fig.51 and Fig.52 The TGA and DSC curves in show that the weight loss is 3.7% up to 150° C., and there are endothermic peaks at 77.6° C. and 164.7° C. The molar ratio of L-tartaric acid:free base is 0.5:1.

[0466] Table 24 XRPD data of Form A L-tartrate of Compound (I)

[0467]

[0468] Example 18

[0469] A-type adipate salt of compound (I)

[0470] About 15 mg of amorphous free base of compound (I) and 4.3 mg of adipic acid (feed molar ratio of 1:1, acid / free base) were suspended in 0.5 mL EtOAc / n-heptane (1:2, v:v) in an HPLC vial. The suspension was magnetically stirred at about 1000 rpm for 3 days at RT. The solid was separated by centrifugation and dried at ambient conditions for 1 day to obtain the A-type adipate salt of compound (I). The XRPD pattern and data are respectively at Fig.53 and as shown in Table 25. Fig.54 and Fig.55 The TGA and DSC curves in show a weight loss of 3.0% up to 150° C. and an endotherm at 106.7° C. (peak temperature). The molar ratio of adipic acid:free base is 1.3:1.

[0471] Table 25 XRPD data of type A adipate salt of compound (I)

[0472]

[0473] Example 19

[0474] Amorphous fumarate of compound (I)

[0475] About 3 g of the A-type fumarate of compound (I) was dissolved in about 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 the amorphous fumarate of compound (I). XRPD pattern Fig.56 shown. Fig.57 The TGA curve in shows a weight loss of 3.6% up to 150 °C. Fig.58 The mDSC curve in shows that the intermediate temperatures of thermogravimetric analysis (TG) are 79.9° C. and 107.5° C. The molar ratio of formic acid:free base is 1.5:1.

[0476] Example 20

[0477] Amorphous free base of compound (I)

[0478] About 2 g of the Form B free base of compound (I) was dissolved in about 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 the amorphous free base of compound (I). The XRPD pattern is shown in FIG. Fig.59 shown. Fig.60 The TGA curve in shows a weight loss of 1.9% up to 150 °C. Fig.61 The mDSC curve in shows that the middle temperature of thermogravimetric analysis (TG) is 58.7 °C.

[0479] Example 21: Comparison of the solubility of amorphous free base, fumarate form B and fumarate form E in FaSSIF

[0480] The kinetic solubility of amorphous free alkali and B / E fumarate was measured in FaSSIF to assess solubility. All solubility samples (initial solid content was 5 mg / mL to 10 mg / mL) were kept rotating on a rotary incubator, and were sampled at 37°C at 1 hour, 4 hours and 24 hours, respectively. After centrifugation, supernatant was collected and HPLC was detected.

[0481] The results are summarized in Table 26. Fumarate Form B and Fumarate Form E showed higher solubility in FaSSIF compared to the amorphous free base seen in the prior art.

[0482] Table 26 Summary of results of kinetic solubility evaluation in FaSSIF

[0483]

[0484] Example 22 Comparison of the solubility of the amorphous free base and the A / B / E fumarate salt in H2O

[0485] The equilibrium solubility of the amorphous free base and the A / B / E fumarate salt forms was assessed in H2O at 37°C. Approximately 5 to 10 mg of the solid was suspended in H2O to obtain a mixture. The suspension was stirred for 24 hours, then centrifuged and filtered to obtain the supernatant for HPLC detection.

[0486] The results are summarized in Table 27. Fumarate Form A, Fumarate Form B and Fumarate Form E showed much better solubility in H2O compared to the amorphous free base seen in the prior art.

[0487] Table 27 Summary of results of equilibrium solubility evaluation in H2O

[0488]

[0489] Example 23 Comparison of the solubility of amorphous free base, Form B free base and Form A / B / E fumarate in pH 4.5 buffer

[0490] At 37°C, the equilibrium solubility of amorphous free base, Form B free base and Form A / B / E fumarate was assessed in pH 4.5 buffer. About 5 mg to 10 mg of solid was suspended in pH 4.5 buffer to obtain a mixture. The suspension was stirred for 24 hours, then centrifuged and filtered to obtain a supernatant for HPLC detection.

[0491] The results are summarized in Table 28. Free base Form B, fumarate Form A, fumarate Form B and fumarate Form E showed better solubility in pH 4.5 buffer compared to the amorphous free base seen in the prior art.

[0492] Table 28 Summary of results of equilibrium solubility evaluation in pH 4.5 buffer

[0493]

[0494] Example 24 Comparison of the solubility of amorphous free base and B / E fumarate salt in pH 6.8 buffer

[0495] The equilibrium solubility of amorphous free alkali and B / E fumarate was evaluated at 37°C in pH 6.8 buffer. About 5 mg to 10 mg of 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 a supernatant for HPLC detection.

[0496] The results are summarized in Table 29. Fumarate Form B and Fumarate Form E showed improved solubility in pH 6.8 buffer compared to the amorphous free base seen in the prior art.

[0497] Table 29 Summary of results of equilibrium solubility evaluation in pH 6.8 buffer

[0498]

[0499] Example 25: Flowability and compressibility

[0500] The bulk density is determined by adding an appropriate amount (m) of material to a 5 mL graduated cylinder and recording its apparent volume (v0). The bulk density is obtained by dividing the amount of material by the apparent volume of the unsettled material (ρ0=m / v0). For the tap density, the graduated cylinder is then tapped 200 times. The tap density is then calculated by dividing the amount of material by its final tap volume (ρ1=m / v1). Carr's Index = (ρ1-ρ0) / ρ1.

[0501] An angle of repose is formed on a fixed base with a retaining edge to retain a layer of powder on the base. A symmetrical powder cone is carefully constructed. By measuring the height (h) and base radius (r) of the powder cone and according to the following equation α = tan -1 (h / r) Calculate the angle of repose α to determine the angle of repose.

[0502] The flowability and compressibility results of amorphous free base, free base type F, fumarate type B and fumarate type E are summarized in Table 30. In general, powders with a smaller Carr's Index will show better compressibility and flowability. And powders with a smaller angle of repose will show better flowability.

[0503] The results showed that compared with the amorphous free base, the free base form F, the fumarate form B and the fumarate form E showed relatively better flowability and compressibility.

[0504] Table 30 Summary of powder properties data

[0505]

[0506] Example 26: Contact Angle

[0507] The wettability of the solid form was evaluated by the contact angle to water. The results summarized in Table 31 show that all samples of the selected solid form are wettable by water. Compared with the amorphous free base sample, the A-type fumarate and the B-type fumarate show relatively smaller contact angles, indicating that the A-type fumarate and the B-type fumarate may be more easily wettable by water.

[0508] Table 31 Summary of contact angle results

[0509] Solid form Contact angle Amorphous free base 37.2° Fumarate Type A 20.3° Fumarate Type B 29.0°

[0510] Example 27: Crystal Habit

[0511] PLM was used to observe the crystal habit of particles (amorphous free alkali and A-type fumarate). The results show that the amorphous free alkali sample is composed of irregularly shaped particles without clear boundaries. A-type fumarate is a rod-shaped particle with a regular shape. Compared with amorphous free alkali, A-type fumarate shows better crystal habit, which is more suitable for further development.

[0512] Example 28: Hygroscopicity

[0513] DVS isotherms were collected at 25°C to study the stability of the selected solid forms as a function of humidity. The results are summarized in Table 32. Form B free base, Form A fumarate, Form B fumarate, and Form E fumarate were less hygroscopic at 80% RH / 25°C than the amorphous free base.

[0514] Table 32 DVS results summary

[0515]

[0516] Example 29: Mechanical stability

[0517] The mechanical stability of solid form was assessed by monitoring the XRPD form changes after grinding (about 5min) and tableting (about 234Mpa). XRPD results show that after grinding or tableting, the form changes (table 33) of Type B free alkali, Type A fumarate and Type E fumarate are not observed, which confirms that Type B free alkali, Type A fumarate and Type E fumarate show good mechanical stability.

[0518] Table 33 Summary of mechanical stability results

[0519] Solid form XRPD form changes after grinding XRPD form changes after tableting B-type free base no no Fumarate Type A no no E-fumarate no no

[0520] Example 30: Solid-state stability

[0521] For evaluating the solid state stability of selected forms (amorphous free alkali, F-type free alkali, A-type fumarate and B-type fumarate), samples were stored for 1 month under 40°C / 75% RH / open air conditions. Stability samples were characterized by XRPD to check any solid form changes, and purity changes were checked by HPLC characterization. All results are summarized in Table 34.

[0522] The results showed that: (1) Form F free base, Form A fumarate and Form B fumarate showed good physical stability, as evidenced by the absence of form change under all conditions; (2) Form F free base, Form A fumarate and Form B fumarate showed better chemical stability and lower purity change compared to the purity change of the amorphous free base after storage at 40°C / 75% RH for 1 month.

[0523] Table 34 Solid state stability evaluation results

[0524]

[0525] Characterization results

[0526] The characterization results of the fumarate form, free base form and crystalline salt form of Compound (I) are summarized in Tables 35 to 37.

[0527] Table 35 Characterization results of fumarate salt form

[0528]

[0529] --: Due to form conversion between Form B and Form C fumarate, Form C fumarate was not characterized and identified.

[0530] *: Intermediate temperature of thermogravimetric analysis

[0531] Table 36 Characterization results of free base form

[0532]

[0533]

[0534] --: The D-freebase was not characterized by TGA / DSC due to limited amount of material and form conversion to the E-freebase after N2 purge. The E-freebase converted to the D-form after exposure to ambient conditions and was not characterized by TGA / DSC.

[0535] *: Tg, intermediate temperature.

[0536] Table 37 Characterization results of crystalline salt

[0537]

[0538] The foregoing description is considered to be merely an illustration of the principles of the present invention. Further, since many modifications and changes will be apparent to those skilled in the art, it is not desirable to limit the present invention to the exact configuration and process as described above. Therefore, it is contemplated that all suitable modifications and equivalents fall within the scope of the present invention as defined by the appended claims.

Claims

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

2. The crystalline form according to claim 1, wherein the complex or free base is a solvate or an unsolvate.

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

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

1.

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

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

7. The crystalline form according to claim 6, wherein the crystalline form is a fumarate form A, characterized in that An X-ray powder diffraction pattern comprising at least peaks at 6.9 and 11.5 2Θ (±0.2°).

8. The crystalline form according to claim 7, wherein the crystalline form is a fumarate form A, characterized in that An X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) of 5.8, 6.9, 11.5, 12.1 and 17.

7.

9. The crystalline form according to claim 8, wherein the crystalline form is a fumarate form A, characterized in that An X-ray powder diffraction pattern comprising at least peaks at 2Θ (±0.2°) of 5.8, 6.9, 11.5, 12.1, 17.7, 20.8 and 24.

0.

10. The crystalline form according to claim 9, wherein the crystalline form is a fumarate form A, characterized in that An X-ray powder diffraction pattern comprising peaks at 2θ (±0.2°) of 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.

11. The crystalline form of claim 10, wherein the crystalline form is a fumarate form A, characterized in that Essentially the same X-ray powder diffraction pattern as in Figure 1.

12. The crystalline form according to any one of claims 7 to 11, characterized in that Differential Scanning Calorimeter peak phase transition temperature of about 167.6°C.

13. The crystalline form of claim 6, wherein the crystalline form is a fumarate form B, characterized in that An X-ray powder diffraction pattern comprising at least peaks at 6.6 and 11.4 2Θ (±0.2°).

14. The crystalline form of claim 13, wherein the crystalline form is a fumarate form B, characterized in that An X-ray powder diffraction pattern comprising at least peaks at 2Θ (±0.2°) at 6.6, 10.7, 11.4, 12.9, 25.1 and 28.

2.

15. The crystalline form of claim 14, wherein the crystalline form is a fumarate form B, characterized in that An X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) at 6.6, 10.7, 11.4, 12.9, 15.8, 17.9, 19.7, 25.1 and 28.

2.

16. The crystalline form of claim 15, wherein the crystalline form is a fumarate form B, characterized in that Essentially the same X-ray powder diffraction pattern as FIG6 .

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

18. The crystalline form of claim 6, wherein the crystalline form is a fumarate form C, characterized in that An X-ray powder diffraction pattern comprising at least peaks at 6.8 and 11.8 2Θ (±0.2°).

19. The crystalline form of claim 18, wherein the crystalline form is a fumarate form C, characterized in that An X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) at 6.8, 11.2, 11.8, 13.6 and 18.

4.

20. The crystalline form of claim 19, wherein the crystalline form is a fumarate form C, characterized in that An X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) of 6.8, 11.2, 11.8, 13.6, 15.1, 16.0, 17.2, 18.4 and 24.

5.

21. The crystalline form of claim 20, wherein the crystalline form is a fumarate form C, characterized in that Essentially the same X-ray powder diffraction pattern as FIG. 10 .

22. The crystalline form of claim 6, wherein the crystalline form is Form E fumarate, characterized in that An X-ray powder diffraction pattern comprising at least peaks at 6.7, 11.6 and 28.5 2Θ (±0.2°).

23. The crystalline form of claim 22, wherein the crystalline form is Form E fumarate, characterized in that An X-ray powder diffraction pattern comprising at least peaks at 6.7, 10.9, 11.6, 16.9, 25.2 and 28.5 2Θ (±0.2°).

24. The crystalline form of claim 23, wherein the crystalline form is Form E fumarate, characterized in that An X-ray powder diffraction pattern comprising peaks at 2θ (±0.2°) of at least 6.7, 10.9, 11.6, 12.9, 15.3, 16.9, 19.9, 25.2 and 28.

5.

25. The crystalline form of claim 24, wherein the crystalline form is Form E fumarate, characterized in that An X-ray powder diffraction pattern comprising peaks at 2θ (±0.2°) of 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.

26. The crystalline form of claim 25, wherein the crystalline form is Form E fumarate, characterized in that Essentially the same X-ray powder diffraction pattern as Figure 11.

27. The crystalline form according to any one of claims 22 to 26, characterized in that Differential Scanning Calorimeter peak phase transition temperatures of about 134.5°C and about 166.0°C.

28. The crystalline form of claim 1 or 2, wherein the crystalline form is a free base Form B, characterized in that An X-ray powder diffraction pattern comprising at least peaks at 8.0 and 11.5 2Θ (±0.2°).

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

30. The crystalline form of claim 29, wherein the crystalline form is free base Form B, characterized in that An X-ray powder diffraction pattern comprising peaks at 2θ (±0.2°) at at least 8.0, 11.5, 16.0, 17.2, 18.2, 18.8, 20.3, 21.9 and 24.

3.

31. The crystalline form of claim 30, wherein the crystalline form is free base Form B, characterized in that An X-ray powder diffraction pattern comprising peaks at 2θ (±0.2°) at at least 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.

32. The crystalline form of claim 31, which is a free base Form B, characterized in that Essentially the same X-ray powder diffraction pattern as FIG. 14 .

33. The crystalline form according to any one of claims 28 to 32, characterized in that Differential Scanning Calorimeter peak phase transition temperature of about 169.4°C.

34. The crystalline form of claim 1 or 2, wherein the crystalline form is a free base Form C, characterized in that An X-ray powder diffraction pattern comprising at least peaks at 6.6 and 18.8 2Θ (± 0.2°).

35. The crystalline form of claim 34, wherein the crystalline form is a free base Form C, characterized in that An X-ray powder diffraction pattern comprising at least peaks at 6.6, 12.7, 18.8, 20.7 and 24.4 2Θ (±0.2°).

36. The crystalline form of claim 35, wherein the crystalline form is free base Form C, characterized in that An X-ray powder diffraction pattern comprising peaks at 2θ (±0.2°) of at least 6.6, 12.7, 14.1, 18.1, 18.8, 20.7, 23.4, 24.4 and 26.

7.

37. The crystalline form of claim 36, wherein the crystalline form is free base Form C, characterized in that An X-ray powder diffraction pattern comprising peaks at 2θ (±0.2°) of 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.

38. The crystalline form of claim 37, wherein the crystalline form is a free base Form C, characterized in that Essentially the same X-ray powder diffraction pattern as Figure 19.

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

40. The crystalline form of claim 1 or 2, wherein the crystalline form is a D-type free base, characterized in that An X-ray powder diffraction pattern comprising at least peaks at 5.7, 5.8 and 18.8 2Θ (±0.2°).

41. The crystalline form of claim 40, wherein the crystalline form is a D-free base, characterized in that An X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) of 5.7, 5.8, 11.8, 12.6, 18.8, 20.6 and 24.

3.

42. The crystalline form of claim 41, wherein the crystalline form is a D-free base, characterized in that An X-ray powder diffraction pattern comprising peaks at 2θ (±0.2°) of at least 5.7, 5.8, 11.8, 12.6, 18.8, 20.6, 22.8, 23.3 and 24.

3.

43. The crystalline form of claim 42, wherein the crystalline form is a D-free base, characterized in that Essentially the same X-ray powder diffraction pattern as Figure 23.

44. The crystalline form of claim 1 or 2, wherein the crystalline form is a free base Form E, characterized in that An X-ray powder diffraction pattern comprising at least peaks at 7.2, 18.2 and 22.3 2Θ (±0.2°).

45. The crystalline form of claim 44, wherein the crystalline form is free base Form E, characterized in that An X-ray powder diffraction pattern comprising at least peaks at 2Θ (±0.2°) of 7.2, 18.2, 19.2, 22.3, 23.0 and 24.

0.

46. ​​The crystalline form of claim 45, wherein the crystalline form is free base Form E, characterized in that An X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) of 7.2, 14.9, 16.7, 18.2, 19.2, 22.3, 23.0, 24.0 and 26.

8.

47. The crystalline form of claim 46, wherein the crystalline form is free base Form E, characterized in that An X-ray powder diffraction pattern comprising peaks at 2θ (±0.2°) of 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.

48. The crystalline form of claim 47, wherein the crystalline form is free base Form E, characterized in that Essentially the same X-ray powder diffraction pattern as Figure 24.

49. The crystalline form of claim 1 or 2, wherein the crystalline form is a free base Form F, characterized in that An X-ray powder diffraction pattern comprising at least peaks at 6.2, 11.6 and 12.6 2Θ (±0.2°).

50. The crystalline form of claim 49, wherein the crystalline form is a free base Form F, characterized in that An X-ray powder diffraction pattern comprising at least peaks at 6.2, 11.6, 12.6, 14.8, 16.5 and 24.4 2Θ (±0.2°).

51. The crystalline form of claim 50, wherein the crystalline form is free base Form F, characterized in that An X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) of 6.2, 11.6, 12.6, 14.8, 16.5, 17.6, 19.3, 24.4 and 26.

0.

52. The crystalline form of claim 51, wherein the crystalline form is free base Form F, characterized in that An X-ray powder diffraction pattern comprising peaks at 2θ (±0.2°) at 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.

53. The crystalline form of claim 52, wherein the crystalline form is free base Form F, characterized in that Essentially the same X-ray powder diffraction pattern as Figure 25.

54. The crystalline form according to any one of claims 49 to 53, characterized in that Differential Scanning Calorimeter peak phase transition temperatures of about 55.4°C and about 109.5°C.

55. The crystalline form of claim 1 or 2, wherein the crystalline form is a free base Form G, characterized in that An X-ray powder diffraction pattern comprising at least peaks at 5.7, 5.9 and 12.7 2Θ (±0.2°).

56. The crystalline form of claim 55, wherein the crystalline form is a free base Form G, characterized in that An X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) of 5.7, 5.9, 11.9, 12.7, 14.5 and 26.

2.

57. The crystalline form of claim 56, wherein the crystalline form is a free base Form G, characterized in that An X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) of 5.7, 5.9, 11.9, 12.7, 14.5, 17.6, 19.7, 22.9 and 26.

2.

58. The crystalline form of claim 57, wherein the crystalline form is a free base Form G, characterized in that An X-ray powder diffraction pattern comprising peaks at 2θ (±0.2°) of 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.

59. The crystalline form of claim 58, wherein the crystalline form is a free base Form G, characterized in that Essentially the same X-ray powder diffraction pattern as Figure 28.

60. The crystalline form according to any one of claims 55 to 59, characterized in that Differential scanning calorimeter peak phase transition temperatures of about 32.9°C, about 59.2°C, and about 110.2°C.

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

62. The crystalline form of claim 61, wherein the crystalline form is an acetone solvate, which is a free base Form A, characterized in that X-ray powder diffraction comprising peaks at 2θ (±0.2°) at at least 7.0, 9.0, 11.6, 13.6, 15.4, 18.1, 19.6 and 23.

3.

63. The crystalline form of claim 62, wherein the crystalline form is an acetone solvate, which is a free base Form A, characterized in that X-ray powder diffraction pattern essentially the same as Figure 31.

64. The crystalline form according to any one of claims 61 to 63, characterized in that Differential scanning calorimeter peak phase transition temperature of about 71.3°C.

65. The crystalline form according to any one of claims 1 to 5, wherein the salt is hydrochloride Form A, characterized in that X-ray powder diffraction comprising at least a peak at 18.1 2θ (±0.2°).

66. The crystalline form of claim 65, wherein the salt is hydrochloride Form A, characterized in that X-ray powder diffraction pattern substantially the same as that shown in Figure 35.

67. The crystalline form according to any one of claims 65 to 66, characterized in that Differential Scanning Calorimeter peak phase transition temperature of about 110.0°C.

68. The crystalline form according to any one of claims 1 to 5, wherein the salt is Form B hydrochloride, characterized in that An X-ray powder diffraction pattern comprising at least peaks at 6.9, 12.4 and 25.0 2Θ (±0.2°).

69. The crystalline form of claim 68, wherein the salt is Form B hydrochloride, characterized in that An X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) at 6.9, 11.9, 12.4, 17.0, 25.0 and 29.

1.

70. The crystalline form of claim 69, wherein the salt is Form B hydrochloride, characterized in that An X-ray powder diffraction pattern comprising at least peaks at 2θ (±0.2°) at 6.9, 9.6, 11.9, 12.4, 17.0, 21.2, 22.7, 25.0 and 29.

1.

71. The crystalline form of claim 70, wherein the salt is Form B hydrochloride, characterized in that An X-ray powder diffraction pattern comprising peaks at 2θ (±0.2°) at 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.

72. The crystalline form of claim 71, wherein the salt is Form B hydrochloride, characterized in that X-ray powder diffraction pattern essentially the same as that shown in Figure 38.

73. The crystalline form according to any one of claims 68 to 72, characterized in that Differential scanning calorimeter peak phase transition temperature of about 241.7°C.

74. The crystalline form according to any one of claims 1 to 5, wherein the salt is a mesylate salt Form A, characterized in that X-ray powder diffraction comprising at least peaks at 6.5, 19.6 and 21.0 2Θ (±0.2°).

75. The crystalline form of claim 74, wherein the salt is a mesylate salt Form A, characterized in that X-ray powder diffraction comprising at least peaks at 2θ (±0.2°) of 5.3, 6.5, 7.8, 13.1, 15.7, 19.6 and 21.

0.

76. The crystalline form of claim 75, wherein the salt is a mesylate salt Form A, characterized in that X-ray powder diffraction pattern essentially the same as that shown in Figure 41.

77. The crystalline form according to any one of claims 74 to 76, characterized in that Differential Scanning Calorimeter peak phase transition temperature of about 65.1°C.

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

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

80. The crystalline form of claim 79, wherein the salt is a mesylate salt Form B, characterized in that X-ray powder diffraction pattern essentially the same as that shown in Figure 44.

81. The crystalline form according to any one of claims 78 to 80, characterized in that Differential scanning calorimeter peak phase transition temperature of about 63.4°C.

82. The crystalline form according to any one of claims 1 to 5, wherein the salt is a phosphate salt Form A, characterized in that X-ray powder diffraction comprising at least peaks at 6.4, 14.0 and 22.9 2Θ (±0.2°).

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

84. The crystalline form of claim 83, wherein the salt is a phosphate salt Form A, characterized in that X-ray powder diffraction comprising peaks at 2θ (±0.2°) at at least 6.4, 14.0, 14.9, 16.3, 18.7, 20.5, 21.4, 22.9 and 24.

5.

85. The crystalline form of claim 84, wherein the salt is a phosphate salt Form A, characterized in that X-ray powder diffraction pattern essentially the same as that shown in Figure 47.

86. The crystalline form according to any one of claims 82 to 85, characterized in that Differential scanning calorimeter peak phase transition temperatures of about 79.1°C and about 194.8°C.

87. The crystalline form according to any one of claims 1 to 5, wherein the salt is L-tartrate Form A, characterized in that X-ray powder diffraction comprising at least peaks at 6.5, 12.7 and 18.8 2Θ (±0.2°).

88. The crystalline form of claim 87, wherein the salt is L-tartrate Form A, characterized in that X-ray powder diffraction comprising peaks at 2θ (±0.2°) at at least 6.5, 9.4, 12.7, 18.8, 20.7, 22.7, 24.4 and 26.

5.

89. The crystalline form of claim 88, wherein the salt is L-tartrate Form A, characterized in that An X-ray powder diffraction pattern essentially the same as that shown in Figure 50.

90. The crystalline form according to any one of claims 87 to 89, characterized in that Differential scanning calorimeter peak phase transition temperatures of about 77.6°C and about 164.7°C.

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

92. The crystalline form of claim 91, wherein the salt is adipate type A, characterized in that X-ray powder diffraction comprising at least peaks at 2θ (±0.2°) of 7.4, 10.8, 16.0, 17.7, 19.7 and 25.

7.

93. The crystalline form of claim 92, wherein the salt is adipate type A, characterized in that X-ray powder diffraction comprising peaks at 2θ (±0.2°) of at least 7.4, 10.8, 12.6, 16.0, 17.7, 19.7, 20.9, 23.6 and 25.

7.

94. The crystalline form of claim 93, wherein the salt is adipate type A, characterized in that X-ray powder diffraction comprising 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.

95. The crystalline form of claim 94, wherein the salt is adipate type A, characterized in that X-ray powder diffraction pattern essentially the same as that shown in Figure 53.

96. The crystalline form according to any one of claims 91 to 95, characterized in that Differential scanning calorimeter peak phase transition temperature of about 106.7°C.

97. An amorphous form of Compound (I) represented by the following structural formula: The amorphous form is a pharmaceutically acceptable salt or free base.

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

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

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

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

102. A method for preparing a crystalline form according to any one of claims 1 to 96, comprising: In the case where the crystalline form is a complex of the free base and a pharmaceutically acceptable acid, a) adding compound (I) and an acid into a solvent, and b) slurrying at a temperature and for a time sufficient to initiate precipitation of the composite; In case the crystalline form is the free base, a) adding compound (I) into a solvent; as well as b) slurrying at a temperature and for a time sufficient to initiate precipitation of the free base.

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

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

1.

105. The method of any one of claims 102 to 104, wherein the solvent is selected from the group consisting of H2O, EtOH, EtOAc, n-heptane, ethyl formate, acetone, cyclohexane, isopropanol, methyl isobutyl ketone, tetrahydrofuran, acetonitrile, methyl tert-butyl ether, and combinations thereof.

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

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

109. A method for preparing a crystalline form of the fumarate salt of compound (I) according to any one of claims 7 to 12, comprising: a) dissolving a free base of compound (I) in an ester or an 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 an alkane dropwise; and then optionally seeding the mixture with a crystalline form of the fumarate salt Form A of Compound (I); e) stirring at 0° C. to 10° C. for 12 to 24 hours; as well as f) The solid was isolated via filtration and then dried under vacuum at 40 to 60 °C.

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

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

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

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

116. A method for preparing a Type B fumarate crystalline form of compound (I) according to any one of claims 13 to 17, comprising: a) suspending the crystalline form of the fumarate salt of compound (I) Form A in H2O; b) magnetically stirring at about 1000 rpm at about room temperature for about 11 days; and c) The solids were separated via centrifugation and stored openly at ambient conditions for about 4 days.

117. A method for preparing a Type C fumarate crystalline form of compound (I) according to any one of claims 18 to 21, comprising: a) suspending the crystalline form of the fumarate salt of compound (I) Form A in H2O; b) magnetically stirring at about 1000 rpm at about room temperature for about 9 days; and c) Separation of wet solids.

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

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

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

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

122. A method for preparing a D-type free base crystalline form of compound (I) according to any one of claims 40 to 43, comprising: a) suspending the amorphous free base of compound (I) in a tetrahydrofuran / H2O solvent having a volume ratio of about 1:4; b) magnetically stirring at about 1000 rpm at about 5° C. for about 3 days; and c) The solids were isolated via centrifugation and dried at ambient conditions for about 2 hours.

123. A method for preparing a free base crystalline form of Type E of Compound (I) according to any one of claims 44 to 48, comprising: a) suspending the amorphous free base of compound (I) in a tetrahydrofuran / H2O solvent having a volume ratio of about 1:4; b) stirring magnetically at about 1000 rpm at about 5° C. for about 4 days; c) isolating the solids via centrifugation and drying the solids at ambient conditions for about 2 hours; and d) Purge the solid with N2 at about 30°C for about 20 min.

124. A method for preparing a free base crystalline form of 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 acetonitrile / n-heptane solvent; b) stirring magnetically at about 1000 rpm at about room temperature for about 2 days; c) separating the solid.

125. A method for preparing a Type G free base crystalline form 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) adding H2O and obtaining a suspension; c) separating the solid from the suspension.

126. A method for preparing the hydrochloride type A of compound (I) according to any one of claims 65 to 67, comprising: a) adding an amorphous free base of compound (I) and concentrated hydrochloric acid at an acid / base molar ratio of about 2:1 to an EtOAc / n-heptane solvent having a volume ratio of about 1:2; b) magnetically stirring at about 1000 rpm at about room temperature for about 3 days; and c) Isolate the solids via centrifugation and dry the solids at ambient conditions for about 1 day.

127. A method for preparing the Type B hydrochloride of compound (I) according to any one of claims 68 to 73, comprising: a) dissolving an amorphous free base of compound (I) in EtOAc to form a free base solution; b) diluting a solution of hydrochloric acid in EtOAc in EtOH to form an acid solution; c) optionally adding seed crystals of Form B hydrochloride 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, and then stirring 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; The molar ratio of acid to base is about 2:

1.

128. A method for preparing the Form A mesylate salt of compound (I) according to any one of claims 74 to 77, comprising: a) suspending an amorphous free base of compound (I) and methanesulfonic acid in an acid / base molar ratio of about 2:1 in an acetone / n-heptane solvent having a volume ratio of about 1:4; b) magnetically stirring at about 1000 rpm at about room temperature for about 3 days; and c) Isolate the solids via centrifugation and dry the solids at ambient conditions for about 1 day.

129. A method for preparing the Form B mesylate salt 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 an isopropanol / cyclohexane solvent having a volume ratio of about 1:4 at an acid / base feed molar ratio of about 2:1; b) magnetically stirring at about 1000 rpm at about room temperature for about 3 days; and c) Isolate the solids via centrifugation and dry the solids at ambient conditions for about 1 day.

130. A method for preparing a type A phosphate salt of compound (I) according to any one of claims 82 to 86, comprising: a) suspending the amorphous free base of compound (I) and concentrated H3PO4 in an acetone / n-heptane solvent having a volume ratio of about 1:4 at an acid / base molar ratio of about 1:1; b) magnetically stirring at about 1000 rpm at room temperature for about 3 days; and c) Isolate the solids via centrifugation and dry the solids at ambient conditions for about 1 day.

131. A method for preparing the Form A L-tartrate salt 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 an acid / base molar ratio of about 1:1 in an EtOAc / n-heptane solvent having a volume ratio of about 1:2; b) magnetically stirring at about 1000 rpm at about room temperature for about 3 days; and c) Isolate the solids via centrifugation and dry the solids at ambient conditions for about 1 day.

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

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

134. The method of claim 133, wherein the solvent is selected from the group consisting of H2O, EtOH, EtOAc, n-heptane, ethyl formate, acetone, cyclohexane, isopropanol, methyl isobutyl ketone, tetrahydrofuran, acetonitrile, methyl tert-butyl ether, and combinations thereof.

135. A method for preparing an amorphous fumarate salt of compound (I) according to claim 98 or 99, comprising: a) dissolving the fumarate type A of compound (I) in MeOH; as well as b) The MeOH was removed by rotary evaporation at about 60 °C.

136. A method for preparing an amorphous free base of compound (I) according to claim 100 or 101, comprising: a) dissolving the free base Form B of compound (I) in DCM; as well as b) The DCM was removed by rotary evaporation at about 40 °C.

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

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

139. 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 the crystalline form according to any one of claims 1 to 96 or the amorphous form according to any one of claims 97 to 101.

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

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

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

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

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

147. The crystalline or amorphous form of claim 145 or 146, wherein the cancer is selected from 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. The crystalline form or amorphous form according to any one of claims 144 to 147, wherein one or more additional compounds having anti-cancer properties are administered in combination.

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

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

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

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

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