Polymorphism as an ERBB inhibitor

Abstract

The present disclosure provides the following form of Compound No. 1, its solvates, its hydrates, and its pharma- ceutically acceptable salts. The present disclosure also provides a process for preparing the form and the use of the form, for example, in the prevention or treatment of cancer. JPEG2024534517000032.jpg4699

Description

[Background technology]

[0001] Related Applications This application claims priority to and the benefit of U.S. Application No. 63 / 246,451, filed September 21, 2021, the entire contents of which are incorporated herein by reference.

[0002] Mutations affecting either the intracellular catalytic domain or the extracellular ligand-binding domain of ErbB receptors can result in oncogenic activity (the ErbB protein family consists of four members, including ErbB-1, also called epidermal growth factor receptor (EGFR), and Erb-2, also called HER2 in humans). ErbB inhibitors are a known treatment for many cancers. However, not all patients respond well to this treatment. Thus, there is a long-felt need in the art for new therapies that can address the varying responsiveness of cancer patients to known therapies. The present disclosure provides compositions and methods for preventing or treating cancer in patients with these oncogenic mutations. Summary of the Invention

[0003] In some embodiments, the present disclosure provides a form of compound number 1, [ka] A solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof is provided.

[0004] In some aspects, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a form of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0005] In some aspects, the disclosure provides a method of inhibiting an oncogenic variant of an ErbB receptor, comprising administering to a subject in need thereof a therapeutically effective amount of a form of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof.

[0006] In some aspects, the present disclosure provides a method for treating or preventing cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a form of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof.

[0007] In some aspects, the present disclosure provides a form of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof, for use in inhibiting an oncogenic variant of an ErbB receptor.

[0008] In some aspects, the present disclosure provides a form of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof for use in the prophylaxis or treatment of cancer.

[0009] In some aspects, the present disclosure provides the use of a form of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for inhibiting an oncogenic variant of an ErbB receptor.

[0010] In some aspects, the present disclosure provides the use of a form of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for preventing or treating 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 belongs. In this specification, the singular form also includes the plural form, unless the context clearly indicates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are hereby incorporated by reference. References cited herein are not admitted to be prior art to the claimed invention. In case of conflict, the present specification, including definitions, will control. Furthermore, the materials, methods, and examples are illustrative only and are not intended to be limiting. In the event of a conflict between a chemical structure and the name of a compound disclosed herein, the chemical structure controls.

[0012] Features and advantages of the present disclosure will become apparent from the following detailed description and claims. [Brief description of the drawings]

[0013] [Figure 1] 1 is a graph showing the XRPD spectrum of Form A of Compound No. 1. [Diagram 2] 1 is a graph showing the XRPD spectrum of Form B of Compound No. 1. [Diagram 3] 1 is a graph showing the XRPD spectrum of Form C of Compound No. 1. [Figure 4] 1 is a graph showing the XRPD spectrum of Form D of Compound No. 1. [Diagram 5] 1 is a graph showing the XRPD spectrum of Form E of Compound No. 1. [Figure 6] 1 is a graph showing the XRPD spectrum of Form F of Compound No. 1. [Figure 7] 1 is a graph showing the XRPD spectrum of Form G of Compound No. 1. [Figure 8] 1 is a graph showing the XRPD spectrum of Form H of Compound No. 1. [Figure 9]1 is a graph showing the XRPD spectrum of Form I of Compound No. 1. [Figure 10] 1 is a graph showing the XRPD spectrum of Form J of Compound No. 1. [Figure 11] 1 is a graph showing the XRPD spectrum of form K of Compound No. 1. [Figure 12] 1 is a graph showing the XRPD spectrum of Form L of Compound No. 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] As used herein, the term "Compound No. 1" is understood to refer to a compound having the following structure: [ka]

[0015] Compound No. 1 can be identified by the IUPAC name (E)-N-(4-((3-chloro-2-fluorophenyl)amino)-7-(((1R,5S)-3-methyl-3-azabicyclo[3.1.0]hexan-1-yl)ethynyl)quinazolin-6-yl)-4-morpholinobuta-2-enamide.

[0016] In some aspects, the present disclosure provides a form of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof.

[0017] In some embodiments, the shape form is a crystalline form.

[0018] In some embodiments, the shape form is a shape form (e.g., a crystalline form) of Compound No. 1, a solvate thereof, or a hydrate thereof.

[0019] In some embodiments, the morphology is a morphology (e.g., a crystalline form) of Compound No. 1.

[0020] In some embodiments, the morphology is a morphology (e.g., a crystalline form) of a solvate (e.g., a heterosolvate) of Compound No. 1.

[0021] In some embodiments, the form is a hydrate form (e.g., a crystalline form) of Compound No. 1.

[0022] In some embodiments, the form is Form A of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof.

[0023] In some embodiments, the form is Form B of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof.

[0024] In some embodiments, the form is Form C of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof.

[0025] In some embodiments, the form is Form D of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof.

[0026] In some embodiments, the form is Form E of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof.

[0027] In some embodiments, the form is Form F of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof.

[0028] In some embodiments, the form is Form G of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof.

[0029] In some embodiments, the form is Form H of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof.

[0030] In some embodiments, the form is Form I of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof.

[0031] In some embodiments, the form is Form J of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof.

[0032] In some embodiments, the form is Form K of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof.

[0033] In some embodiments, the form is Form L of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof.

[0034] In some aspects, the present disclosure provides a method for preparing a form of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof.

[0035] Form A Characterization by X-ray powder diffraction (XRPD) In some embodiments, the form is Form A of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof.

[0036] In some embodiments, the shape form is Form A of Compound No. 1.

[0037] In some embodiments, Form A is characterized by an X-ray diffraction ("XRPD") pattern including peaks at 4.8±0.2, 5.6±0.2, and 17.6±0.2 degrees 2θ (e.g., 4.8±0.1, 5.6±0.1, and 17.6±0.1 degrees 2θ (e.g., 4.8, 5.6, and 17.6 degrees 2θ) using Cu Kα radiation.

[0038] In some embodiments, the XRPD pattern of Form A further comprises at least one peak selected from 9.6±0.2, 20.0±0.2, and 24.6±0.2 degrees 2θ (e.g., 9.6±0.1, 20.0±0.1, and 24.6±0.1 degrees 2θ (e.g., 9.6, 20.0, and 24.6 degrees 2θ) using Cu Kα radiation.

[0039] In some embodiments, the XRPD pattern of Form A further comprises at least two peaks selected from 9.6±0.2, 20.0±0.2, and 24.6±0.2 degrees 2θ (e.g., 9.6±0.1, 20.0±0.1, and 24.6±0.1 degrees 2θ (e.g., 9.6, 20.0, and 24.6 degrees 2θ) using Cu Kα radiation.

[0040] In some embodiments, the XRPD pattern of Form A further comprises peaks at 9.6±0.2, 20.0±0.2, and 24.6±0.2 degrees 2θ (e.g., 9.6±0.1, 20.0±0.1, and 24.6±0.1 degrees 2θ (e.g., 9.6, 20.0, and 24.6 degrees 2θ) using Cu Kα radiation.

[0041] In some embodiments, Form A is characterized by an X-ray diffraction ("XRPD") pattern comprising at least three peaks selected from 4.8±0.2, 5.6±0.2, 9.6±0.2, 17.6±0.2, 20.0±0.2, and 24.6±0.2 degrees 2θ (e.g., 4.8±0.1, 5.6±0.1, 9.6±0.1, 17.6±0.1, 20.0±0.1, and 24.6±0.1 degrees 2θ (e.g., 4.8, 5.6, 9.6, 17.6, 20.0, and 24.6 degrees 2θ) using Cu Kα radiation.

[0042] In some embodiments, the XRPD pattern of Form A includes at least four peaks selected from 4.8±0.2, 5.6±0.2, 9.6±0.2, 17.6±0.2, 20.0±0.2, and 24.6±0.2 degrees 2θ (e.g., 4.8±0.1, 5.6±0.1, 9.6±0.1, 17.6±0.1, 20.0±0.1, and 24.6±0.1 degrees 2θ (e.g., 4.8, 5.6, 9.6, 17.6, 20.0, and 24.6 degrees 2θ) using Cu Kα radiation.

[0043] In some embodiments, the XRPD pattern of Form A includes at least five peaks selected from 4.8±0.2, 5.6±0.2, 9.6±0.2, 17.6±0.2, 20.0±0.2, and 24.6±0.2 degrees 2θ (e.g., 4.8±0.1, 5.6±0.1, 9.6±0.1, 17.6±0.1, 20.0±0.1, and 24.6±0.1 degrees 2θ (e.g., 4.8, 5.6, 9.6, 17.6, 20.0, and 24.6 degrees 2θ) using Cu Kα radiation.

[0044] In some embodiments, the XRPD pattern of Form A includes peaks at 4.8±0.2, 5.6±0.2, 9.6±0.2, 17.6±0.2, 20.0±0.2, and 24.6±0.2 degrees 2θ (e.g., 4.8±0.1, 5.6±0.1, 9.6±0.1, 17.6±0.1, 20.0±0.1, and 24.6±0.1 degrees 2θ (e.g., 4.8, 5.6, 9.6, 17.6, 20.0, and 24.6 degrees 2θ) using Cu Kα radiation.

[0045] In some embodiments, Form A is characterized by an XRPD pattern substantially similar to that shown in FIG.

[0046] In some embodiments, Form A is characterized by an XRPD pattern comprising peaks at approximately the positions shown in the table below, where it is understood that the values ​​in the table are approximate and subject to instrumental and experimental variation. [Table 1]

[0047] Characterization by Differential Scanning Calorimetry (DSC) In some embodiments, Form A can be heated to 76±20, 141±20, 156±20, and 170±20° C. (e.g., 76±10, 141±10, 156±10, and 170±10° C. (e.g., 76±5, 141±5, 156±5, and 170±5° C. (e.g., 76±4, 141±4, 156±4, and 170±4° C. (e.g., 76±3, 141±3, 15 and 170±3° C. (e.g., 76±2, 141±2, 156±2, and 170±2° C. (e.g., 76±1, 141±1, 156±1, 170±1° C. (e.g., 76±0.5, 141±0.5, 156±0.5, and 170±0.5° C.)).

[0048] In some embodiments, Form A can be heated to 76±20, 141±20, 156±20, and 170±20° C. (e.g., 76±10, 141±10, 156±10, and 170±10° C. (e.g., 76±5, 141±5, 156±5, and 170±5° C. (e.g., 76±4, 141±4, 156±4, and 170±4° C. (e.g., 76±3, 141±3, 15 and 170±3° C. (e.g., 76±2, 141±2, 156±2, and 170±2° C. (e.g., 76±1, 141±1, 156±1, 170±1° C. (e.g., 76±0.5, 141±0.5, 156±0.5, and 170±0.5° C.)).

[0049] In some embodiments, Form A can be heated to 76±20, 141±20, 156±20, and 170±20° C. (e.g., 76±10, 141±10, 156±10, and 170±10° C. (e.g., 76±5, 141±5, 156±5, and 170±5° C. (e.g., 76±4, 141±4, 156±4, and 170±4° C. (e.g., 76±3, 141±3, 15 and 170±3° C. (e.g., 76±2, 141±2, 156±2, and 170±2° C. (e.g., 76±1, 141±1, 156±1, 170±1° C. (e.g., 76±0.5, 141±0.5, 156±0.5, and 170±0.5° C.)).

[0050] In some embodiments, Form A can be heated to 76±20, 141±20, 156±20, and 170±20° C. (e.g., 76±10, 141±10, 156±10, and 170±10° C. (e.g., 76±5, 141±5, 156±5, and 170±5° C. (e.g., 76±4, 141±4, 156±4, and 170±4° C. (e.g., 76±3, 1 and characterized by a DSC curve having endothermic peaks at 41±3, 156±3, and 170±3° C. (e.g., 76±2, 141±2, 156±2, and 170±2° C. (e.g., 76±1, 141±1, 156±1, 170±1° C. (e.g., 76±0.5, 141±0.5, 156±0.5, and 170±0.5° C.)).

[0051] In some embodiments, Form A of Compound No. 1 is characterized by a DSC curve with an endothermic peak at 76° C. In some embodiments, Form A of Compound No. 1 is characterized by a DSC curve with an endothermic peak at 141° C. In some embodiments, Form A of Compound No. 1 is characterized by a DSC curve with an endothermic peak at 156° C. In some embodiments, Form A of Compound No. 1 is characterized by a DSC curve with an endothermic peak at 170° C.

[0052] Characterization by Thermogravimetric Analysis (TGA) In some embodiments, Form A exhibits approximately 1-3% weight loss at about 28±20° C. (e.g., 28±10° C. (e.g., 28±5° C. (e.g., 28±4° C. (e.g., 28±3° C. (e.g., 28±2° C. (e.g., 28±1° C. (e.g., 28±0.5° C.)))))))) to about 130±20° C. (e.g., 130±10° C. (e.g., 130±5° C. (e.g., 130° C.±4° C. (e.g., 130±3° C. (e.g., 130±2° C. (e.g., 130±1° C. (e.g., 150±0.5° C.))))))))).

[0053] In some embodiments, Form A exhibits approximately 2.2% weight loss from about 28° C. to about 130° C. as measured by TGA.

[0054] Form B Characterization by X-ray powder diffraction (XRPD) In some embodiments, the form is Form B of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof.

[0055] In some embodiments, the shape form is Form B of Compound No. 1.

[0056] In some embodiments, the disclosure provides a form of Compound No. 1 (“Form B”) characterized by an X-ray diffraction (“XRPD”) pattern using Cu Kα radiation including peaks at 6.5±0.2, 16.7±0.2, and 18.6±0.2 degrees 2θ (e.g., 6.5±0.1, 16.7±0.1, and 18.6±0.1 degrees 2θ (e.g., 6.5, 16.7, and 18.6 degrees 2θ).

[0057] In some embodiments, the XRPD pattern of form B further comprises at least one peak selected from 3.2±0.2, 13.4±0.2, and 17.7±0.2 degrees 2θ (e.g., 3.2±0.1, 13.4±0.1, and 17.7±0.1 degrees 2θ (e.g., 3.2, 13.4, and 17.7 degrees 2θ) using Cu Kα radiation.

[0058] In some embodiments, the XRPD pattern of form B further comprises at least two peaks selected from 3.2±0.2, 13.4±0.2, and 17.7±0.2 degrees 2θ (e.g., 3.2±0.1, 13.4±0.1, and 17.7±0.1 degrees 2θ (e.g., 3.2, 13.4, and 17.7 degrees 2θ) using Cu Kα radiation.

[0059] In some embodiments, the XRPD pattern of form B further comprises peaks at 3.2±0.2, 13.4±0.2, and 17.7±0.2 degrees 2θ (e.g., 3.2±0.1, 13.4±0.1, and 17.7±0.1 degrees 2θ (e.g., 3.2, 13.4, and 17.7 degrees 2θ) using Cu Kα radiation.

[0060] In some aspects, the disclosure provides a form of Compound No. 1 ("Form B") characterized by an X-ray diffraction ("XRPD") pattern including at least three peaks selected from 3.2±0.2, 6.5±0.2, 13.4±0.2, 16.7±0.2, 17.7±0.2, and 18.6±0.2 degrees 2θ (e.g., 3.2±0.1, 6.5±0.1, 13.4±0.1, 16.7±0.1, 17.7±0.1, and 18.6±0.1 degrees 2θ (e.g., 3.2, 6.5, 13.4, 16.7, 17.7, and 18.6 degrees 2θ) using Cu Kα radiation.

[0061] In some embodiments, the XRPD pattern of form B includes at least four peaks selected from 3.2±0.2, 6.5±0.2, 13.4±0.2, 16.7±0.2, 17.7±0.2, and 18.6±0.2 degrees 2θ (e.g., 3.2±0.1, 6.5±0.1, 13.4±0.1, 16.7±0.1, 17.7±0.1, and 18.6±0.1 degrees 2θ (e.g., 3.2, 6.5, 13.4, 16.7, 17.7, and 18.6 degrees 2θ) using Cu Kα radiation.

[0062] In some embodiments, the XRPD pattern of form B includes at least five peaks selected from 3.2±0.2, 6.5±0.2, 13.4±0.2, 16.7±0.2, 17.7±0.2, and 18.6±0.2 degrees 2θ (e.g., 3.2±0.1, 6.5±0.1, 13.4±0.1, 16.7±0.1, 17.7±0.1, and 18.6±0.1 degrees 2θ (e.g., 3.2, 6.5, 13.4, 16.7, 17.7, and 18.6 degrees 2θ) using Cu Kα radiation.

[0063] In some embodiments, the XRPD pattern of form B includes peaks at 3.2±0.2, 6.5±0.2, 13.4±0.2, 16.7±0.2, 17.7±0.2, and 18.6±0.2 degrees 2θ (e.g., 3.2±0.1, 6.5±0.1, 13.4±0.1, 16.7±0.1, 17.7±0.1, and 18.6±0.1 degrees 2θ (e.g., 3.2, 6.5, 13.4, 16.7, 17.7, and 18.6 degrees 2θ) using Cu Kα radiation.

[0064] In some embodiments, Form B is characterized by an XRPD pattern substantially similar to that shown in FIG.

[0065] In some embodiments, Form B is characterized by an XRPD pattern comprising peaks at approximately the positions shown in the table below, where it is understood that the values ​​in the table are approximate and subject to instrumental and experimental variation. [Table 2]

[0066] Characterization by Differential Scanning Calorimetry (DSC) In some embodiments, form B of Compound No. 1 is characterized by a DSC curve having at least one endothermic peak selected from 155±20 and 176±20° C. (e.g., 155±10 and 176±10° C. (e.g., 155±5 and 176±5° C. (e.g., 155±4 and 176±4° C. (e.g., 155±3 and 176±3° C. (e.g., 155±2 and 176±2° C. (e.g., 155±1 and 176±1° C. (e.g., 155±0.5 and 176±0.5° C.))))).

[0067] In some embodiments, form B of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 155±20 and 176±20° C. (e.g., 155±10 and 176±10° C. (e.g., 155±5 and 176±5° C. (e.g., 155±4 and 176±4° C. (e.g., 155±3 and 176±3° C. (e.g., 155±2 and 176±2° C. (e.g., 155±1 and 176±1° C. (e.g., 155±0.5 and 176±0.5° C.))))).

[0068] In some embodiments, form B of compound number 1 is characterized by a DSC curve with an endothermic peak at 155° C. In some embodiments, form B of compound number 1 is characterized by a DSC curve with an endothermic peak at 176° C. Characterization by Thermogravimetric Analysis (TGA)

[0069] In some embodiments, Form B of Compound No. 1 exhibits approximately 1-3% weight loss at about 35±20° C. (e.g., 35±10° C. (e.g., 35±5° C. (e.g., 35±4° C. (e.g., 35±3° C. (e.g., 35±2° C. (e.g., 35±1° C. (e.g., 35±0.5° C.))))))) to about 150±20° C. (e.g., 150±10° C. (e.g., 150±5° C. (e.g., 150±4° C. (e.g., 150±3° C. (e.g., 150±2° C. (e.g., 150±1° C. (e.g., 150±0.5° C.))))))))))))

[0070] In some embodiments, Form B of Compound No. 1 exhibits approximately 1.5% weight loss at about 35° C. to about 150° C. as measured by TGA.

[0071] Form C Characterization by X-ray powder diffraction (XRPD) In some embodiments, the form is Form C of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof.

[0072] In some embodiments, the shape form is Form C of Compound No. 1.

[0073] In some embodiments, the disclosure provides a form of Compound No. 1 (“Form C”) characterized by an X-ray diffraction (“XRPD”) pattern using Cu Kα radiation including peaks at 16.1±0.2, 16.7±0.2, and 19.1±0.2 degrees 2θ (e.g., 16.1±0.1, 16.7±0.1, and 19.1±0.1 degrees 2θ (e.g., 16.1, 16.7, and 19.1 degrees 2θ).

[0074] In some embodiments, the XRPD pattern of form C further comprises at least one peak selected from 4.0±0.2, 12.6±0.2, and 14.1±0.2 degrees 2θ (e.g., 4.0±0.1, 12.6±0.1, and 14.1±0.1 degrees 2θ (e.g., 4.0, 12.6, and 14.1 degrees 2θ) using Cu Kα radiation.

[0075] In some embodiments, the XRPD pattern of form C further comprises at least two peaks selected from 4.0±0.2, 12.6±0.2, and 14.1±0.2 degrees 2θ (e.g., 4.0±0.1, 12.6±0.1, and 14.1±0.1 degrees 2θ (e.g., 4.0, 12.6, and 14.1 degrees 2θ) using Cu Kα radiation.

[0076] In some embodiments, the XRPD pattern of form C further comprises peaks at 4.0±0.2, 12.6±0.2, and 14.1±0.2 degrees 2θ (e.g., 4.0±0.1, 12.6±0.1, and 14.1±0.1 degrees 2θ (e.g., 4.0, 12.6, and 14.1 degrees 2θ) using Cu Kα radiation.

[0077] In some aspects, the disclosure provides a form of Compound No. 1 ("Form C") characterized by an X-ray diffraction ("XRPD") pattern including at least three peaks selected from 4.0±0.2, 12.6±0.2, 14.1±0.2, 16.1±0.2, 16.7±0.2, and 19.1±0.2 degrees 2θ (e.g., 4.0±0.1, 12.6±0.1, 14.1±0.1, 16.1±0.1, 16.7±0.1, and 19.1±0.1 degrees 2θ (e.g., 4.0, 12.6, 14.1, 16.1, 16.7, and 19.1 degrees 2θ) using Cu Kα radiation.

[0078] In some embodiments, the XRPD pattern of Form C includes at least four peaks selected from 4.0±0.2, 12.6±0.2, 14.1±0.2, 16.1±0.2, 16.7±0.2, and 19.1±0.2 degrees 2θ (e.g., 4.0±0.1, 12.6±0.1, 14.1±0.1, 16.1±0.1, 16.7±0.1, and 19.1±0.1 degrees 2θ (e.g., 4.0, 12.6, 14.1, 16.1, 16.7, and 19.1 degrees 2θ) using Cu Kα radiation.

[0079] In some embodiments, the XRPD pattern of Form C includes at least five peaks selected from 4.0±0.2, 12.6±0.2, 14.1±0.2, 16.1±0.2, 16.7±0.2, and 19.1±0.2 degrees 2θ (e.g., 4.0±0.1, 12.6±0.1, 14.1±0.1, 16.1±0.1, 16.7±0.1, and 19.1±0.1 degrees 2θ (e.g., 4.0, 12.6, 14.1, 16.1, 16.7, and 19.1 degrees 2θ) using Cu Kα radiation.

[0080] In some embodiments, the XRPD pattern of Form C includes peaks at 4.0±0.2, 12.6±0.2, 14.1±0.2, 16.1±0.2, 16.7±0.2, and 19.1±0.2 degrees 2θ (e.g., 4.0±0.1, 12.6±0.1, 14.1±0.1, 16.1±0.1, 16.7±0.1, and 19.1±0.1 degrees 2θ (e.g., 4.0, 12.6, 14.1, 16.1, 16.7, and 19.1 degrees 2θ) using Cu Kα radiation.

[0081] In some embodiments, Form C is characterized by an XRPD pattern substantially similar to that shown in FIG.

[0082] In some embodiments, Form C is characterized by an XRPD pattern comprising peaks at approximately the positions indicated in the table below, where it is understood that the values ​​in the table are approximate and subject to instrumental and experimental variation. [Table 3-1] [Table 3-2]

[0083] Characterization by Differential Scanning Calorimetry (DSC) In some embodiments, Form C of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 181±20° C. (e.g., 181±10° C. (e.g., 181±5° C. (e.g., 181±4° C. (e.g., 181±3° C. (e.g., 181±2° C. (e.g., 181±1° C. (e.g., 181±0.5° C.))))).

[0084] In some embodiments, Form C of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 181° C. Characterization by Thermogravimetric Analysis (TGA)

[0085] In some embodiments, Form C of Compound No. 1 exhibits approximately 1-3% weight loss at about 28±20° C. (e.g., 28±10° C. (e.g., 28±5° C. (e.g., 28±4° C. (e.g., 28±3° C. (e.g., 28±2° C. (e.g., 28±1° C. (e.g., 28±0.5° C.))))))) to about 170±20° C. (e.g., 170±10° C. (e.g., 170±5° C. (e.g., 170±4° C. (e.g., 170±3° C. (e.g., 170±2° C. (e.g., 170±1° C. (e.g., 170±0.5° C.)))))))))))))

[0086] In some embodiments, Form C of Compound No. 1 exhibits approximately 1.3% weight loss from about 28° C. to about 170° C. as measured by TGA.

[0087] Form D Characterization by X-ray powder diffraction (XRPD) In some embodiments, the form is Form D of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof.

[0088] In some embodiments, the physical form is Form D of the dioxane solvate of Compound No. 1.

[0089] In some embodiments, the shape form is Form D of Compound No. 1.

[0090] In some embodiments, the disclosure provides a form of Compound No. 1 (“Form D”) characterized by an X-ray diffraction (“XRPD”) pattern using Cu Kα radiation including peaks at 15.3±0.2, 19.3±0.2, and 23.5±0.2 degrees 2θ (e.g., 5.3±0.1, 19.3±0.1, and 23.5±0.1 degrees 2θ (e.g., 5.3, 19.3, and 23.5 degrees 2θ).

[0091] In some embodiments, the XRPD pattern of form D further comprises at least one peak selected from 5.4±0.2, 9.7±0.2, and 18.8±0.2 degrees 2θ (e.g., 5.4±0.1, 9.7±0.1, and 18.8±0.1 degrees 2θ (e.g., 5.4, 9.7, and 18.8 degrees 2θ)) using Cu Kα radiation.

[0092] In some embodiments, the XRPD pattern of form D further comprises at least two peaks selected from 5.4±0.2, 9.7±0.2, and 18.8±0.2 degrees 2θ (e.g., 5.4±0.1, 9.7±0.1, and 18.8±0.1 degrees 2θ (e.g., 5.4, 9.7, and 18.8 degrees 2θ)) using Cu Kα radiation.

[0093] In some embodiments, the XRPD pattern of form D further comprises peaks at 5.4±0.2, 9.7±0.2, and 18.8±0.2 degrees 2θ (e.g., 5.4±0.1, 9.7±0.1, and 18.8±0.1 degrees 2θ (e.g., 5.4, 9.7, and 18.8 degrees 2θ) using Cu Kα radiation.

[0094] In some aspects, the disclosure provides a form of Compound No. 1 ("Form D") characterized by an X-ray diffraction ("XRPD") pattern including at least three peaks selected from 5.4±0.2, 9.7±0.2, 15.3±0.2, 18.8±0.2, 19.3±0.2, and 23.5±0.2 degrees 2θ (e.g., 5.4±0.1, 9.7±0.1, 15.3±0.1, 18.8±0.1, 19.3±0.1, and 23.5±0.1 degrees 2θ (e.g., 5.4, 9.7, 15.3, 18.8, 19.3, and 23.5 degrees 2θ) using Cu Kα radiation.

[0095] In some embodiments, the XRPD pattern of form D includes at least four peaks selected from 5.4±0.2, 9.7±0.2, 15.3±0.2, 18.8±0.2, 19.3±0.2, and 23.5±0.2 degrees 2θ (e.g., 5.4±0.1, 9.7±0.1, 15.3±0.1, 18.8±0.1, 19.3±0.1, and 23.5±0.1 degrees 2θ (e.g., 5.4, 9.7, 15.3, 18.8, 19.3, and 23.5 degrees 2θ) using Cu Kα radiation.

[0096] In some embodiments, the XRPD pattern of form D includes at least five peaks selected from 5.4±0.2, 9.7±0.2, 15.3±0.2, 18.8±0.2, 19.3±0.2, and 23.5±0.2 degrees 2θ (e.g., 5.4±0.1, 9.7±0.1, 15.3±0.1, 18.8±0.1, 19.3±0.1, and 23.5±0.1 degrees 2θ (e.g., 5.4, 9.7, 15.3, 18.8, 19.3, and 23.5 degrees 2θ) using Cu Kα radiation.

[0097] In some embodiments, the XRPD pattern of form D includes peaks at 5.4±0.2, 9.7±0.2, 15.3±0.2, 18.8±0.2, 19.3±0.2, and 23.5±0.2 degrees 2θ (e.g., 5.4±0.1, 9.7±0.1, 15.3±0.1, 18.8±0.1, 19.3±0.1, and 23.5±0.1 degrees 2θ (e.g., 5.4, 9.7, 15.3, 18.8, 19.3, and 23.5 degrees 2θ) using Cu Kα radiation.

[0098] In some embodiments, form D is characterized by an XRPD pattern substantially similar to that shown in FIG.

[0099] In some embodiments, Form D is characterized by an XRPD pattern comprising peaks at approximately the locations shown in the table below, where it is understood that the values ​​in the table are approximate and subject to instrumental and experimental variation. [Table 4-1] [Table 4-2]

[0100] Characterization by Differential Scanning Calorimetry (DSC) In some embodiments, Form D of Compound No. 1 is characterized by a DSC curve having at least one endothermic peak selected from 128±20, 149±20, and 175±20° C. (e.g., 128±10, 149±10, and 175±10° C. (e.g., 128±5, 149±5, and 175±5° C. (e.g., 128±4, 149±4, and 175±4° C. (e.g., 128±3, 149±3, and 175±3° C. (e.g., 128±2, 149±2, and 175±2° C. (e.g., 128±1, 149±1, and 175±1° C. (e.g., 128±0.5, 149±0.5, and 175±0.5° C.)))).

[0101] In some embodiments, Form D of Compound No. 1 is characterized by a DSC curve having at least two endothermic peaks selected from 128±20, 149±20, and 175±20° C. (e.g., 128±10, 149±10, and 175±10° C. (e.g., 128±5, 149±5, and 175±5° C. (e.g., 128±4, 149±4, and 175±4° C. (e.g., 128±3, 149±3, and 175±3° C. (e.g., 128±2, 149±2, and 175±2° C. (e.g., 128±1, 149±1, and 175±1° C. (e.g., 128±0.5, 149±0.5, and 175±0.5° C.)))).

[0102] In some embodiments, Form D of Compound No. 1 is characterized by a DSC curve having endothermic peaks at 128±20, 149±20, and 175±20° C. (e.g., 128±10, 149±10, and 175±10° C. (e.g., 128±5, 149±5, and 175±5° C. (e.g., 128±4, 149±4, and 175±4° C. (e.g., 128±3, 149±3, and 175±3° C. (e.g., 128±2, 149±2, and 175±2° C. (e.g., 128±1, 149±1, and 175±1° C. (e.g., 128±0.5, 149±0.5, and 175±0.5° C.)))).

[0103] In some embodiments, Form D of Compound No. 1 is characterized by a DSC curve with an endothermic peak at 128° C. In some embodiments, Form D of Compound No. 1 is characterized by a DSC curve with an endothermic peak at 149° C. In some embodiments, Form D of Compound No. 1 is characterized by a DSC curve with an endothermic peak at 175° C. Characterization by Thermogravimetric Analysis (TGA)

[0104] In some embodiments, Form D of Compound No. 1 exhibits approximately 12-15% weight loss at about 33±20° C. (e.g., 33±10° C. (e.g., 33±5° C. (e.g., 33±4° C. (e.g., 33±3° C. (e.g., 33±2° C. (e.g., 33±1° C. (e.g., 33±0.5° C.) ...

[0105] In some embodiments, Form D of Compound No. 1 exhibits approximately 13.8% weight loss from about 33° C. to about 185° C. as measured by TGA.

[0106] Form E Characterization by X-ray powder diffraction (XRPD) In some embodiments, the form is Form E of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof.

[0107] In some embodiments, the shape form is Form E of Compound No. 1.

[0108] In some embodiments, the disclosure provides a form of Compound No. 1 (“Form E”) characterized by an X-ray diffraction (“XRPD”) pattern using Cu Kα radiation including peaks at 7.4±0.2, 15.8±0.2, and 16.3±0.2 degrees 2θ (e.g., 7.4±0.1, 15.8±0.1, and 16.3±0.1 degrees 2θ (e.g., 7.4, 15.8, and 16.3 degrees 2θ).

[0109] In some embodiments, the XRPD pattern of Form E further comprises at least one peak selected from 13.3±0.2, 19.2±0.2, and 22.4±0.2 degrees 2θ (e.g., 13.3±0.1, 19.2±0.1, and 22.4±0.1 degrees 2θ (e.g., 13.3, 19.2, and 22.4 degrees 2θ) using Cu Kα radiation.

[0110] In some embodiments, the XRPD pattern of Form E further comprises at least two peaks selected from 13.3±0.2, 19.2±0.2, and 22.4±0.2 degrees 2θ (e.g., 13.3±0.1, 19.2±0.1, and 22.4±0.1 degrees 2θ (e.g., 13.3, 19.2, and 22.4 degrees 2θ) using Cu Kα radiation.

[0111] In some embodiments, the XRPD pattern of Form E further comprises peaks at 13.3±0.2, 19.2±0.2, and 22.4±0.2 degrees 2θ (e.g., 13.3±0.1, 19.2±0.1, and 22.4±0.1 degrees 2θ (e.g., 13.3, 19.2, and 22.4 degrees 2θ) using Cu Kα radiation.

[0112] In some aspects, the disclosure provides a form of Compound No. 1 ("Form E") characterized by an X-ray diffraction ("XRPD") pattern including at least three peaks selected from 7.4±0.2, 13.3±0.2, 15.8±0.2, 16.3±0.2, 19.2±0.2, and 22.4±0.2 degrees 2θ (e.g., 7.4±0.1, 13.3±0.1, 15.8±0.1, 16.3±0.1, 19.2±0.1, and 22.4±0.1 degrees 2θ (e.g., 7.4, 13.3, 15.8, 16.3, 19.2, and 22.4 degrees 2θ).

[0113] In some embodiments, the XRPD pattern of Form E includes at least four peaks selected from 7.4±0.2, 13.3±0.2, 15.8±0.2, 16.3±0.2, 19.2±0.2, and 22.4±0.2 degrees 2θ (e.g., 7.4±0.1, 13.3±0.1, 15.8±0.1, 16.3±0.1, 19.2±0.1, and 22.4±0.1 degrees 2θ (e.g., 7.4, 13.3, 15.8, 16.3, 19.2, and 22.4 degrees 2θ) using Cu Kα radiation.

[0114] In some embodiments, the XRPD pattern of Form E includes at least five peaks selected from 7.4±0.2, 13.3±0.2, 15.8±0.2, 16.3±0.2, 19.2±0.2, and 22.4±0.2 degrees 2θ (e.g., 7.4±0.1, 13.3±0.1, 15.8±0.1, 16.3±0.1, 19.2±0.1, and 22.4±0.1 degrees 2θ (e.g., 7.4, 13.3, 15.8, 16.3, 19.2, and 22.4 degrees 2θ) using Cu Kα radiation.

[0115] In some embodiments, the XRPD pattern of Form E includes peaks at 7.4±0.2, 13.3±0.2, 15.8±0.2, 16.3±0.2, 19.2±0.2, and 22.4±0.2 degrees 2θ (e.g., 7.4±0.1, 13.3±0.1, 15.8±0.1, 16.3±0.1, 19.2±0.1, and 22.4±0.1 degrees 2θ (e.g., 7.4, 13.3, 15.8, 16.3, 19.2, and 22.4 degrees 2θ) using Cu Kα radiation.

[0116] In some embodiments, form E is characterized by an XRPD pattern substantially similar to that shown in FIG.

[0117] In some embodiments, Form E is characterized by an XRPD pattern comprising peaks at approximately the positions indicated in the table below, where it is understood that the values ​​in the table are approximate and subject to instrumental and experimental variation. [Table 5]

[0118] Characterization by Differential Scanning Calorimetry (DSC) In some embodiments, form E of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 173±20° C. (e.g., 173±10° C. (e.g., 173±5° C. (e.g., 173±4° C. (e.g., 173±3° C. (e.g., 173±2° C. (e.g., 173±1° C. (e.g., 173±0.5° C.))))).

[0119] In some embodiments, Form E of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 173°C.

[0120] Characterization by Thermogravimetric Analysis (TGA) In some embodiments, Form E of Compound No. 1 exhibits approximately 1-3% weight loss at about 34±20° C. (e.g., 34±10° C. (e.g., 34±5° C. (e.g., 34±4° C. (e.g., 34±3° C. (e.g., 34±2° C. (e.g., 34±1° C. (e.g., 34±0.5° C.))))))) to about 165±20° C. (e.g., 165±10° C. (e.g., 165±5° C. (e.g., 165±4° C. (e.g., 165±3° C. (e.g., 165±2° C. (e.g., 165±1° C. (e.g., 165±0.5° C.)))))))))))))

[0121] In some embodiments, Form E of Compound No. 1 exhibits approximately 1.3% weight loss from about 34° C. to about 165° C. as measured by TGA.

[0122] Form F Characterization by X-ray powder diffraction (XRPD) In some embodiments, the form is Form F of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof.

[0123] In some embodiments, the form is Form F of a hydrate of Compound No. 1.

[0124] In some embodiments, the shape form is Form F of Compound No. 1.

[0125] In some embodiments, the disclosure provides a form of Compound No. 1 (“Form F”) characterized by an X-ray diffraction (“XRPD”) pattern using Cu Kα radiation including peaks at 5.5±0.2, 16.4±0.2, and 21.9±0.2 degrees 2θ (e.g., 5.5±0.1, 16.4±0.1, and 21.9±0.1 degrees 2θ (e.g., 5.5, 16.4, and 21.9 degrees 2θ).

[0126] In some embodiments, the XRPD pattern of form F further comprises at least one peak selected from 7.2±0.2, 14.5±0.2, and 15.2±0.2 degrees 2θ (e.g., 7.2±0.1, 14.5±0.1, and 15.2±0.1 degrees 2θ (e.g., 7.2, 14.5, and 15.2 degrees 2θ) using Cu Kα radiation.

[0127] In some embodiments, the XRPD pattern of form F further comprises at least two peaks selected from 7.2±0.2, 14.5±0.2, and 15.2±0.2 degrees 2θ (e.g., 7.2±0.1, 14.5±0.1, and 15.2±0.1 degrees 2θ (e.g., 7.2, 14.5, and 15.2 degrees 2θ) using Cu Kα radiation.

[0128] In some embodiments, the XRPD pattern of form F further comprises peaks at 7.2±0.2, 14.5±0.2, and 15.2±0.2 degrees 2θ (e.g., 7.2±0.1, 14.5±0.1, and 15.2±0.1 degrees 2θ (e.g., 7.2, 14.5, and 15.2 degrees 2θ) using Cu Kα radiation.

[0129] In some aspects, the disclosure provides a form of Compound No. 1 ("Form F") characterized by an X-ray diffraction ("XRPD") pattern including at least three peaks selected from 5.5±0.2, 7.2±0.2, 14.5±0.2, 15.2±0.2, 16.4±0.2, and 21.9±0.2 degrees 2θ (e.g., 5.5±0.1, 7.2±0.1, 14.5±0.1, 15.2±0.1, 16.4±0.1, and 21.9±0.1 degrees 2θ (e.g., 5.5, 7.2, 14.5, 15.2, 16.4, and 21.9 degrees 2θ) using Cu Kα radiation.

[0130] In some embodiments, the XRPD pattern of form F includes at least four peaks selected from 5.5±0.2, 7.2±0.2, 14.5±0.2, 15.2±0.2, 16.4±0.2, and 21.9±0.2 degrees 2θ (e.g., 5.5±0.1, 7.2±0.1, 14.5±0.1, 15.2±0.1, 16.4±0.1, and 21.9±0.1 degrees 2θ (e.g., 5.5, 7.2, 14.5, 15.2, 16.4, and 21.9 degrees 2θ) using Cu Kα radiation.

[0131] In some embodiments, the XRPD pattern of form F includes at least five peaks selected from 5.5±0.2, 7.2±0.2, 14.5±0.2, 15.2±0.2, 16.4±0.2, and 21.9±0.2 degrees 2θ (e.g., 5.5±0.1, 7.2±0.1, 14.5±0.1, 15.2±0.1, 16.4±0.1, and 21.9±0.1 degrees 2θ (e.g., 5.5, 7.2, 14.5, 15.2, 16.4, and 21.9 degrees 2θ) using Cu Kα radiation.

[0132] In some embodiments, the XRPD pattern of form F includes peaks at 5.5±0.2, 7.2±0.2, 14.5±0.2, 15.2±0.2, 16.4±0.2, and 21.9±0.2 degrees 2θ (e.g., 5.5±0.1, 7.2±0.1, 14.5±0.1, 15.2±0.1, 16.4±0.1, and 21.9±0.1 degrees 2θ (e.g., 5.5, 7.2, 14.5, 15.2, 16.4, and 21.9 degrees 2θ) using Cu Kα radiation.

[0133] In some embodiments, form F is characterized by an XRPD pattern substantially similar to that shown in FIG.

[0134] In some embodiments, Form F is characterized by an XRPD pattern comprising peaks at approximately the locations indicated in the table below, where it is understood that the values ​​in the table are approximate and subject to instrumental and experimental variation. [Table 6-1] [Table 6-2]

[0135] Characterization by Differential Scanning Calorimetry (DSC) In some embodiments, Form F of Compound No. 1 can be heated to 48±20, 80±20, 146±20, and 174±20° C. (e.g., 48±10, 80±10, 146±10, and 174±10° C. (e.g., 48±5, 80±5, 146±5, and 174±5° C. (e.g., 48±4, 80±4, 146±4, and 174±4° C. (e.g., 48±3, 80±3, 146±3, and 174±3° C. (e.g., 48±2, 80±2, 146±2, and 174±2° C. (e.g., 48±1, 80±1, 146±1, and 174±1° C. (e.g., 48±0.5, 80±0.5, 146±0.5, and 174±0.5° C.)))))).

[0136] In some embodiments, Form F of Compound No. 1 can be heated to 48±20, 80±20, 146±20, and 174±20° C. (e.g., 48±10, 80±10, 146±10, and 174±10° C. (e.g., 48±5, 80±5, 146±5, and 174±5° C. (e.g., 48±4, 80±4, 146±4, and 174±4° C. (e.g., 48±3, 80±3, 146±3, and 174±3° C. (e.g., 48±2, 80±2, 146±2, and 174±2° C. (e.g., 48±1, 80±1, 146±1, and 174±1° C. (e.g., 48±0.5, 80±0.5, 146±0.5, and 174±0.5° C.)))))).

[0137] In some embodiments, Form F of Compound No. 1 can be heated to 48±20, 80±20, 146±20, and 174±20° C. (e.g., 48±10, 80±10, 146±10, and 174±10° C. (e.g., 48±5, 80±5, 146±5, and 174±5° C. (e.g., 48±4, 80±4, 146±4, and 174±4° C. (e.g., 48±3, 80±3, 146±3, and 174±3° C. (e.g., 48±2, 80±2, 146±2, and 174±2° C. (e.g., 48±1, 80±1, 146±1, and 174±1° C. (e.g., 48±0.5, 80±0.5, 146±0.5, and 174±0.5° C.)))))).

[0138] In some embodiments, Form F of Compound No. 1 can be heated to 48±20, 80±20, 146±20, and 174±20° C. (e.g., 48±10, 80±10, 146±10, and 174±10° C. (e.g., 48±5, 80±5, 146±5, and 174±5° C. (e.g., 48±4, 80±4, 146±4, and 174±4° C. (e.g., 48± and 174±0.3, 80±3, 146±3, and 174±3° C. (e.g., 48±2, 80±2, 146±2, and 174±2° C. (e.g., 48±1, 80±1, 146±1, and 174±1° C. (e.g., 48±0.5, 80±0.5, 146±0.5, and 174±0.5° C.)).

[0139] In some embodiments, form F of compound No. 1 is characterized by a DSC curve with an endothermic peak at 48° C. In some embodiments, form F of compound No. 1 is characterized by a DSC curve with an endothermic peak at 80° C. In some embodiments, form F of compound No. 1 is characterized by a DSC curve with an endothermic peak at 144° C. In some embodiments, form F of compound No. 1 is characterized by a DSC curve with an endothermic peak at 146° C. In some embodiments, form F of compound No. 1 is characterized by a DSC curve with an endothermic peak at 174° C. Characterization by Thermogravimetric Analysis (TGA)

[0140] In some embodiments, Form F of Compound No. 1 exhibits approximately 2-5% weight loss at about 33±20° C. (e.g., 33±10° C. (e.g., 33±5° C. (e.g., 33±4° C. (e.g., 33±3° C. (e.g., 33±2° C. (e.g., 33±1° C. (e.g., 33±0.5° C.))))))) to about 55±20° C. (e.g., 55±10° C. (e.g., 55±5° C. (e.g., 55±4° C. (e.g., 55±3° C. (e.g., 55±2° C. (e.g., 55±1° C. (e.g., 55±0.5° C.))))))))))))

[0141] In some embodiments, Form F of Compound No. 1 exhibits approximately 3.8% weight loss at about 33° C. to about 55° C. as measured by TGA.

[0142] In some embodiments, Form F of Compound No. 1 exhibits approximately 1-4% weight loss at about 55±20° C. (e.g., 55±10° C. (e.g., 55±5° C. (e.g., 55±4° C. (e.g., 55±3° C. (e.g., 55±2° C. (e.g., 55±1° C. (e.g., 55±0.5° C.) ...

[0143] In some embodiments, Form F of Compound No. 1 exhibits approximately 2.7% weight loss at about 55° C. to about 100° C. as measured by TGA.

[0144] In some embodiments, Form F of Compound No. 1 exhibits approximately 2-8% weight loss at about 33±20° C. (e.g., 33±10° C. (e.g., 33±5° C. (e.g., 33±4° C. (e.g., 33±3° C. (e.g., 33±2° C. (e.g., 33±1° C. (e.g., 33±0.5° C.))))))) to about 100±20° C. (e.g., 100±10° C. (e.g., 100±5° C. (e.g., 100±4° C. (e.g., 100±3° C. (e.g., 100±2° C. (e.g., 100±1° C. (e.g., 100±0.5° C.)))))))))))))

[0145] In some embodiments, Form F of Compound No. 1 exhibits approximately 6.5% weight loss from about 33° C. to about 100° C. as measured by TGA.

[0146] In some embodiments, Form F of Compound No. 1 exhibits approximately 3.7% weight loss from about 33° C. to about 100° C. as measured by TGA.

[0147] Form G Characterization by X-ray powder diffraction (XRPD) In some embodiments, the form is Form G of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof.

[0148] In some embodiments, the shape form is Form G of Compound No. 1.

[0149] In some embodiments, the disclosure provides a form of Compound No. 1 ("Form G") characterized by an X-ray diffraction ("XRPD") pattern using Cu Kα radiation including peaks at 4.0±0.2, 5.3±0.2, and 16.0±0.2 degrees 2θ (e.g., 4.0±0.1, 5.3±0.1, and 16.0±0.1 degrees 2θ (e.g., 4.0, 5.3, and 16.0 degrees 2θ).

[0150] In some embodiments, the XRPD pattern of form G further comprises at least one peak selected from 7.1±0.2, 16.7±0.2, and 19.2±0.2 degrees 2θ (e.g., 7.1±0.1, 16.7±0.1, and 19.2±0.1 degrees 2θ (e.g., 7.1, 16.7, and 19.2 degrees 2θ) using Cu Kα radiation.

[0151] In some embodiments, the XRPD pattern of form G further comprises at least two peaks selected from 7.1±0.2, 16.7±0.2, and 19.2±0.2 degrees 2θ (e.g., 7.1±0.1, 16.7±0.1, and 19.2±0.1 degrees 2θ (e.g., 7.1, 16.7, and 19.2 degrees 2θ) using Cu Kα radiation.

[0152] In some embodiments, the XRPD pattern of form G further comprises peaks at 7.1±0.2, 16.7±0.2, and 19.2±0.2 degrees 2θ (e.g., 7.1±0.1, 16.7±0.1, and 19.2±0.1 degrees 2θ (e.g., 7.1, 16.7, and 19.2 degrees 2θ) using Cu Kα radiation.

[0153] In some aspects, the disclosure provides a form of Compound No. 1 ("Form G") characterized by an X-ray diffraction ("XRPD") pattern including at least three peaks selected from 4.0±0.2, 5.3±0.2, 7.1±0.2, 16.0±0.2, 16.7±0.2, and 19.2±0.2 degrees 2θ (e.g., 4.0±0.1, 5.3±0.1, 7.1±0.1, 16.0±0.1, 16.7±0.1, and 19.2±0.1 degrees 2θ (e.g., 4.0, 5.3, 7.1, 16.0, 16.7, and 19.2 degrees 2θ) using Cu Kα radiation.

[0154] In some embodiments, the XRPD pattern of form G includes at least four peaks selected from 4.0±0.2, 5.3±0.2, 7.1±0.2, 16.0±0.2, 16.7±0.2, and 19.2±0.2 degrees 2θ (e.g., 4.0±0.1, 5.3±0.1, 7.1±0.1, 16.0±0.1, 16.7±0.1, and 19.2±0.1 degrees 2θ (e.g., 4.0, 5.3, 7.1, 16.0, 16.7, and 19.2 degrees 2θ) using Cu Kα radiation.

[0155] In some embodiments, the XRPD pattern of form G includes at least five peaks selected from 4.0±0.2, 5.3±0.2, 7.1±0.2, 16.0±0.2, 16.7±0.2, and 19.2±0.2 degrees 2θ (e.g., 4.0±0.1, 5.3±0.1, 7.1±0.1, 16.0±0.1, 16.7±0.1, and 19.2±0.1 degrees 2θ (e.g., 4.0, 5.3, 7.1, 16.0, 16.7, and 19.2 degrees 2θ) using Cu Kα radiation.

[0156] In some embodiments, the XRPD pattern of form G includes peaks at 4.0±0.2, 5.3±0.2, 7.1±0.2, 16.0±0.2, 16.7±0.2, and 19.2±0.2 degrees 2θ (e.g., 4.0±0.1, 5.3±0.1, 7.1±0.1, 16.0±0.1, 16.7±0.1, and 19.2±0.1 degrees 2θ (e.g., 4.0, 5.3, 7.1, 16.0, 16.7, and 19.2 degrees 2θ) using Cu Kα radiation.

[0157] In some embodiments, form G is characterized by an XRPD pattern substantially similar to that shown in FIG.

[0158] In some embodiments, Form G is characterized by an XRPD pattern comprising peaks at approximately the locations shown in the table below, where it is understood that the values ​​in the table are approximate and subject to instrumental and experimental variation. [Table 7]

[0159] Characterization by Differential Scanning Calorimetry (DSC) In some embodiments, Form G of Compound No. 1 is characterized by a DSC curve having at least one endothermic peak selected from 34±20, 175±20, and 182±20° C. (e.g., 34±10, 175±10, and 182±10° C. (e.g., 34±5, 175±5, and 182±5° C. (e.g., 34±4, 175±4, and 182±4° C. (e.g., 34±3, 175±3, and 182±3° C. (e.g., 34±2, 175±2, and 182±2° C. (e.g., 34±1, 175±1, and 182±1° C. (e.g., 34±0.5, 175±0.5, and 182±0.5° C.))))).

[0160] In some embodiments, Form G of Compound No. 1 is characterized by a DSC curve having at least two endothermic peaks selected from 34±20, 175±20, and 182±20° C. (e.g., 34±10, 175±10, and 182±10° C. (e.g., 34±5, 175±5, and 182±5° C. (e.g., 34±4, 175±4, and 182±4° C. (e.g., 34±3, 175±3, and 182±3° C. (e.g., 34±2, 175±2, and 182±2° C. (e.g., 34±1, 175±1, and 182±1° C. (e.g., 34±0.5, 175±0.5, and 182±0.5° C.))))).

[0161] In some embodiments, form G of Compound No. 1 is characterized by a DSC curve having endothermic peaks at 34±20, 175±20, and 182±20° C. (e.g., 34±10, 175±10, and 182±10° C. (e.g., 34±5, 175±5, and 182±5° C. (e.g., 34±4, 175±4, and 182±4° C. (e.g., 34±3, 175±3, and 182±3° C. (e.g., 34±2, 175±2, and 182±2° C. (e.g., 34±1, 175±1, and 182±1° C. (e.g., 34±0.5, 175±0.5, and 182±0.5° C.))))).

[0162] In some embodiments, form G of compound No. 1 is characterized by a DSC curve with an endothermic peak at 34° C. In some embodiments, form G of compound No. 1 is characterized by a DSC curve with an endothermic peak at 175° C. In some embodiments, form G of compound No. 1 is characterized by a DSC curve with an endothermic peak at 182° C.

[0163] Characterization by Thermogravimetric Analysis (TGA) In some embodiments, Form G of Compound No. 1 exhibits approximately 2-5% weight loss at about 33±20° C. (e.g., 33±10° C. (e.g., 33±5° C. (e.g., 33±4° C. (e.g., 33±3° C. (e.g., 33±2° C. (e.g., 33±1° C. (e.g., 33±0.5° C.))))))) to about 100±20° C. (e.g., 100±10° C. (e.g., 100±5° C. (e.g., 100±4° C. (e.g., 100±3° C. (e.g., 100±2° C. (e.g., 100±1° C. (e.g., 100±0.5° C.)))))))))))))

[0164] In some embodiments, Form G of Compound No. 1 exhibits approximately 3.4% weight loss from about 33° C. to about 100° C. as measured by TGA.

[0165] Form H Characterization by X-ray powder diffraction (XRPD) In some embodiments, the form is Form H of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof.

[0166] In some embodiments, the shape form is Form H of Compound No. 1.

[0167] In some embodiments, the disclosure provides a form of Compound No. 1 (“Form H”) characterized by an X-ray diffraction (“XRPD”) pattern using Cu Kα radiation including peaks at 4.6±0.2, 13.8±0.2, and 17.0±0.2 degrees 2θ (e.g., 4.6±0.1, 13.8±0.1, and 17.0±0.1 degrees 2θ (e.g., 4.6, 13.8, and 17.0 degrees 2θ).

[0168] In some embodiments, the XRPD pattern of Form H further comprises at least one peak selected from 5.6±0.2, 8.6±0.2, and 17.8±0.2 degrees 2θ (e.g., 5.6±0.1, 8.6±0.1, and 17.8±0.1 degrees 2θ (e.g., 5.6, 8.6, and 17.8 degrees 2θ)) using Cu Kα radiation.

[0169] In some embodiments, the XRPD pattern of Form H further comprises at least two peaks selected from 5.6±0.2, 8.6±0.2, and 17.8±0.2 degrees 2θ (e.g., 5.6±0.1, 8.6±0.1, and 17.8±0.1 degrees 2θ (e.g., 5.6, 8.6, and 17.8 degrees 2θ)) using Cu Kα radiation.

[0170] In some embodiments, the XRPD pattern of Form H further comprises peaks at 5.6±0.2, 8.6±0.2, and 17.8±0.2 degrees 2θ (e.g., 5.6±0.1, 8.6±0.1, and 17.8±0.1 degrees 2θ (e.g., 5.6, 8.6, and 17.8 degrees 2θ) using Cu Kα radiation.

[0171] In some aspects, the disclosure provides a form of Compound No. 1 ("Form H") characterized by an X-ray diffraction ("XRPD") pattern including at least three peaks selected from 4.6±0.2, 5.6±0.2, 8.6±0.2, 13.8±0.2, 17.0±0.2, and 17.8±0.2 degrees 2θ (e.g., 4.6±0.1, 5.6±0.1, 8.6±0.1, 13.8±0.1, 17.0±0.1, and 17.8±0.1 degrees 2θ (e.g., 4.6, 5.6, 8.6, 13.8, 17.0, and 17.8 degrees 2θ) using Cu Kα radiation.

[0172] In some embodiments, the XRPD pattern of Form H includes at least four peaks selected from 4.6±0.2, 5.6±0.2, 8.6±0.2, 13.8±0.2, 17.0±0.2, and 17.8±0.2 degrees 2θ (e.g., 4.6±0.1, 5.6±0.1, 8.6±0.1, 13.8±0.1, 17.0±0.1, and 17.8±0.1 degrees 2θ (e.g., 4.6, 5.6, 8.6, 13.8, 17.0, and 17.8 degrees 2θ) using Cu Kα radiation.

[0173] In some embodiments, the XRPD pattern of Form H includes at least five peaks selected from 4.6±0.2, 5.6±0.2, 8.6±0.2, 13.8±0.2, 17.0±0.2, and 17.8±0.2 degrees 2θ (e.g., 4.6±0.1, 5.6±0.1, 8.6±0.1, 13.8±0.1, 17.0±0.1, and 17.8±0.1 degrees 2θ (e.g., 4.6, 5.6, 8.6, 13.8, 17.0, and 17.8 degrees 2θ) using Cu Kα radiation.

[0174] In some embodiments, the XRPD pattern of Form H includes peaks at 4.6±0.2, 5.6±0.2, 8.6±0.2, 13.8±0.2, 17.0±0.2, and 17.8±0.2 degrees 2θ (e.g., 4.6±0.1, 5.6±0.1, 8.6±0.1, 13.8±0.1, 17.0±0.1, and 17.8±0.1 degrees 2θ (e.g., 4.6, 5.6, 8.6, 13.8, 17.0, and 17.8 degrees 2θ) using Cu Kα radiation.

[0175] In some embodiments, the present disclosure provides a form of Compound No. 1 ("Form H") characterized by an XRPD pattern substantially similar to that shown in FIG.

[0176] In some embodiments, Form H is characterized by an XRPD pattern comprising peaks at approximately the positions indicated in the table below, where it is understood that the values ​​in the table are approximate and subject to instrumental and experimental variation. [Table 8]

[0177] Characterization by Differential Scanning Calorimetry (DSC) In some aspects, the disclosure provides a form of Compound No. 1 ("Form H") characterized by a DSC curve having at least one endothermic peak selected from 62±20 and 153±20° C. (e.g., 62±10 and 153±10° C. (e.g., 62±5 and 153±5° C. (e.g., 62±4 and 153±4° C. (e.g., 62±3 and 153±3° C. (e.g., 62±2 and 153±2° C. (e.g., 62±1 and 153±1° C. (e.g., 62±0.5 and 153±0.5° C.).

[0178] In some embodiments, Form H of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 62±20 and 153±20° C. (e.g., 62±10 and 153±10° C. (e.g., 62±5 and 153±5° C. (e.g., 62±4 and 153±4° C. (e.g., 62±3 and 153±3° C. (e.g., 62±2 and 153±2° C. (e.g., 62±1 and 153±1° C. (e.g., 62±0.5 and 153±0.5° C.))))).

[0179] In some embodiments, Form H of Compound No. 1 is characterized by a DSC curve with an endothermic peak at 62° C. In some embodiments, Form H of Compound No. 1 is characterized by a DSC curve with an endothermic peak at 153° C.

[0180] Form I Characterization by X-ray powder diffraction (XRPD) In some embodiments, the form is Form I of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof.

[0181] In some embodiments, the physical form is Form I of the methanol solvate of Compound No. 1.

[0182] In some embodiments, the shape form is Form I of Compound No. 1.

[0183] In some embodiments, the disclosure provides a form of Compound No. 1 (“Form I”) characterized by an X-ray diffraction (“XRPD”) pattern using Cu Kα radiation including peaks at 5.1±0.2, 20.4±0.2, and 21.5±0.2 degrees 2θ (e.g., 5.1±0.1, 20.4±0.1, and 21.5±0.1 degrees 2θ (e.g., 5.1, 20.4, and 21.5 degrees 2θ).

[0184] In some embodiments, the XRPD pattern of Form I further comprises at least one peak selected from 17.0±0.2, 22.3±0.2, and 25.5±0.2 degrees 2θ (e.g., 17.0±0.1, 22.3±0.1, and 25.5±0.1 degrees 2θ (e.g., 17.0, 22.3, and 25.5 degrees 2θ) using Cu Kα radiation.

[0185] In some embodiments, the XRPD pattern of Form I further comprises at least two peaks selected from 17.0±0.2, 22.3±0.2, and 25.5±0.2 degrees 2θ (e.g., 17.0±0.1, 22.3±0.1, and 25.5±0.1 degrees 2θ (e.g., 17.0, 22.3, and 25.5 degrees 2θ) using Cu Kα radiation.

[0186] In some embodiments, the XRPD pattern of Form I further comprises peaks at 17.0±0.2, 22.3±0.2, and 25.5±0.2 degrees 2θ (e.g., 17.0±0.1, 22.3±0.1, and 25.5±0.1 degrees 2θ (e.g., 17.0, 22.3, and 25.5 degrees 2θ) using Cu Kα radiation.

[0187] In some aspects, the disclosure provides a form of Compound No. 1 ("Form I") characterized by an X-ray diffraction ("XRPD") pattern including at least three peaks selected from 5.1±0.2, 17.0±0.2, 20.4±0.2, 21.5±0.2, 22.3±0.2, and 25.5±0.2 degrees 2θ (e.g., 5.1±0.1, 17.0±0.1, 20.4±0.1, 21.5±0.1, 22.3±0.1, and 25.5±0.1 degrees 2θ (e.g., 5.1, 17.0, 20.4, 21.5, 22.3, and 25.5 degrees 2θ).

[0188] In some embodiments, the XRPD pattern of Form I includes at least four peaks selected from 5.1±0.2, 17.0±0.2, 20.4±0.2, 21.5±0.2, 22.3±0.2, and 25.5±0.2 degrees 2θ (e.g., 5.1±0.1, 17.0±0.1, 20.4±0.1, 21.5±0.1, 22.3±0.1, and 25.5±0.1 degrees 2θ (e.g., 5.1, 17.0, 20.4, 21.5, 22.3, and 25.5 degrees 2θ) using Cu Kα radiation.

[0189] In some embodiments, the XRPD pattern of Form I includes at least five peaks selected from 5.1±0.2, 17.0±0.2, 20.4±0.2, 21.5±0.2, 22.3±0.2, and 25.5±0.2 degrees 2θ (e.g., 5.1±0.1, 17.0±0.1, 20.4±0.1, 21.5±0.1, 22.3±0.1, and 25.5±0.1 degrees 2θ (e.g., 5.1, 17.0, 20.4, 21.5, 22.3, and 25.5 degrees 2θ) using Cu Kα radiation.

[0190] In some embodiments, the XRPD pattern of Form I includes peaks at 5.1±0.2, 17.0±0.2, 20.4±0.2, 21.5±0.2, 22.3±0.2, and 25.5±0.2 degrees 2θ (e.g., 5.1±0.1, 17.0±0.1, 20.4±0.1, 21.5±0.1, 22.3±0.1, and 25.5±0.1 degrees 2θ (e.g., 5.1, 17.0, 20.4, 21.5, 22.3, and 25.5 degrees 2θ) using Cu Kα radiation.

[0191] In some embodiments, Form I is characterized by an XRPD pattern substantially similar to that shown in FIG.

[0192] In some embodiments, Form I is characterized by an XRPD pattern comprising peaks at approximately the positions shown in the table below, where it is understood that the values ​​in the table are approximate and subject to instrumental and experimental variation. [Table 9]

[0193] Form J In some embodiments, the form is Form J of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof.

[0194] In some embodiments, the shape form is hydrate form J of Compound No. 1.

[0195] In some embodiments, the shape form is Form J of Compound No. 1.

[0196] In some embodiments, the disclosure provides a form of Compound No. 1 (“Form J”) characterized by an X-ray diffraction (“XRPD”) pattern using Cu Kα radiation including peaks at 4.5±0.2, 17.9±0.2, and 22.5±0.2 degrees 2θ (e.g., 4.5±0.1, 17.9±0.1, and 22.5±0.1 degrees 2θ (e.g., 4.5, 17.9, and 22.5 degrees 2θ).

[0197] In some embodiments, the XRPD pattern of Form J further comprises at least one peak selected from 5.1±0.2, 10.4±0.2, and 16.0±0.2 degrees 2θ (e.g., 5.1±0.1, 10.4±0.1, and 16.0±0.1 degrees 2θ (e.g., 5.1, 10.4, and 16.0 degrees 2θ) using Cu Kα radiation.

[0198] In some embodiments, the XRPD pattern of Form J further comprises at least two peaks selected from 5.1±0.2, 10.4±0.2, and 16.0±0.2 degrees 2θ (e.g., 5.1±0.1, 10.4±0.1, and 16.0±0.1 degrees 2θ (e.g., 5.1, 10.4, and 16.0 degrees 2θ) using Cu Kα radiation.

[0199] In some embodiments, the XRPD pattern of Form J further comprises peaks at 5.1±0.2, 10.4±0.2, and 16.0±0.2 degrees 2θ (e.g., 5.1±0.1, 10.4±0.1, and 16.0±0.1 degrees 2θ (e.g., 5.1, 10.4, and 16.0 degrees 2θ) using Cu Kα radiation.

[0200] In some aspects, the disclosure provides a form of Compound No. 1 (“Form J”) characterized by an X-ray diffraction (“XRPD”) pattern including at least three peaks selected from 4.5±0.2, 5.1±0.2, 10.4±0.2, 16.0±0.2, 17.9±0.2, and 22.5±0.2 degrees 2θ (e.g., 4.5±0.1, 5.1±0.1, 10.4±0.1, 16.0±0.1, 17.9±0.1, and 22.5±0.1 degrees 2θ (e.g., 4.5, 5.1, 10.4, 16.0, 17.9, and 22.5 degrees 2θ) using Cu Kα radiation.

[0201] In some embodiments, the XRPD pattern of Form J includes at least four peaks selected from 4.5±0.2, 5.1±0.2, 10.4±0.2, 16.0±0.2, 17.9±0.2, and 22.5±0.2 degrees 2θ (e.g., 4.5±0.1, 5.1±0.1, 10.4±0.1, 16.0±0.1, 17.9±0.1, and 22.5±0.1 degrees 2θ (e.g., 4.5, 5.1, 10.4, 16.0, 17.9, and 22.5 degrees 2θ) using Cu Kα radiation.

[0202] In some embodiments, the XRPD pattern of Form J includes at least five peaks selected from 4.5±0.2, 5.1±0.2, 10.4±0.2, 16.0±0.2, 17.9±0.2, and 22.5±0.2 degrees 2θ (e.g., 4.5±0.1, 5.1±0.1, 10.4±0.1, 16.0±0.1, 17.9±0.1, and 22.5±0.1 degrees 2θ (e.g., 4.5, 5.1, 10.4, 16.0, 17.9, and 22.5 degrees 2θ) using Cu Kα radiation.

[0203] In some embodiments, the XRPD pattern of Form J includes peaks at 4.5±0.2, 5.1±0.2, 10.4±0.2, 16.0±0.2, 17.9±0.2, and 22.5±0.2 degrees 2θ (e.g., 4.5±0.1, 5.1±0.1, 10.4±0.1, 16.0±0.1, 17.9±0.1, and 22.5±0.1 degrees 2θ (e.g., 4.5, 5.1, 10.4, 16.0, 17.9, and 22.5 degrees 2θ) using Cu Kα radiation.

[0204] In some embodiments, form J is characterized by an XRPD pattern substantially similar to that shown in FIG.

[0205] In some embodiments, Form J is characterized by an XRPD pattern comprising peaks at approximately the locations shown in the table below, where it is understood that the values ​​in the table are approximate and subject to instrumental and experimental variation. [Table 10]

[0206] Characterization by Differential Scanning Calorimetry (DSC) In some embodiments, Form J of Compound No. 1 is characterized by a DSC curve having at least one endothermic peak selected from 137±20 and 166±20° C. (e.g., 137±10 and 166±10° C. (e.g., 137±5 and 166±5° C. (e.g., 137±4 and 166±4° C. (e.g., 137±3 and 166±3° C. (e.g., 137±2 and 166±2° C. (e.g., 137±1 and 166±1° C. (e.g., 137±0.5 and 166±0.5° C.))))).

[0207] In some embodiments, form J of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 137±20 and 166±20° C. (e.g., 137±10 and 166±10° C. (e.g., 137±5 and 166±5° C. (e.g., 137±4 and 166±4° C. (e.g., 137±3 and 166±3° C. (e.g., 137±2 and 166±2° C. (e.g., 137±1 and 166±1° C. (e.g., 137±0.5 and 166±0.5° C.)))).

[0208] In some embodiments, form J of compound No. 1 is characterized by a DSC curve with an endothermic peak at 137° C. In some embodiments, form J of compound No. 1 is characterized by a DSC curve with an endothermic peak at 166° C. Characterization by Thermogravimetric Analysis (TGA)

[0209] In some embodiments, Form J of Compound No. 1 exhibits approximately 1-2% weight loss at about 33±20° C. (e.g., 33±10° C. (e.g., 33±5° C. (e.g., 33±4° C. (e.g., 33±3° C. (e.g., 33±2° C. (e.g., 33±1° C. (e.g., 33±0.5° C.))))))) to about 75±20° C. (e.g., 75±10° C. (e.g., 75±5° C. (e.g., 75±4° C. (e.g., 75±3° C. (e.g., 75±2° C. (e.g., 75±1° C. (e.g., 75±0.5° C.))))))))))))

[0210] In some embodiments, Form J of Compound No. 1 exhibits approximately 1.1% weight loss from about 33° C. to about 75° C. as measured by TGA.

[0211] In some embodiments, Form J of Compound No. 1 exhibits approximately 6-8% weight loss at about 75±20° C. (e.g., 75±10° C. (e.g., 75±5° C. (e.g., 75±4° C. (e.g., 75±3° C. (e.g., 75±2° C. (e.g., 75±1° C. (e.g., 75±0.5° C.))))))) to about 175±20° C. (e.g., 175±10° C. (e.g., 175±5° C. (e.g., 175±4° C. (e.g., 175±3° C. (e.g., 175±2° C. (e.g., 175±1° C. (e.g., 175±0.5° C.))))))))))))))

[0212] In some embodiments, Form J of Compound No. 1 exhibits approximately 7.0% weight loss from about 75° C. to about 175° C. as measured by TGA.

[0213] In some embodiments, Form J of Compound No. 1 exhibits approximately 7-10% weight loss at about 33±20° C. (e.g., 33±10° C. (e.g., 33±5° C. (e.g., 33±4° C. (e.g., 33±3° C. (e.g., 33±2° C. (e.g., 33±1° C. (e.g., 33±0.5° C.))))))) to about 175±20° C. (e.g., 175±10° C. (e.g., 175±5° C. (e.g., 175±4° C. (e.g., 175±3° C. (e.g., 175±2° C. (e.g., 175±1° C. (e.g., 175±0.5° C.))))))))))))))

[0214] In some embodiments, Form J of Compound No. 1 exhibits approximately 8.2% weight loss from about 33° C. to about 175° C. as measured by TGA.

[0215] Form K Characterization by X-ray powder diffraction (XRPD) In some embodiments, the form is Form K of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof.

[0216] In some embodiments, the shape form is Form K of Compound No. 1.

[0217] In some embodiments, the disclosure provides a form of Compound No. 1 (“Form K”) characterized by an X-ray diffraction (“XRPD”) pattern using Cu Kα radiation including peaks at 5.2±0.2, 17.0±0.2, and 20.5±0.2 degrees 2θ (e.g., 5.2±0.1, 17.0±0.1, and 20.5±0.1 degrees 2θ (e.g., 5.2, 17.0, and 20.5 degrees 2θ).

[0218] In some embodiments, the XRPD pattern of Form K further comprises at least one peak selected from 6.8±0.2, 21.6±0.2, and 22.4±0.2 degrees 2θ (e.g., 6.8±0.1, 21.6±0.1, and 22.4±0.1 degrees 2θ (e.g., 6.8, 21.6, and 22.4 degrees 2θ) using Cu Kα radiation.

[0219] In some embodiments, the XRPD pattern of Form K further comprises at least two peaks selected from 6.8±0.2, 21.6±0.2, and 22.4±0.2 degrees 2θ (e.g., 6.8±0.1, 21.6±0.1, and 22.4±0.1 degrees 2θ (e.g., 6.8, 21.6, and 22.4 degrees 2θ) using Cu Kα radiation.

[0220] In some embodiments, the XRPD pattern of Form K further comprises peaks at 6.8±0.2, 21.6±0.2, and 22.4±0.2 degrees 2θ (e.g., 6.8±0.1, 21.6±0.1, and 22.4±0.1 degrees 2θ (e.g., 6.8, 21.6, and 22.4 degrees 2θ) using Cu Kα radiation.

[0221] In some aspects, the disclosure provides a form of Compound No. 1 ("Form K") characterized by an X-ray diffraction ("XRPD") pattern including at least three peaks selected from 5.2±0.2, 6.8±0.2, 17.0±0.2, 20.5±0.2, 21.6±0.2, and 22.4±0.2 degrees 2θ (e.g., 5.2±0.1, 6.8±0.1, 17.0±0.1, 20.5±0.1, 21.6±0.1, and 22.4±0.1 degrees 2θ (e.g., 5.2, 6.8, 17.0, 20.5, 21.6, and 22.4 degrees 2θ) using Cu Kα radiation.

[0222] In some embodiments, the XRPD pattern of Form K includes at least four peaks selected from 5.2±0.2, 6.8±0.2, 17.0±0.2, 20.5±0.2, 21.6±0.2, and 22.4±0.2 degrees 2θ (e.g., 5.2±0.1, 6.8±0.1, 17.0±0.1, 20.5±0.1, 21.6±0.1, and 22.4±0.1 degrees 2θ (e.g., 5.2, 6.8, 17.0, 20.5, 21.6, and 22.4 degrees 2θ) using Cu Kα radiation.

[0223] In some embodiments, the XRPD pattern of Form K includes at least five peaks selected from 5.2±0.2, 6.8±0.2, 17.0±0.2, 20.5±0.2, 21.6±0.2, and 22.4±0.2 degrees 2θ (e.g., 5.2±0.1, 6.8±0.1, 17.0±0.1, 20.5±0.1, 21.6±0.1, and 22.4±0.1 degrees 2θ (e.g., 5.2, 6.8, 17.0, 20.5, 21.6, and 22.4 degrees 2θ) using Cu Kα radiation.

[0224] In some embodiments, the XRPD pattern of Form K includes peaks at 5.2±0.2, 6.8±0.2, 17.0±0.2, 20.5±0.2, 21.6±0.2, and 22.4±0.2 degrees 2θ (e.g., 5.2±0.1, 6.8±0.1, 17.0±0.1, 20.5±0.1, 21.6±0.1, and 22.4±0.1 degrees 2θ (e.g., 5.2, 6.8, 17.0, 20.5, 21.6, and 22.4 degrees 2θ) using Cu Kα radiation.

[0225] In some embodiments, form K is characterized by an XRPD pattern substantially similar to that shown in FIG.

[0226] In some embodiments, Form K is characterized by an XRPD pattern comprising peaks at approximately the locations shown in the table below, where it is understood that the values ​​in the table are approximate and subject to instrumental and experimental variation. [Table 11]

[0227] Form L Characterization by X-ray powder diffraction (XRPD) In some embodiments, the form is Form L of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof.

[0228] In some embodiments, the shape form is Form L of Compound No. 1.

[0229] In some embodiments, the disclosure provides a form of Compound No. 1 ("Form L") characterized by an X-ray diffraction ("XRPD") pattern using Cu Kα radiation including peaks at 5.4±0.2, 7.8±0.2, and 19.3±0.2 degrees 2θ (e.g., 5.4±0.1, 7.8±0.1, and 19.3±0.1 degrees 2θ (e.g., 5.4, 7.8, and 19.3 degrees 2θ).

[0230] In some embodiments, the XRPD pattern of form L further comprises at least one peak selected from 14.8±0.2, 15.3±0.2, and 16.6±0.2 degrees 2θ (e.g., 14.8±0.1, 15.3±0.1, and 16.6±0.1 degrees 2θ (e.g., 14.8, 15.3, and 16.6 degrees 2θ) using Cu Kα radiation.

[0231] In some embodiments, the XRPD pattern of form L further comprises at least two peaks selected from 14.8±0.2, 15.3±0.2, and 16.6±0.2 degrees 2θ (e.g., 14.8±0.1, 15.3±0.1, and 16.6±0.1 degrees 2θ (e.g., 14.8, 15.3, and 16.6 degrees 2θ) using Cu Kα radiation.

[0232] In some embodiments, the XRPD pattern of form L further comprises peaks at 14.8±0.2, 15.3±0.2, and 16.6±0.2 degrees 2θ (e.g., 14.8±0.1, 15.3±0.1, and 16.6±0.1 degrees 2θ (e.g., 14.8, 15.3, and 16.6 degrees 2θ) using Cu Kα radiation.

[0233] In some aspects, the disclosure provides a form of Compound No. 1 ("Form L") characterized by an X-ray diffraction ("XRPD") pattern including at least three peaks selected from 5.4±0.2, 7.8±0.2, 14.8±0.2, 15.3±0.2, 16.6±0.2, and 19.3±0.2 degrees 2θ (e.g., 5.4±0.1, 7.8±0.1, 14.8±0.1, 15.3±0.1, 16.6±0.1, and 19.3±0.1 degrees 2θ (e.g., 5.4, 7.8, 14.8, 15.3, 16.6, and 19.3 degrees 2θ) using Cu Kα radiation.

[0234] In some embodiments, the XRPD pattern of form L includes at least four peaks selected from 5.4±0.2, 7.8±0.2, 14.8±0.2, 15.3±0.2, 16.6±0.2, and 19.3±0.2 degrees 2θ (e.g., 5.4±0.1, 7.8±0.1, 14.8±0.1, 15.3±0.1, 16.6±0.1, and 19.3±0.1 degrees 2θ (e.g., 5.4, 7.8, 14.8, 15.3, 16.6, and 19.3 degrees 2θ) using Cu Kα radiation.

[0235] In some embodiments, the XRPD pattern of form L includes at least five peaks selected from 5.4±0.2, 7.8±0.2, 14.8±0.2, 15.3±0.2, 16.6±0.2, and 19.3±0.2 degrees 2θ (e.g., 5.4±0.1, 7.8±0.1, 14.8±0.1, 15.3±0.1, 16.6±0.1, and 19.3±0.1 degrees 2θ (e.g., 5.4, 7.8, 14.8, 15.3, 16.6, and 19.3 degrees 2θ) using Cu Kα radiation.

[0236] In some embodiments, the XRPD pattern of form L includes peaks at 5.4±0.2, 7.8±0.2, 14.8±0.2, 15.3±0.2, 16.6±0.2, and 19.3±0.2 degrees 2θ (e.g., 5.4±0.1, 7.8±0.1, 14.8±0.1, 15.3±0.1, 16.6±0.1, and 19.3±0.1 degrees 2θ (e.g., 5.4, 7.8, 14.8, 15.3, 16.6, and 19.3 degrees 2θ) using Cu Kα radiation.

[0237] In some embodiments, form L is characterized by an XRPD pattern substantially similar to that shown in FIG.

[0238] In some embodiments, form L is characterized by an XRPD pattern comprising peaks at approximately the positions shown in the table below, where it is understood that the values ​​in the table are approximate and subject to instrumental and experimental variation. [Table 12]

[0239] Methods for preparing crystalline forms In some aspects, the disclosure features a method of preparing a crystalline form of Compound No. 1 or a pharma- ceutically acceptable salt thereof.

[0240] In some aspects, the disclosure features a method of preparing a crystalline form of Compound No. 1, or a pharma- ceutically acceptable salt thereof, the method including one or more steps described herein.

[0241] In some aspects, the present disclosure provides compounds obtainable by, obtained by, or obtained directly by a process for preparing a crystalline form of Compound No. 1 or a pharma- ceutically acceptable salt thereof.

[0242] The crystalline forms of Compound No. 1 or its pharma- ceutically acceptable salts can be prepared by any suitable technique known in the art. Specific processes for the preparation of these compounds are further described in the accompanying examples.

[0243] Pharmaceutical Compositions In some aspects, the disclosure features a pharmaceutical composition that includes a form of Compound No. 1 described herein, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable carriers or excipients.

[0244] The pharmaceutical composition containing the active compound of the present disclosure can be prepared in a generally known manner, for example, by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, encapsulating, or lyophilizing processes.The pharmaceutical composition can be formulated in a conventional manner using one or more pharma-ceutically acceptable carriers, including excipients and / or auxiliaries that facilitate the processing of the active compound into a preparation that can be used medicaments.Of course, the appropriate formulation depends on the selected route of administration.

[0245] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. Suitable carriers for intravenous administration include physiological saline, bacteriostatic water for injection, Cremophor EL™ (BASF, Parsippany, NJ), or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. The composition must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. The action of microorganisms can be prevented by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal. In many cases, it is preferable to include isotonic agents, such as sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable composition can be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin, in the composition.

[0246] Sterile injectable solution can be prepared by mixing the required amount of active compound in appropriate solvent with one or a combination of the above-listed components, as required, followed by sterilization by filtration.Dispersion is usually prepared by incorporating active compound into a sterile vehicle that contains a basic dispersion medium and other components required from the above-listed components.In the case of sterile powder for preparing sterile injectable solution, the preparation method is vacuum drying and freeze-drying, which obtains powder of active ingredient and any additional desired ingredient from the solution that has been previously sterilized and filtered.

[0247] Oral compositions generally contain an inert diluent or edible pharma- ceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of therapeutic oral administration, active compounds can be mixed with excipients and used in the form of tablets, lozenges, or capsules. Oral compositions can also be prepared with a fluid carrier for use as a mouthwash, in which case the compound in the fluid carrier is orally applied and expectorated or swallowed. Pharmaceutically acceptable binders and / or auxiliary materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavor.

[0248] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

[0249] Systemic administration can also be achieved by transmucosal or transdermal means. For transmucosal or transdermal administration, a penetrant suitable for the barrier to be permeated is used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished by using nasal sprays or suppositories. For transdermal administration, the active compound is formulated into ointments, salves, gels, or creams, as is generally known in the art.

[0250] The active compound can be prepared with a pharma- ceutically acceptable carrier that protects the compound from rapid elimination from the body, such as a release control formulation, including a placement agent and a microencapsulated delivery system.Biodegradable biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid.The method of preparing such formulations will be clear to those skilled in the art.

[0251] Formulation of oral or parenteral compositions in dosage unit form can be particularly advantageous for ease of administration and uniformity of dosage.As used herein, dosage unit form refers to a physically discrete unit suitable as a unitary dosage for a subject to be treated, each unit containing a predetermined amount of active compound calculated to produce a desired therapeutic effect in association with the required pharmaceutical carrier.The specification for dosage unit form of the present disclosure is determined and directly depends on the inherent characteristics of the active compound and the specific therapeutic effect to be achieved.

[0252] In therapeutic applications, dosages of pharmaceutical compositions used in accordance with the present disclosure will vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the treatment, among other factors which will affect the selected dosage. In general, the dosage should be sufficient to slow, and preferably cause regression of, the symptoms of the disease, and preferably cause complete regression of the disease.

[0253] It will be appreciated that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0254] How to use In some aspects, the disclosure provides a method of treating or preventing cancer in a subject, comprising administering to the subject a pharma- ceutical effective amount of a form of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutical acceptable salt thereof.

[0255] In some aspects, the disclosure provides a method of treating or preventing cancer in a subject, comprising administering to the subject a pharma- ceutical effective amount of a form of Compound No. 1 (e.g., Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, or Form L), a solvate thereof, a hydrate thereof, or a pharma- ceutical acceptable salt thereof.

[0256] In some aspects, the disclosure provides a form of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof, for use in treating or preventing cancer in a subject.

[0257] In some aspects, the disclosure provides a form of Compound No. 1 (e.g., Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, or Form L), a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof, for use in treating or preventing cancer in a subject.

[0258] In some aspects, the disclosure provides the use of a form of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing cancer in a subject.

[0259] In some aspects, the disclosure provides for the use of a form of Compound No. 1 (e.g., Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, or Form L), a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing cancer in a subject.

[0260] In some embodiments, Form A of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof is administered.

[0261] In some embodiments, Form B of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof is administered.

[0262] In some embodiments, Form C of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof is administered.

[0263] In some embodiments, Form D of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof is administered.

[0264] In some embodiments, Form E of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof is administered.

[0265] In some embodiments, Form F of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof is administered.

[0266] In some embodiments, Form G of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof is administered.

[0267] In some embodiments, Form H of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof is administered.

[0268] In some embodiments, Form I of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof is administered.

[0269] In some embodiments, Form J of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof is administered.

[0270] In some embodiments, Form K of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof is administered.

[0271] In some embodiments, Form L of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof is administered.

[0272] Suitable subjects and diseases In some embodiments, the subject is a mammal.

[0273] In some embodiments, the subject is a human.

[0274] In some embodiments, the subject is a mouse.

[0275] The compounds of the present disclosure inhibit or modulate the activity of receptor tyrosine kinases, in particular ErbB-receptors, such as, but not limited to, extracellular mutants such as EGFR-Viii, EGFR-Vii, EGFR-Vvi, EGFR-A289V and EGFR-G598V, and HER2-S310F. Thus, the compounds and compositions of the present disclosure may be useful as medicaments, i.e., more specifically, in therapeutic methods for the prevention or treatment of cancer, as described in more detail below. Thus, in a further aspect, the present disclosure provides a method of prevention or treatment of a mammal, e.g., a human, suffering from cancer, as described in more detail below.

[0276] The terms "prevention" or "preventing" refer to reducing or eliminating the onset of symptoms or complications of a disease (e.g., cancer). Such prevention includes the step of administering a therapeutically effective amount of a compound of Formula I or a salt thereof (or a pharmaceutical composition containing a compound of Formula I or a salt thereof) to the mammal, e.g., a human.

[0277] The term "treatment" or "treating" is intended to encompass therapy and cure. Such treatment comprises the step of administering a therapeutically effective amount of a compound of Formula I or a salt thereof (or a pharmaceutical composition containing a compound of Formula I or a salt thereof) to said mammal, e.g., a human.

[0278] Thus, the present disclosure provides the use of a compound of the present disclosure, or a pharma- ceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition thereof, for the treatment of cancer in a mammal, e.g., a human, as detailed below.

[0279] In some aspects, the disclosure is directed to a method of inhibiting an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of EGFR), comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[0280] In some aspects, the present disclosure is directed to methods of inhibiting an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of EGFR), comprising administering to a subject in need thereof a composition described herein.

[0281] In some aspects, the present disclosure is directed to a method of preventing or treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[0282] In some aspects, the present disclosure is directed to a method of preventing or treating cancer comprising administering to a subject in need thereof a composition described herein.

[0283] In some aspects, the disclosure is directed to a compound described herein for use in inhibiting an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of EGFR).

[0284] In some aspects, the disclosure is directed to a compound described herein for use in the prevention or treatment of cancer.

[0285] In some aspects, the disclosure is directed to a composition described herein for use in inhibiting an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of EGFR).

[0286] In some aspects, the present disclosure is directed to a composition described herein for use in the prevention or treatment of cancer.

[0287] In some aspects, the disclosure is directed to the use of a compound described herein in the manufacture of a medicament for inhibiting an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of EGFR).

[0288] In some aspects, the disclosure is directed to the use of a compound described herein in the manufacture of a medicament for preventing or treating cancer.

[0289] In some embodiments, the compound is selected from the compounds set forth in Tables 1 and 2, pharma- ceutically acceptable salts, and stereoisomers thereof.

[0290] In some embodiments, the compound is selected from the compounds set forth in Tables 1 and 2, and pharma- ceutically acceptable salts thereof.

[0291] In some embodiments, the compound is selected from the compounds listed in Tables 1 and 2.

[0292] In some embodiments, the cancer comprises a solid tumor.

[0293] In some embodiments, 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.

[0294] In some embodiments, the cancer is glioblastoma (GBM) or any subtype thereof.

[0295] In some embodiments, the cancer is glioblastoma.

[0296] In some embodiments, the cancer or tumor, or cells thereof, express an oncogenic variant of an ErbB receptor.

[0297] In some embodiments, the oncogenic variant of an ErbB receptor comprises an allosteric mutation.

[0298] In some embodiments, the oncogenic variant of an ErbB receptor is an allosteric variant of an ErbB receptor.

[0299] In some embodiments, the ErbB receptor is the epidermal growth factor receptor (EGFR) or the human epidermal growth factor receptor 2 (HER2) receptor.

[0300] In some embodiments, the ErbB receptor is epidermal growth factor receptor (EGFR).

[0301] In some embodiments, the ErbB receptor is a HER2 receptor.

[0302] In some embodiments, the cancer or tumor, or cells thereof, express an oncogenic variant of the epidermal growth factor receptor (EGFR).

[0303] In some embodiments, the oncogenic variant of EGFR is an allosteric variant of EGFR.

[0304] In some embodiments, the oncogenic variant of EGFR comprises an allosteric mutation.

[0305] In some embodiments, the cancer or tumor, or cells thereof, express an oncogenic variant of the HER2 receptor.

[0306] In some embodiments, the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor.

[0307] In some embodiments, the oncogenic variant of the HER2 receptor comprises an allosteric mutation.

[0308] In some embodiments, the oncogenic variant of EGFR comprises an EGFR variant III (EGFR-Viii) mutation.

[0309] In some embodiments, the oncogenic variant of EGFR comprises an EGFR variant II (EGFR-Vii) mutation.

[0310] In some embodiments, the oncogenic variant of EGFR comprises an EGFR variant VI (EGFR-Vvi) mutation.

[0311] In some embodiments, the oncogenic variant of EGFR comprises a substitution of valine (V) for alanine (A) at position 289 of SEQ ID NO:1.

[0312] In some embodiments, the oncogenic variant of EGFR comprises a substitution of valine (V) for glycine (G) at position 598 of SEQ ID NO:1.

[0313] In some embodiments, the cancer or tumor, or cells thereof, express an oncogenic variant of EGFR, wherein the oncogenic variant of EGFR is an allosteric variant of EGFR, and wherein the oncogenic variant of EGFR comprises a structural modification of EGFR, wherein the oncogenic variant of EGFR can form a covalently linked dimer, wherein the covalently linked dimer is structurally active, and wherein the covalently linked dimer enhances the activity of EGFR when contacted with a type I ErbB inhibitor. In some embodiments, the structural modification of EGFR comprises one or more of a modification of the nucleic acid sequence, the amino acid sequence, the secondary structure, the tertiary structure, and the quaternary structure. In some embodiments, the oncogenic variant comprises a mutation, a splicing event, a post-translational process, a conformational change, or any combination thereof. In some embodiments, the structural modification of EGFR occurs within the first cysteine-rich (CR1) and / or second cysteine-rich (CR2) regions of EGFR. In some embodiments, the first cysteine-rich (CR1) and / or second cysteine-rich (CR2) regions of EGFR comprise amino acid residues T211 to R334 and / or C526 to S645 of SEQ ID NO: 1, respectively. In some embodiments, the oncogenic variants of EGFR create a physical barrier to disulfide bond formation within the CR1 and / or CR2 regions. In some embodiments, the oncogenic variants of EGFR remove a physical barrier to disulfide bond formation within the CR1 and / or CR2 regions. In some embodiments, the oncogenic variants of EGFR comprise one or more free or unpaired cysteine ​​(C) residues located at the dimer interface of EGFR.In some embodiments, the oncogenic variants of EGFR are C190-C199, C194-C207, C215-C223, C219-C231, C232-C240, C236-C248, C251-C260, C264-C291, C295-C307, C311-C326, C329-C33 according to SEQ ID NO:1. 3. Contains one or more free or unpaired cysteine ​​(C) residues at sites selected from the group consisting of C506 to C515, C510 to C523, C526 to C535, C539 to C555, C558 to C571, C562 to C579, C582 to C591, C595 to C617, C620 to C628, and C624 to C636. In some embodiments, the modification occurs at an intramolecular disulfide bond within a range of 10 angstroms or less at a site selected from the group consisting of C190 to C199, C194 to C207, C215 to C223, C219 to C231, C232 to C240, C236 to C248, C251 to C260, C264 to C291, C295 to C307, C311 to C326, C329 to C333, C506 to C515, C510 to C523, C526 to C535, C539 to C555, C558 to C571, C562 to C579, C582 to C591, C595 to C617, C620 to C628, and C624 to C636 according to SEQ ID NO:1.

[0314] In some embodiments, the cancer or tumor, or cells thereof, expresses an oncogenic variant of EGFR, the oncogenic variant of EGFR is a mutation of EGFR, and the nucleotide sequence encoding the oncogenic variant of EGFR comprises a deletion or substitution that includes one or more amino acids encoding an adenosine triphosphate (ATP) binding site. In some embodiments, the ATP binding site comprises amino acids E746-A750 of SEQ ID NO:1. In some embodiments, the ATP binding site or the deletion or substitution thereof comprises K858 of SEQ ID NO:1. In some embodiments, the deletion comprises K858 of SEQ ID NO:1. In some embodiments, at position 858 of SEQ ID NO:1, a lysine (K) is substituted with arginine (R) (K858R).

[0315] In some embodiments, the cancer or tumor, or cells thereof, expresses an oncogenic variant of EGFR, wherein the oncogenic variant of EGFR is an allosteric variant of EGFR, and the nucleotide sequence encoding the oncogenic variant of EGFR comprises an insertion within a sequence encoding exon 20, or a portion thereof. In some embodiments, the sequence encoding exon 20, or a portion thereof, comprises a sequence encoding KEILDEAYVMASVDNPHVCAR (SEQ ID NO: 7). In some embodiments, the sequence encoding exon 20, or a portion thereof, comprises a sequence encoding the C-helix, the end of the C-helix, or a loop after the C-helix. In some embodiments, the insertion comprises the amino acid sequence of ASV, SVD, NPH, or FQEA. In some embodiments, the sequence encoding exon 20 or a portion thereof comprises one or more of the following: (a) an insertion of the amino acid sequence ASV between positions V769 and D770 of SEQ ID NO:1; (b) an insertion of the amino acid sequence SVD between positions D770 and N771 of SEQ ID NO:1; (c) an insertion of the amino acid sequence NPH between positions H773 and V774 of SEQ ID NO:1; (d) an insertion of the amino acid sequence FQEA between positions A763 and Y764 of SEQ ID NO:1; (e) an insertion of the amino acid sequence PH between positions H773 and V774 of SEQ ID NO:1; (f) an insertion of the amino acid G between positions D770 and N771 of SEQ ID NO:1; (g) an insertion of the amino acid H between positions H773 and V774 of SEQ ID NO:1; (h) an insertion of the amino acid sequence HV between positions V774 and C775 of SEQ ID NO:1; 1, (j) insertion of amino acid sequence SVA between positions A767 and S768 of SEQ ID NO: 1, (k) insertion of amino acid sequence GYN between positions 770 and 771 of SEQ ID NO: 1, (l) insertion of amino acid H between positions N771 and P772 of SEQ ID NO: 1, (m) insertion of amino acid Y between positions H773 and V774 of SEQ ID NO: 1, (n) insertion of amino acid sequence PHVC between positions C775 and R776 of SEQ ID NO: 1, (o) replacement of H at position 773 of SEQ ID NO: 1 with amino acid sequence YNPY, (p) insertion of amino acid sequence DNP between positions P772 and H773 of SEQ ID NO: 1, (q) insertion of amino acid sequence VDS between positions S768 and V769 of SEQ ID NO: 1, (r) insertion of amino acid H between positions D770 and N771 of SEQ ID NO: 1,(s) insertion of the amino acid N between positions N771 and P772 of SEQ ID NO: 1; (t) insertion of the amino acid sequence PNP between positions P772 and H773 of SEQ ID NO: 1; (u) replacement of the amino acid sequence GSVDN with DN between positions 770 and 771 of SEQ ID NO: 1; (v) replacement of the amino acid sequence GYP with NP between positions 771 and 772 of SEQ ID NO: 1; (w) insertion of the amino acid G between positions N771 and P772 of SEQ ID NO: 1; (x) insertion of the amino acid sequence GNP between positions P772 and H773 of SEQ ID NO: 1; (y) insertion of the amino acid sequence GSV between positions V769 and D770 of SEQ ID NO: 1; (z) replacement of the amino acid sequence GNPHVC with VC between positions 774 and 775 of SEQ ID NO: 1; (aa) insertion of the amino acid sequence LQEA between positions A763 and Y764 of SEQ ID NO: 1; (bb ) insertion of the amino acid sequence GL between positions D770 and N771 of SEQ ID NO: 1, (cc) insertion of the amino acid Y between positions D770 and N771 of SEQ ID NO: 1, (dd) insertion of the amino acid sequence NPY between positions H773 and V774 of SEQ ID NO: 1, (ee) insertion of the amino acid sequence TH between positions H773 and V774 of SEQ ID NO: 1, (ff) replacement of the amino acid sequence KGP with the NP between positions 771 and 772 of SEQ ID NO: 1, (gg) replacement of the amino acid sequence SVDNP with the NP between positions 771 and 772 of SEQ ID NO: 1, (hh) insertion of the amino acid sequence NN between positions N771 and P772 of SEQ ID NO: 1, (ii) insertion of the amino acid T between positions N771 and P772 of SEQ ID NO: 1, and (jj) replacement of the amino acid sequence STLASV with the SV between positions 768 and 769 of SEQ ID NO: 1.

[0316] In some embodiments, the cancer or tumor, or cells thereof, express an oncogenic variant of EGFR, wherein the oncogenic variant of EGFR is an allosteric variant of EGFR, and the oncogenic variant of EGFR is selected from the group consisting of EGFR-Vii, EGFR-Vvi, EGFR-R222C, EGFR-R252C, EGFR-R252P, EGFR-R256Y, EGFR-T263P, EGFR-Y270C, EGFR-A289T, EGFR-T263P ... -A289V, EGFR-A289D, EGFR-H304Y, EGFR-G331R, EGFR-P596S, EGFR-P596L, EGFR-P596R, EGFR-G598V, EGFR-G598A, EGFR-G614D, EGFR-C620Y, EGFR-C614W, EGFR-C628F, EGFR-C628Y, EGFR-C636Y, EGFR-G645C, EGFR-660, EGFR-768, or any combination thereof.

[0317] In some embodiments, the cancer or tumor, or cells thereof, express one or more of: (a) wild-type human epidermal growth factor receptor 2 (HER2) receptor or an oncogenic variant of the HER-2 receptor.

[0318] In some embodiments, the cancer or tumor, or cells thereof, expresses a wild-type HER-2 receptor, wherein the wild-type HER2 receptor comprises the amino acid sequence of SEQ ID NO: 2, 3, 4, 5, or 6.

[0319] In some embodiments, the cancer or tumor, or cells thereof, express an oncogenic variant of the HER-2 receptor, and the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor.

[0320] In some embodiments, the cancer or tumor, or cells thereof, express an oncogenic variant of the HER-2 receptor, wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor comprises a substitution of serine (S) with phenylalanine (F) at position 310 of SEQ ID NO: 2 or 5.

[0321] In some embodiments, the cancer or tumor, or cells thereof, express an oncogenic variant of the HER-2 receptor, wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor comprises a substitution of serine (S) with tyrosine (Y) at position 310 of SEQ ID NO: 2 or 5.

[0322] In some embodiments, the cancer or tumor, or cells thereof, express an oncogenic variant of the HER-2 receptor, wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor comprises a substitution of arginine (R) with glutamine (Q) at position 678 of SEQ ID NO: 2 or 5.

[0323] In some embodiments, the cancer or tumor, or cells thereof, express an oncogenic variant of the HER-2 receptor, wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor comprises a substitution of valine (V) with leucine (L) at position 777 of SEQ ID NO: 2 or 5.

[0324] In some embodiments, the cancer or tumor, or cells thereof, express an oncogenic variant of the HER-2 receptor, wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor comprises a substitution of valine (V) with methionine (M) at position 777 of SEQ ID NO: 2 or 5.

[0325] In some embodiments, the cancer or tumor, or cells thereof, express an oncogenic variant of the HER-2 receptor, wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor comprises a substitution of valine (V) with isoleucine (I) at position 842 of SEQ ID NO: 2 or 5.

[0326] In some embodiments, the cancer or tumor, or cells thereof, express an oncogenic variant of the HER-2 receptor, wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor comprises a substitution of leucine (L) with alanine (A) at position 755 of SEQ ID NO: 2 or 5.

[0327] In some embodiments, the cancer or tumor, or cells thereof, express an oncogenic variant of the HER-2 receptor, wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor comprises a substitution of leucine (L) with proline (P) at position 755 of SEQ ID NO: 2 or 5.

[0328] In some embodiments, the cancer or tumor, or cells thereof, express an oncogenic variant of the HER-2 receptor, wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor comprises a substitution of leucine (L) with serine (S) at position 755 of SEQ ID NO: 2 or 5.

[0329] In some embodiments, the cancer or tumor, or cells thereof, expresses an oncogenic variant of the HER-2 receptor, wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the nucleotide sequence encoding the oncogenic variant of the HER2 receptor comprises an insertion within a sequence encoding exon 20 or a portion thereof. In some embodiments, the sequence encoding exon 20 or a portion thereof comprises a sequence encoding KEILDEAYVMAGVGSPYVSR (SEQ ID NO:8). In some embodiments, the sequence encoding exon 20 or a portion thereof comprises a sequence encoding the C-helix, the end of the C-helix, or a loop after the C-helix. In some embodiments, the insertion comprises the amino acid sequence of GSP or YVMA. In some embodiments, the sequence encoding exon 20 or a portion thereof comprises one or more of the following: (a) an insertion of the amino acid sequence YVMA between positions A775 and G776 of SEQ ID NO:2; (b) an insertion of the amino acid sequence GSP between positions P780 and Y781 of SEQ ID NO:2; (c) an insertion of the amino acid sequence YVMA between positions A771 and Y772 of SEQ ID NO:2; (d) an insertion of the amino acid sequence YVMA between positions A775 and G776 of SEQ ID NO:2; (e) an insertion of the amino acid V between positions V777 and G778 of SEQ ID NO:2; (f) an insertion of the amino acid V between positions V777 and G778 of SEQ ID NO:2; (g) a substitution of the amino acid sequence AVGCV with GV between positions 776 and 777 of SEQ ID NO:2; (h) a substitution of the amino acid sequence LC with G between position 776 of SEQ ID NO:2. (i) substitution of G at position 776 of SEQ ID NO:2 with the amino acid sequence LCV; (j) insertion of the amino acid sequence GSP between positions V777 and G778 of SEQ ID NO:2; (k) substitution of LRE at positions 755 and 757 of SEQ ID NO:2 with the amino acid sequence PS; (l) substitution of SP at positions 779 and 780 of SEQ ID NO:2 with the amino acid sequence CPGSP; (m) insertion of an amino acid C between positions V777 and G778 of SEQ ID NO:2; (n) substitution of AG at positions 775 and 776 of SEQ ID NO:2 with the amino acid sequence VVMA; (o) substitution of G at position 776 of SEQ ID NO:2 with the amino acid sequence VV; (p) substitution of GV at positions 776 and 777 of SEQ ID NO:2 with the amino acid sequence AVCV; (q) substitution of GV at positions 776 and 777 of SEQ ID NO:2 with the amino acid sequence VCV;(r) insertion of the amino acid G between positions G778 and S779 of SEQ ID NO:2; (s) insertion of an LRE and an amino acid sequence PK between positions 755 and 757 of SEQ ID NO:2; (t) insertion of an amino acid V between positions A775 and G776 of SEQ ID NO:2; (u) insertion of an amino acid sequence YAMA between positions A775 and G776 of SEQ ID NO:2; (v) replacement of the amino acid sequence CV with the G at position 776 of SEQ ID NO:2; (w) replacement of the amino acid sequence AVCGG with the GVG at positions 776 and 778 of SEQ ID NO:2; (x) replacement of the amino acid sequence AVCGG with the GVG at positions 776 and 778 of SEQ ID NO:2 (y) replacement of GVG between positions 776 and 778 of SEQ ID NO:2 with the amino acid sequence VVVG; (z) replacement of GVGS between positions 776 and 779 of SEQ ID NO:2 with the amino acid sequence SVGG; (aa) replacement of GVGS between positions 776 and 779 of SEQ ID NO:2 with the amino acid sequence VVGES; (bb) replacement of GV between positions 776 and 777 of SEQ ID NO:2 with the amino acid sequence AVGSGV; (cc) replacement of GV between positions 776 and 777 of SEQ ID NO:2 with the amino acid sequence CVC. (dd) substitution of the amino acid sequence HVC with GV between positions 776 and 777 of SEQ ID NO:2; (ee) substitution of the amino acid sequence VAAGV with GV between positions 776 and 777 of SEQ ID NO:2; (ff) substitution of the amino acid sequence VAGV with GV between positions 776 and 777 of SEQ ID NO:2; (gg) substitution of the amino acid sequence VVV with GV between positions 776 and 777 of SEQ ID NO:2; (hh) insertion of the amino acid sequence FPG between positions G778 and S779 of SEQ ID NO:2; (ii) insertion of the amino acid sequence FPG between positions S779 and P780 of SEQ ID NO:2; (jj) substitution of the amino acid sequence VPS with VLRE between positions 754 and 757 of SEQ ID NO:2; (kk) insertion of the amino acid E between positions V777 and G778 of SEQ ID NO:2; (ll) insertion of the amino acid sequence MAGV between positions V777 and G778 of SEQ ID NO:2; (mm) insertion of the amino acid S between positions V777 and G778 of SEQ ID NO:2; (nn) insertion of the amino acid sequence SCV between positions V777 and G778 of SEQ ID NO:2; and (oo) insertion of the amino acid sequence LMAY between positions Y772 and V773 of SEQ ID NO:2.

[0330] In some embodiments, the cancer or tumor, or cells thereof, express an oncogenic variant of the HER-2 receptor, where the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor comprises HER2-16, HER2-C311R, HER2-S310F, p95-HER2-M611, or any combination thereof.

[0331] In some embodiments, the cancer or tumor, or cells thereof, express an oncogenic variant of the HER-4 receptor. In some embodiments, the oncogenic variant of the HER-4 receptor is an allosteric variant of the HER4 receptor. In some embodiments, the oncogenic variant of the HER4 receptor comprises a deletion of exon 16 (HER4-Δ16).

[0332] In some embodiments, the cancer, tumor, or cells thereof express an oncogenic variant of EGFR, where the sequence encoding the oncogenic variant of EGFR comprises a deletion of exon 20 or a portion thereof, and where the cancer, tumor, or cells thereof does not comprise a second oncogenic variation in a sequence of EGFR outside of exon 20. In some embodiments, the second oncogenic variation comprises a sequence encoding one or more of the EGFR kinase domain (KD), BRAF, NTRK, and KRAS.

[0333] In some embodiments, the cancer or tumor, or cells thereof, expresses an oncogenic variant of EGFR, where the sequence encoding the oncogenic variant of EGFR comprises a deletion of exon 20 or a portion thereof, and where the cancer, tumor, or cells thereof does not comprise a marker indicative of responsiveness to immunotherapy.

[0334] In some embodiments, the oncogenic variant (eg, allosteric variant) or oncogenic mutation (eg, allosteric mutation) is detected by a Food and Drug Administration (FDA) approved diagnostic method.

[0335] In some embodiments, prior to treatment with a compound of the present disclosure, the subject is treated with a therapeutic agent that is different from the compound of the present disclosure.

[0336] In some embodiments, the cancer or tumor, or cells thereof, is insensitive or resistant to treatment with a therapeutic agent other than the compound of the present disclosure. In some embodiments, the cancer or tumor, or cells thereof, is insensitive or resistant to treatment with a type I inhibitor. In some embodiments, the cancer or tumor, or cells thereof, is insensitive or resistant to treatment with one or more of gefitinib, erlotinib, afatinib, osimertinib, necitunumab, crizotinib, alectinib, ceritinib, dabrafenib, trametinib, afatinib, sapitinib, dacomitinib, canertinib, pelitinib, WZ4002, WZ8040, WZ3146, CO-1686, and AZD9291.

[0337] In some embodiments, the subject has an adverse reaction to treatment with a therapeutic agent other than the compound of the present disclosure. In some embodiments, the subject has an adverse reaction to treatment with a type I inhibitor. In some embodiments, the subject has an adverse reaction to treatment with one or more of gefitinib, erlotinib, afatinib, osimertinib, necitunumab, crizotinib, alectinib, ceritinib, dabrafenib, trametinib, afatinib, sapitinib, dacomitinib, canertinib, pelitinib, WZ4002, WZ8040, WZ3146, CO-1686, and AZD9291. In some embodiments, the adverse reaction is activation of an oncogenic variant of EGFR, the oncogenic variant comprising a mutation in the extracellular domain of the receptor. In some embodiments, the adverse reaction is activation of an oncogenic variant of the HER-2 receptor, where the oncogenic variant comprises a mutation in the extracellular domain of the receptor.

[0338] In some embodiments, the method further comprises administering to a subject in need of such inhibition a therapeutically effective amount of a non-type I inhibitor, hi some embodiments, the non-type I inhibitor comprises a small molecule type II inhibitor.

[0339] In some embodiments, the method further comprises administering to a subject in need of such inhibition a therapeutically effective amount of a non-type I inhibitor, hi some embodiments, the non-type I inhibitor comprises a small molecule type II inhibitor.

[0340] In some embodiments, the compound is used in combination with a therapeutically effective amount of a non-type I inhibitor. In some embodiments, the non-type I inhibitor comprises a small molecule type II inhibitor.

[0341] In some embodiments, the composition further comprises a non-type I inhibitor. In some embodiments, the non-type I inhibitor comprises a small molecule type II inhibitor.

[0342] In some embodiments, the therapeutically effective amount reduces the severity of a sign or symptom of the cancer.

[0343] In some embodiments, the symptom of cancer comprises tumor grade, and reducing the severity of the symptom comprises a decrease in tumor grade.

[0344] In some embodiments, the symptom of cancer comprises tumor metastasis, and reducing the severity of the symptom comprises elimination of metastasis or reducing the rate or extent of metastasis.

[0345] In some embodiments, the symptom of cancer comprises tumor volume, and reducing the severity of the symptom comprises elimination or reduction in volume of the tumor.

[0346] In some embodiments, the symptom of cancer comprises pain, and reducing the severity of the symptoms comprises elimination or reduction of pain.

[0347] In some embodiments, the therapeutically effective amount induces a period of remission.

[0348] In some embodiments, the therapeutically effective amount improves the prognosis of the subject.

[0349] Such subject uses (or methods of treatment or prevention) include administering to a subject in need of such prevention or treatment a therapeutically effective amount of a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, by targeting allosteric and / or oncogenic variants of the EGFR and HER-2 receptors.

[0350] definition It is understood that the compounds described herein include the compounds themselves, as well as their salts and their solvates, if applicable.Salts can be formed, for example, between an anion and a positively charged group (e.g., amino) on a substituted benzene compound.Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronic acid, glutaric acid, malate, maleate, succinate, fumarate, tartaric acid, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).

[0351] Unless expressly indicated otherwise, the terms "approximately" and "about" are synonymous. In some embodiments, "approximately" and "about" refer to ±20%, ±15%, ±10%, ±8%, ±6%, ±5%, ±4%, ±2%, ±1%, or ±0.5% of the recited amount, value, dose, or duration. In some embodiments, "approximately" and "about" refer to ±10%, ±8%, ±6%, ±5%, ±4%, or ±2% of the recited amount or duration. In some embodiments, "approximately" and "about" refer to ±5% of the recited amount, value, dose, or duration. In some embodiments, "approximately" and "about" refer to ±2% of the recited amount, value, dose, or duration. In some embodiments, "approximately" and "about" refer to ±1% of the recited amount, value, dose, or duration.

[0352] As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Similarly, salts may also be formed between a cation and a negatively charged group (e.g., carboxylic acid) on a substituted benzene compound. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and ammonium cation, such as tetramethylammonium ion. The substituted benzene compound also includes salts containing a quaternary nitrogen atom.

[0353] It is understood that the compounds of the present disclosure, for example, the salts of the compounds, can exist in either hydrated or non-hydrated (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.

[0354] As used herein, unless otherwise indicated, 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, or C," and the like are used interchangeably and all refer to a selection from the group consisting of A, B, and / or C, i.e., one or more A, one or more B, one or more C, or combinations thereof.

[0355] It should be understood that throughout the description, compositions are described as having, including, or comprising certain components, and it is contemplated that the compositions also consist essentially of or consist of the recited components. Similarly, when a method or process is described as having, including, or comprising certain process steps, the process also consists essentially of or consists of the recited process steps. It should further be understood that the order of steps, or order for performing certain actions, is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be performed simultaneously.

[0356] It is understood that the compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or easily prepared intermediates by employing standard synthetic methods and procedures that are known to those of skill in the art or that will be apparent to those of skill in the art in light of the teachings herein. Standard synthetic methods and procedures for the creation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or standard textbooks in the field. For example, but not limited to, any one or more sources, see Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 th edition, John Wiley & Sons: New York, 2001, Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3 rdedition, 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, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), are useful and widely recognized references on organic synthesis known to those of skill in the art and are incorporated herein by reference.

[0357] Unless otherwise stated, any description of a method of treatment or prevention should be understood to include the use of a crystalline form of Compound No. 1 or a pharma- ceutically acceptable salt thereof to provide treatment or prevention as described herein. Unless otherwise stated, any description of a method of treatment or prevention should be further understood to include the use of a crystalline form of Compound No. 1 or a pharma- ceutically acceptable salt thereof to prepare a medicament for treating or preventing such a condition. Treatment or prevention includes treatment or prevention of humans or non-human animals, including rodents and other disease models.

[0358] Unless otherwise stated, any description of a method of treatment should be understood to include the use of a crystalline form of Compound No. 1 or a pharma- ceutically acceptable salt thereof to provide treatment as described herein. Unless otherwise stated, any description of a method of treatment should be further understood to include the use of a crystalline form of Compound No. 1 or a pharma- ceutically acceptable salt thereof to prepare a medicament for treating such a condition. Treatment includes treatment of humans or non-human animals, including rodents and other disease models.

[0359] As used herein, the term "subject" refers to a subject having a disease or at increased risk of developing a disease. "Subject" includes mammals. The mammal may be, for example, a human or a suitable non-human mammal, such as a primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep, or pig. The subject may also be a bird or poultry. In some embodiments, the mammal is a human.

[0360] The term "subject in need thereof" may be a subject previously diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof may also be a subject suffering from a disease or disorder disclosed herein. Alternatively, a subject in need thereof may be a subject at high risk of developing such a disease or disorder compared to the population as a whole (i.e., a subject who is more prone to developing such a disorder compared to the population as a whole). A subject in need thereof may be refractory or resistant to a disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment). A subject in need thereof may be resistant at the start of treatment or may become resistant during treatment. In some embodiments, a subject in need thereof has undergone all known effective therapies for a disease or disorder disclosed herein to no avail. In some embodiments, a subject in need thereof has undergone at least one previous therapy.

[0361] As used herein, the term "treating" or "treat" refers to the management and care of a patient to combat a disease, condition, or disorder, and includes the administration of a compound of the present disclosure, or a pharma- ceutically acceptable salt, polymorph, or solvate thereof, to alleviate the symptoms or complications of the disease, condition, or disorder, or to eliminate the disease, condition, or disorder. The term "treat" can also include the treatment of a cell in vitro or in an animal model.

[0362] It is understood that compound No. 1 or a pharma- ceutically acceptable salt thereof can or may be used to prevent the associated disease, condition, or disorder, or to identify suitable candidates for such purposes.

[0363] As used herein, the terms "preventing," "prevent" or "protecting from" refer to reducing or eliminating the onset of symptoms or complications of such a disease, condition or disorder.

[0364] It should be understood that "solubility" or "solubility rating" refers to the property of a polymorph disclosed herein (e.g., Forms A, B, C, D, E, F, G, H, I, J, K, or L) to dissolve in a liquid solvent to form a homogenous solution. In some embodiments, solubility is expressed as a concentration by mass of solute per unit volume of solvent (e.g., g of solute per kg of solvent, g per dL (100 mL), mg / ml, etc.), molality, molality, mole fraction, or other similar description of concentration. One of ordinary skill in the art can understand that the maximum equilibrium amount of solute that can be dissolved per amount of solvent is the solubility of the solute in that solvent under specific conditions including temperature, pressure, pH, and the nature of the solvent.

[0365] As used herein, "stable" refers to a polymorph that maintains purity, appearance, and / or analytical parameters over a specified time and temperature compared to the isolated polymorph. In some embodiments, a "stable" polymorph exhibits less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, or less than about 0.1% impurities over a period of time (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).

[0366] As used herein, the term "pharmaceutical composition" refers to a formulation containing the disclosed compound in a form suitable for administration to a subject. In one embodiment, the composition is in bulk or unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump of an aerosol inhaler, or a vial. The amount of active ingredient (e.g., a formulation of the disclosed compound or its salt, its hydrate, its solvate, or its isomer) in a unit dose of the composition is an effective amount and varies according to the specific treatment involved. Those skilled in the art will recognize that it may be necessary to routinely vary the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. Various routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, etc. Dosage forms for topical or transdermal administration of a compound of the present disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharma- ceutically acceptable carrier, and with any required preservatives, buffers, or propellants.

[0367] As used herein, the term "pharmacologically acceptable" refers to compounds, anions, cations, substances, compositions, carriers, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0368] "Pharmaceutically acceptable excipient" means an excipient that is generally safe, non-toxic, and not biologically or otherwise harmful, useful in the preparation of a pharmaceutical composition, and includes excipients that are applicable for veterinary use as well as human pharmaceutical use. "Pharmaceutically acceptable excipient," as used in the specification and claims, includes both one and more excipients.

[0369] As used herein, the term "therapeutically effective amount" refers to an amount of a pharmaceutical agent that treats, ameliorates, or prevents a specified disease or condition, or that exhibits a detectable therapeutic or suppressive effect. The effect can be detected by any assay method known in the art. The exact effective amount for a subject will depend on the subject's weight, size, and health; the nature and extent of the condition; and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

[0370] For compounds of the present disclosure that are capable of further forming salts, it is understood that all of these forms are also contemplated within the scope of the claimed disclosure.

[0371] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of a compound of the present disclosure, in which the parent compound is modified by making its acid salt or base salt. In some embodiments, the pharmaceutically acceptable salt of a 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, alkali or organic salts of acidic residues such as carboxylic acids, and the like. Pharmaceutically acceptable salts include, for example, the common non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such common non-toxic salts include, but are not limited to, 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycolylarsanilic acid, hexylresorcylic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobi acid, and the like. and the like. Examples of suitable salts include salts obtained from inorganic and organic acids selected from carboxylic acid, laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, naphsylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, subacetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid, and commonly occurring amino acids such as glycine, alanine, phenylalanine, arginine, etc.

[0372] Other examples of pharma- ceutically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvic acid, 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-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, and muconic acid, etc. The present disclosure also encompasses salts formed when an acidic proton in the parent compound is replaced with a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion, or coordinated with an organic base, e.g., ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc. It is understood that in the salt form, the ratio of the compound to the cation or anion of the salt can be 1:1, or any ratio other than 1:1, for example, 3:1, 2:1, 1:2, or 1:3.

[0373] It is understood that all references to pharma- ceutically acceptable salts include the solvent addition forms (solvates) or crystal forms (polymorphs), as defined herein, of the same salt.

[0374] The compound, or a pharma- ceutically acceptable salt thereof, is administered orally, nasally, transdermally, pulmonary, inhalationally, bucally, 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 administration routes.

[0375] Dosage regimens using the present compounds are selected according to a variety of factors, including the type, species, age, weight, sex, and medical condition of the patient, the severity of the condition being treated, the route of administration, the renal and hepatic function of the patient, the particular compound or salt thereof being used, etc. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

[0376] Techniques for formulation and administration of the disclosed compounds of this disclosure are described in Remington: The Science and Practice of Pharmacy, 1999. th edition, Mack Publishing Co., Easton, PA (1995). In some embodiments, the compounds described herein and their pharma- ceutically acceptable salts are used in pharmaceutical preparations in combination with a pharma- ceutically acceptable carrier or diluent. Suitable pharma- ceutically acceptable carriers include inert solid fillers or diluents, and sterile aqueous or organic solutions. The compounds will be included in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the range described herein.

[0377] All percentages and ratios used herein are by weight unless otherwise specified. Other features and advantages of the present disclosure will become apparent from the various examples. The examples provided illustrate various components and methods useful in implementing the present disclosure. The examples do not limit the disclosure as claimed. Based on the present disclosure, one skilled in the art will be able to identify and use other components and methods useful in implementing the present disclosure.

[0378] All publications and patent documents cited in this specification are incorporated by reference herein as if such publications or documents were specifically and individually indicated to be incorporated by reference herein. Citation of publications and patent documents does not imply an admission that any is pertinent prior art, nor does it constitute any admission as to the contents or date. Although the invention has been described by way of description, those skilled in the art will recognize that the invention can be practiced in various embodiments, and that the above description and the examples set forth below are intended to be illustrative and not limiting of the scope of the claims which follow.

[0379] Exemplary embodiments Embodiment 1. A form of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof. Embodiment 2. The shape form of embodiment 1, wherein the shape form is a crystalline form. Embodiment 3. The form according to embodiment 1 or 2, wherein the form is Form A, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof. Embodiment 4. The shape form of embodiment 3, wherein Form A is characterized by an X-ray diffraction ("XRPD") pattern comprising peaks at 4.8±0.2, 5.6±0.2, and 17.6±0.2 degrees 2θ (e.g., 4.8±0.1, 5.6±0.1, and 17.6±0.1 degrees 2θ (e.g., 4.8, 5.6, and 17.6 degrees 2θ) using Cu Kα radiation. Embodiment 5. The shape form of embodiment 4, wherein Form A further comprises at least one peak selected from 9.6±0.2, 20.0±0.2, and 24.6±0.2 degrees 2θ (e.g., 9.6±0.1, 20.0±0.1, and 24.6±0.1 degrees 2θ (e.g., 9.6, 20.0, and 24.6 degrees 2θ) using Cu Kα radiation. Embodiment 6. The shape form of embodiment 3, wherein Form A is characterized by an X-ray diffraction ("XRPD") pattern comprising at least three peaks selected from 4.8±0.2, 5.6±0.2, 9.6±0.2, 17.6±0.2, 20.0±0.2, and 24.6±0.2 degrees 2θ (e.g., 4.8±0.1, 5.6±0.1, 9.6±0.1, 17.6±0.1, 20.0±0.1, and 24.6±0.1 degrees 2θ (e.g., 4.8, 5.6, 9.6, 17.6, 20.0, and 24.6 degrees 2θ) using Cu Kα radiation. Embodiment 7. The geometric form of embodiment 3, wherein Form A is characterized by an XRPD pattern substantially similar to that shown in FIG. Embodiment 8. Form A is in a range of 76±20, 141±20, 156±20, and 170±20° C. (e.g., 76±10, 141±10, 156±10, and 170±10° C. (e.g., 76±5, 141±5, 156±5, and 170±5° C. (e.g., 76±4, 141±4, 156±4, and 170±4° C. (e.g., 76±3, 141±3, 156±3, and 170± 3° C. (e.g., 76±2, 141±2, 156±2, and 170±2° C. (e.g., 76±1, 141±1, 156±1, and 170±1° C. (e.g., 76±0.5, 141±0.5, 156±0.5, and 170±0.5° C.))))). Embodiment 9. The form according to embodiment 1 or 2, wherein the form is Form B, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof. Embodiment 10. The shape form of embodiment 9, wherein Form B is characterized by an X-ray diffraction ("XRPD") pattern comprising peaks at 6.5±0.2, 16.7±0.2, and 18.6±0.2 degrees 2θ (e.g., 6.5±0.1, 16.7±0.1, and 18.6±0.1 degrees 2θ (e.g., 6.5, 16.7, and 18.6 degrees 2θ) using Cu Kα radiation. Embodiment 11. The shape form of embodiment 10, wherein Form B further comprises at least one peak selected from 3.2±0.2, 13.4±0.2, and 17.7±0.2 degrees 2θ (e.g., 3.2±0.1, 13.4±0.1, and 17.7±0.1 degrees 2θ (e.g., 3.2, 13.4, and 17.7 degrees 2θ) using Cu Kα radiation. Embodiment 12. The shape form of embodiment 9, wherein Form B is characterized by an X-ray diffraction ("XRPD") pattern comprising at least three peaks selected from 3.2±0.2, 6.5±0.2, 13.4±0.2, 16.7±0.2, 17.7±0.2, and 18.6±0.2 degrees 2θ (e.g., 3.2±0.1, 6.5±0.1, 13.4±0.1, 16.7±0.1, 17.7±0.1, and 18.6±0.1 degrees 2θ (e.g., 3.2, 6.5, 13.4, 16.7, 17.7, and 18.6 degrees 2θ) using Cu Kα radiation. Embodiment 13. The shape form of embodiment 9, wherein Form B is characterized by an XRPD pattern substantially similar to that shown in FIG. Embodiment 14. The shape form of embodiment 9, wherein form B is characterized by a DSC curve having at least one endothermic peak selected from 155±20°C and 176±20°C (e.g., 155±10°C and 176±10°C (e.g., 155±5°C and 176±5°C (e.g., 155±4°C and 176±4°C (e.g., 155±3°C and 176±3°C (e.g., 155±2 and 176±2°C (e.g., 155±1 and 176±1°C (e.g., 155±0.5 and 176±0.5°C))))). Embodiment 15. The form according to embodiment 1 or 2, wherein the form is Form C, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof. Embodiment 16. The shape form of embodiment 15, wherein Form C is characterized by an X-ray diffraction ("XRPD") pattern comprising peaks at 16.1±0.2, 16.7±0.2, and 19.1±0.2 degrees 2θ (e.g., 16.1±0.1, 16.7±0.1, and 19.1±0.1 degrees 2θ (e.g., 16.1, 16.7, and 19.1 degrees 2θ) using Cu Kα radiation. Embodiment 17. The shape form of embodiment 16, wherein Form C further comprises at least one peak selected from 4.0±0.2, 12.6±0.2, and 14.1±0.2 degrees 2θ (e.g., 4.0±0.1, 12.6±0.1, and 14.1±0.1 degrees 2θ (e.g., 4.0, 12.6, and 14.1 degrees 2θ) using Cu Kα radiation. Embodiment 18. The shape form of embodiment 15, wherein Form C is characterized by an X-ray diffraction ("XRPD") pattern comprising at least three peaks selected from 4.0±0.2, 12.6±0.2, 14.1±0.2, 16.1±0.2, 16.7±0.2, and 19.1±0.2 degrees 2θ (e.g., 4.0±0.1, 12.6±0.1, 14.1±0.1, 16.1±0.1, 16.7±0.1, and 19.1±0.1 degrees 2θ (e.g., 4.0, 12.6, 14.1, 16.1, 16.7, and 19.1 degrees 2θ) using Cu Kα radiation. Embodiment 19. The geometric form of embodiment 15, wherein Form C is characterized by an XRPD pattern substantially similar to that shown in FIG. Embodiment 20. The shape form of embodiment 15, wherein Form C is characterized by a DSC curve having an endothermic peak at 181±20°C (e.g., 181±10°C (e.g., 181±5°C (e.g., 181±4°C (e.g., 181±3°C (e.g., 181±2°C (e.g., 181±1°C (e.g., 181±0.5°C)))))). Embodiment 21. The form according to embodiment 1 or 2, wherein the form is form D, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof. Embodiment 22. The shape form of embodiment 21, wherein Form D is characterized by an X-ray diffraction ("XRPD") pattern comprising peaks at 15.3±0.2, 19.3±0.2, and 23.5±0.2 degrees 2θ (e.g., 5.3±0.1, 19.3±0.1, and 23.5±0.1 degrees 2θ (e.g., 5.3, 19.3, and 23.5 degrees 2θ) using Cu Kα radiation. Embodiment 23. The shape form of embodiment 22, wherein Form D further comprises at least one peak selected from 5.4±0.2, 9.7±0.2, and 18.8±0.2 degrees 2θ (e.g., 5.4±0.1, 9.7±0.1, and 18.8±0.1 degrees 2θ (e.g., 5.4, 9.7, and 18.8 degrees 2θ)) using Cu Kα radiation. Embodiment 24. The shape form of embodiment 21, wherein Form D is characterized by an X-ray diffraction ("XRPD") pattern comprising at least three peaks selected from 5.4±0.2, 9.7±0.2, 15.3±0.2, 18.8±0.2, 19.3±0.2, and 23.5±0.2 degrees 2θ (e.g., 5.4±0.1, 9.7±0.1, 15.3±0.1, 18.8±0.1, 19.3±0.1, and 23.5±0.1 degrees 2θ (e.g., 5.4, 9.7, 15.3, 18.8, 19.3, and 23.5 degrees 2θ) using Cu Kα radiation. Embodiment 25. The shape form of embodiment 21, wherein Form D is characterized by an XRPD pattern substantially similar to that shown in FIG. Embodiment 26. The shape form of embodiment 21, wherein form D is characterized by a DSC curve having at least one endothermic peak selected from 128±20, 149±20, and 175±20°C (e.g., 128±10, 149±10, and 175±10°C (e.g., 128±5, 149±5, and 175±5°C (e.g., 128±4, 149±4, and 175±4°C (e.g., 128±3, 149±3, and 175±3°C (e.g., 128±2, 149±2, and 175±2°C (e.g., 128±1, 149±1, and 175±1°C (e.g., 128±0.5, 149±0.5, and 175±0.5°C)))). Embodiment 27. The form according to embodiment 1 or 2, wherein the form is form E, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof. Embodiment 28. The shape form of embodiment 27, wherein Form E is characterized by an X-ray diffraction ("XRPD") pattern comprising peaks at 7.4±0.2, 15.8±0.2, and 16.3±0.2 degrees 2θ (e.g., 7.4±0.1, 15.8±0.1, and 16.3±0.1 degrees 2θ (e.g., 7.4, 15.8, and 16.3 degrees 2θ) using Cu Kα radiation. Embodiment 29. The shape form of embodiment 28, wherein Form E further comprises at least one peak selected from 13.3±0.2, 19.2±0.2, and 22.4±0.2 degrees 2θ (e.g., 13.3±0.1, 19.2±0.1, and 22.4±0.1 degrees 2θ (e.g., 13.3, 19.2, and 22.4 degrees 2θ) using Cu Kα radiation. Embodiment 30. The shape form of embodiment 27, wherein Form E is characterized by an X-ray diffraction ("XRPD") pattern comprising at least three peaks selected from 7.4±0.2, 13.3±0.2, 15.8±0.2, 16.3±0.2, 19.2±0.2, and 22.4±0.2 degrees 2θ (e.g., 7.4±0.1, 13.3±0.1, 15.8±0.1, 16.3±0.1, 19.2±0.1, and 22.4±0.1 degrees 2θ (e.g., 7.4, 13.3, 15.8, 16.3, 19.2, and 22.4 degrees 2θ) using Cu Kα radiation. Embodiment 31. The shape form of embodiment 27, wherein Form E is characterized by an XRPD pattern substantially similar to that shown in FIG. Embodiment 32. The shape form of embodiment 27, wherein form E is characterized by a DSC curve having an endothermic peak at 173±20°C (e.g., 173±10°C (e.g., 173±5°C (e.g., 173±4°C (e.g., 173±3°C (e.g., 173±2°C (e.g., 173±1°C (e.g., 173±0.5°C)))))). Embodiment 33. The form according to embodiment 1 or 2, wherein the form is form F, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof. Embodiment 34. The shape form of embodiment 33, wherein form F is characterized by an X-ray diffraction ("XRPD") pattern comprising peaks at 5.5±0.2, 16.4±0.2, and 21.9±0.2 degrees 2θ (e.g., 5.5±0.1, 16.4±0.1, and 21.9±0.1 degrees 2θ (e.g., 5.5, 16.4, and 21.9 degrees 2θ) using Cu Kα radiation. Embodiment 35. The shape form of embodiment 34, wherein Form F further comprises at least one peak selected from 7.2±0.2, 14.5±0.2, and 15.2±0.2 degrees 2θ (e.g., 7.2±0.1, 14.5±0.1, and 15.2±0.1 degrees 2θ (e.g., 7.2, 14.5, and 15.2 degrees 2θ) using Cu Kα radiation. Embodiment 36. The shape form of embodiment 33, wherein Form F is characterized by an X-ray diffraction ("XRPD") pattern comprising at least three peaks selected from 5.5±0.2, 7.2±0.2, 14.5±0.2, 15.2±0.2, 16.4±0.2, and 21.9±0.2 degrees 2θ (e.g., 5.5±0.1, 7.2±0.1, 14.5±0.1, 15.2±0.1, 16.4±0.1, and 21.9±0.1 degrees 2θ (e.g., 5.5, 7.2, 14.5, 15.2, 16.4, and 21.9 degrees 2θ) using Cu Kα radiation. Embodiment 37. The geometric form of embodiment 33, wherein Form F is characterized by an XRPD pattern substantially similar to that shown in FIG. Embodiment 38. Form F is in a range of 48±20, 80±20, 146±20, and 174±20°C (e.g., 48±10, 80±10, 146±10, and 174±10°C (e.g., 48±5, 80±5, 146±5, and 174±5°C (e.g., 48±4, 80±4, 146±4, and 174±4°C (e.g., 48±3, 80±3, 146±3, and 174±3 34. The shape form of embodiment 33, characterized by a DSC curve having at least one endothermic peak selected from among 48±2, 80±2, 146±2, and 174±2°C (e.g., 48±1, 80±1, 146±1, and 174±1°C (e.g., 48±0.5, 80±0.5, 146±0.5, and 174±0.5°C)). Embodiment 39. The form according to embodiment 1 or 2, wherein the form is form G, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof. Embodiment 40. The shape form of embodiment 39, wherein form G is characterized by an X-ray diffraction ("XRPD") pattern comprising peaks at 4.0±0.2, 5.3±0.2, and 16.0±0.2 degrees 2θ (e.g., 4.0±0.1, 5.3±0.1, and 16.0±0.1 degrees 2θ (e.g., 4.0, 5.3, and 16.0 degrees 2θ) using Cu Kα radiation. Embodiment 41. The shape form of embodiment 40, wherein form G further comprises at least one peak selected from 7.1±0.2, 16.7±0.2, and 19.2±0.2 degrees 2θ (e.g., 7.1±0.1, 16.7±0.1, and 19.2±0.1 degrees 2θ (e.g., 7.1, 16.7, and 19.2 degrees 2θ) using Cu Kα radiation. Embodiment 42. The shape form of embodiment 39, wherein Form G is characterized by an X-ray diffraction ("XRPD") pattern comprising at least three peaks selected from 4.0±0.2, 5.3±0.2, 7.1±0.2, 16.0±0.2, 16.7±0.2, and 19.2±0.2 degrees 2θ (e.g., 4.0±0.1, 5.3±0.1, 7.1±0.1, 16.0±0.1, 16.7±0.1, and 19.2±0.1 degrees 2θ (e.g., 4.0, 5.3, 7.1, 16.0, 16.7, and 19.2 degrees 2θ) using Cu Kα radiation. Embodiment 43. The shape form of embodiment 39, wherein Form G is characterized by an XRPD pattern substantially similar to that shown in FIG. Embodiment 44. The shape form of embodiment 39, wherein form G is characterized by a DSC curve having at least one endothermic peak selected from 34±20, 175±20, and 182±20°C (e.g., 34±10, 175±10, and 182±10°C (e.g., 34±5, 175±5, and 182±5°C (e.g., 34±4, 175±4, and 182±4°C (e.g., 34±3, 175±3, and 182±3°C (e.g., 34±2, 175±2, and 182±2°C (e.g., 34±1, 175±1, and 182±1°C (e.g., 34±0.5, 175±0.5, and 182±0.5°C))))). Embodiment 45. The form according to embodiment 1 or 2, wherein the form is form H, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof. Embodiment 46. The shape form of embodiment 45, wherein form H is characterized by an X-ray diffraction ("XRPD") pattern comprising peaks at 4.6±0.2, 13.8±0.2, and 17.0±0.2 degrees 2θ (e.g., 4.6±0.1, 13.8±0.1, and 17.0±0.1 degrees 2θ (e.g., 4.6, 13.8, and 17.0 degrees 2θ) using Cu Kα radiation. Embodiment 47. The shape form of embodiment 46, wherein Form H further comprises at least one peak selected from 5.6±0.2, 8.6±0.2, and 17.8±0.2 degrees 2θ (e.g., 5.6±0.1, 8.6±0.1, and 17.8±0.1 degrees 2θ (e.g., 5.6, 8.6, and 17.8 degrees 2θ)) using Cu Kα radiation. Embodiment 48. The shape form of embodiment 45, wherein Form H is characterized by an X-ray diffraction ("XRPD") pattern comprising at least three peaks selected from 4.6±0.2, 5.6±0.2, 8.6±0.2, 13.8±0.2, 17.0±0.2, and 17.8±0.2 degrees 2θ (e.g., 4.6±0.1, 5.6±0.1, 8.6±0.1, 13.8±0.1, 17.0±0.1, and 17.8±0.1 degrees 2θ (e.g., 4.6, 5.6, 8.6, 13.8, 17.0, and 17.8 degrees 2θ) using Cu Kα radiation. Embodiment 49. The geometric form of embodiment 45, wherein form H is characterized by an XRPD pattern substantially similar to that shown in FIG. Embodiment 50. The shape form of embodiment 45, wherein Form H is characterized by a DSC curve having at least one endothermic peak selected from 62±20 and 153±20°C (e.g., 62±10 and 153±10°C (e.g., 62±5 and 153±5°C (e.g., 62±4 and 153±4°C (e.g., 62±3 and 153±3°C (e.g., 62±2 and 153±2°C (e.g., 62±1 and 153±1°C (e.g., 62±0.5 and 153±0.5°C))))). Embodiment 51. The form according to embodiment 1 or 2, wherein the form is Form I, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof. Embodiment 52. The shape form of embodiment 51, wherein Form I is characterized by an X-ray diffraction ("XRPD") pattern comprising peaks at 5.1±0.2, 20.4±0.2, and 21.5±0.2 degrees 2θ (e.g., 5.1±0.1, 20.4±0.1, and 21.5±0.1 degrees 2θ (e.g., 5.1, 20.4, and 21.5 degrees 2θ) using Cu Kα radiation. Embodiment 53. The shape form of embodiment 52, wherein Form I further comprises at least one peak selected from 17.0±0.2, 22.3±0.2, and 25.5±0.2 degrees 2θ (e.g., 17.0±0.1, 22.3±0.1, and 25.5±0.1 degrees 2θ (e.g., 17.0, 22.3, and 25.5 degrees 2θ) using Cu Kα radiation. Embodiment 54. The shape form of embodiment 51, wherein Form I is characterized by an X-ray diffraction ("XRPD") pattern comprising at least three peaks selected from 5.1±0.2, 17.0±0.2, 20.4±0.2, 21.5±0.2, 22.3±0.2, and 25.5±0.2 degrees 2θ (e.g., 5.1±0.1, 17.0±0.1, 20.4±0.1, 21.5±0.1, 22.3±0.1, and 25.5±0.1 degrees 2θ (e.g., 5.1, 17.0, 20.4, 21.5, 22.3, and 25.5 degrees 2θ) using Cu Kα radiation. Embodiment 55. The shape form of embodiment 51, wherein Form I is characterized by an XRPD pattern substantially similar to that shown in FIG. Embodiment 56. The form according to embodiment 1 or 2, wherein the form is form J, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof. Embodiment 57. The shape form of embodiment 56, wherein Form J is characterized by an X-ray diffraction ("XRPD") pattern comprising peaks at 4.5±0.2, 17.9±0.2, and 22.5±0.2 degrees 2θ (e.g., 4.5±0.1, 17.9±0.1, and 22.5±0.1 degrees 2θ (e.g., 4.5, 17.9, and 22.5 degrees 2θ) using Cu Kα radiation. Embodiment 58. The shape form of embodiment 57, wherein Form J further comprises at least one peak selected from 5.1±0.2, 10.4±0.2, and 16.0±0.2 degrees 2θ (e.g., 5.1±0.1, 10.4±0.1, and 16.0±0.1 degrees 2θ (e.g., 5.1, 10.4, and 16.0 degrees 2θ)) using Cu Kα radiation. Embodiment 59. The shape form of embodiment 56, wherein Form J is characterized by an X-ray diffraction ("XRPD") pattern comprising at least three peaks selected from 4.5±0.2, 5.1±0.2, 10.4±0.2, 16.0±0.2, 17.9±0.2, and 22.5±0.2 degrees 2θ (e.g., 4.5±0.1, 5.1±0.1, 10.4±0.1, 16.0±0.1, 17.9±0.1, and 22.5±0.1 degrees 2θ (e.g., 4.5, 5.1, 10.4, 16.0, 17.9, and 22.5 degrees 2θ) using Cu Kα radiation. Embodiment 60. The shape form of embodiment 59, wherein Form J is characterized by an XRPD pattern substantially similar to that shown in FIG. Embodiment 61. The shape form of embodiment 56, wherein form J is characterized by a DSC curve having at least one endothermic peak selected from 137±20 and 166±20°C (e.g., 137±10 and 166±10°C (e.g., 137±5 and 166±5°C (e.g., 137±4 and 166±4°C (e.g., 137±3 and 166±3°C (e.g., 137±2 and 166±2°C (e.g., 137±1 and 166±1°C (e.g., 137±0.5 and 166±0.5°C))))). Embodiment 62. The form according to embodiment 1 or 2, wherein the form is form K, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof. Embodiment 63. The shape form of embodiment 62, wherein form K is characterized by an X-ray diffraction ("XRPD") pattern comprising peaks at 5.2±0.2, 17.0±0.2, and 20.5±0.2 degrees 2θ (e.g., 5.2±0.1, 17.0±0.1, and 20.5±0.1 degrees 2θ (e.g., 5.2, 17.0, and 20.5 degrees 2θ) using Cu Kα radiation. Embodiment 64. The shape form of embodiment 63, wherein form K further comprises at least one peak selected from 6.8±0.2, 21.6±0.2, and 22.4±0.2 degrees 2θ (e.g., 6.8±0.1, 21.6±0.1, and 22.4±0.1 degrees 2θ (e.g., 6.8, 21.6, and 22.4 degrees 2θ) using Cu Kα radiation. Embodiment 65. The shape form of embodiment 62, wherein form K is characterized by an X-ray diffraction ("XRPD") pattern comprising at least three peaks selected from 5.2±0.2, 6.8±0.2, 17.0±0.2, 20.5±0.2, 21.6±0.2, and 22.4±0.2 degrees 2θ (e.g., 5.2±0.1, 6.8±0.1, 17.0±0.1, 20.5±0.1, 21.6±0.1, and 22.4±0.1 degrees 2θ (e.g., 5.2, 6.8, 17.0, 20.5, 21.6, and 22.4 degrees 2θ) using Cu Kα radiation. Embodiment 66 The shape form of embodiment 62, wherein form K is characterized by an XRPD pattern substantially similar to that shown in FIG. Embodiment 67. The form according to embodiment 1 or 2, wherein the form is form L, a solvate thereof, a hydrate thereof, or a pharma- ceutically acceptable salt thereof. Embodiment 68. The shape form of embodiment 67, wherein form L is characterized by an X-ray diffraction ("XRPD") pattern comprising peaks at 5.4±0.2, 7.8±0.2, and 19.3±0.2 degrees 2θ (e.g., 5.4±0.1, 7.8±0.1, and 19.3±0.1 degrees 2θ (e.g., 5.4, 7.8, and 19.3 degrees 2θ) using Cu Kα radiation. Embodiment 69. The shape form of embodiment 68, wherein form L further comprises at least one peak selected from 14.8±0.2, 15.3±0.2, and 16.6±0.2 degrees 2θ (e.g., 14.8±0.1, 15.3±0.1, and 16.6±0.1 degrees 2θ (e.g., 14.8, 15.3, and 16.6 degrees 2θ) using Cu Kα radiation. Embodiment 70. The shape form of embodiment 67, wherein Form L is characterized by an X-ray diffraction ("XRPD") pattern comprising at least three peaks selected from 5.4±0.2, 7.8±0.2, 14.8±0.2, 15.3±0.2, 16.6±0.2, and 19.3±0.2 degrees 2θ (e.g., 5.4±0.1, 7.8±0.1, 14.8±0.1, 15.3±0.1, 16.6±0.1, and 19.3±0.1 degrees 2θ (e.g., 5.4, 7.8, 14.8, 15.3, 16.6, and 19.3 degrees 2θ)) using Cu Kα radiation. Embodiment 71. The shape form of embodiment 67, wherein form L is characterized by an XRPD pattern substantially similar to that shown in FIG. Embodiment 72. The shape form of any of the preceding embodiments, which is at least 90, 95, 96, 97, 98, or 99% pure. Embodiment 73. A pharmaceutical composition comprising a therapeutically effective amount of any one or combination of the form forms described in any one of the preceding embodiments and a pharma- ceutically acceptable excipient. Embodiment 74. A method of inhibiting an oncogenic variant of an ErbB receptor, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical formulation according to any one of the preceding embodiments. Embodiment 75. A method for inhibiting an oncogenic variant of an ErbB receptor, comprising administering to a subject in need thereof a pharmaceutical composition according to any one of the preceding embodiments. Embodiment 76. A method for preventing or treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a form of any one of the preceding embodiments. Embodiment 77. A method for preventing or treating cancer, comprising administering to a subject in need thereof a pharmaceutical composition described in any one of the preceding embodiments. Embodiment 78. A method for preventing or treating cancer, comprising: i) identifying a potential subject as one in need of treatment if at least one oncogenic variant of an ErbB receptor is present in the subject; and ii) administering to the subject in need of treatment a therapeutically effective amount of a form of any one of the preceding embodiments. Embodiment 79. A method for preventing or treating cancer, comprising: i) identifying a potential subject as a subject in need of treatment if at least one oncogenic variant of an ErbB receptor is present in the subject; and ii) administering to the subject in need of treatment a pharmaceutical composition described in any one of the preceding embodiments. Embodiment 80. A method for preventing or treating cancer, comprising: i) identifying a potential subject as being in need of treatment if at least one oncogenic variant of an ErbB receptor is present in a biological sample from the subject; and ii) administering to the subject in need of treatment a therapeutically effective amount of a form of any one of the preceding embodiments. Embodiment 81. A method for preventing or treating cancer, comprising: i) identifying a potential subject as a subject in need of treatment if at least one oncogenic variant of an ErbB receptor is present in a biological sample from the subject; and ii) administering to the subject in need of treatment a pharmaceutical composition described in any one of the preceding embodiments. Embodiment 82. A method for preventing or treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a form of any one of the preceding embodiments when at least one oncogenic variant of an ErbB receptor is identified as being present in the subject. Embodiment 83. A method of preventing or treating cancer, comprising administering to a subject in need thereof a form of any one of the preceding embodiments when at least one oncogenic variant of an ErbB receptor is identified as being present in the subject. Embodiment 84. A method for preventing or treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a form of any one of the preceding embodiments when at least one oncogenic variant of an ErbB receptor is identified as being present in a biological sample from the subject. Embodiment 85. A method for preventing or treating cancer, comprising administering to a subject in need thereof a pharmaceutical composition according to any one of the preceding embodiments, when said at least one oncogenic variant of an ErbB receptor is identified as being present in a biological sample from said subject. Embodiment 86 A form according to any one of the preceding embodiments for use in inhibiting an oncogenic variant of an ErbB receptor. Embodiment 87. A pharmaceutical composition according to any one of the preceding embodiments for use in inhibiting an oncogenic variant of an ErbB receptor. Embodiment 88. A form according to any one of the preceding embodiments for use in the prevention or treatment of cancer. Embodiment 89. A pharmaceutical composition according to any one of the preceding embodiments for use in the prevention or treatment of cancer. Embodiment 90. A form according to any one of the preceding embodiments for use in the prevention or treatment of cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor is present in the subject. Embodiment 91. A pharmaceutical composition according to any one of the preceding embodiments for use in the prevention or treatment of cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor is present in the subject. Embodiment 92. A form according to any one of the preceding embodiments for use in the prevention or treatment of cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor is present in a biological sample from the subject. Embodiment 93. A pharmaceutical composition according to any one of the preceding embodiments, for use in the prevention or treatment of cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor is present in a biological sample from the subject. Embodiment 94. Use of a shape form according to any one of the preceding embodiments in the manufacture of a medicament for inhibiting an oncogenic variant of an ErbB receptor. Embodiment 95. Use of a shape form according to any one of the preceding embodiments in the manufacture of a medicament for preventing or treating cancer. Embodiment 96. The form, pharmaceutical composition, method, or use of any one of the preceding embodiments, wherein the cancer is a solid tumor. Embodiment 97. The form, pharmaceutical composition, method, or use of any one of the preceding embodiments, wherein 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. Embodiment 98. The form, pharmaceutical composition, method, or use of any one of the preceding embodiments, wherein the cancer is glioblastoma (GBM) or any subtype thereof. Embodiment 99. The form, pharmaceutical composition, method, or use of any one of the preceding embodiments, wherein the cancer is glioblastoma. Embodiment 100. The form, pharmaceutical composition, method, or use of any one of the preceding embodiments, wherein the cancer or tumor, or cells thereof, express an oncogenic variant of the epidermal growth factor receptor (EGFR). Embodiment 101. The form, pharmaceutical composition, method, or use of any one of the preceding embodiments, wherein the oncogenic variant is an oncogenic variant in an ErbB receptor. Embodiment 102. The form, pharmaceutical composition, method or use according to any one of the preceding embodiments, wherein the oncogenic variant in the ErbB receptor is an allosteric variant. Embodiment 103. The form, pharmaceutical composition, method, or use according to any one of the preceding embodiments, wherein the oncogenic variant is an oncogenic variant in the epidermal growth factor receptor (EGFR). Embodiment 104. The form, pharmaceutical composition, method or use according to any one of the preceding embodiments, wherein the oncogenic variant in EGFR is an allosteric variant. Embodiment 105. The form, pharmaceutical composition, method or use according to any one of the preceding embodiments, wherein the oncogenic variant is an oncogenic variant of the HER2 receptor. Embodiment 106. The form, pharmaceutical composition, method or use according to any one of the preceding embodiments, wherein the oncogenic variant in the HER2 receptor is an allosteric variant. Embodiment 107. The form, pharmaceutical composition, method, or use according to any one of the preceding embodiments, wherein the oncogenic variant is an oncogenic variant in the HER-4 receptor. Embodiment 108. The form, pharmaceutical composition, method, or use of any one of the preceding embodiments, wherein the subject or cancer is insensitive or resistant to treatment with one or more of gefinitinib, erlotinib, afatinib, osimertinib, and necitunumab. Embodiment 109. The form, pharmaceutical composition, method, or use of any one of the preceding embodiments, wherein the sequence encoding the oncogenic variant of EGFR comprises a deletion of exon 20 or a portion thereof, and the cancer, tumor, or cells thereof does not contain a sequence encoding or an oncogenic variant therein of one or more of the following: the EGFR kinase domain (KD), BRAF, NTRK, and KRAS. Embodiment 110. The form, pharmaceutical composition, method, or use of any one of the preceding embodiments, wherein the sequence encoding the oncogenic variant of EGFR comprises a deletion of exon 20 or a portion thereof, and the cancer, tumor, or cells thereof do not comprise a marker indicative of responsiveness to immunotherapy. Embodiment 111. The form, pharmaceutical composition, method, or use of any one of the preceding embodiments, wherein the oncogenic variant or oncogenic mutation is detected by a Food and Drug Administration (FDA) approved diagnostic method. Embodiment 112. The form, pharmaceutical composition, method, or use of any one of the preceding embodiments, wherein the subject has an adverse reaction to treatment with a type I inhibitor. Embodiment 113. The form, pharmaceutical composition, method, or use of any one of the preceding embodiments, wherein the subject has an adverse reaction to treatment with one or more of gefitinib, erlotinib, afatinib, osimertinib, necitunumab, crizotinib, alectinib, ceritinib, dabrafenib, trametinib, afatinib, sapitinib, dacomitinib, canertinib, pelitinib, WZ4002, WZ8040, WZ3146, CO-1686, and AZD9291. EXAMPLES

[0380] It is understood that the experimental values ​​reported in this application are approximate and subject to instrument variation.

[0381] X-ray Powder Diffractometer (XRPD): XRPD analysis was performed using a Bruker D8 Advance X-ray powder diffractometer. The analysis was performed using the parameters described below. [Table 13]

[0382] Differential Scanning Calorimetry (DSC): DSC analysis was performed using a TA Discover 2500. The analysis was performed using the parameters described below. [Table 14]

[0383] Thermogravimetric Analysis (TGA): TGA analysis was performed using a Discover 5500. The analysis was performed using the parameters described below. [Table 15]

[0384] Dynamic Vapor Sorption (DVS): DVS analysis was performed using Intrinsic. The analysis was performed using the parameters listed below. [Table 16]

[0385] Karl Fischer Analysis: Karl Fischer analysis was performed using a Mettler Toledo Coulometric KF Titrator C30 using the coulometric method.

[0386] Polarized Light Microscopy (PLM): PLM analysis was performed using a BX53LED OLYMPUS with crossed polarizers doped with silicone oil.

[0387] Nuclear Magnetic Resonance (NMR): NMR analyses were performed using a Bruker Avance-AV 400M with 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.

[0388] High performance liquid chromatography (HPLC): HPLC analysis was performed using a SHIMADZU LC-20AD / Agilent 1260 infinity II Binary Pump. The analysis was performed using the parameters described below. [Table 17]

[0389] Example 1. Preparation of Crystalline Forms The crystalline forms of the present disclosure may be prepared according to one or more of the protocols described herein. Protocol 1: Equilibration with solvent for 2 weeks at 25° C. Approximately 20 mg of Form A was equilibrated in a suitable amount of solvent using a stir plate for 2 weeks at 25° C. The resulting suspension was filtered. Protocol 2: Equilibration with solvent at 50° C. for 1 week. Approximately 30 mg of Form A was equilibrated in a suitable amount of solvent using a stir plate at 50° C. for 1 week. The resulting suspension was filtered. Protocol 3: Equilibration with Solvent under Temperature Cycling Approximately 30 mg of Form A was equilibrated in a suitable amount of solvent under temperature cycling from 5° C. to 50° C. at a heating / cooling rate of 0.2° C. / min for 10 cycles. Protocol 4: Crystallization by slow evaporation at room temperature. Approximately 10 mg of Form A was dissolved in a suitable amount of solvent. The resulting solution was filtered through a 0.45 μm nylon filter. The filtered solution was then allowed to slowly evaporate under ambient conditions. Protocol 5: Crystallization by rapid evaporation under a stream of nitrogen. Approximately 10 mg of Form A was dissolved in a suitable amount of solvent. The resulting solution was filtered through a 0.45 μm nylon filter. The filtered solution was then rapidly evaporated under a stream of nitrogen. Protocol 6: Crystallization from hot saturated solution by slow cooling. Approximately 20 mg of Form A was dissolved in a minimum amount of selected solvent at 50° C. The resulting solution was filtered through a 0.45 μm nylon filter. The filtered solution was then cooled to 5° C. at 0.1° C. / min. The precipitate was collected by filtration. Protocol 7: Crystallization from hot saturated solution by rapid cooling. Approximately 20 mg of Form A was dissolved in a minimum amount of selected solvent at 50° C. The resulting solution was filtered through a 0.45 μm nylon filter. The filtered solution was then placed at 5° C. and stirred at a speed of 400 rpm. The precipitate was collected by filtration. Protocol 8: Precipitation by addition of anti-solvent. Approximately 20 mg of Form A was dissolved in a minimum amount of good solvent. The solution was filtered. Anti-solvent was slowly added to the filtered solution. The precipitate was collected by filtration. If a cloudy sample was obtained from the anti-solvent experiment, a slow evaporation experiment was performed at 25° C. Protocol 9: Variable Relative Humidity Experiment. Form F was investigated by a variable humidity XRPD experiment. Form F was converted to a new crystalline form assigned as Form L at 0% RH. Form L reverted to Form F at >10% RH. This suggests that Form L is a metastable anhydrate, stable only at about 0% RH. See Example 8 for details.

[0390] Preparation of Crystalline Forms The forms of the present disclosure may be prepared by one or more of the protocols set forth in Table A below. [Table 18]

[0391] Example 2. Preparation of Anhydrous Form C Preparation of seed crystals of Form C. Approximately 20 mg of Compound No. 1 Form A was equilibrated in a suitable amount of solvent using a stir plate at 25° C. for 2 weeks. The resulting suspension was filtered.

[0392] Preparation of anhydrous form C. Approximately 300 mg of compound number 1 form A was weighed into a 40 mL bottle. 3 mL of acetone was added to the bottle. The resulting suspension was stirred at 25° C. at 300 rpm. Approximately 3 mg of form C seeds were added to the suspension. After a precipitate formed, another 8 mL of acetone was added to the bottle. The suspension was kept stirred at 25° C. at 400 rpm for 48 hours. The resulting suspension was removed and the solid was separated by centrifugation. The solid was dried under vacuum at 30° C. for 1 hour. Approximately 240 mg of free base form C was obtained as a brown powder in 80% yield. This batch showed high crystallinity (see, for example, FIG. 3).

[0393] Example 3. Preparation of Hydrate Form F Preparation of seed crystals of Form F. Approximately 30 mg of Compound No. 1 Form A was equilibrated in a suitable amount of MeOH / HO (v:v=7:3) under temperature cycling from 5° C. to 50° C. with a heating / cooling rate of 0.2° C. / min for 10 cycles.

[0394] Preparation of anhydrous form F. Approximately 300 mg of compound number 1 form A was added to a 20 mL bottle. Then, 2 mL of MeOH:H2O (v:v=7:3) was added to the bottle. The resulting suspension was stirred at 25° C. at a speed of 400 rpm. Approximately 3 mg of form F seeds were added to the suspension. After a precipitate was formed, another 1.6 mL of MeOH:H2O (v:v=7:3) was added to the bottle. The suspension was kept stirring at 25° C. at a speed of 400 rpm for one week. The resulting suspension was removed and the solid was separated by centrifugation. The solid was dried under vacuum at 25° C. for 14 hours. Approximately 175 mg of form F was obtained as a brown powder in 58% yield and was characterized accordingly by XRPD (FIG. 6). Example 4. Competitive equilibration experiments

[0395] To determine the thermodynamic relationships of the anhydrate polymorphs, competitive equilibration experiments were performed at 25° C. in five solvent systems, as shown in Table B below. [Table 19]

[0396] Example 5. Bulk Stability Anhydrous Form C and hydrate Form F were placed under three accelerated conditions for 2 and 4 weeks. The solids obtained after bulk stability testing were characterized by XRPD and HPLC. As shown in Table C-1 below, Forms C and F do not change morphology under various storage conditions and storage times. [Table 20]

[0397] Anhydrous Form C was analyzed for stability after one month as shown in Table C-2 below. [Table 21]

[0398] Example 6. Solubility test 2.01 mg of free base form C (equivalent to 2 mg of free base after correcting for water content) was weighed into a 2 mL vial. 2.09 mg of free base form F (equivalent to 2 mg of free base after correcting for water content) was weighed into a 2 mL vial. 1 mL of aqueous medium was added to each. The suspensions were stirred at 37° C. and a speed of 400 rpm. The suspensions were removed after 2 hours and 24 hours and then centrifuged at 14,000 rpm for 5 minutes. The supernatants were analyzed by HPLC. The pH of the supernatants was tested.

[0399] As shown in Table D, Forms C and F exhibited pH-dependent solubility and similar solubility profiles in these aqueous media. They showed good solubility (>2 mg / mL) in HCl solution at pH 1.0, acetate buffer (50 mM) at pH 4.5, and SGF. They showed low solubility (~20 μg / mL) in phosphate buffer (50 mM) at pH 6.8 and in pure water (<10 μg / mL). Both degraded in FeSSIF-v1 and FaSSIF-v1. [Table 22]

[0400] Example 7. Hygroscopicity test of Forms C and F The hygroscopicity of Forms C and F was investigated. See, for example, Table E. [Table 23]

[0401] Example 8. Variable Relative Humidity Experiments of Form F Form F was investigated by variable humidity XRPD experiments. See, for example, Table F. Form F converted to a new crystalline form assigned as Form L at 0% RH. Form L reverted to Form F at >10% RH. This suggests that Form L is a metastable anhydrate, stable only near about 0% RH. [Table 24]

[0402] Equivalent It is understood that the present application may be embodied in other specific forms without departing from its spirit or essential characteristics. The foregoing embodiments are therefore to be considered in all respects as illustrative and not limiting of the invention described herein. The scope of the present application is therefore indicated by the appended claims, rather than the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

1. Compound No. 1: 【Chemical 1】 A crystalline form of, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

2. 2. The crystalline form of claim 1, wherein the crystalline form is Form A, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and is characterized by an X-ray diffraction (XRPD) pattern comprising at least three peaks selected from 4.8±0.2, 5.6±0.2, 9.6±0.2, 17.6±0.2, 20.0±0.2, and 24.6±0.2 degrees 2θ using Cu Kα radiation.

3. The crystalline form of claim 1, wherein the crystalline form is Form A, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and is characterized by a DSC curve having at least one endothermic peak selected from 76±5, 141±5, 156±5, and 170±5°C.

4. 2. The crystalline form of claim 1, wherein the crystalline form is Form B, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and is characterized by an X-ray diffraction (XRPD) pattern comprising at least three peaks selected from 3.2±0.2, 6.5±0.2, 13.4±0.2, 16.7±0.2, 17.7±0.2, and 18.6±0.2 degrees two-theta (e.g., 3.2±0.1, 6.5±0.1, 13.4±0.1, 16.7±0.1, 17.7±0.1, and 18.6±0.1 degrees two-theta) using Cu Kα radiation.

5. The crystalline form of claim 1, wherein the crystalline form is form B, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and is characterized by a DSC curve having at least one endothermic peak selected from 155±5 and 176±5°C.

6. 2. The crystalline form of claim 1, wherein the crystalline form is Form C, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and is characterized by an X-ray diffraction (XRPD) pattern comprising at least three peaks selected from 4.0±0.2, 12.6±0.2, 14.1±0.2, 16.1±0.2, 16.7±0.2, and 19.1±0.2 degrees two-theta (e.g., 4.0±0.1, 12.6±0.1, 14.1±0.1, 16.1±0.1, 16.7±0.1, and 19.1±0.1 degrees two-theta) using Cu Kα radiation.

7. The crystalline form of claim 1, wherein the crystalline form is Form C, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and is characterized by a DSC curve having at least one endothermic peak selected from 181±5°C.

8. 2. The crystalline form of claim 1, wherein the crystalline form is Form D, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and is characterized by an X-ray diffraction ("XRPD") pattern comprising at least three peaks selected from 5.4±0.2, 9.7±0.2, 15.3±0.2, 18.8±0.2, 19.3±0.2, and 23.5±0.2 degrees 2θ using Cu Kα radiation.

9. The crystalline form of claim 1, wherein the crystalline form is form D, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and is characterized by a DSC curve having at least one endothermic peak selected from 128±5, 149±5, and 175±5°C.

10. 2. The crystalline form of claim 1, wherein the crystalline form is Form E, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and is characterized by an X-ray diffraction ("XRPD") pattern comprising at least three peaks selected from 7.4±0.2, 13.3±0.2, 15.8±0.2, 16.3±0.2, 19.2±0.2, and 22.4±0.2 degrees two-theta (e.g., 7.4±0.1, 13.3±0.1, 15.8±0.1, 16.3±0.1, 19.2±0.1, and 22.4±0.1 degrees two-theta using Cu Kα radiation.

11. The crystalline form of claim 1, wherein the crystalline form is form E, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and is characterized by a DSC curve having at least one endothermic peak selected from 173±5°C.

12. 2. The crystalline form of claim 1, wherein the crystalline form is Form F, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and is characterized by an X-ray diffraction (XRPD) pattern comprising at least three peaks selected from 5.5±0.2, 7.2±0.2, 14.5±0.2, 15.2±0.2, 16.4±0.2, and 21.9±0.2 degrees two-theta (e.g., 5.5±0.1, 7.2±0.1, 14.5±0.1, 15.2±0.1, 16.4±0.1, and 21.9±0.1 degrees two-theta) using Cu Kα radiation.

13. The crystalline form of claim 1, wherein the crystalline form is form F, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and is characterized by a DSC curve having at least one endothermic peak selected from 174±5°C.

14. 2. The crystalline form of claim 1, wherein the crystalline form is Form G, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and is characterized by an X-ray diffraction (XRPD) pattern comprising at least three peaks selected from 4.0±0.2, 5.3±0.2, 7.1±0.2, 16.0±0.2, 16.7±0.2, and 19.2±0.2 degrees 2θ using Cu Kα radiation.

15. The crystalline form of claim 1, wherein the crystalline form is form G, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and is characterized by a DSC curve having at least one endothermic peak selected from 34±5, 175±5, and 182±5°C.

16. 2. The crystalline form of claim 1, wherein the crystalline form is Form H, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and is characterized by an X-ray diffraction ("XRPD") pattern using Cu Kα radiation comprising at least three peaks selected from 4.6±0.2, 5.6±0.2, 8.6±0.2, 13.8±0.2, 17.0±0.2, and 17.8±0.2 degrees 2θ (e.g., 4.6±0.1, 5.6±0.1, 8.6±0.1, 13.8±0.1, 17.0±0.1, and 17.8±0.1 degrees 2θ (e.g., 4.6, 5.6, 8.6, 13.8, 17.0, and 17.8 degrees 2θ)).

17. The crystalline form of claim 1, wherein the crystalline form is form H, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and is characterized by a DSC curve having at least one endothermic peak selected from 62±5, 153±5°C.

18. 2. The crystalline form of claim 1, wherein the crystalline form is Form I, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and is characterized by an X-ray diffraction (XRPD) pattern comprising at least three peaks selected from 5.1±0.2, 17.0±0.2, 20.4±0.2, 21.5±0.2, 22.3±0.2, and 25.5±0.2 degrees 2θ using Cu Kα radiation.

19. 2. The crystalline form of claim 1, wherein the crystalline form is Form J, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and is characterized by an X-ray diffraction (XRPD) pattern comprising at least three peaks selected from 4.5±0.2, 5.1±0.2, 10.4±0.2, 16.0±0.2, 17.9±0.2, and 22.5±0.2 degrees two-theta (e.g., 4.5±0.1, 5.1±0.1, 10.4±0.1, 16.0±0.1, 17.9±0.1, and 22.5±0.1 degrees two-theta) using Cu Kα radiation.

20. The crystalline form of claim 1, wherein the crystalline form is form J, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and is characterized by a DSC curve having at least one endothermic peak selected from 137±5, 166±5°C.

21. 2. The crystalline form of claim 1, wherein the crystalline form is Form K, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and is characterized by an X-ray diffraction ("XRPD") pattern comprising at least three peaks selected from 5.2±0.2, 6.8±0.2, 17.0±0.2, 20.5±0.2, 21.6±0.2, and 22.4±0.2 degrees two-theta (e.g., 5.2±0.1, 6.8±0.1, 17.0±0.1, 20.5±0.1, 21.6±0.1, and 22.4±0.1 degrees two-theta) using Cu Kα radiation.

22. 2. The crystalline form of claim 1, wherein the crystalline form is Form L, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and is characterized by an X-ray diffraction (XRPD) pattern comprising at least three peaks selected from 5.4±0.2, 7.8±0.2, 14.8±0.2, 15.3±0.2, 16.6±0.2, and 19.3±0.2 degrees 2θ using Cu Kα radiation.

23. 10. The crystalline form of claim 1, which is at least 90%, 95%, 96%, 97%, 98%, or 99% pure.

24. 10. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form of claim 1 and a pharmaceutically acceptable carrier, adjuvant, diluent, or excipient.

25. 25. The pharmaceutical composition of claim 24 for use in inhibiting an oncogenic variant of an ErbB receptor.

26. 25. The pharmaceutical composition of claim 24 for use in the prevention or treatment of cancer.

27. 27. The pharmaceutical composition of claim 26, 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, or non-small cell lung cancer (NSCLC), or any subtype thereof.

28. 28. The pharmaceutical composition of claim 27, wherein the cancer is GBM or NSCLC.

29. The pharmaceutical composition of claim 26, wherein the cancer, or tumor or its cells express an oncogenic mutant of an ErbB receptor, an oncogenic mutant of an epidermal growth factor receptor (EGFR), an oncogenic mutant of a HER2 receptor, or an oncogenic mutant of a HER-4 receptor.

30. 27. The pharmaceutical composition of claim 26, wherein the cancer is insensitive or resistant to treatment with gefitinib, erlotinib, afatinib, osimertinib, or necitumumab, or a combination thereof.

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