ERBB inhibitors in solid form

Abstract

This disclosure provides a pharmaceutically acceptable crystal form of a salt of compound 1: (compound 1), its solvate, and its hydrate. This disclosure also provides methods for preparing said crystal form and its use, for example, in the prevention or treatment of cancer.

Description

Related applications

[0001] This application claims priority and benefit to U.S. Provisional Application No. 63 / 613,537, filed December 21, 2023, the contents of which are incorporated herein by reference in their entirety. Background Technology

[0002] Mutations affecting the intracellular catalytic domain or extracellular ligand-binding domain of the ErbB receptor can produce oncogenic activity (the ErbB protein family consists of four members, including ErbB-1, also known as the epidermal growth factor receptor (EGFR), and Erb-2, also known as HER2 in humans). ErbB inhibitors are known treatments for many cancers. However, not every patient responds satisfactorily to such treatments. Therefore, there has long been a need in the art for novel therapies that address the variable responsiveness of cancer patients to known therapies. This disclosure provides compositions and methods for the prevention or treatment of cancer in patients with these oncogenic mutations. Summary of the Invention

[0003] In some respects, this disclosure provides a crystal form of compound 1: Its solvates, its hydrates, or its pharmaceutically acceptable salts.

[0004] In some aspects, this disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a crystal form of compound 1, its solvate, its hydrate or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0005] In some aspects, this disclosure provides a method for inhibiting an oncogenic variant of the ErbB receptor, comprising administering to a subject in need a therapeutically effective amount of a crystal form of compound 1, its solvate, its hydrate, or a pharmaceutically acceptable salt thereof.

[0006] In some respects, this disclosure provides a method for preventing or treating cancer, comprising administering to a subject in need a therapeutically effective amount of a crystal form of compound 1, its solvate, its hydrate, or a pharmaceutically acceptable salt thereof.

[0007] In some aspects, this disclosure provides a crystal form of compound 1, its solvate, its hydrate or a pharmaceutically acceptable salt thereof, for use in oncogenic variants that inhibit ErbB receptors.

[0008] In some respects, this disclosure provides a crystal form of compound 1, its solvate, its hydrate or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of cancer.

[0009] In some respects, this disclosure provides the use of the crystal form of compound 1, its solvate, its hydrate or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting an oncogenic variant of the ErbB receptor.

[0010] In some respects, this disclosure provides the use of the crystal form of compound 1, its solvates, its hydrates or pharmaceutically acceptable salts thereof in the manufacture of a medicament for the prevention or treatment of cancer.

[0011] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. In this specification, the singular form includes the plural form unless the context clearly requires otherwise. Although similar or equivalent methods and materials described herein may be used to practice or test this disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference. References cited herein are not considered prior art to the claimed invention. In case of conflict, this specification, including the definitions, shall prevail. Furthermore, materials, methods, and examples are illustrative only and are not intended to be restrictive. In case of conflict between the chemical structure and name of the compounds disclosed herein, the chemical structure shall prevail.

[0012] Other features and advantages of this disclosure will become apparent from the following detailed description and claims. Attached Figure Description

[0013] Figure 1 An XRPD diagram of form M of compound 1 was depicted.

[0014] Figure 2 The DSC thermogram of compound 1 in form M was depicted.

[0015] Figure 3 The TGA thermogram of compound 1 in form M was depicted. Detailed Implementation

[0016] It should be understood that, as used herein, the term "compound 1" refers to a compound having the following structure: (Compound 1) Compound 1 can be identified by its IUPAC name (E)-N-(4-((3-chloro-2-fluorophenyl)amino)-7-(((1R,5S)-3-methyl-3-azabicyclo[3.1.0]hex-1-yl)ethynyl)quinazolin-6-yl)-4-morpholinobut-2-enamide.

[0017] In some respects, this disclosure provides a pharmaceutically acceptable salt crystal form of compound 1, its solvate, or its hydrate.

[0018] In some implementations, the crystal form is the crystalline form.

[0019] In some implementations, the crystal form is the crystal form (e.g., crystalline form) of a pharmaceutically acceptable salt of compound 1.

[0020] In some implementations, the crystal form (e.g., crystalline form) is form M.

[0021] In some aspects, this disclosure provides a method for preparing a pharmaceutically acceptable crystal form of a salt of compound 1, its solvate, or its hydrate.

[0022] Form M X-ray powder diffraction (XRPD) characterization In some implementations, the crystal form is a pharmaceutically acceptable salt of compound 1 in the form M, its solvate, or its hydrate.

[0023] In some implementations, form M is a pharmaceutically acceptable salt of compound 1.

[0024] In some embodiments, form M is the malate of compound 1.

[0025] In some embodiments, form M is the L-malate of compound 1.

[0026] In some implementations, form M is the crystalline form.

[0027] In some implementations, form M is a crystalline form of a pharmaceutically acceptable salt of compound 1.

[0028] In some embodiments, form M is the crystalline form of the malate of compound 1.

[0029] In some embodiments, compound 1 and malate are present in form M in ratios of about 1:1.5, about 1:1.6, about 1:1.7, about 1:1.8, about 1:1.9, about 1:2.0, about 1:2.1, about 1:2.2, about 1:2.3, about 1:2.4, about 1:2.5, about 1:2.6, about 1:2.7, about 1:2.8, about 1:2.9, or about 1:3.0.

[0030] In some embodiments, form M is the crystalline form of the L-malate of compound 1.

[0031] In some embodiments, form M is characterized by the use of Cu Kα radiation, and the X-ray powder diffraction (“XRPD”) pattern contains signals (e.g., peaks) at 4.5 ± 0.2, 8.9 ± 0.2, and 21.7 ± 0.2 °2θ (e.g., 4.5 ± 0.1, 8.9 ± 0.1, and 21.7 ± 0.1 °2θ (e.g., 4.5, 8.9, and 21.7 °2θ)).

[0032] In some embodiments, using Cu Kα radiation, the XRPD plot of form M also includes at least one signal (e.g., a peak) selected from 13.3±0.2, 13.9±0.2 and 19.7±0.2 °2θ (e.g. 13.3±0.1, 13.9±0.1 and 19.7±0.1 °2θ (e.g. 13.3, 13.9 and 19.7 °2θ)).

[0033] In some implementations, Cu Kα radiation is used, and the XRPD plot of form M also includes at least two signals (e.g., peaks) selected from 13.3±0.2, 13.9±0.2 and 19.7±0.2 °2θ (e.g. 13.3±0.1, 13.9±0.1 and 19.7±0.1 °2θ (e.g. 13.3, 13.9 and 19.7 °2θ)).

[0034] In some implementations, using Cu Kα radiation, the XRPD plot of form M also includes signals (e.g., peaks) at 13.3±0.2, 13.9±0.2, and 19.7±0.2 °2θ (e.g., 13.3±0.1, 13.9±0.1, and 19.7±0.1 °2θ (e.g., 13.3, 13.9, and 19.7 °2θ)).

[0035] In some embodiments, form M is characterized by the use of Cu Kα radiation, and the X-ray powder diffraction (“XRPD”) pattern contains at least three signals (e.g., peaks) selected from 4.5±0.2, 8.9±0.2, 13.3±0.2, 13.9±0.2, 19.7±0.2, and 21.7±0.2 °2θ (e.g., 4.5±0.1, 8.9±0.1, 13.3±0.1, 13.9±0.1, 19.7±0.1, and 21.7±0.1 °2θ (e.g., 4.5, 8.9, 13.3, 13.9, 19.7, and 21.7 °2θ)).

[0036] In some embodiments, Cu Kα radiation is used, and the XRPD pattern of form M contains at least four signals (e.g., peaks) selected from 4.5±0.2, 8.9±0.2, 13.3±0.2, 13.9±0.2, 19.7±0.2, and 21.7±0.2 °2θ (e.g., 4.5±0.1, 8.9±0.1, 13.3±0.1, 13.9±0.1, 19.7±0.1, and 21.7±0.1 °2θ (e.g., 4.5, 8.9, 13.3, 13.9, 19.7, and 21.7 °2θ)).

[0037] In some embodiments, Cu Kα radiation is used, and the XRPD pattern of form M contains at least five signals (e.g., peaks) selected from 4.5±0.2, 8.9±0.2, 13.3±0.2, 13.9±0.2, 19.7±0.2, and 21.7±0.2 °2θ (e.g., 4.5±0.1, 8.9±0.1, 13.3±0.1, 13.9±0.1, 19.7±0.1, and 21.7±0.1 °2θ (e.g., 4.5, 8.9, 13.3, 13.9, 19.7, and 21.7 °2θ)).

[0038] In some embodiments, Cu Kα radiation is used, and the XRPD plot of form M contains signals (e.g., peaks) at 4.5±0.2, 8.9±0.2, 13.3±0.2, 13.9±0.2, 19.7±0.2, and 21.7±0.2 °2θ (e.g., 4.5±0.1, 8.9±0.1, 13.3±0.1, 13.9±0.1, 19.7±0.1, and 21.7±0.1 °2θ (e.g., 4.5, 8.9, 13.3, 13.9, 19.7, and 21.7 °2θ)).

[0039] In some embodiments, using Cu Kα radiation, the XRPD plot of form M also includes at least one signal (e.g., a peak) selected from 17.9±0.2, 18.9±0.2, 22.2±0.2 and 26.7±0.2 °2θ (e.g. 17.9±0.1, 18.9±0.1, 22.2±0.1 and 26.7±0.1 °2θ (e.g. 17.9, 18.9, 22.2 and 26.7 °2θ)).

[0040] In some implementations, using Cu Kα radiation, the XRPD plot of form M also includes at least two signals (e.g., peaks) selected from 17.9±0.2, 18.9±0.2, 22.2±0.2 and 26.7±0.2 °2θ (e.g. 17.9±0.1, 18.9±0.1, 22.2±0.1 and 26.7±0.1 °2θ (e.g. 17.9, 18.9, 22.2 and 26.7 °2θ)).

[0041] In some implementations, Cu Kα radiation is used, and the XRPD plot of form M also includes at least three signals (e.g., peaks) selected from 17.9±0.2, 18.9±0.2, 22.2±0.2 and 26.7±0.2 °2θ (e.g. 17.9±0.1, 18.9±0.1, 22.2±0.1 and 26.7±0.1 °2θ (e.g. 17.9, 18.9, 22.2 and 26.7 °2θ)).

[0042] In some embodiments, Cu Kα radiation is used, and XRPD maps of form M are contained at 4.5±0.2, 8.9±0.2, 13.3±0.2, 13.9±0.2, 17.9±0.2, 18.9±0.2, 19.7±0.2, 21.7±0.2, 22.2±0.2, and 26.7±0.2 °2θ (e.g., 4.5±0.1, 8.9±0.1, 13.3±0.1, 13.9±0.1, 17.9±0.1, 18.9±0.1, 19.7±0.1, 21.7±0.1, 22.2±0.1, and 26.7±0.1 °2θ). (e.g., peaks) at 4.5, 8.9, 13.3, 13.9, 17.9, 18.9, 19.7, 21.7, 22.2 and 26.7 °2θ.

[0043] In some implementations, form M is characterized in that the XRPD graph is essentially the same as... Figure 1 The XRPD diagram shown is similar.

[0044] In some implementations, form M is characterized by the XRPD graph containing three or more signals (e.g., peaks) at approximately the locations shown in Table A.

[0045] In some implementations, form M is characterized by the XRPD graph containing four or more signals (e.g., peaks) at approximately the locations shown in Table A.

[0046] In some implementations, form M is characterized by the XRPD graph containing five or more signals (e.g., peaks) at approximately the locations shown in Table A.

[0047] In some implementations, form M is characterized by the XRPD graph containing six or more signals (e.g., peaks) at approximately the locations shown in Table A.

[0048] In some implementations, form M is characterized by the XRPD graph containing seven or more signals (e.g., peaks) at approximately the locations shown in Table A.

[0049] In some implementations, form M is characterized by the XRPD graph containing eight or more signals (e.g., peaks) at approximately the locations shown in Table A.

[0050] In some implementations, form M is characterized by the XRPD graph containing nine or more signals (e.g., peaks) at approximately the locations shown in Table A.

[0051] In some implementations, form M is characterized by the XRPD graph containing 10 or more signals (e.g., peaks) at approximately the locations shown in Table A.

[0052] In some implementations, form M is characterized by the XRPD plot containing signals (e.g., peaks) at approximately the locations shown in Table 1.

[0053] It should be understood that the values ​​in the table are approximate and are affected by variations in instruments and experiments.

[0054] Table A: List of exemplary XRPD signals for form M

[0055] Differential Scanning Calorimetry (DSC) Characterization In some embodiments, form M is characterized by the DSC curve having an endothermic signal (e.g., a peak) at 143±20℃ (e.g., 143±10℃ (e.g., 143±5℃ (e.g., 143±4℃ (e.g., 143±3℃ (e.g., 143±2℃ (e.g., 143±1℃ (e.g., 143±0.5℃)))))))

[0056] In some implementations, form M is characterized by a DSC curve having an endothermic signal (e.g., a peak) at approximately 143°C.

[0057] In some embodiments, form M is characterized by a DSC curve having an endothermic signal (e.g., a peak) associated with an enthalpy of about 6.1 ± 4.0 J / g (e.g., 6.1 ± 3.0 J / g (e.g., 6.1 ± 2.0 J / g (e.g., 6.1 ± 1.0 J / g (e.g., 6.1 ± 0.5 J / g)))).

[0058] In some implementations, form M is characterized by a DSC curve having an endothermic signal (e.g., a peak) associated with enthalpy of approximately 6.1 J / g.

[0059] In some embodiments, form M is characterized by the DSC curve having an endothermic signal (e.g., a peak) at 153±20℃ (e.g., 153±10℃ (e.g., 153±5℃ (e.g., 153±4℃ (e.g., 153±3℃ (e.g., 153±2℃ (e.g., 153±1℃ (e.g., 153±0.5℃)))))))

[0060] In some implementations, form M is characterized by a DSC curve having an endothermic signal (e.g., a peak) at approximately 153°C.

[0061] In some embodiments, form M is characterized by a DSC curve having an endothermic signal (e.g., a peak) associated with an enthalpy of about 9.7 ± 4.0 J / g (e.g., 9.7 ± 3.0 J / g (e.g., 9.7 ± 2.0 J / g (e.g., 9.7 ± 1.0 J / g (e.g., 9.7 ± 0.5 J / g)))).

[0062] In some implementations, form M is characterized by a DSC curve having an endothermic signal (e.g., a peak) associated with enthalpy of approximately 9.7 J / g.

[0063] In some implementations, form M is characterized in that the DSC curve is substantially the same as... Figure 2 The DSC curve shown is similar.

[0064] Thermogravimetric analysis (TGA) characterization In some embodiments, as measured by TGA, Form M exhibits a weight loss of approximately 0.5% to approximately 10% in temperatures ranging from approximately 34±20°C (e.g., 34±10°C, 34±5°C, 34±4°C, 34±3°C, 34±2°C, 34±1°C, 34±0.5°C) to approximately 145±20°C (e.g., 145±10°C, 145±5°C, 145±4°C, 145±3°C, 145±2°C, 145±1°C, 145±0.5°C)).

[0065] In some implementations, as measured by TGA, form M shows a weight loss of approximately 4.7% at temperatures ranging from approximately 34°C to approximately 145°C.

[0066] In some implementations, form M is characterized in that the TGA curve is substantially the same as... Figure 3 The TGA curve shown is similar.

[0067] Methods for preparing crystalline forms In some respects, this disclosure is characterized by a method for preparing a pharmaceutically acceptable salt of compound 1 in its crystal form (e.g., crystalline form), its solvate, or its hydrate.

[0068] In some aspects, this disclosure provides a method for preparing a pharmaceutically acceptable salt of compound 1 in a crystal form (e.g., crystalline form), a solvate thereof, or a hydrate thereof, comprising one or more steps as described herein.

[0069] In some aspects, this disclosure provides a compound that can be obtained by or directly obtained by a method for preparing a pharmaceutically acceptable salt of compound 1 in its crystal form (e.g., crystalline form), its solvate, or its hydrate.

[0070] Pharmaceutically acceptable salts of compound 1, in their crystal form (e.g., crystalline form), solvates, or hydrates thereof, can be prepared by any suitable technique known in the art. Specific processes for preparing these compounds are further described in the accompanying examples.

[0071] Preparation of form M In some embodiments, the method includes: (i) preparing a mixture comprising compound 1, an acid, and a solvent, and (ii) removing the solvent from the mixture.

[0072] In some implementations, the acid is malic acid.

[0073] In some implementations, the acid is L-malic acid.

[0074] In some implementations, the solvent is tetrahydrofuran (THF).

[0075] In some implementations, the solvent is a mixture of methanol and water (e.g., in a ratio of about 95:5 v / v).

[0076] In some implementations, the solvent is a mixture of methanol and water (e.g., in a ratio of about 98:2 v / v).

[0077] In some implementations, the solvent is a mixture of methanol and water (e.g., in a ratio of about 10:1 v / v).

[0078] In some embodiments, the method further includes equilibrating the mixture, for example, at a temperature of about 5°C or about 10°C.

[0079] In some embodiments, the solvent is removed from the mixture at a temperature of about 35±15°C, about 35±10°C, about 35±9°C, about 35±8°C, about 35±7°C, about 35±6°C, about 35±5°C, about 35±4°C, about 35±3°C, about 35±2°C, or about 35±1°C (e.g., about 35°C).

[0080] Pharmaceutical Composition In some respects, this disclosure is characterized by pharmaceutical compositions comprising a pharmaceutically acceptable salt of compound 1 in a crystal form (e.g., crystalline form), a solvate thereof or a hydrate thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0081] Pharmaceutical compositions comprising the active compounds of this disclosure can be prepared in a manner commonly known. For example It is manufactured using conventional processes such as mixing, dissolving, granulation, forming into sugar-coated pellets, grinding, emulsification, encapsulation, entrapping, or lyophilization. The pharmaceutical composition can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, said carriers containing excipients and / or adjuvants that facilitate the processing of the active compound into a pharmaceutically usable formulation. Of course, the appropriate formulation depends on the chosen route of administration.

[0082] Suitable pharmaceutical compositions for injectable applications include sterile aqueous solutions (in the water-soluble case) or dispersions, as well as sterile powders for the ad hoc preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, antibacterial water, and polyoxyethylene castor oil (Cremophor). (BASF, Parsippany, NJ) or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to facilitate injection. The composition must be stable under the conditions of preparation and storage and must be preserved against contamination by microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.) and suitable mixtures thereof. Appropriate flowability can be achieved, for example, by using coatings such as lecithin, by maintaining the desired particle size in the case of a dispersion, and by using surfactants. Antimicrobial action can be achieved by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc.). In many cases, including isotonic agents, such as sugars, polyols such as mannitol and sorbitol, and sodium chloride in the composition is preferred. Prolonged absorption of the injectable composition can be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin, in the composition.

[0083] Sterile injectable solutions can be prepared by incorporating the desired amount of the active compound with one or a combination of the ingredients listed above (as needed) into a suitable solvent, followed by filtration and sterilization. Typically, dispersions are prepared by incorporating the active compound into a sterile medium containing a basic dispersion medium and any other desired ingredients from the ingredients listed above. In the case of sterile powders used to prepare sterile injectable solutions, the preparation method involves vacuum drying and freeze-drying of a powder containing the active ingredient plus any other desired ingredients from its previously sterile filtered solution.

[0084] Oral compositions typically include an inert diluent or an edible, pharmaceutically acceptable carrier. They may be encapsulated in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound may be incorporated with excipients and used in tablet, lozenge, or capsule form. Oral compositions may also be prepared using a fluid carrier used as a mouthwash, wherein the compound in the fluid carrier is administered orally and rinsed and spat out or swallowed. Pharmaceutically compatible binders and / or adjuvant materials may be included as part of the composition. Tablets, pills, capsules, lozenges, etc., may contain any of the following components or compounds with similar properties: binders, such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients, such as starch or lactose; disintegrants, such as alginate, primordial gluten, or corn starch; lubricants, such as magnesium stearate or strobilurin; gliding agents, such as colloidal silica; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint, methyl salicylate, or orange flavoring.

[0085] For administration by inhalation, the compound is delivered as an aerosol spray from a source containing a suitable propellant ( For exampleGases (such as carbon dioxide) are delivered via pressurized containers or dispensers or atomizers.

[0086] Systemic application can also be performed transmucosal or transdermal. For transmucosal or transdermal application, a penetrant suitable for the target barrier can be used in the formulation. Such penetrants are generally known in the art and, for example, for transmucosal application, include cleansers, bile salts, and clostridial acid derivatives. Transmucosal application can be achieved by using nasal sprays or suppositories. For transdermal application, as is generally known in the art, the active compound is formulated as an ointment, cream, gel, or lotion.

[0087] The active compound can be prepared with a pharmaceutically acceptable carrier that protects the compound from rapid elimination from the body, such as controlled-release formulations, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such formulations will be apparent to those skilled in the art.

[0088] For ease of administration and uniform dosage, it may be particularly advantageous to formulate oral or parenteral compositions in dose-unit form. As used herein, dose-unit form refers to a physically discrete unit suitable as a unit dose to a subject to be treated; each unit contains a predetermined amount of active compound calculated to bind with the desired drug carrier to produce the desired therapeutic effect. The specifications of the dose-unit form of this disclosure are determined by and directly dependent on the unique properties of the active compound and the specific therapeutic effect to be achieved.

[0089] In therapeutic applications, the dosage of the pharmaceutical composition used according to this disclosure varies depending on the pharmaceutical agent, the age, weight, and clinical condition of the receiving patient, the experience and judgment of the clinician or practitioner administering the therapy, and other factors that influence the selected dosage. Generally, the dosage should be sufficient to alleviate, and preferably eliminate, the symptoms of the disease, and even more preferably to cause complete remission of the disease.

[0090] It should be understood that the pharmaceutical composition may be included in a container, package or dispenser along with the instructions for use.

[0091] How to use In some aspects, this disclosure provides a method for treating or preventing cancer in a subject, comprising administering to the subject a pharmaceutically effective amount of a pharmaceutically acceptable salt of compound 1 in a crystalline form (e.g., a crystalline form), a solvate thereof, or a hydrate thereof.

[0092] In some aspects, this disclosure provides a pharmaceutically acceptable salt of compound 1 in a crystal form (e.g., crystalline form), a solvate thereof, or a hydrate thereof, for use in the treatment or prevention of cancer in a subject.

[0093] In some respects, this disclosure provides the use of a pharmaceutically acceptable salt of compound 1 in a crystal form (e.g., crystalline form), a solvate thereof, or a hydrate thereof in the manufacture of a medicament for treating or preventing cancer in a subject.

[0094] In some embodiments, the pharmaceutically acceptable salt of compound 1 (e.g., L-malate) is administered as M.

[0095] Suitable subjects and diseases In some implementations, the subject is a mammal.

[0096] In some implementations, the subject is a human being.

[0097] In some implementations, the subject is a mouse.

[0098] In some implementations, cancer is a solid tumor.

[0099] In some implementation schemes, the cancer is bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, glioblastoma (GBM), head and neck cancer, lung cancer, non-small cell lung cancer (NSCLC), or any subtype thereof.

[0100] In some implementations, the cancer is glioblastoma (GBM) or any subtype thereof.

[0101] In some implementations, the cancer is glioblastoma, and the cancer is characterized by EGFR overexpression.

[0102] In some embodiments, the cancer is methylated glioblastoma. In other embodiments, the cancer is unmethylated glioblastoma.

[0103] In some implementations, the cancer is recurrent glioblastoma.

[0104] In some implementations, the cancer is a recurrent glioblastoma.

[0105] In some implementations, the cancer is glioblastoma, and the cancer or its tumor or cells express at least one oncogenic variant of EGFR.

[0106] In some implementations, the cancer is a recurrent glioblastoma, and the cancer or its tumor or cells express at least one oncogenic variant of EGFR.

[0107] In some implementations, the cancer is a recurrent glioblastoma, and the cancer or its tumor or cells express at least one oncogenic variant of EGFR.

[0108] In some implementations, the cancer is non-small cell lung cancer (NSCLC) or any subtype thereof.

[0109] In some implementations, the cancer is non-small cell lung cancer (NSCLC).

[0110] In some implementations, the cancer is recurrent non-small cell lung cancer (NSCLC).

[0111] In some implementations, the cancer is recurrent non-small cell lung cancer (NSCLC).

[0112] In some implementations, the cancer is NSCLC, and the cancer or its tumor or cells express at least one oncogenic variant of EGFR.

[0113] In some implementations, the cancer is recurrent NSCLC, and the cancer or its tumors or cells express at least one oncogenic variant of EGFR.

[0114] In some implementations, the cancer is recurrent NSCLC, and the cancer or its tumor or cells express at least one oncogenic variant of EGFR.

[0115] In some implementations, the cancer is advanced or metastatic NSCLC.

[0116] In some implementations, the cancer is advanced or metastatic NSCLC, and the cancer or its tumors or cells express at least one oncogenic variant of EGFR.

[0117] In some implementations, the cancer is NSCLC, where the cancer has metastasized to the central nervous system (CNS).

[0118] In some implementations, the cancer is advanced or metastatic NSCLC, wherein the cancer or its tumors or cells express at least one oncogenic variant of EGFR, and wherein the cancer has metastasized to the central nervous system (CNS).

[0119] In some implementations, the cancer is advanced or metastatic NSCLC, wherein the cancer or its tumor or cells express at least one oncogenic variant of EGFR, and wherein the cancer has not yet metastasized to the central nervous system (CNS).

[0120] In some implementations, the cancer is NSCLC, where the cancer has not yet metastasized to the cerebrospinal fluid (CSF).

[0121] In some implementations, the cancer is NSCLC, where the cancer has metastasized to the cerebrospinal fluid (CSF).

[0122] In some implementations, the cancer is glioblastoma, in which the cancer has not yet metastasized to the cerebrospinal fluid (CSF).

[0123] In some implementations, the cancer is glioblastoma, in which the cancer has metastasized to the cerebrospinal fluid (CSF).

[0124] In some implementations, the cancer is NSCLC, where the cancer has not yet metastasized to the brain.

[0125] In some implementations, the cancer is NSCLC, where the cancer has metastasized to the brain.

[0126] In some implementations, the subjects have a central nervous system (CNS) disease.

[0127] In some implementations, the subjects did not have any CNS disease.

[0128] In some implementations, the subjects had leptomeningeal disease.

[0129] In some implementations, the subjects did not have any leptomeningeal disease.

[0130] In some implementations, the cancer is NSCLC, and the subject has leptomeningeal disease.

[0131] In some implementations, the cancer is glioblastoma, and the subject has leptomeningeal disease.

[0132] In some implementations, the cancer or its tumor or cells express an oncogenic variant of the ErbB receptor.

[0133] It should be understood that oncogenic variants of the ErbB receptor are ErbB receptor proteins that contain at least one oncogenic mutation and are produced by the expression of a gene encoding an ErbB receptor containing at least one oncogenic mutation.

[0134] As technicians will understand, in genes ( For exampleIn the context of the gene encoding the ErbB receptor, oncogenic mutations can include, but are not limited to, mutations that result in the substitution of one amino acid for another at a specific position within the ErbB receptor, mutations that result in the insertion of one or more amino acids between two positions within the ErbB receptor, mutations that result in the deletion of one or more amino acids between two positions within the ErbB receptor, and mutations that result in the fusion of the ErbB receptor or a portion thereof with another protein or a portion thereof. As those skilled in the art will understand, in the context of a gene, oncogenic mutations can include, but are not limited to, missense mutations, nonsynonymous mutations, insertions of one or more nucleotides, deletions of one or more nucleotides, inversions, and deletion-insertion combinations.

[0135] As technicians will understand, in proteins ( For example In the context of the ErbB receptor, oncogenic mutations may include, but are not limited to, one amino acid replacing another at a specific position within the ErbB receptor, one or more amino acids being inserted between two positions within the ErbB receptor, one or more amino acids being deleted between two positions within the ErbB receptor, and the fusion of the ErbB receptor or a portion thereof with another protein or a portion thereof.

[0136] In some implementations, oncogenic variants of the ErbB receptor contain allosteric mutations.

[0137] In some implementations, the oncogenic variant of the ErbB receptor is an allosteric variant of the ErbB receptor.

[0138] In some implementations, the ErbB receptor is the epidermal growth factor receptor (EGFR) or the human epidermal growth factor receptor 2 (HER2) receptor.

[0139] In some implementations, the ErbB receptor is the epidermal growth factor receptor (EGFR).

[0140] In some implementations, the ErbB receptor is the HER2 receptor.

[0141] In some implementations, the ErbB receptor is the HER3 receptor.

[0142] In some implementations, the ErbB receptor is the HER4 receptor.

[0143] In some implementations, the cancer or its tumors or cells express oncogenic variants of the epidermal growth factor receptor (EGFR).

[0144] In some implementations, the carcinogenic variant of EGFR is an allosteric variant of EGFR.

[0145] In some implementations, oncogenic variants of EGFR contain allosteric mutations.

[0146] In some implementations, the cancer or its tumor or cells express an oncogenic variant of the HER2 receptor.

[0147] In some implementations, the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor.

[0148] In some implementations, oncogenic variants of the HER2 receptor contain allosteric mutations.

[0149] In some implementations, the oncogenic variant of EGFR includes the EGFR variant III (EGFR-Viii) mutation.

[0150] In some implementations, the oncogenic variant of EGFR includes the EGFR variant II (EGFR-Vii) mutation.

[0151] In some implementations, the oncogenic variant of EGFR includes the EGFR variant VI (EGFR-Vvi) mutation.

[0152] definition It should be understood that the compounds described herein include the compounds themselves, as well as their salts and their solvates, if applicable. For example, salts can be formed between an anion and a positively charged group (e.g., an amino group) on a substituted benzene compound. Suitable anions include chlorides, bromides, iodides, sulfates, hydrogen sulfates, aminosulfonates, nitrates, phosphates, citrates, methanesulfonates, trifluoroacetates, glutamates, glucurons, glutarates, malates, maleates, succinates, fumarates, tartrates, toluenesulfonates, salicylates, lactates, naphthalenesulfonates, and acetates (e.g., trifluoroacetates).

[0153] Unless otherwise expressly stated, the terms "about" and "about" are synonymous. In some embodiments, "about" and "about" refer to the amount, value, dose, or duration ±20%, ±15%, ±10%, ±8%, ±6%, ±5%, ±4%, ±2%, ±1%, or ±0.5%. In some embodiments, "about" and "about" refer to the listed amount or duration ±10%, ±8%, ±6%, ±5%, ±4%, or ±2%. In some embodiments, "about" and "about" refer to the listed amount, value, dose, or duration ±5%. In some embodiments, "about" and "about" refer to the listed amount, value, dose, or duration ±2%. In some embodiments, "about" and "about" refer to the listed amount, value, dose, or duration ±1%. In some implementations, when referring to the value of an X-ray diffraction (“XRPD”) signal (e.g., a peak), “about” and “approximately” mean the listed value of ±0.2, ±0.15, ±0.1, ±0.05, ±0.02, or ±0.01.

[0154] As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Similarly, salts can also be formed between a cation and a negatively charged group (e.g., a carboxyl group) on a substituted benzene compound. Suitable cations include sodium, potassium, magnesium, calcium, and ammonium cations such as tetramethylammonium ions. Substituted benzene compounds also include those containing a quaternary nitrogen atom.

[0155] It should be understood that the compounds of this disclosure (e.g., salts of the compounds) may exist in hydrated or unhydrated (anhydrous) form or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates and dihydrates. Non-limiting examples of solvates include ethanol solvates and acetone solvates.

[0156] As used herein, unless otherwise specified, the expressions “one or more of A, B or C”, “one or more of A, B or C”, “one or more of A, B and C”, “one or more of A, B and C”, “selected from the group consisting of A, B and C”, “selected from A, B and C”, etc., are used interchangeably and all refer to the group consisting of A, B and / or C, that is, one or more A, one or more B, one or more C or any combination thereof.

[0157] It should be understood that throughout the specification, when a composition is described as having, including, or comprising a specific component, it is anticipated that the composition is substantially composed of, or composed of, said component. Similarly, when a method or process is described as having, including, or comprising specific process steps, the process is also substantially composed of, or composed of, said processing steps. Furthermore, it should be understood that the order of steps or the sequence of certain actions is irrelevant as long as the invention remains operable. Moreover, two or more steps or actions may be performed simultaneously.

[0158] It should be understood that the compounds disclosed herein can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or readily prepared intermediates, employing standard synthetic methods and procedures known to those skilled in the art or obvious to those skilled in the art based on the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and for the transformation and manipulation of functional groups are available from relevant scientific literature or from standard textbooks in the field. While not limited to any one or more sources, classic texts incorporated herein by reference, such as Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th ed., John Wiley&Sons: New York, 2001; Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis , 3rd ed., John Wiley&Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations , VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis John Wiley and Sons (1994); and L. Paquette (eds.), Encyclopedia of Reagents for Organic Synthesis John Wiley and Sons (1995) is a useful and well-regarded reference textbook for organic synthesis known to those skilled in the art.

[0159] It should be understood that, unless otherwise stated, any description of a treatment or prevention method includes the use of the crystalline form of Compound 1 or a pharmaceutically acceptable salt thereof to provide the treatment or prevention as described herein. It should be further understood that, unless otherwise stated, any description of a treatment or prevention method includes the use of the crystalline form of Compound 1 or a pharmaceutically acceptable salt thereof to prepare a medicament for the treatment or prevention of this condition. Treatment or prevention includes the treatment or prevention of human or non-human animals, including rodents and other disease models.

[0160] It should be understood that, unless otherwise stated, any description of a treatment method includes the use of the crystalline form of Compound 1 or a pharmaceutically acceptable salt thereof to provide the treatment as described herein. It should be further understood that, unless otherwise stated, any description of a treatment method includes the use of the crystalline form of Compound 1 or a pharmaceutically acceptable salt thereof to prepare a medicament for treating this condition. Treatment includes treatment of humans or non-human animals, including rodents and other disease models.

[0161] As used herein, the term "subject" refers to a subject who has a disease or has an increased risk of developing the disease. "Subject" includes mammals. Mammals can be, for example, humans or suitable non-human mammals such as primates, mice, rats, dogs, cats, cattle, horses, goats, camels, sheep, or pigs. Subjects can also be birds or poultry. In one embodiment, the mammal is a human.

[0162] In some embodiments, the term "subject in need" can refer to a subject who has been previously diagnosed or identified as having a disease or condition disclosed herein. A subject in need can also be a subject suffering from a disease or condition disclosed herein. Alternatively, a subject in need can be a subject with an increased risk of developing such a disease or condition relative to the general population (i.e., a subject who is more susceptible to developing such a condition relative to the general population). A subject in need can suffer from a treatment-resistant or drug-resistant disease or condition disclosed herein (i.e., a disease or condition disclosed herein that is unresponsive to treatment or has not yet responded). A subject in need may be drug-resistant at the start of treatment or may become drug-resistant during treatment. In some embodiments, a subject in need has received all known effective therapies for the disease or condition disclosed herein but treatment has failed. In some embodiments, a subject in need has received at least one prior therapy.

[0163] As used herein, the terms "treating" or "treatment" describe the management and care of a patient in order to combat a disease, symptom, or condition, and include the administration of compounds of this disclosure or their pharmaceutically acceptable salts, polymorphs, or solvates to alleviate or eliminate symptoms or complications of the disease, symptom, or condition. The term "treatment" may also include treatment in in vitro cell or animal models.

[0164] It should be understood that the crystalline form of compound 1 or its pharmaceutically acceptable salt may or may be used to prevent related diseases, symptoms or conditions or to identify suitable candidates for such purposes.

[0165] As used herein, the terms “preventing,” “prevent,” or “protecting against” describe reducing or eliminating the onset of symptoms or complications of such diseases, conditions, or ailments.

[0166] It should be understood that "solubility" or "solubility grade" refers to the property of the polymorph disclosed herein (e.g., form M) to dissolve in a liquid solvent and form a homogeneous solution. In some embodiments, solubility is expressed as concentration by the mass of solute per unit volume of solvent (e.g., g solute / kg solvent, g / dL (100 mL), mg / ml, etc.), molar concentration, weight molality, mole fraction, or other similar concentration descriptions. Those skilled in the art will understand that the maximum equilibrium amount of solute that can be dissolved per volume of solvent is the solubility of that solute in that solvent under specified conditions (including temperature, pressure, pH, and the properties of the solvent).

[0167] As used herein, “stable” means a polymorph that maintains its purity, appearance, and / or analytical parameters within a defined time and temperature range compared to the separated polymorph. In some embodiments, the “stable” polymorph exhibits less than about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, about 1 month, about 2 months, about 3 months, or about 4 months of impurities within a defined time period (e.g., 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, or 4 months).

[0168] As used herein, the term "pharmaceutical composition" refers to a formulation containing a compound of the present disclosure in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or unit dosage form. Unit dosage form is any of a variety of forms, including, for example, capsules, IV bags, tablets, single pumps on an aerosol inhaler, or vials. The amount of active ingredient (e.g., a formulation of the disclosed compound or its salts, hydrates, solvates, or isomers) in a unit dose of the composition is an effective amount and varies depending on the specific treatment involved. Those skilled in the art will understand that it is sometimes necessary to routinely change the dosage according to the patient's age and condition. The dosage will also depend on the route of administration. A variety of routes are considered, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, oral, sublingual, intrapleural, intrathecal, intranasal, etc. Dosage forms for topical or transdermal application of the compounds of the present disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any desired preservatives, buffers, or propellants.

[0169] As used herein, the term “pharmaceutically acceptable” means those compounds, anions, cations, materials, compositions, carriers, and / or dosage forms that are suitable for use in human and animal tissues to the extent of correct medical judgment without causing excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0170] As used herein, the term "pharmaceuticalally acceptable excipient" means an excipient that can be used to prepare pharmaceutical compositions that are generally safe and non-toxic and are biologically or otherwise desirable and include excipients acceptable for veterinary and human pharmaceutical use. "Pharmaceuticalally acceptable excipient" as used in the specification and claims includes one or more such excipients.

[0171] As used herein, the term "therapeutic effective amount" refers to the amount of a drug agent used to treat, improve, or prevent an identified disease or symptom, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend on the subject's weight, body type, and health status; the nature and severity of the symptom; and the choice of treatment or combination of treatments to be administered. The therapeutic effective amount for a given situation can be determined through routine laboratory testing within the skill and judgment of a clinician.

[0172] It should be understood that all these forms are also contemplated within the scope of the claimed disclosure for compounds of this disclosure that are capable of further forming salts.

[0173] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of a compound of the present disclosure, wherein the parent compound is modified by preparing an acid or a basic salt thereof. In some embodiments, the pharmaceutically acceptable salt of the compound is also a prodrug of the compound. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, and basic or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of parent compounds formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, non-toxic salts derived from inorganic and organic acids selected from: 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edemacid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheponic acid, gluconic acid, glutamic acid, glycolic acid, glycolamide arsine, hexylresorcinol, hydrabamic acid, hydrobromic acid, hydrochloric acid, and hydroiodine. Acids, including hydroxymaleic acid, hydroxynaphthyl carboxylic acid, hydroxyethanesulfonic acid, lactic acid, lactobionic acid, lauryl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, naphthalenesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, aminosulfonic acid, p-aminobenzenesulfonic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid; and common amino acids such as glycine, alanine, phenylalanine, and arginine.

[0174] Other pharmaceutically acceptable examples of salts include hexanoic acid, cyclopentanepropionic acid, pyruvate, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-en-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, mucoconic acid, etc. This disclosure also covers salts formed when an acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, alkaline earth ion, or aluminum ion) or coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucosamine, etc. In salt form, it should be understood that the ratio of the compound to the cation or anion of the salt can be 1:1, or any quantitative ratio other than 1:1, such as 3:1, 2:1, 1:2, or 1:3.

[0175] It should be understood that all references to pharmaceutically acceptable salts include the same salt in its solvation form (solvent) or crystalline form (polymorph) as defined herein.

[0176] The compound or a pharmaceutically acceptable salt thereof may be administered orally, nasally, dermally, pulmonaryly, by inhalation, sublingually, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, and parenterally. In one embodiment, the compound is administered orally. Those skilled in the art will recognize the advantages of certain routes of administration.

[0177] The dosing regimen for a compound is selected based on a number of factors, including the patient's type, species, age, weight, sex, and medical condition; the severity of the condition to be treated; the route of administration; the patient's renal and hepatic function; and the specific compound or its salt used. A generally skilled physician or veterinarian can readily determine and prescribe the effective amount of drug required to prevent, counteract, or halt the progression of the condition.

[0178] Techniques for preparing and applying the disclosed compounds can be found in [the following text is missing from the original] Remington: the Science and Practice of Pharmacy , 19th edition, Mack Publishing Co., Easton, PA (1995). In one embodiment, the compounds described herein and their pharmaceutically acceptable salts are used in combination with pharmaceutically acceptable carriers or diluents in a pharmaceutical formulation. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds will be present in such pharmaceutical compositions in an amount sufficient to provide the desired dose within the range described herein.

[0179] Unless otherwise specified, all percentages and ratios used herein are by weight. Other features and advantages of this disclosure will be apparent from various examples. The examples provided illustrate different components and methods useful in practicing this disclosure. The examples do not limit the scope of the claimed disclosure. Based on this disclosure, those skilled in the art can identify and employ other components and methods that can be used in practicing this disclosure.

[0180] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document were specifically and individually indicated to be incorporated herein by reference. The citation of publications and patent documents does not constitute an admission of any applicable prior art, nor does it constitute any admission of the content or date of the said publications and patent documents. The invention has now been described in writing, and those skilled in the art will recognize that the invention can be practiced in various embodiments, and that the foregoing description and examples are for illustrative purposes and not for limiting the scope of the following claims.

[0181] Exemplary Implementation Exemplary Implementation 1. A crystal form of a pharmaceutically acceptable salt of compound 1: Its solvates or hydrates.

[0182] Exemplary Implementation 2. The crystal form as described in Exemplary Implementation 1, wherein the crystal form is a crystalline form.

[0183] Exemplary Implementation 3. The crystal form as described in any of the foregoing exemplary implementations, wherein the crystal form is a pharmaceutically acceptable salt form M of compound 1, its solvate, or its hydrate.

[0184] Exemplary Embodiment 4. The crystal form as described in any of the foregoing exemplary embodiments, wherein the form M is characterized by using Cu Kα radiation, and the X-ray powder diffraction (“XRPD”) pattern contains signals at 4.5±0.2, 8.9±0.2, and 21.7±0.2°2θ.

[0185] Exemplary Implementation 5. The crystal form as described in any of the foregoing exemplary implementations, wherein Cu Kα radiation is used, and the XRPD pattern of form M further includes at least one signal selected from 13.3±0.2, 13.9±0.2, and 19.7±0.2 °2θ.

[0186] Exemplary Implementation 6. The crystal form as described in any of the foregoing exemplary implementations, wherein Cu Kα radiation is used, and the XRPD plot of form M further includes at least one signal selected from 17.9±0.2, 18.9±0.2, 22.2±0.2, and 26.7±0.2 °2θ.

[0187] Exemplary Implementation 7. The crystal form as described in any of the foregoing exemplary embodiments, wherein form M is characterized in that the XRPD pattern is substantially the same as... Figure 1 The XRPD diagram shown is similar.

[0188] Exemplary Implementation 8. The crystal form as described in any of the foregoing exemplary implementations, wherein the form M is characterized in that the XRPD plot contains one or more signals (e.g., peaks) at approximately the locations shown in Table A.

[0189] Exemplary Implementation 9. The crystal form as described in any of the foregoing exemplary implementations, wherein form M is characterized in that the DSC curve has an endothermic signal at 143±20°C.

[0190] Exemplary Embodiment 10. The crystal form as described in any of the foregoing exemplary embodiments, wherein the form M is characterized in that the DSC curve has an endothermic signal at 153±20°C.

[0191] Exemplary Embodiment 11. The crystal form as described in any of the foregoing exemplary embodiments, wherein, as measured by TGA, form M exhibits a weight loss of about 0.5% to about 10% at temperatures ranging from about 34 ± 20°C to about 145 ± 20°C.

[0192] Exemplary Embodiment 12. A pharmaceutical composition comprising a therapeutically effective amount of a crystal form as described in any one of the foregoing exemplary embodiments and a pharmaceutically acceptable excipient.

[0193] Exemplary Embodiment 13. A method of inhibiting an oncogenic variant of the ErbB receptor, comprising administering to a subject in need a therapeutically effective amount of a crystalline or pharmaceutical composition as described in any of the foregoing exemplary embodiments.

[0194] Exemplary Embodiment 14. A method of preventing or treating cancer, comprising administering to a subject in need a therapeutically effective amount of a crystalline or pharmaceutical composition as described in any of the foregoing exemplary embodiments.

[0195] Exemplary Implementation 15. A method for preventing or treating cancer, comprising: i) identifying a subject candidate as a subject requiring treatment when at least one oncogenic variant of the ErbB receptor is present in a subject or a biological sample from said subject; and ii) administering a therapeutically effective amount of a crystalline or pharmaceutical composition as described in any of the foregoing exemplary implementations to said subject requiring treatment.

[0196] Exemplary Embodiment 16. A method for preventing or treating cancer, comprising administering to the subject in need a crystalline or pharmaceutical composition as described in any of the foregoing exemplary embodiments when at least one oncogenic variant of the ErbB receptor is identified as being present in a subject or a biological sample from said subject.

[0197] Exemplary Embodiment 17. The crystal form or pharmaceutical composition as described in any of the foregoing exemplary embodiments, used in an oncogenic variant that inhibits the ErbB receptor.

[0198] Exemplary Embodiment 18. A crystal form or pharmaceutical composition as described in any of the foregoing exemplary embodiments, used in the prevention or treatment of cancer.

[0199] Exemplary Embodiment 19. A crystal form or pharmaceutical composition as described in any of the foregoing exemplary embodiments, used in the prevention or treatment of cancer in a subject, wherein at least one oncogenic variant of the ErbB receptor is present in the subject or a biological sample from the subject.

[0200] Exemplary Embodiment 20. Use of the crystal form as described in any of the foregoing exemplary embodiments in the manufacture of a medicament for inhibiting an oncogenic variant of the ErbB receptor.

[0201] Exemplary Implementation 21. Use of the crystal form as described in any of the foregoing exemplary implementations in the manufacture of a medicament for the prevention or treatment of cancer.

[0202] Exemplary Implementation 22. The crystal form, pharmaceutical composition, method, or use as described in any of the foregoing exemplary implementations, wherein the cancer is a solid tumor, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, glioblastoma (GBM), head and neck cancer, lung cancer, non-small cell lung cancer (NSCLC), or any subtype thereof.

[0203] Exemplary Embodiment 23. The crystal form, pharmaceutical composition, method, or use as described in any of the foregoing exemplary embodiments, wherein the cancer or its tumor or cells express an oncogenic variant of the epidermal growth factor receptor (EGFR).

[0204] Exemplary Embodiment 24. The crystal form, pharmaceutical composition, method, or use as described in any of the foregoing exemplary embodiments, wherein the oncogenic variant is an oncogenic variant of the ErbB receptor epidermal growth factor receptor (EGFR) or HER-4 receptor of the HER2 receptor, and wherein the oncogenic variant of the ErbB receptor EGFR or the HER2 receptor is an allosteric variant.

[0205] Exemplary Embodiment 25. The crystal form, pharmaceutical composition, method, or use as described in any of the foregoing exemplary embodiments, wherein the subject or the cancer is insensitive to or resistant to treatment with one or more of gefitinib, erlotinib, afatinib, osimertinib, and nexituzumab.

[0206] Exemplary Embodiment 26. A crystal form, pharmaceutical composition, method, or use as described in any of the foregoing exemplary embodiments, wherein the sequence encoding the oncogenic variant of the EGFR includes a deletion of exon 20 or a portion thereof, and wherein the cancer, its tumor, or cells do not contain oncogenic variants or markers indicating responsiveness to immunotherapy in sequences encoding one or more of the EGFR kinase domain (KD), BRAF, NTRK, and KRAS.

[0207] Exemplary Implementation 27. The crystal form, pharmaceutical composition, method, or use as described in any of the foregoing exemplary implementations, wherein the carcinogenic variant or carcinogenic mutation is detected by a diagnostic approved by the Food and Drug Administration (FDA).

[0208] Exemplary Embodiment 28. The crystal form, pharmaceutical composition, method, or use as described in any of the foregoing exemplary embodiments, wherein the subject has an adverse reaction to treatment with a type I inhibitor.

[0209] Exemplary Embodiment 29. The crystal form, pharmaceutical composition, method, or use as described in any of the foregoing exemplary embodiments, wherein the subject has an adverse reaction to treatment with one or more of gefitinib, erlotinib, afatinib, osimertinib, nexituzumab, crizotinib, alectinib, ceritinib, dabrafenib, trametinib, afatinib, saprotinib, dacomitinib, cannetinib, peritrinib, WZ4002, WZ8040, WZ3146, CO-1686, and AZD9291.

[0210] Example It should be understood that the experimental values ​​described in this application are approximate and are affected by instrument variations.

[0211] X-ray powder diffractometer (XRPD): Analysis was performed using a Bruker D8 Advance X-ray powder diffractometer. The parameters described below were used for the analysis.

[0212] Differential scanning calorimetry (DSC): Analysis was performed using a TA Discover 2500 or Q2000. The parameters described below were used for the analysis.

[0213] Thermogravimetric analysis (TGA): The analysis was performed using a Discover 5500. The parameters described below were used for the analysis.

[0214] Dynamic vapor adsorption (DVS): The analysis was performed using Intrinsic. The parameters described below were used for the analysis.

[0215] Nuclear magnetic resonance (NMR): NMR analysis was performed using a Bruker Avance-AV 400M at a frequency of 400 MHz, a 5 mm PABBO BB-1H / D probe, 8 scans, a temperature of 297.6 K, and a relaxation delay of 1 second.

[0216] High Performance Liquid Chromatography (HPLC): HPLC analysis was performed using a SHIMADZU LC-20AD / Agilent 1260infinity II binary pump. The parameters described below were used for analysis.

[0217] Example 1. Exemplary preparation of crystalline form M Approximately 250 mg of L-malic acid (approximately 2.0 equivalents) was weighed into a 40 mL glass bottle. 2 mL of THF was added to dissolve the L-malic acid. The clear solution was stirred at 250 rpm at 25°C. Approximately 500 mg of Compound 1 was weighed into an 8 mL glass bottle, and 4 mL of THF was added to dissolve the free base. Then, 200 µL of the Compound 1 solution was added dropwise to the L-malic acid THF solution. An oily substance was obtained first. Simultaneously, approximately 5 mg of L-malate seed crystals were added to the 40 mL bottle. A suspension was obtained. The remaining free base solution was slowly added to the suspension. After a large amount of solid precipitated, 1.5 mL of THF was added to the suspension. The suspension was stirred at 400 rpm at 25°C for 3 days. The obtained suspension was collected, and the solid was separated by centrifugation. The solid fraction was dried under vacuum at 30°C for 3 h. Approximately 700 mg of L-malate form M, appearing as an orange solid, was obtained in approximately 90% yield. The dried filter cake was characterized by XRPD and 1H-NMR. Approximately 2.8 equivalents of L-malic acid were detected in the dried filter cake by 1H-NMR.

[0218] To further optimize the crystallinity of the salt, approximately 25 mg of the dried filter cake was reequilibrated for 3 days in seven different solvents. The obtained solids were analyzed by XRPD and 1H-NMR. The solid fraction was dried under vacuum at 35 °C for 2 h. The results are summarized in Table 1. After reequilibration in methanol / water (v:v = 95:5), the crystallinity of L-malate increased, and it showed a reasonable stoichiometry. For L-malate form M, its crystallinity decreased after drying under vacuum at 50 °C for 2 h.

[0219] Table 1. Preparation of Form M: Results of Re-slurry Experiment.

[0220] The solvent system of MeOH and H₂O was selected to optimize crystallization. Approximately 100 µL of the suspension in the methanol / water (v:v = 98:2) system was added to a 2 mL glass vial. More water was added to adjust the solvent system to methanol / water (v:v = 95:5). The suspension was stirred at 10 °C for 2 days. The suspension was then removed and centrifuged at 10 °C. The solid was characterized by XRPD. The crystallinity of the L-malate was improved, and its stoichiometry was more reasonable (approximately 2.2 equivalents of L-malic acid).

[0221] To further optimize the stoichiometry of the L-malate, more water was added to adjust the solvent system to methanol / water (v:v = 10:1). The resulting suspension was stirred at 10°C for 4 days. The resulting suspension was collected, and the orange solid was separated by centrifugation. The solid fraction was dried at 25°C / 50% RH for 16 h. Approximately 180 mg of the brown solid L-malate form M was obtained in approximately 50% yield. The stoichiometric ratio of its free form to L-malic acid was 1:2.1.

[0222] Example 2. Study on the characteristics of form M.

[0223] Bulk stability: Form M was evaluated for bulk stability. Bulk stability studies were conducted under three conditions: 25°C / 92% RH in open containers, 40°C / 75% RH in open containers, and 60°C in tightly packed containers, for 1 week, 2 weeks, and 4 weeks, respectively. Table 2 summarizes the observations from the stability studies.

[0224] Table 2 Solubility: 6.39 mg of L-malate form M (equivalent to 4 mg of free base) was weighed into 8 mL vials. 2 mL of aqueous medium was added. The suspension was stirred at 400 rpm for 2 h and 24 h at 37 °C. After 2 h and 24 h, the suspensions were collected and centrifuged at 14,000 rpm for 5 min. The supernatant was analyzed by HPLC. The pH of the supernatant was determined. The obtained solid (wet filter cake) was characterized by XRPD. Table 3 summarizes the observations of the solubility study.

[0225] Table 3 Hygroscopicity: The hygroscopicity of form M was examined by DVS. Table 4 summarizes the observations of the hygroscopicity study.

[0226] Table 4 Equivalent form It should be understood that the invention may be embodied in other specific forms without departing from the spirit or essential characteristics of the invention. Therefore, the foregoing embodiments are to be considered illustrative in all respects and not limiting of the invention described herein. Accordingly, the scope of the invention is indicated by the appended claims rather than by the foregoing specific embodiments, and all variations within the meaning and scope of equivalents of the claims are intended to be included therein.

Claims

1. A pharmaceutically acceptable salt crystal form of compound 1: Its solvates or hydrates.

2. The crystal form as described in claim 1, wherein the crystal form is a crystalline form.

3. The crystal form as described in any of the preceding claims, wherein the crystal form is a pharmaceutically acceptable salt of compound 1 in the form M, its solvate, or its hydrate.

4. The crystal form as described in any of the preceding claims, wherein form M is characterized by using Cu Kα radiation, and the X-ray powder diffraction ("XRPD") pattern contains signals at 4.5 ± 0.2, 8.9 ± 0.2, and 21.7 ± 0.2 °2θ.

5. The crystal form as described in any of the preceding claims, wherein Cu Kα radiation is used, and the XRPD pattern of form M further includes at least one signal selected from 13.3±0.2, 13.9±0.2, and 19.7±0.2 °2θ.

6. The crystal form as claimed in any of the preceding claims, wherein Cu Kα radiation is used, and the XRPD pattern of form M further includes at least one signal selected from 17.9±0.2, 18.9±0.2, 22.2±0.2, and 26.7±0.2 °2θ.

7. The crystal form as described in any of the preceding claims, wherein the form M is characterized in that the XRPD diagram is substantially similar to the XRPD diagram shown in FIG1.

8. The crystal form as described in any of the preceding claims, wherein the form M is characterized in that the XRPD plot contains one or more signals (e.g., peaks) at approximately the positions shown in Table A.

9. The crystal form as described in any of the preceding claims, wherein form M is characterized by having an endothermic signal in the DSC curve at 143±20°C.

10. The crystal form as described in any of the preceding claims, wherein form M is characterized in that the DSC curve has an endothermic signal at 153±20°C.

11. The crystal form as described in any of the preceding claims, wherein, as measured by TGA, form M exhibits a weight loss of about 0.5% to about 10% at temperatures ranging from about 34 ± 20°C to about 145 ± 20°C.

12. A pharmaceutical composition comprising a therapeutically effective amount of the crystal form as described in any one of the preceding claims and a pharmaceutically acceptable excipient.

13. A method of preventing or treating cancer, comprising administering to a subject in need a therapeutically effective amount of a crystalline or pharmaceutical composition as described in any of the preceding claims.

14. The crystal form or pharmaceutical composition as described in any of the preceding claims, used in the prevention or treatment of cancer.

15. Use of the crystal form as described in any of the preceding claims in the manufacture of a medicament for the prevention or treatment of cancer.

16. The crystal form, pharmaceutical composition, method, or use as claimed in any of the preceding claims, wherein the cancer is a solid tumor, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, glioblastoma (GBM), head and neck cancer, lung cancer, non-small cell lung cancer (NSCLC), or any subtype thereof.

17. The crystal form, pharmaceutical composition, method, or use as claimed in any of the preceding claims, wherein the oncogenic variant is an oncogenic variant of the ErbB receptor epidermal growth factor receptor (EGFR) or the HER-4 receptor of the HER2 receptor, and wherein the oncogenic variant of the ErbB receptor EGFR or the HER2 receptor is an allosteric variant.

18. The crystal form, pharmaceutical composition, method, or use as claimed in any of the preceding claims, wherein the subject or the cancer is insensitive to or resistant to treatment with one or more of gefitinib, erlotinib, afatinib, osimertinib, and nexituzumab.

19. The crystal form, pharmaceutical composition, method, or use as claimed in any of the preceding claims, wherein the sequence encoding the oncogenic variant of said EGFR comprises a deletion of exon 20 or a portion thereof, and wherein said cancer, its tumor, or cells do not contain oncogenic variants or markers indicating responsiveness to immunotherapy in sequences encoding one or more of the EGFR kinase domain (KD), BRAF, NTRK, and KRAS.

20. The crystal form, pharmaceutical composition, method, or use as claimed in any of the preceding claims, wherein the subject has an adverse reaction to treatment with a type I inhibitor.

21. The crystal form, pharmaceutical composition, method, or use as claimed in any of the preceding claims, wherein the subject has an adverse reaction to treatment with one or more of gefitinib, erlotinib, afatinib, osimertinib, nexituzumab, crizotinib, alectinib, ceritinib, dabrafenib, trametinib, afatinib, saprotinib, dacomitinib, cannetinib, peritrinib, WZ4002, WZ8040, WZ3146, CO-1686, and AZD9291.

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