Crystalline forms of a her2 inhibitor compound

Abstract

The present application relates to crystalline forms of a compound of formula (I), processes for their preparation, pharmaceutical compositions containing said crystalline forms as active ingredient and the use of said crystalline forms for the prevention and treatment of related diseases such as tumors. (I).

Description

Technical Field

[0001] This application relates to a crystalline form of a HER2 inhibitor compound, a method for preparing the same, a pharmaceutical composition comprising the crystalline form as an active ingredient, and the use of the crystalline form in the prevention and treatment of related diseases such as tumors. Background Technology

[0002] The EGF receptor family includes four members: erbB1 (EGFR, HER1), erbB2 (also known as HER2), erbB3 (HER3), and erbB4 (HER4). The receptor tyrosine protein kinase erbB-2, also known as HER2, is a member of the EGFR receptor tyrosine kinase family. The heterodimerization of this receptor with other members of the EGFR family, usually due to HER2 overexpression, leads to autophosphorylation of tyrosine residues in the cytoplasmic domain of the heterodimer, initiating various signaling pathways that result in cell proliferation and tumorigenesis. While expression levels are typically low in normal tissues, they are significantly elevated in various malignant tumors and are closely associated with tumor invasiveness, recurrence, and metastasis risk, making them a key indicator for assessing tumor prognosis.

[0003] Aberrant activation of HER2 signaling has been observed in various human malignancies, possibly through mechanisms such as gene amplification, protein overexpression, or point mutations. This drives cancer initiation, tumor maintenance, and growth (Connell et al., ESMO Open, 2017, 2(5), e000279). Similarly, HER2 overexpression increases HER2 amplification and forms the basis for tumor transformation and tumor maintenance in various indications, including breast cancer, gastric cancer, and lung cancer.

[0004] Small molecule inhibitors of the HER2 kinase domain (such as afatinib, neratinib, lapatinib, and poziotinib) lack EGFR selectivity. Their strong EGFR activity, coupled with a lack of or weak selectivity, leads to side effects and limits the pharmacological efficacy of HER2 inhibitors. Furthermore, these HER2 inhibitors are ineffective against HER2 exon 20 insertion mutations.

[0005] Recently, HER2 inhibitors, represented by zongertinib, have demonstrated excellent exon 20 insertion mutation inhibitory activity in addition to HER2 inhibitory activity and EGFR selectivity. However, preliminary validation results indicate that intracranial activity has not been reported in HER2-mutant NSCLC patients (Yamamoto et al., IASLC World Conference of Lung 2023). Furthermore, according to literature reports, nearly 50% of HER2-mutant metastatic NSCLC patients develop brain metastases (Offin et al., Cancer 2019). Therefore, there is a significant unmet medical need to develop oral, selective, and brain-penetrating HER2 inhibitors for the treatment of NSCLC and breast cancer, addressing the side effects of insufficient EGFR selectivity and the presence of brain metastases. While NVL-330 and ELVN-002 represent drug molecules with this target, they suffer from insufficient drug development.

[0006] The inventors previously developed a class of HER2 inhibitor compounds, specifically compounds of formula (I) with excellent HER2 inhibitory activity: (I).

[0007] Polymorphism is the phenomenon of a single compound exhibiting different crystalline forms, and it is a characteristic of some compounds. Therefore, polymorphs are different solids with the same molecular formula, but each polymorph can have different solid-state physical properties. Thus, a single compound can produce multiple polymorphic forms, each with different and unique solid-state physical properties, such as different solubility characteristics, melting point temperatures, flowability, dissolution rates, stability, hygroscopicity, and / or different X-ray diffraction peaks. These actual physical properties are influenced by the conformation and orientation of the molecules in the unit cell, which defines the specific polymorphic form of the substance. The polymorphic forms of a compound can be distinguished in the laboratory by X-ray diffraction spectroscopy (such as X-ray powder diffraction (“XRPD”)) and by other methods (such as infrared spectroscopy). Furthermore, polymorphic forms of the same active pharmaceutical ingredient or active pharmaceutical ingredient can be administered alone or formulated into pharmaceutical compositions, and are well known in the pharmaceutical industry to affect, for example, the solubility, stability, flowability, handlingability, and compressibility of the active pharmaceutical ingredient, as well as the safety and efficacy of the pharmaceutical product.

[0008] The discovery of new polymorphic forms of pharmaceutically useful compounds offers new opportunities to improve the performance characteristics of drug products. Therefore, continued research is needed on the polymorphic forms of the aforementioned compounds exhibiting HER2 inhibitory activity. New polymorphic forms of compounds of formula (I) have now been discovered. Summary of the Invention

[0009] In one aspect, the present invention relates to the crystalline form of a compound (I) represented by the following structural formula: (I).

[0010] In some embodiments, the compound (I) is in the form of a solvate (e.g., a hydrate) or a non-solvent (e.g., an anhydrous). In some embodiments, the crystalline form is form A, form B, form C, form D, or form E.

[0011] In another aspect, the present invention relates to a method for preparing the crystalline form of compound (I).

[0012] In another aspect, the present invention relates to a pharmaceutical composition comprising a crystalline form of compound (I) and optionally a pharmaceutical carrier or excipient.

[0013] In another aspect, the present invention relates to a dosage form comprising a therapeutically effective amount of the crystalline form or pharmaceutical composition described herein.

[0014] In another aspect, the present invention relates to a method for preventing and / or treating HER2-related diseases in subjects, the method comprising administering a therapeutically effective amount of a crystalline form of compound (I) to a subject in need of such treatment.

[0015] In another respect, the present invention relates to the crystalline form of compound (I) for the prevention and / or treatment of HER2-related diseases.

[0016] In another aspect, the present invention relates to the use of the crystalline form of compound (I) in the preparation of medicaments for the prevention and / or treatment of HER2-related diseases. Attached Figure Description

[0017] The invention and the following detailed description can be further understood when read in conjunction with the accompanying drawings. Exemplary embodiments of the invention are shown in the drawings for illustrative purposes; however, the invention is not limited to the specific disclosure in the drawings. In the drawings: Figure 1 shows a representative XRPD diagram of form A.

[0018] Figure 2 shows a representative TGA curve for form A.

[0019] Figure 3 shows a representative DSC curve for form A.

[0020] Figure 4 shows a representative XRPD diagram of form B.

[0021] Figure 5 shows a representative TGA curve for form B.

[0022] Figure 6 shows a representative DSC curve for form B.

[0023] Figure 7 shows a representative XRPD diagram of form C.

[0024] Figure 8 shows a representative TGA curve for form C.

[0025] Figure 9 shows a representative DSC curve for form C.

[0026] Figure 10 shows a representative XRPD diagram of form D.

[0027] Figure 11 shows a representative TGA curve for form D.

[0028] Figure 12 shows a representative DSC curve for form D.

[0029] Figure 13 shows a representative XRPD diagram of form E.

[0030] Figure 14 shows a representative TGA curve for form E.

[0031] Figure 15 shows a representative DSC curve for form E. Detailed Implementation

[0032] Certain embodiments will now be described in detail, examples of which are shown in the accompanying detailed description. Although enumerated embodiments will be described, it should be understood that they are not intended to limit the invention to those embodiments. Rather, the invention is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many methods and materials similar to or equivalent to those described herein can be used in the practice of the invention. The invention is by no means limited to the methods and materials described herein. If any one or more of the incorporated documents and similar materials differ from or contradict this application, including but not limited to defined terminology, usage of terminology, described techniques, or similar content, this application shall prevail.

[0033] It should be understood that, for clarity, certain features of the invention described in the context of a standalone implementation may also be provided in combination in a single implementation. Conversely, for brevity, various features of the invention described in the context of a single implementation may also be provided individually or in any suitable sub-combination.

[0034] definition The terms used herein have their general meanings, and the meaning of such terms is independent each time they appear. However, unless otherwise stated, the following definitions apply throughout the specification and claims.

[0035] As used herein, the terms “comprising,” “included in,” “including,” and “included in” are intended to specify the presence of the stated feature, whole, component, or step, but do not exclude the presence or addition of one or more other features, wholes, components, steps, or groups thereof.

[0036] As used herein, the term “about” means approximately, roughly, roughly, or around. When the term “about” is used in conjunction with a numerical range, it modifies the range by extending the boundaries above and below that value. Generally, the term “about” is used herein to modify values ​​with a 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 ranges may fall within the range of experimental errors (standard types of methods used to measure and / or determine a given value or range). When the term “about” is used with reference to temperatures derived from differential scanning calorimetry (DSC) curves (e.g., the onset of an endothermic transition, melting, etc.), unless otherwise stated, each temperature value should be understood to mean ±5°C, more typically ±2°C, of ​​the given value.

[0037] As used herein, the term "substantially identical" in reference X-ray powder diffraction means taking into account variations in reflection position and relative intensity. For example, typical accuracy for 2-Theta (2θ) values ​​is within ±0.2° of a given value in 2θ, and more typically within ±0.1°. Thus, for example, a reflection typically occurring at 2θ 6.9° on most X-ray diffractometers under standard conditions may occur between 2θ 6.7° and 7.1°, and more typically between 2θ 6.8° and 7.0°. Furthermore, those skilled in the art will recognize that relative reflection intensity 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.

[0038] As used herein, when using one or more temperatures from differential scanning calorimetry (DSC) curves (e.g., the onset of endothermic transition, melting, etc.) to identify polymorphic forms, unless otherwise stated, each temperature value should be understood to mean a given value ± 5°C, more typically ± 2°C.

[0039] Crystalline form In one aspect, this document provides crystalline forms of compound (I), specifically designated as those of form A, form B, form C, form D, or form E. Additionally, methods for preparing the crystalline forms are provided, as well as pharmaceutical compositions comprising the crystalline forms.

[0040] As used herein, the term "crystalline form" refers to a crystalline structure in which a compound (or its salt or solvate) can crystallize in different crystalline stacks, all having the same elemental composition. Different crystalline forms typically exhibit different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can cause one crystalline form to dominate. Crystalline polymorphs of a compound can be prepared by crystallization under different conditions.

[0041] As used herein, the terms "polymorphic form" or "polymorphic substance" in the context of this specification refer to crystalline and amorphous forms, as well as solvated and hydrated forms. Crystalline forms have different molecular arrangements and / or conformations in a crystal lattice. Amorphous forms consist of randomly arranged molecules and do not have a distinguishable crystal lattice. Solvated substances are crystalline forms containing stoichiometric or non-stoichiometric amounts of solvent. When a drug substance exists in polymorphic forms, it is said to exhibit polymorphism.

[0042] As used herein, the term "salt" refers to any of a number of compounds obtained by replacing some or all of the hydrogen acids of an acid to form an ionic or electrovalent compound.

[0043] As used herein, the term "pharmaceutical" means that the substance or composition is chemically and / or toxicologically compatible with other ingredients comprising the formulation and / or with the subject being treated.

[0044] Unless otherwise stated, the term "medicinal salt" as used herein includes salts that retain the bioavailability of the free base of the specified compound and are not biologically or otherwise undesirable. Contemplated forms of medicinal salts include, but are not limited to, monosalts, disalts, trisalts, tetrasalts, etc. Medicinal salts are non-toxic at the amount and concentration at which they are administered. The preparation of such salts can facilitate pharmacological use by altering the physical properties of the compound without preserving its physiological effects. Useful alterations to physical properties include lowering the melting point to facilitate transmucosal administration and increasing solubility to facilitate administration of higher concentrations of the drug.

[0045] Pharmaceutical salts can be prepared using standard techniques. For example, the free base form of a compound can be dissolved in a suitable solvent (such as an aqueous solution or a water-alcohol solution containing a suitable acid) and then separated by evaporation of the solution. Thus, when a particular compound is a base, the desired pharmaceutical salt can be prepared by any suitable method available in the art (e.g., treatment of the free base with an inorganic acid or an organic acid).

[0046] It should be understood that the crystalline compounds described herein may exist in non-solventized or solvated forms, and the present invention is intended to cover all such forms.

[0047] As used herein, the terms "solvent" and "solventized" refer to a solvation form containing stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in a crystalline solid state, thereby forming a solvate. For example, if the solvent is water, the solvate formed is a hydrate; if the solvent is an alcohol, the solvate formed is an alcohol; and if the solvent is acetone, the solvate formed is an acetone solvate. A hydrate is formed by the combination of one or more water molecules with a molecule of a substance, wherein the water retains 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.

[0048] As used herein, the terms "unsolvable" and "nonsolvable" mean the absence of organic solvents contained or contained within a solid structure, including both crystalline and amorphous structures. The nonsolvable form may still contain residual organic solvents that are not part of the solid structure but may be adsorbed on the surface of the solid structure or in disordered regions of the solid structure. Typically, the nonsolvable form does not contain more than 2.0% by weight of the crystalline form, typically no more than 1.0% by weight, and more typically no more than 0.5% by weight of organic solvents. The organic solvent content can be determined by thermogravimetric analysis (TGA), for example by determining the weight loss from 25°C to the melting point of the solid form at a heating rate of 10 K / min and / or by gas chromatography.

[0049] Therefore, in one respect, this paper provides a crystalline form of compound (I) represented by the following structural formula: (I).

[0050] In some embodiments, compound (I) is in solvated or non-solventized form.

[0051] In some implementations, the crystalline form is form A, form B, form C, form D, or form E.

[0052] Form A In some embodiments, this document provides a crystalline form of compound (I), which is form A, characterized by an X-ray powder diffraction (XRPD) pattern containing at least peaks at 2θ (± 0.2°) at 6.8, 16.0, and 23.1. In some embodiments, this document provides a crystalline form of compound (I), which is form A, characterized by an X-ray powder diffraction pattern containing at least peaks at 2θ (± 0.2°) at 6.8, 8.7, 16.0, and 23.1. In some embodiments, it is characterized by an X-ray powder diffraction pattern substantially identical to that of Figure 1. In some embodiments, it is characterized by one or more of the following: (i) The weight loss during thermogravimetric analysis (TGA) measurements at 180°C is approximately 5.51%; (ii) The TGA curve is essentially the same as that in Figure 2.

[0053] (iii) Endothermic peaks in differential scanning calorimetry (DSC) measurements at approximately 57.0, 142.4, 168.6, and 226.8 °C; and / or (iv) The DSC curve is essentially the same as that in Figure 3.

[0054] Form B In some embodiments, this document provides a crystalline form of compound (I), which is form B, characterized by an X-ray powder diffraction pattern containing at least peaks at 2θ (± 0.2°) at 5.6, 11.2, and 23.4. In some embodiments, this document provides a crystalline form of compound (I), which is form B, characterized by an X-ray powder diffraction pattern containing at least peaks at 2θ (± 0.2°) at 5.6, 11.2, 16.0, 16.6, and 23.4. In some embodiments, this document provides a crystalline form of compound (I), which is form B, characterized by an X-ray powder diffraction pattern containing at least peaks at 2θ (± 0.2°) at 5.6, 8.6, 9.2, 11.2, 16.0, 16.6, and 23.4. In some embodiments, it is characterized by an X-ray powder diffraction pattern substantially the same as that in FIG. 4. In some embodiments, it is characterized by one or more of the following: (i) The weight loss during thermogravimetric analysis (TGA) measurements at 180°C is approximately 5.52%; (ii) The TGA curve is essentially the same as that in Figure 5.

[0055] (iii) Endothermic peaks in differential scanning calorimetry (DSC) measurements at approximately 60.4, 119.9, 145.4, 164.8, 202.9, and 228.0 °C; and / or (iv) The DSC curve is essentially the same as that in Figure 6.

[0056] Form C In some embodiments, this document provides a crystalline form of compound (I), which is form C, characterized by X-ray powder diffraction patterns of peaks at 2θ (±0.2°) at least 7.5, 9.9, and 16.9. In some embodiments, this document provides a crystalline form of compound (I), which is form C, characterized by X-ray powder diffraction patterns of peaks at 2θ (±0.2°) at at least 4.7, 7.5, 9.9, 16.9, and 19.8. In some embodiments, this document provides a crystalline form of compound (I), which is form C, characterized by X-ray powder diffraction patterns of peaks at 2θ (±0.2°) at at least 4.7, 7.5, 9.9, 13.6, 15.3, 16.9, and 19.8. In some embodiments, this document provides a crystalline form of compound (I), which is form C, characterized by an X-ray powder diffraction pattern containing at least the peaks at 2θ (±0.2°) of 4.7, 7.5, 9.9, 13.6, 15.3, 16.9, 18.0, 19.8, 21.2, 23.4, 26.3, 26.9, 27.7, 29.0, and 29.8. In some embodiments, form C is an anhydrous form. In some embodiments, it is characterized by an X-ray powder diffraction pattern substantially the same as that in FIG. 7. In some embodiments, it is characterized by one or more of the following: (i) The weight loss during thermogravimetric analysis (TGA) measurements at 150°C is approximately 1.07%; (ii) with Figure 8 The TGA curves are essentially the same.

[0057] (iii) An endothermic peak in a differential scanning calorimetry (DSC) measurement at approximately 249.7 °C; and / or (iv) The DSC curve is essentially the same as that in Figure 9.

[0058] Form D In some embodiments, this document provides a crystalline form of compound (I), which is form D, characterized by X-ray powder diffraction patterns of peaks at 2θ (±0.2°) at at least 6.6, 12.1, and 12.4. In some embodiments, this document provides a crystalline form of compound (I), which is form D, characterized by X-ray powder diffraction patterns of peaks at 2θ (±0.2°) at at least 6.6, 12.1, 12.4, 13.2, and 16.1. In some embodiments, this document provides a crystalline form of compound (I), which is form D, characterized by X-ray powder diffraction patterns of peaks at 2θ (±0.2°) at at least 5.3, 6.6, 12.1, 12.4, 13.2, 16.1, and 18.4. In some embodiments, this document provides a crystalline form of compound (I), which is form D, characterized by an X-ray powder diffraction pattern containing at least the peaks at 2θ (± 0.2°) of 5.3, 6.6, 8.0, 12.1, 12.4, 13.2, 14.5, 15.2, 16.1, 17.0, 18.0, 18.4, 19.1, 19.9, 21.2, 22.0, 22.6, 24.3, 25.0, 26.5, 28.2, 29.3, and 30.3. In some embodiments, form D is a hydrated form. In some embodiments, it is characterized by an X-ray powder diffraction pattern substantially the same as that in FIG. 10. In some embodiments, it is characterized by one or more of the following: (i) The weight loss during thermogravimetric analysis (TGA) measurements at 180°C is approximately 2.93%; (ii) with Figure 11 The TGA curves are essentially the same.

[0059] (iii) Endothermic peaks in differential scanning calorimetry (DSC) measurements at approximately 51.2 and 204.8 °C; and / or (iv) The DSC curve is essentially the same as that in Figure 12.

[0060] Form E In some embodiments, this document provides a crystalline form of compound (I), which is form E, characterized by X-ray powder diffraction patterns containing at least peaks at 2θ (± 0.2°) at 4.8, 13.8, and 17.6. In some embodiments, this document provides a crystalline form of compound (I), which is form E, characterized by X-ray powder diffraction patterns containing at least peaks at 2θ (± 0.2°) at 4.8, 13.1, 13.8, 14.8, 16.1, 17.6, and 20.8. In some embodiments, this document provides a crystalline form of compound (I), which is form E, characterized by X-ray powder diffraction patterns containing at least peaks at 2θ (± 0.2°) at 4.8, 13.1, 13.8, 14.8, 16.1, 17.6, and 20.8. In some embodiments, this document provides a crystalline form of compound (I), which is form E, characterized by an X-ray powder diffraction pattern containing at least the peaks at 2θ (±0.2°) of 4.8, 9.5, 13.1, 13.8, 14.8, 16.1, 17.6, 19.1, 20.1, 20.8, 22.6, 23.1, 24.2, 25.0, 26.1, 27.0, 28.7, 29.1, and 29.8. In some embodiments, form E is a hydrated form. In some embodiments, it is characterized by an X-ray powder diffraction pattern substantially the same as that in FIG. 13. In some embodiments, it is characterized by one or more of the following: (i) The weight loss during thermogravimetric analysis (TGA) measurements at 150°C is approximately 5.46%; (ii) with Figure 14 The TGA curves are essentially the same.

[0061] (iii) Endothermic peaks in differential scanning calorimetry (DSC) measurements at approximately 80.9 and 160.1 °C; and / or (iv) The DSC curve is essentially the same as that in Figure 15.

[0062] In some embodiments, the crystalline form of compound (I) described herein may be provided in a substantially pure form. 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 some embodiments, the substantially pure polymorphic form or amorphous material includes less than about 10% by weight of impurities (including other polymorphic forms). In some embodiments, the substantially pure polymorphic form or amorphous material includes less than about 5% by weight of impurities (including other polymorphic forms). In some embodiments, the substantially pure polymorphic form or amorphous material includes less than about 1% by weight of impurities (including other polymorphic forms). In some embodiments, the substantially pure polymorphic form or amorphous material does not include impurities (including other polymorphic forms).

[0063] The present invention also includes crystalline forms of isotopically labeled compounds (I), which are identical, but in fact, one or more atoms are replaced by atoms having atomic masses or mass numbers different from those commonly 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 aforementioned isotopes and / or other atoms, as described herein, are within the scope of this invention. Certain isotope-labeled compounds of this invention, for example, those doped with radioactive isotopes (such as... 3 H and 14 Those in category C) can be used for the determination of drug and / or substrate tissue distribution. Tritium (i.e., tritium) is particularly widely used. 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 can provide certain therapeutic advantages due to greater metabolic stability (e.g., increased half-life in vivo or reduced dose requirements).

[0064] Preparation of crystalline form In one aspect, this article provides a method for preparing the crystalline form of compound (I), the method comprising: a) Adding compound (I) to a solvent; and b) The crystalline form is obtained by adding an antisolvent or by suspension stirring.

[0065] In some embodiments, the method described herein further includes seeding the solvent in the crystalline form described herein.

[0066] In some implementations, in step b), the temperature is approximately 5°C to 50°C.

[0067] In some implementations, the time in step b) is approximately 1 hour to 24 hours.

[0068] In some embodiments, this document provides a method for preparing form A of the compound (I) described herein, the method comprising: a) Adding compound (I) to a solvent; and b) Obtain form A by adding an antisolvent.

[0069] In one embodiment, the solvent is selected from dichloromethane (DCM) and tetrahydrofuran (THF).

[0070] In one embodiment, the antisolvent is selected from n-heptane and methyl tert-butyl ether (MTBE).

[0071] In some embodiments, this document provides a method for preparing form B of the compound (I) described herein, the method comprising: a) Adding compound (I) to a solvent; and b) Obtain form B by suspension stirring.

[0072] In one embodiment, the solvent is isopropanol (IPA).

[0073] In one embodiment, the suspension stirring is a cyclic stirring between 50°C and 5°C. In one embodiment, the cycle is one or more times (e.g., two, three, or four times).

[0074] In some embodiments, this document provides a method for preparing form C of the compound (I) described herein, the method comprising: a) Adding compound (I) to a solvent; and b) Obtain form C by suspension stirring.

[0075] In one embodiment, the solvent is selected from acetone, ethyl acetate (EtOAc), isopropyl acetate (IPAc), methyl tert-butyl ether (MTBE), methyl isobutyl ketone (MIBK), acetonitrile (ACN), tetrahydrofuran (THF), n-heptane, and / or dimethyl sulfoxide (DMSO). In one embodiment, the suspension stirring is room temperature suspension stirring or cyclic stirring between 50°C and 5°C. In one embodiment, the cycle is one or more times (e.g., two, three, or four times).

[0076] In some embodiments, this document provides a method for preparing form D of the compound (I) described herein, the method comprising: a) Adding compound (I) to a solvent; and b) Obtain form D by suspension stirring.

[0077] In one embodiment, the solvent is selected from anisole, toluene, and ethyl acetate (EtOAc).

[0078] In one embodiment, the suspension stirring is room temperature suspension stirring or cyclic stirring between 50°C and 5°C. In one embodiment, the cycle is one or more times (e.g., two, three, or four times).

[0079] In some embodiments, this document provides a method for preparing form E of the compound (I) described herein, the method comprising: a) Adding compound (I) to a solvent; and b) Obtain the form E by suspension stirring.

[0080] In one embodiment, the solvent is selected from 1,4-dioxane, water, tetrahydrofuran (THF), and n-heptane.

[0081] In one embodiment, the suspension stirring is room temperature suspension stirring or cyclic stirring between 50°C and 5°C. In one embodiment, the cycle is one or more times (e.g., two, three, or four times).

[0082] As used herein, the term “inoculation” or “seedling” refers to the addition of crystalline material to a solution or mixture to initiate crystallization or recrystallization.

[0083] use The crystalline form of compound (I) described in this article exhibits high HER2 inhibitory activity.

[0084] As used herein, the term "HER2 inhibitory activity" refers to a reduction in HER2 activity in response to the presence or absence of the crystalline form of compound (I), either directly or indirectly. This reduction in activity may be due to a direct interaction between the crystalline form of compound (I) and HER2, or due to the interaction between the crystalline form of compound (I) and one or more other factors that subsequently affect HER2 activity. For example, the crystalline form of compound (I) described herein may reduce HER2 activity by directly binding to HER2.

[0085] Due to their inhibitory activity against HER2, the crystalline form of compound (I) can be used in therapies, such as for the prevention and / or treatment of HER2-related diseases (including cancer / tumors).

[0086] As used herein, the terms “cancer” or “tumor” refer to or describe a physiological condition in mammals typically characterized by abnormal or uncontrolled cell growth. The terms “tumor” or “cancer” include, but are not limited to, the following diseases: Heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung: bronchial carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma, hamartoma, mesothelioma; Gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, hemangioma), small intestine (adenocarcinoma, Lymphoma, carcinoid tumors), Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma); colorectal cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); urogenital tract: kidneys (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testes (seminoma, teratoma, embryonal carcinoma, teratoma), choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver: hepatocellular carcinoma, bile duct carcinoma, hepatoblastoma, angiosarcoma Hepatocellular adenoma, hemangioma; Biliary tract: gallbladder cancer, ampullary cancer, bile duct cancer; Bone: osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, chronic exostosis, benign chondroma, chondroblastoma, fibrochondroma, chondromycinous fibroma, osteoid osteoma, and giant cell tumor; Nervous system: Skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningeal sarcoma, glioma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pine Gastrointestinal tumors include: glioblastoma, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors; spinal neurofibroma, meningioma, glioma, sarcoma; gynecological tumors include: uterus (endometrial cancer), cervix (cervical cancer, precancerous cervical dysplasia, etc.), ovary (ovarian cancer, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa cell tumor, Sertoli stromal cell tumor, dysgerminoma, malignant teratoma; vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma); vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tube (cancer);Hematology: Blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, mantle cell lymphoma (MCL), follicular lymphoma, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and Adrenal glands: neuroblastoma. In some embodiments, cancer or tumors include, but are not limited to, lung cancer, breast cancer, gastric cancer, bladder cancer, urothelial carcinoma, colorectal cancer, bile duct cancer, malignant tumors of the bile duct, esophageal cancer, salivary gland cancer, ovarian cancer, endometrial cancer, kidney cancer, peritoneal cancer, head and neck cancer, pancreatic cancer, neuroendocrine tumors, melanosarcoma, brain cancer, prostate cancer, thyroid cancer, and leukemia. As used in this article, the term "cancer" is intended to encompass both non-metastatic and metastatic cancer. In this context, treating cancer involves treating both the primary tumor and the metastatic tumors.

[0087] As used herein, the term “mammal” means a warm-blooded animal that suffers from or is at risk of developing the diseases described herein, and includes, but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters, and primates (including humans).

[0088] As used herein, the term "therapy" is intended to have its usual meaning as the treatment of a disease to completely or partially alleviate one, some, or all of its symptoms, or to correct or compensate for underlying pathology, thereby achieving a beneficial or desired clinical outcome. For the purposes of this invention, beneficial or desired clinical outcomes include, but are not limited to, remission of detectable or undetectable symptoms, reduction in disease severity, stabilization of the disease state (i.e., no worsening), delay or slowing of disease progression, improvement or reduction of the disease state, and remission (whether partial or complete). "Therapy" may also mean a prolonged survival compared to expected survival without the therapy. Individuals in need of therapy include individuals who already have a condition or disease, individuals who are susceptible to a condition or disease, or individuals with a condition or disease to be prevented. Unless specifically indicated to the contrary, the term "therapy" also encompasses prevention. The terms "therapeutic" and "therapeutically" should be interpreted in a corresponding manner.

[0089] As used herein, the term “prevention” is intended to have its usual meaning and includes primary prevention of disease progression, as well as secondary prevention in which disease has progressed and temporarily or permanently protects the patient from disease deterioration or aggravation or the development of new symptoms associated with the disease.

[0090] The term “treatment” is used synonymously with “therapeutic treatment.” Similarly, the term “treatment” can be considered as “the application of a therapeutic treatment,” where “therapeutic treatment” is as defined herein.

[0091] Therefore, in one aspect, this document provides a crystalline form of the compound (I) described herein for use in a therapeutic context. In some embodiments, this document provides a crystalline form of the compound (I) described herein for use as a medicament. In some embodiments, the present invention provides a crystalline form of the compound (I) described herein for use in the treatment of diseases or conditions mediated solely or partially by HER2. In some embodiments, the present invention provides a crystalline form of the compound (I) described herein for use in the prevention and / or treatment of HER2-related diseases (typically cancer / tumor, more typically HER2-positive cancer / tumor).

[0092] On the other hand, this document provides the use of the crystalline form of the compound (I) described herein in the preparation of a medicament for the prevention and / or treatment of HER2-related diseases. In one embodiment, the HER2-related disease is a HER2-positive tumor. In one embodiment, the tumor is selected from the following cancers: lung cancer, breast cancer, gastric cancer, bladder cancer, urothelial carcinoma, colorectal cancer, bile duct cancer, biliary tract malignancies, esophageal cancer, salivary gland cancer, ovarian cancer, endometrial cancer, kidney cancer, peritoneal cancer, head and neck cancer, pancreatic cancer, neuroendocrine tumors, melanoma, brain cancer, prostate cancer, thyroid cancer, or leukemia.

[0093] Pharmaceutical Compositions / Dosage Forms The crystalline form of compound (I) described herein can be administered via any convenient route suitable for the condition to be treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intra-arterial, intradermal, intrathecal, and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), ocular, vaginal, intraperitoneal, intrapulmonary, and intranasal administration.

[0094] The crystalline form of compound (I) described herein can be administered in any convenient form, such as tablets, powders, capsules, solutions, dispersants, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional to pharmaceutical formulations, such as diluents, carriers, pH adjusters, sweeteners, fillers, and other active agents. For example, if parenteral administration is required, the composition will be sterile and in the form of a solution or suspension suitable for injection or infusion.

[0095] Typical formulations are prepared by mixing the crystalline form of the compound (I) described herein with a pharmaceutical carrier or excipient.

[0096] As used herein, the term "pharmaceutical 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 nor otherwise undesirable, and includes carriers or excipients acceptable for veterinary use as well as for human pharmaceutical use. As used in this specification and claims, "pharmaceutical carrier or excipient" includes one or more such carriers or excipients. The specific excipient, carrier, or diluent used will depend on the manner and purpose of application of the compounds of the present invention. Suitable carriers and excipients are well known to those skilled in the art, and are found, for example, in 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, RaymondC. Handbook of Pharmaceutical Excipients Detailed description is available in Chicago, Pharmaceutical Press, 2005. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, flow aids, processing aids, colorants, sweeteners, flavoring agents, tasters, diluents, and other known additives to provide an aesthetically pleasing presentation of the medicine (i.e., the crystalline form of the compound (I) described herein or a pharmaceutical composition thereof) or to facilitate the manufacture of the pharmaceutical product.

[0097] Therefore, in one aspect, this document provides a pharmaceutical composition comprising, as an active ingredient, the crystalline form of the compound (I) described herein. In some embodiments, this document provides a pharmaceutical composition comprising, as a pharmaceutical carrier or excipient, the crystalline form of the compound (I) described herein.

[0098] The pharmaceutical compositions described herein can be formulated into dosage forms containing a therapeutically effective amount of the crystalline form or pharmaceutical composition described herein.

[0099] As used herein, the term "therapeutic effective amount" refers to the amount of a pharmaceutical agent that treats, improves, or prevents an identified disease or condition, or that exhibits a detectable therapeutic or inhibitory effect. This effect can be detected by any assay known in the art. The precise effective amount for a subject will depend on the subject's weight, body type, and health status; the nature and severity of the condition; the rate of administration; the therapeutic agent or combination of therapeutic agents selected for administration; and the prescribing physician's discretion. The therapeutic effective amount for a given situation can be determined through routine testing within the skill and judgment of a clinician.

[0100] In some embodiments, the pharmaceutical composition may be formulated to allow administration at doses from 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, 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). The crystalline form of compound (I) described herein is available in doses ranging from 1 mg / kg body weight / day to 40 mg / kg body weight / day. In some cases, dose levels below the lower limit of the above range may be sufficient, while in others, larger doses may be used without causing any harmful side effects, provided that such larger doses are first divided into several smaller doses for administration throughout the day. For further information on routes of administration and dosing regimens, see [link to relevant documentation]. Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), PergamonPress 1990, Volume 5, Chapter 25.3, which is specifically incorporated herein by reference.

[0101] Treatment On the other hand, this article provides a method for preventing and / or treating HER2-related diseases in subjects with such need, the method comprising administering to the subject a therapeutically effective amount of the crystalline form described herein, which is attributed to the HER2-inhibiting activity, selectivity and brain penetration of the compounds of the present invention.

[0102] As used herein, the term "subject in need" refers to a subject with a HER2-related disease or condition (e.g., cancer / tumor), or a subject with an increased risk of developing a HER2-related disease relative to the general population. In the case of cancer, a subject in need may have a precancerous condition. The term "subject" includes homeothermic animals. In some embodiments, homeothermic animals are mammals. In some embodiments, homeothermic animals are humans.

[0103] In some implementations, HER2-related disease is HER2-positive tumors.

[0104] In some embodiments, the tumor is selected from lung cancer, breast cancer, gastric cancer, bladder cancer, urothelial carcinoma, colorectal cancer, bile duct cancer, malignant tumors of the bile duct, esophageal cancer, salivary gland cancer, ovarian cancer, endometrial cancer, kidney cancer, peritoneal cancer, head and neck cancer, pancreatic cancer, neuroendocrine tumors, melanoma, brain cancer, prostate cancer, thyroid cancer, or leukemia.

[0105] In some implementations, one or more additional compounds with antitumor properties are applied in combination.

[0106] Combination therapy The crystalline forms and pharmaceutical compositions described herein can be used alone or in combination with other therapeutic agents for treatment. Useful other therapeutic agents include, but are not limited to, antitumor agents, such as other compounds with anticancer properties. The additional therapeutic agents in the pharmaceutical formulation or dosing regimen preferably have complementary activities to the compounds described herein, such that they do not adversely affect each other. Such molecules are suitably present in combinations at amounts effective for the intended purpose.

[0107] As used herein, the term "combination" means simultaneous, individual, or sequential application. In some embodiments, "combination" means simultaneous application. In some embodiments, "combination" means individual application. In some embodiments, "combination" means sequential application. When applied sequentially or individually, a delay in the application of the second component should not result in the loss of the beneficial effects of the combination.

[0108] Example For illustrative purposes, the following examples are included. However, it should be understood that these examples are not intended to limit the invention, but rather to describe methods of carrying out the invention. Those skilled in the art will recognize that the chemical reactions described herein can be readily adapted to prepare the crystalline forms described herein, and that alternative methods for preparing the crystalline forms are considered to be within the scope of the invention. For example, the preparation of the compounds described herein and their crystalline forms can be successfully carried out with modifications obvious to those skilled in the art, such as by utilizing other suitable reagents known in the art besides the described reagents and / or by conventional modifications to the reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be considered suitable for preparing the compounds or crystalline forms described herein. Those skilled in the art will also recognize that alternative methods for preparing the compounds and their crystalline forms are within the scope of the invention.

[0109] 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.

[0110] Compound (I) via 1 H solution nuclear magnetic resonance (NMR) 1 The compound (I) was characterized by 1H NMR and LC-MS. The crystalline form of compound (I) was characterized by X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and high performance liquid chromatography (HPLC).

[0111] Crystallization analysis conditions X-ray powder diffraction (XRPD) XRPD analysis was performed using a Panaco X-ray powder diffractometer. Table 1 lists the typical XRPD parameters used in the study of polymorphs.

[0112] Table 1 Typical XRPD Parameters

[0113] Thermogravimetric analysis and differential scanning calorimetry (TGA and DSC) For salt screening and evaluation, as well as polymorph studies, TGA analysis was performed using a TA Discovery TGA 5500 or TA Discovery TGA 550 thermogravimetric analyzer. DSC analysis was performed using a TA Discovery DSC 2500 or TA Discovery DSC 250 differential scanning calorimeter. Typical parameters are listed in Table 2.

[0114] Table 2. Parameters for TGA and DSC tests used in polymorph studies.

[0115] High-performance liquid chromatography (HPLC) The Agilent 1260 instrument was used, and the detailed chromatographic conditions used for purity analysis are listed in Table 3.

[0116] Table 3 Chromatographic conditions and parameters

[0117] Example 1 - Preparation of Compound (I) First, intermediate 11 (INT 11) was prepared using the following synthetic route and steps: Step 1: To a solution of 3-amino-5-bromopyridin-2-carboxynitrile (10.0 g, 50.5 mmol) in acetic acid (200 mL), N-chlorosuccinimide (7.42 g, 55.5 mmol) was added. The mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. Water (300 mL) was then added, and the mixture was extracted with ethyl acetate (200 mL x 2). The combined organic phases were washed with water (300 mL) and saturated brine (400 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution gradient V). EA / V 石油醚 = 1:4~2:3) to obtain compound INT 11-2. LCMS: m / z =232.2 [M+H] + .

[0118] Step 2: N,N-dimethylformamide dimethyl acetal (9.5 g, 79.7 mmol) was added to an ethanol (200 mL) solution of compound INT11-2 (10.1 g, 43.4 mmol). The mixture was stirred at 75°C for 2 hours, and then concentrated under reduced pressure. The resulting concentrate was slurried with water (100 mL) and stirred for 30 min, then filtered and washed with water (100 mL). The resulting filter cake was dried to obtain compound INT 11. 1 H NMR (400 MHz, CDCl3) δ 7.66 (s, 1H), 7.61 (s, 1H), 3.13 (d, J = 5.8 Hz, 6H).

[0119] Secondly, the compound (I) of the present invention was prepared using the following synthetic route: Step 1: Potassium carbonate (42.15 g, 305.02 mmol) and benzyl bromide (34.78 g, 203.34 mmol) were added to a solution of compound 5-1 (15 g, 101.67 mmol) in N,N-dimethylformamide (100 mL). After stirring at 25 °C for 2 hours, the mixture was diluted with water (400 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic phases were washed successively with water (200 mL x 3) and saturated brine (150 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution gradient V). EA / V 石油醚 Compound 5-2 was obtained by mixing ratios of 0:1 to 1:4. LCMS: m / z =238.0 [M+H] + .

[0120] Step 2: Cyclopropamide (7.91 g, 92.91 mmol), tris(dibenzylacetone)dipalladium(O) (1.77 g, 1.94 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene (2.24 g, 3.87 mmol), and potassium carbonate (21.4 g, 154.84 mmol) were added to a 1,4-dioxane (150 mL) solution of compound 5-2 (18.4 g, 77.42 mmol). After stirring at 95 °C for 16 hours, the mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic phases were washed successively with water (160 mL x 3) and saturated brine (160 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution gradient V). EA / V 石油醚 = 0:1~3:7) to obtain compound 5-3. LCMS: m / z = 287.0 [M+H] + .

[0121] Step 3: A 50 mL solution of sodium hydroxide (43.73 g, 1093.23 mmol) in water was slowly added to a 200 mL solution of compound 5-3 (31.3 g, 103.32 mmol) in methanol. The mixture was stirred at 80 °C for 4 hours, then diluted with 200 mL of water and extracted with ethyl acetate (500 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (elution gradient V). EA / V 石油醚= 0:1~3:7) to obtain compound 5-4. LCMS: m / z = 218.7 [M+H] + .

[0122] Step 4: N,N-Dimethylformamide dimethyl acetal (18.02 g, 151.22 mmol) was added to a 150 mL ethanol solution of compound 5-4 (22.0 g, 108.81 mmol), followed by the addition of trifluoroacetic acid (1.26 g, 11.09 mmol). The mixture was stirred at 50 °C for 4 h and then concentrated under reduced pressure. The concentrate was added to 100 mL of water and stirred for 15 min, then filtered. The filter cake was dried to obtain the crude product of compound 5-5, which can be used directly in the next step without further purification. LCMS: m / z = 274.2 [M+H] + .

[0123] Step 5: Compound 5-5 (10.0 g, 36.59 mmol) was dissolved in a mixed solvent of isopropanol (100 mL) and tetrahydrofuran (25 mL), followed by the addition of hydroxylamine hydrochloride (3.05 g, 43.91 mmol). The mixture was stirred at 50 °C for 8 h, then concentrated under reduced pressure. Water (100 mL) was added to the concentrate, and the mixture was stirred for 15 min before filtration. The resulting filter cake was dried to give compound 5-6. LCMS: m / z = 261.6 [M+H] + .

[0124] Step 6: At 0°C, trifluoroacetic anhydride (3.96 g, 18.83 mmol) was slowly added dropwise to a tetrahydrofuran (50 mL) solution of compounds 5-6 (4.1 g, 15.70 mmol). After stirring at 25°C for 16 hours, the solution was concentrated under reduced pressure. The concentrate was poured into a sodium hydroxide solution (1 N, 0°C, 150 mL), stirred for 2 hours, and then extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution gradient V). EA / V 石油醚 Compounds 5-7 were obtained by mixing ratios of 0:1 to 1:4. LCMS: m / z = 244.2 [M+H] + .

[0125] Step 7: Palladium on carbon (10%, 210 mg) was added to a methanol (30 mL) solution of compound 5-7 (2.1 g, 8.63 mmol). The mixture was stirred for 1 hour at 25°C under a hydrogen atmosphere (15 psi), filtered, and washed with methanol. The filtrate was concentrated under reduced pressure to give compound 5-8. LC-MS: m / z = 154.0 [M+H] + .

[0126] Step 8: Compounds 5-8 (1.0 g, 6.53 mmol) and 2,4-difluoro-5-nitrotoluene (2.26 g, 13.06 mmol) were dissolved in N,N-dimethylformamide (5 mL), potassium carbonate (5.42 g, 39.19 mmol) was added, and the mixture was stirred at 60 °C for 16 h. The mixture was then diluted with water (40 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed successively with water (20 mL x 3) and saturated brine (15 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution gradient V). EA / V 石油醚 Compounds 5-9 were obtained by mixing ratios of 0:1 to 1:4. LC-MS: m / z =307.0 [M+H] + .

[0127] Step 9: Palladium on carbon (100 mg, 10% by mass) and ammonia (1 mL) were added to a methanol (30 mL) solution of compounds 5-9 (1.0 g, 6.53 mmol). The mixture was stirred at 25°C for 1 hour under a hydrogen atmosphere (15 psi), filtered, and washed with methanol. The filtrate was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (elution gradient V). EA / V 石油醚 Compounds 5-10 were obtained (ratios 0:1 to 7:13). LC-MS: m / z = 277.0 [M+H] + .

[0128] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.46 (d, J = 5.6 Hz, 1H), 8.40 (s, 1H), 7.04 (d, J = 11.6 Hz, 1H), 6.70-6.77 (m, 2H), 5.19 (s, 2H), 2.01 (s, 3H).

[0129] Step 10: INT 11 (187 mg, 0.65 mmol) was added to an acetic acid (8 mL) solution of compound 5-10 (150 mg, 0.54 mmol). The mixture was stirred at 85 °C for 16 hours under a nitrogen atmosphere, and then concentrated under reduced pressure. The concentrate was slurried with water (20 mL) and filtered. The filter cake was dried to obtain the crude product of compound 5-11. This crude product did not require further purification and could be used directly in the next reaction.

[0130] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.55 (d, J = 5.6 Hz, 1H), 8.75 (s, 1H), 8.63 (s, 1H), 8.52 – 8.45 (m, 2H), 7.74 (t, J = 6.8 Hz, 1H), 7.34 (d, J =10.8 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 2.25 (s, 3H).

[0131] Step 11: Compound 5-11 (270 mg, 0.52 mmol) and 2-hydroxymethyl-piperazine (225 mg, 1.04 mmol) were dissolved in N,N-dimethylformamide (6 mL), potassium carbonate (216 mg, 1.56 mmol) was added, and the mixture was stirred at 80 °C for 16 hours under nitrogen protection. The mixture was then diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed successively with water (150 mL x 3) and saturated brine (150 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (elution gradient V). EA / V 石油醚 Compound 5-12 was obtained after purification (ratio = 0:1~19:1). LC-MS: m / z = 698.2 [M+H] + .

[0132] Step 12: Methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (24 mg, 0.03 mmol), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (28 mg, 0.05 mmol), and potassium carbonate (71 mg, 0.51 mmol) were added to a solution of compound 5-12 (90 mg, 0.13 mmol) in dioxane (3 mL). The mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was filtered and washed with ethyl acetate (50 mL). The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (elution gradient V). EA / V 石油醚 Compound 5-13 was obtained by purification (ratio = 0:1~4:1).

[0133] 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.54 (d, J = 5.6 Hz, 1H), 9.36 (s, 1H), 8.44 (d, J = 17.6 Hz, 2H), 8.02 (d, J = 8.8 Hz, 1H), 7.50 (s, 1H), 7.36 (d, J= 10.8 Hz, 1H), 7.08 (d, J = 7.6 Hz, 1H), 4.69 – 4.49 (m, 3H), 4.21 – 4.12(m, 1H), 4.09 – 3.99 (m, 1H), 3.69 (s, 1H), 3.40 (s, 1H), 3.27 – 3.20 (m,2H), 2.24 (s, 3H), 1.41 (s, 9H).

[0134] Step 13: An HCl / 1,4-dioxane solution (4 M, 5 mL) was added to a methanol solution (1 mL) of compound 5-13 (49 mg, 0.08 mmol). After stirring at room temperature for 16 hours, the solution was concentrated under reduced pressure to obtain the crude product (hydrochloride) of compound 5-14. This crude product requires no further purification and can be used directly in the next reaction. LCMS: m / z = 518.2 [M+H] + .

[0135] Step 14: Compound 7-1, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (56.2 mg, 0.34 mmol), 1-hydroxybenzotriazole (30.6 mg, 0.23 mmol), and N,N-diisopropylethylamine (292 mg, 2.26 mmol) were dissolved in N,N-dimethylformamide (3 mL), followed by the addition of compound 5-14 (117 mg, 0.23 mmol). After stirring at room temperature for 16 hours, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed successively with water (90 mL x 3) and saturated brine (90 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained concentrate was purified by high performance liquid chromatography (column: JB-C235-34, Prime C18, 30 x 150 mm x 5 μm; eluent gradient: V). H2O(0.05%NH3·H2O) / V CH3CN = 31:19~12:13; flow rate: 25 mL / min; retention time: 11.2 min) to obtain compound (I), which is an amorphous solid. LC-MS: m / z = 629.2 [M+H] + .

[0136] 1 H NMR (400 MHz, DMSO- d6 ) δ 9.54 (d, J = 5.6 Hz, 1H), 9.39 (s, 1H), 8.44 (d, J = 16.8 Hz, 2H), 8.00 (d, J = 8.8 Hz, 1H), 7.52 (s, 1H), 7.36 (d, J= 10.8 Hz, 1H), 7.08 (d, J = 7.6 Hz, 1H), 6.71 – 6.57 (m, 2H), 5.14 – 4.52(m, 3H), 4.26 – 4.05 (m, 2H), 3.92 – 3.62 (m, 1H), 3.49 – 3.36 (m, 2H), 3.25– 3.08 (m, 3H), 2.24 – 2.17 (m, 9H).

[0137] Example 2 - Cell proliferation inhibition activity test of compound (I) Ba / F3-ERBB2-A775-G776insYVMA in vitro cell proliferation experiment This embodiment aims to verify the inhibitory effect of compound (I) of the present invention on the proliferation of Ba / F3-ERBB2-A775-G776insYVMA cells.

[0138] Experimental materials: The cell line Ba / F3-ERBB2-A775-G776insYVMA was constructed by KYINNO (KYinnoBiotechnology Co., Ltd.); RPMI-1640 medium was purchased from HyClone Laboratories, Inc.; penicillin / streptomycin antibiotics (P / S) were purchased from Solarbio (Beijing Solarbio Science & Technology Co., Ltd.); fetal bovine serum (PBS) was purchased from Gibco; Trypsin-EDTA (1×) was purchased from Solarbio; and the Luminescent Cell Viability Detection Kit (luciferase-based cell viability detection kit) was purchased from Vkeybio (Shanghai VKEYBiotechnologies Co., Ltd.). The culture medium required for this example was RPMI-1640 medium (containing 10% FBS and 1% P / S).

[0139] Experimental Methods: Ba / F3-ERBB2-A775-G776insYVMA cell line was seeded in culture medium and cultured at 37°C with 5% CO2. When the cells reached the logarithmic growth phase, the cell suspension was collected and centrifuged at 1000 rpm for 5 minutes, and the supernatant was discarded. The cells were then resuspended in culture medium and counted. The cell suspension was prepared and seeded at 500 cells / 30 μL / well in 384-well plates, which were incubated overnight at 37°C with 5% CO2. ELVN-002 was used as a positive reference. The positive reference and the test compound (compound (I)) were diluted 3-fold at 10 concentration points using a non-contact microdispensing system to a final concentration of 1 μM. After culturing the cell culture plates in a 37°C, 5% CO2 incubator for 5 days, add 30 μL of Luminescent Cell Viability Detection Kit reagent to each well, then centrifuge at 1000 rpm for 1 min, shake for 2 min, and incubate at room temperature for 28 min.

[0140] Data Analysis: Luminescence values ​​of each well were read using a BMG multi-mode microplate reader. Wells treated with DMSO solvent served as negative controls (H, set at 0% inhibition rate), and wells containing only culture medium served as positive controls (L, set at 100% inhibition rate). The inhibition rate of the test compound was calculated using the following formula: Inhibition % = (Ave_H - Sample) / (Ave_H - Ave_L), where Ave_H is the average luminescence value of the wells treated with DMSO solvent, Ave_L is the average luminescence value of the wells containing the culture medium, and Sample is the luminescence value of the well containing the test compound. Experimental quality was evaluated using the Z' factor, calculated as follows: Z': Z' = 1 - 3(SD_H + SD_L) / (AVE_H – AVE_L), where SD_H and SD_L are the standard deviations of the negative and positive control wells, respectively. A four-parameter nonlinear regression model was used to fit the concentration-response curve of the test compound, and the IC50 was calculated. 50 The fitting formula is as follows: Y = Bottom + (Top - Bottom) / (1 + 10^(LogIC)) 50 -X) HillSlope), where X is the logarithm of the concentration of the analyte, Y is the inhibition rate (%) at the corresponding concentration, Top and Bottom are the upper and lower plateau values ​​of the curve, HillSlope is the slope of the curve, and LogIC 50 This is the logarithm of the half-maximal inhibitory concentration (IC50). The IC50 of the analyte is calculated based on the fitting results. 50 The experimental results are shown in Table 4 below: Table 4. Test results of the in vitro inhibitory activity of compound (I) of the present invention on the proliferation of NCI-H2170 cells.

[0141] As shown in Table 4, the compound (I) of this invention exhibits significant inhibitory activity against the in vitro proliferation of NCI-H2170 cells.

[0142] Example 3 - Preparation and characterization of compound (I) form A Compound (I) in form A is prepared according to one of the following methods: Method 1: Weigh 9.2 mg of the starting material (amorphous form of compound (I) prepared in Example 1) into a 20-mL sample vial. Add 0.1 mL of THF to dissolve the solid, obtaining a solution. Add 1 mL of the antisolvent MTBE to the solution, precipitating a solid. Dry the solid at room temperature and pressure for 2 days.

[0143] Method 2: Weigh 9.6 mg of the starting material (amorphous form of compound (I) prepared in Example 1) into a 20-mL sample vial. Add 0.1 mL of dichloromethane (DCM) to dissolve the solid, obtaining a solution. Add 1 mL of the antisolvent n-heptane to this solution, precipitating a solid.

[0144] The solid of form A described above was characterized by XRPD, TGA, and DSC. The XRPD plots and data are shown in Figure 1 and Table 5, respectively. The TGA / DSC results in Figures 2 and 3 show that the weight loss is approximately 5.51% when heated to 150 °C, and endothermic peaks are present at approximately 57.0, 142.4, 168.6, and 226.8 °C.

[0145] Table 5. XRPD data for form A of compound (I)

[0146] Example 4 - Preparation and characterization of compound (I) form B Compound (I) in form B was prepared by the following method: Preparation method: Weigh 9.1 mg of starting material (amorphous form of compound (I) prepared in Example 1) into an HPLC vial. Add 0.25 mL of isopropanol (IPA) to form a suspension. Circulate the mixture between 50 °C and 5 °C with stirring (specific procedure: hold at 50 °C for 2 hours; cool from 50 °C to 5 °C at a rate of 0.1 °C / min; hold at 5 °C for 2 hours; increase to 50 °C over 0.5 hours; repeat 3 cycles; finally cool from 50 °C to 5 °C at a rate of 0.1 °C / min and hold at 5 °C). Separate the solid by centrifugation (10000 rpm, 3 minutes). Dry the solid at room temperature and pressure for 3 days.

[0147] The solid of form B described above was characterized by XRPD, TGA, and DSC. The XRPD plots and data are shown in Figure 4 and Table 6, respectively. The TGA / DSC results in Figures 5 and 6 show that the weight loss is approximately 5.52% when heated to 180 °C, and endothermic peaks exist at approximately 60.4, 119.9, 145.4, 164.8, 202.9, and 228.0 °C.

[0148] Table 6. XRPD data for form B of compound (I)

[0149] Example 5 - Preparation and characterization of compound (I) form C Compound (I) in form C is prepared according to one of the following methods: Method 1: Weigh 9.4 mg of the starting material (amorphous form of compound (I) prepared in Example 1) into an HPLC sample vial. Add 0.25 mL of isopropyl acetate (IPAc) to form a suspension. Circulate the solution between 50 and 5 °C (program: 50 °C for 2 hours, cooling from 50 °C to 5 °C at a rate of 0.1 °C / min, holding at 5 °C for 2 hours, then heating back to 50 °C over 0.5 hours, for a total of 3 cycles; finally cooling from 50 °C to 5 °C at a rate of 0.1 °C / min and holding at 5 °C). Separate the solid by centrifugation (10000 rpm, 2 minutes). Dry the solid at room temperature and pressure for 3 days.

[0150] Method 2: Weigh 9.1 mg of the starting material (amorphous form of compound (I) prepared in Example 1) into an HPLC sample vial. Add 0.25 mL of acetone to form a suspension. Stir at room temperature for 5 days. Separate the solid by centrifugation (10000 rpm, 2 min).

[0151] Method 3: Weigh 8.9 mg of the starting material (amorphous form of compound (I) prepared in Example 1) into an HPLC sample vial. Add 0.25 mL of methyl tert-butyl ether (MTBE) to form a suspension. Stir at room temperature for 5 days. Separate the solid by centrifugation (10,000 rpm, 2 min).

[0152] Method 4: Weigh 9.4 mg of the starting material (amorphous form of compound (I) prepared in Example 1) into an HPLC sample vial. Add 0.25 mL of acetonitrile (ACN) to form a suspension. Stir at room temperature for 5 days. Separate the solid by centrifugation (10000 rpm, 2 min).

[0153] Method 5: Weigh 9.2 mg of the starting material (amorphous form of compound (I) prepared in Example 1) into an HPLC sample vial. Add 0.25 mL of DMSO / MTBE (1:9, v / v) mixed solvent to form a suspension. Stir at room temperature for 5 days. Separate the solid by centrifugation (10000 rpm, 2 min).

[0154] Method 6: Weigh 9.3 mg of starting material (amorphous form of compound (I) prepared in Example 1) into an HPLC vial. Add 0.25 mL of MIBK to form a suspension. Circulate the suspension between 50 and 5 °C (specific procedure: hold at 50 °C for 2 hours, cool from 50 °C to 5 °C at a rate of 0.1 °C / min, hold at 5 °C for 2 hours, then heat back to 50 °C over 0.5 hours; repeat 3 cycles, finally cool from 50 °C to 5 °C at a rate of 0.1 °C / min and hold at 5 °C). Separate the solid by centrifugation (10000 rpm, 2 minutes).

[0155] The solid of form C described above was characterized by XRPD, TGA, and DSC. XRPD plots and data are shown in Figure 7 and Table 7, respectively. Figure 8 and... Figure 9 The TGA / DSC results showed that the weight loss was about 1.07% when heated to 150°C, and there was an endothermic peak at about 249.7°C.

[0156] Table 7 XRPD data for form C of compound (I)

[0157] Example 6 - Preparation and characterization of compound (I) form D Compound (I) in form D was prepared by the following method: Preparation method: Weigh 9.3 mg of starting material (amorphous form of compound (I) prepared in Example 1) into an HPLC sample vial, and add 0.25 mL of anisole to form a suspension. The suspension is circulated and stirred between 50 and 5 °C (program: 50 °C for 2 hours, decreasing from 50 °C to 5 °C at a rate of 0.1 °C / min, remaining at 5 °C for 2 hours, increasing to 50 °C over 0.5 hours for 3 cycles, followed by decreasing from 50 °C to 5 °C at a rate of 0.1 °C / min and remaining at 5 °C). The solid is separated by centrifugation (10000 rpm, 3 minutes) and vacuum dried at room temperature for 3 days.

[0158] The solid of form D described above was characterized by XRPD, TGA, and DSC. The XRPD plots and data are shown in Figure 10 and Table 8, respectively. Figure 11 The TGA / DSC results in Figure 12 show that the weight loss is approximately 2.93% when heated to 180°C, and there are endothermic peaks at approximately 51.2°C and 204.8°C.

[0159] Table 8. XRPD data for form D of compound (I)

[0160] Example 7 - Preparation and characterization of compound (I) form E Compound (I) in form E was prepared by the following method: Preparation method: Weigh 9.1 mg of starting material (amorphous form of compound (I) prepared in Example 1) into an HPLC sample vial, add 0.25 mL of solvent (1,4-dioxane / water, volume ratio 1:2) to form a suspension. Stir at room temperature for 5 days. Dry the solid under vacuum at room temperature for 19 hours.

[0161] The solid of form E described above was characterized by XRPD, TGA, and DSC. The XRPD plots and data are shown in Figure 13 and Table 9, respectively. Figure 14 The TGA / DSC results in Figure 15 show that the weight loss is approximately 5.46% when heated to 150°C, and there are endothermic peaks at approximately 80.9°C and 160.1°C.

[0162] Table 9. XRPD data for form E of compound (I)

[0163] Example 8 - Competition experiment of suspension of compound (I) in form C / D / E This embodiment aims to study the transformation relationships between compound (I) in forms C, D and E.

[0164] The suspension competition experiment method is as follows: 1) Weigh a certain mass of the amorphous form of compound (I) prepared in Example 1 into an HPLC vial, add 0.5 mL of solvent (ACN (theoretical water activity a)). w ~0) or water (theoretical water activity a) w =1) After stirring magnetically at room temperature for 5 hours, filter (0.45 μm PTFE filter membrane) to obtain a clear solution; 2) Weigh about 2 mg of the mixture of compound (I) in forms C, D and E into a new HPLC vial and add the clear solution obtained in step 1); 3) Stir magnetically at room temperature for 3 days and perform XRPD test on the obtained solid.

[0165] XRPD results showed that a physical mixture of compounds (I) in forms C, D, and E at room temperature was soluble in ACN (a w After 3 days of competitive suspension in ~0), compound (I) transforms into form C. A physical mixture of forms C, D, and E of compound (I) at room temperature is reacted with H2O (aw =1.0) After 3 days of competition, the suspension transforms into form E.

[0166] Example 9 - Accelerated stability study of compound (I) in forms A / BC / D / E This embodiment aims to study the stability of compounds (I) in forms A, B, C, D and E under high temperature and high humidity (80°C / 80%RH accelerated conditions).

[0167] The experimental methods are as follows: 1) Samples of compound (I) in forms A, B, C, D, and E were placed in the open at 80 ℃ / 80%RH for 3 days; 2) Samples were taken for XRPD and HPLC purity testing. The experimental results are shown in Table 9 below.

[0168] Table 10 Accelerated stability data for compounds (I) in forms A / BC / D / E

[0169] ND: Not measured.

[0170] As shown in Table 10, forms A and B transformed into amorphous forms after three days at 80 °C / 80%RH, while forms C, D, and E remained unchanged. Furthermore, HPLC results indicated that the purity of forms C and E decreased only slightly under 80 °C / 80%RH conditions, with the purity of form C decreasing from 99.34% to 96.31% and the purity of form E decreasing from 97.27% to 96.23%. These data suggest that forms C and E exhibit relatively superior stability.

[0171] The foregoing description is considered to be merely illustrative of the principles of the invention. Furthermore, since many modifications and alterations will be apparent to those skilled in the art, it is not intended to limit the invention to the exact process described above. Therefore, all suitable modifications and equivalents are to be considered to fall within the scope of the invention as defined by the appended claims.

Claims

1. A crystalline form of a compound (I) represented by the following structural formula: (I)。 2. The crystalline form according to claim 1, wherein the compound (I) is in a solvated or non-solventized form.

3. The crystalline form according to claim 1, wherein the crystalline form is form A, form B, form C, form D or form E.

4. The crystalline form according to claim 1, wherein the crystalline form is form A, characterized in that... X-ray powder diffraction (XRPD) patterns containing at least the peaks at 2θ (± 0.2°) at 6.8, 16.0, and 23.

1.

5. The crystalline form according to claim 4, characterized in that... X-ray powder diffraction patterns containing at least the peaks at 2θ (± 0.2°) at 6.8, 8.7, 16.0 and 23.

1.

6. The crystalline form according to claim 4, characterized in that... The X-ray powder diffraction pattern is essentially the same as that in Figure 1.

7. The crystalline form according to any one of claims 4 to 6, characterized by the following: One or more of the following: (i) The weight loss during thermogravimetric analysis (TGA) measurements at 180°C is approximately 5.51%; (ii) The TGA curve is essentially the same as that in Figure 2; (iii) Endothermic peaks in differential scanning calorimetry (DSC) measurements at approximately 57.0, 142.4, 168.6, and 226.8 °C; and / or (iv) The DSC curve is essentially the same as that in Figure 3.

8. The crystalline form according to claim 1, wherein the crystalline form is form B, characterized in that... X-ray powder diffraction patterns containing at least the peaks at 2θ (± 0.2°) at 5.6, 11.2, and 23.

4.

9. The crystalline form according to claim 8, characterized in that... X-ray powder diffraction patterns containing at least the peaks at 2θ (± 0.2°) at 5.6, 11.2, 16.0, 16.6 and 23.

4.

10. The crystalline form according to claim 8, characterized in that... X-ray powder diffraction patterns of peaks at 2θ (± 0.2°) at least 5.6, 8.6, 9.2, 11.2, 16.0, 16.6 and 23.

4.

11. The crystalline form according to claim 8, characterized in that... The X-ray powder diffraction pattern is essentially the same as that in Figure 4.

12. The crystalline form according to any one of claims 8 to 11, characterized by the following: One or more of the following: (i) The weight loss during thermogravimetric analysis (TGA) measurements at 180°C is approximately 5.52%; (ii) The TGA curve is essentially the same as that in Figure 5; (iii) Endothermic peaks in differential scanning calorimetry (DSC) measurements at approximately 60.4, 119.9, 145.4, 164.8, 202.9, and 228.0 °C; and / or (iv) The DSC curve is essentially the same as that in Figure 6.

13. The crystalline form according to claim 1, wherein the crystalline form is form C, characterized in that... X-ray powder diffraction patterns containing at least the peaks at 2θ (± 0.2°) at 7.5, 9.9 and 16.

9.

14. The crystalline form according to claim 13, characterized in that... X-ray powder diffraction patterns containing at least the peaks at 2θ (± 0.2°) at 4.7, 7.5, 9.9, 16.9 and 19.

8.

15. The crystalline form according to claim 13, characterized in that... X-ray powder diffraction patterns of peaks at 2θ (± 0.2°) at least 4.7, 7.5, 9.9, 13.6, 15.3, 16.9 and 19.

8.

16. The crystalline form according to claim 13, characterized in that... X-ray powder diffraction patterns of peaks at 2θ (± 0.2°) at least 4.7, 7.5, 9.9, 13.6, 15.3, 16.9, 18.0, 19.8, 21.2, 23.4, 26.3, 26.9, 27.7, 29.0 and 29.

8.

17. The crystalline form according to claim 13, characterized in that... The X-ray powder diffraction pattern is essentially the same as that in Figure 7.

18. The crystalline form according to any one of claims 13 to 17, characterized by the following One or more of the following: (i) The weight loss during thermogravimetric analysis (TGA) measurements at 150°C is approximately 1.07%; (ii) TGA curves that are essentially the same as those in Figure 8; (iii) An endothermic peak in a differential scanning calorimetry (DSC) measurement at approximately 249.7 °C; and / or (iv) The DSC curve is essentially the same as that in Figure 9.

19. The crystalline form according to claim 1, wherein the crystalline form is form D, characterized in that... X-ray powder diffraction patterns of peaks at 2θ (± 0.2°) at least 6.6, 12.1 and 12.

4.

20. The crystalline form according to claim 19, characterized in that... X-ray powder diffraction patterns of peaks at 2θ (± 0.2°) at least 6.6, 12.1, 12.4, 13.2 and 16.

1.

21. The crystalline form according to claim 19, characterized in that... X-ray powder diffraction patterns of peaks at 2θ (± 0.2°) at least 5.3, 6.6, 12.1, 12.4, 13.2, 16.1 and 18.

4.

22. The crystalline form according to claim 19, characterized in that... X-ray powder diffraction patterns of peaks at 2θ (± 0.2°) at least 5.3, 6.6, 8.0, 12.1, 12.4, 13.2, 14.5, 15.2, 16.1, 17.0, 18.0, 18.4, 19.1, 19.9, 21.2, 22.0, 22.6, 24.3, 25.0, 26.5, 28.2, 29.3, and 30.

3.

23. The crystalline form according to claim 19, characterized in that... The X-ray powder diffraction pattern is essentially the same as that in Figure 10.

24. The crystalline form according to any one of claims 19 to 23, characterized by the following One or more of the following: (i) The weight loss during thermogravimetric analysis (TGA) measurements at 180°C is approximately 2.93%; (ii) The TGA curve is essentially the same as that in Figure 11; (iii) Endothermic peaks in differential scanning calorimetry (DSC) measurements at approximately 51.2 and 204.8 °C; and / or (iv) The DSC curve is essentially the same as that in Figure 12.

25. The crystalline form according to claim 1, wherein the crystalline form is form E, characterized in that... X-ray powder diffraction patterns containing at least peaks at 2θ (± 0.2°) at 4.8, 13.8, and 17.

6.

26. The crystalline form according to claim 25, characterized in that... X-ray powder diffraction patterns containing at least the peaks at 2θ (± 0.2°) at 4.8, 13.1, 13.8, 16.1 and 17.

6.

27. The crystalline form according to claim 25, characterized in that... X-ray powder diffraction patterns of peaks at 2θ (± 0.2°) at least 4.8, 13.1, 13.8, 14.8, 16.1, 17.6 and 20.

8.

28. The crystalline form according to claim 25, characterized in that... X-ray powder diffraction patterns of peaks at 2θ (± 0.2°) at least 4.8, 9.5, 13.1, 13.8, 14.8, 16.1, 17.6, 19.1, 20.1, 20.8, 22.6, 23.1, 24.2, 25.0, 26.1, 27.0, 28.7, 29.1, and 29.

8.

29. The crystalline form according to claim 25, characterized in that... The X-ray powder diffraction pattern is essentially the same as that in Figure 13.

30. The crystalline form according to any one of claims 25 to 29, characterized in that... One or more of the following: (i) The weight loss during thermogravimetric analysis (TGA) measurements at 150°C is approximately 5.46%; (ii) The TGA curve is essentially the same as that in Figure 14; (iii) Endothermic peaks in differential scanning calorimetry (DSC) measurements at approximately 80.9 and 160.1 °C; and / or (iv) The DSC curve is essentially the same as that in Figure 15.

31. A method for preparing the crystalline form according to any one of claims 1 to 30, comprising: a) Add compound (I) to the solvent; as well as b) The crystalline form is obtained by adding an antisolvent or by suspension stirring.

32. The method of claim 31, wherein the crystalline form is form A, and the method comprises: a) Add compound (I) to a solvent; as well as b) Obtain form A by adding an antisolvent.

33. The method of claim 32, wherein the solvent is selected from dichloromethane (DCM) and tetrahydrofuran (THF), and / or the antisolvent is selected from n-heptane and methyl tert-butyl ether (MTBE).

34. The method of claim 31, wherein the crystalline form is form B, and the method comprises: a) Add compound (I) to a solvent; as well as b) Obtain form B by suspension stirring.

35. The method of claim 34, wherein the solvent is isopropanol (IPA), and / or the suspension stirring is cyclic stirring between 50 °C and 5 °C.

36. The method of claim 31, wherein the crystalline form is form C, and the method comprises: a) Add compound (I) to the solvent; as well as b) Obtain form C by suspension stirring.

37. The method of claim 36, wherein the solvent is selected from acetone, ethyl acetate (EtOAc), isopropyl acetate (IPAc), methyl tert-butyl ether (MTBE), methyl isobutyl ketone (MIBK), acetonitrile (ACN), tetrahydrofuran (THF), n-heptane and / or dimethyl sulfoxide (DMSO), and / or the suspension stirring is room temperature suspension stirring or circulating stirring between 50 °C and 5 °C.

38. The method of claim 31, wherein the crystalline form is form D, and the method comprises: a) Add compound (I) to the solvent; as well as b) Obtain form D by suspension stirring.

39. The method of claim 38, wherein the solvent is selected from anisole, toluene, and ethyl acetate (EtOAc), and / or the suspension stirring is room temperature suspension stirring or circulating stirring between 50°C and 5°C.

40. The method of claim 31, wherein the crystalline form is form E, and the method comprises: a) Add compound (I) to the solvent; as well as b) Obtain the form E by suspension stirring.

41. The method according to claim 40, wherein the solvent is selected from 1,4-dioxane, water, tetrahydrofuran (THF) and n-heptane, and / or the suspension stirring is room temperature suspension stirring or circulating stirring between 50 °C and 5 °C.

42. A pharmaceutical composition comprising a crystalline form according to any one of claims 1 to 30, and optionally a pharmaceutical carrier or excipient.

43. A dosage form comprising a therapeutically effective amount of the crystalline form according to any one of claims 1 to 30, or the pharmaceutical composition according to claim 42.

44. Use of the crystalline form according to any one of claims 1 to 30 in the preparation of a medicament for the prevention and / or treatment of HER2-related diseases.

45. The use according to claim 44, wherein the HER2-related disease is a HER2-positive tumor.

46. ​​The use according to claim 45, wherein the tumor is selected from lung cancer, breast cancer, gastric cancer, bladder cancer, urothelial carcinoma, colorectal cancer, bile duct cancer, malignant tumors of the bile duct, esophageal cancer, salivary gland cancer, ovarian cancer, endometrial cancer, kidney cancer, peritoneal cancer, head and neck cancer, pancreatic cancer, neuroendocrine tumors, melanoma, brain cancer, prostate cancer, thyroid cancer, or leukemia.

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