Polymorphs as ERBB inhibitors

Abstract

The present disclosure provides a morphological form of a compound No. 1: # imgabs0, a solvate thereof, a hydrate thereof, and a pharmaceutically acceptable salt thereof. The present disclosure also provides methods for preparing the morphological forms and uses of the morphological forms, for example, for the prevention or treatment of cancer.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to and the benefit of U.S. Application No. 63 / 246,451, filed on September 21, 2021, the entire contents of which are incorporated herein by reference. Background Art

[0003] Mutations that affect the intracellular catalytic domain or the extracellular ligand binding domain of ErbB receptors may produce oncogenic activity (the ErbB protein family consists of 4 members, including ErbB-1, also known as epidermal growth factor receptor (EGFR) and Erb-2, also known as HER2 in humans). ErbB inhibitors are known treatments for a variety of cancers. However, not every patient responds satisfactorily to this treatment. Therefore, there has long been a need in the art for new therapies that can address the variable 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

[0004] In some aspects, the present disclosure provides a morphological form of Compound No. 1:

[0005]

[0006] Its solvate, its hydrate or its pharmaceutically acceptable salt.

[0007] In some aspects, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a morphological form of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0008] In some aspects, the present disclosure provides a method of inhibiting oncogenic variants of ErbB receptors, comprising administering to a subject in need thereof a therapeutically effective amount of a morphological form of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0009] In some aspects, the present disclosure provides a method for preventing or treating cancer, comprising administering a therapeutically effective amount of a morphological form of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0010] In some aspects, the present disclosure provides a morphological form of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof for use in inhibiting oncogenic variants of ErbB receptors.

[0011] In some aspects, the present disclosure provides a morphological form of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, for use in preventing or treating cancer.

[0012] In some aspects, the present disclosure provides use of a morphological form of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting an oncogenic variant of an ErbB receptor.

[0013] In some aspects, the present disclosure provides use of a morphological form of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for preventing or treating cancer.

[0014] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art to which the present disclosure belongs. In this specification, unless the context clearly specifies otherwise, the singular also includes the plural. Although methods and materials similar to or equivalent to the methods and materials described herein can be used to practice or test the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated herein by reference. It is not recognized that the references cited herein are prior art for the claimed invention. In the event of a conflict, the present specification including the definition shall prevail. In addition, materials, methods and examples are illustrative only and are not intended to be restrictive. In the event of a conflict between the chemical structure and the name of the compound disclosed herein, the chemical structure shall prevail.

[0015] Other features and advantages of the disclosure will be apparent from the following detailed description, and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 is a graph depicting the XRPD spectrum of Form A of Compound No. 1.

[0017] Figure 2 is a graph depicting the XRPD spectrum of Form B of Compound No. 1.

[0018] Figure 3 is a graph depicting the XRPD spectrum of Form C of Compound No. 1.

[0019] Figure 4 is a graph depicting the XRPD spectrum of Form D of Compound No. 1.

[0020] Figure 5 is a graph depicting the XRPD spectrum of Form E of Compound No. 1.

[0021] Figure 6is a graph depicting the XRPD spectrum of Form F of Compound No. 1.

[0022] Figure 7 is a graph depicting the XRPD spectrum of Form G of Compound No. 1.

[0023] Figure 8 is a graph depicting the XRPD spectrum of Form H of Compound No. 1.

[0024] Fig. 9 is a graph depicting the XRPD spectrum of Form I of Compound No. 1.

[0025] Fig.10 is a graph depicting the XRPD spectrum of Form J of Compound No. 1.

[0026] Fig.11 is a graph depicting the XRPD spectrum of Form K of Compound No. 1.

[0027] Fig.12 is a graph depicting the XRPD spectrum of Form L of Compound No. 1. DETAILED DESCRIPTION

[0028] It should be understood that, as used herein, the term "Compound No. 1" refers to a compound having the following structure:

[0029]

[0030] Compound No. 1 can be identified by the IUPAC name of (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-morpholinobut-2-enamide.

[0031] In some aspects, the present disclosure provides a morphological form of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0032] In some embodiments, the morphological form is a crystalline form.

[0033] In some embodiments, the morphological form is a morphological form (eg, a crystalline form) of Compound No. 1, a solvate thereof, or a hydrate thereof.

[0034] In some embodiments, the morphological form is a morphological form (eg, a crystalline form) of Compound No. 1.

[0035] In some embodiments, the morphological form is a morphological form (eg, a crystalline form) of a solvate (eg, a heterosolvate) of Compound No. 1.

[0036] In some embodiments, the morphological form is a morphological form (eg, a crystalline form) of a hydrate of Compound No. 1.

[0037] In some embodiments, the morphological form is Form A of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0038] In some embodiments, the morphological form is Form B of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0039] In some embodiments, the morphological form is Form C of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0040] In some embodiments, the morphological form is Form D of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0041] In some embodiments, the morphological form is Form E of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0042] In some embodiments, the morphological form is Form F of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0043] In some embodiments, the morphological form is Form G of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0044] In some embodiments, the morphological form is Form H of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0045] In some embodiments, the morphological form is Form I of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0046] In some embodiments, the morphological form is Form J of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0047] In some embodiments, the morphological form is Form K of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0048] In some embodiments, the morphological form is Form L of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0049] In some aspects, the present disclosure provides a method for preparing a morphological form of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0050] Form A

[0051] X-ray powder diffraction (XRPD) characterization

[0052] In some embodiments, the morphological form is Form A of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0053] In some embodiments, the morphological form is Form A of Compound No. 1.

[0054] In some embodiments, 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 °2θ (e.g., 4.8±0.1, 5.6±0.1, and 17.6±0.1 °2θ (e.g., 4.8, 5.6, and 17.6 °2θ) using Cu Ka radiation.

[0055] 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° 2θ (e.g., 9.6±0.1, 20.0±0.1, and 24.6±0.1° 2θ (e.g., 9.6, 20.0, and 24.6° 2θ) using Cu Ka radiation.

[0056] 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° 2θ (e.g., 9.6±0.1, 20.0±0.1, and 24.6±0.1° 2θ (e.g., 9.6, 20.0, and 24.6° 2θ) using Cu Ka radiation.

[0057] 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° 2θ (e.g., 9.6±0.1, 20.0±0.1, and 24.6±0.1° 2θ (e.g., 9.6, 20.0, and 24.6° 2θ) using Cu Ka radiation.

[0058] 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 °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 °2θ (e.g., 4.8, 5.6, 9.6, 17.6, 20.0, and 24.6 °2θ) using Cu Ka radiation.

[0059] In some embodiments, the XRPD pattern of Form A comprises 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 °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 °2θ (e.g., 4.8, 5.6, 9.6, 17.6, 20.0, and 24.6 °2θ)) using Cu Ka radiation.

[0060] In some embodiments, the XRPD pattern of Form A comprises 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 °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 °2θ (e.g., 4.8, 5.6, 9.6, 17.6, 20.0, and 24.6 °2θ)) using Cu Ka radiation.

[0061] In some embodiments, the XRPD pattern of Form A comprises 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 °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 °2θ (e.g., 4.8, 5.6, 9.6, 17.6, 20.0, and 24.6 °2θ)) using Cu Ka radiation.

[0062] In some embodiments, Form A is characterized by an XRPD pattern substantially similar to Figure 1 XRPD pattern shown in .

[0063] In some embodiments, Form A is characterized by an XRPD pattern comprising peaks at the approximate locations shown in the table below. It should be understood that the values ​​in the table are approximate and are subject to instrumental and experimental variations.

[0064] Table 1: XRPD Peak Listing of Form A

[0065]

[0066]

[0067] Differential Scanning Calorimeter (DSC) Characterization

[0068] In some embodiments, Form A is characterized by a DSC curve having a value selected from 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))))))) at least one endothermic peak.

[0069] In some embodiments, Form A is characterized by a DSC curve having a value selected from 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))))))) at least two endothermic peaks.

[0070] In some embodiments, Form A is characterized by a DSC curve having a value selected from 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±40°C). At least three endothermic peaks of 0±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)))))))

[0071] In some embodiments, Form A is characterized by a DSC curve having an endothermic peak at 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))))))).

[0072] In some embodiments, Form A is characterized by a DSC curve having an endothermic peak at 76° C. In some embodiments, Form A of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 141° C. In some embodiments, Form A of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 156° C. In some embodiments, Form A of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 170° C.

[0073] Thermogravimetric analysis (TGA) characterization

[0074] In some embodiments, Form A exhibits an approximately 1-3% weight loss between 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)))))) and about 130±20°C (e.g., 130±10°C (e.g., 130±5°C (e.g., 130±4°C (e.g., 130±3°C (e.g., 130±2°C (e.g., 130±1°C (e.g., 150±0.5°C))))))) as measured by TGA.

[0075] In some embodiments, Form A exhibits a weight loss of about 2.2% between about 28°C and about 130°C as measured by TGA.

[0076] Form B

[0077] X-ray powder diffraction (XRPD) characterization

[0078] In some embodiments, the morphological form is Form B of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0079] In some embodiments, the morphological form is Form B of Compound No. 1.

[0080] In some embodiments, the present disclosure provides a form of Compound No. 1 ("Form B") characterized by an X-ray diffraction ("XRPD") pattern comprising peaks at 6.5±0.2, 16.7±0.2, and 18.6±0.2°2θ (e.g., 6.5±0.1, 16.7±0.1, and 18.6±0.1°2θ (e.g., 6.5, 16.7, and 18.6°2θ)) using Cu Ka radiation.

[0081] 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° 2θ (e.g., 3.2±0.1, 13.4±0.1, and 17.7±0.1° 2θ (e.g., 3.2, 13.4, and 17.7° 2θ)) using Cu Ka radiation.

[0082] 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° 2θ (e.g., 3.2±0.1, 13.4±0.1, and 17.7±0.1° 2θ (e.g., 3.2, 13.4, and 17.7v2θ)) using Cu Ka radiation.

[0083] 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° 2θ (e.g., 3.2±0.1, 13.4±0.1, and 17.7±0.1° 2θ (e.g., 3.2, 13.4, and 17.7° 2θ)) using Cu Ka radiation.

[0084] In some aspects, the present disclosure provides a form of Compound No. 1 (“Form B”) characterized in that an X-ray diffraction (“XRPD”) pattern comprises 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°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°2θ (e.g., 3.2, 6.5, 13.4, 16.7, 17.7, and 18.6°2θ)) using Cu Ka radiation.

[0085] In some embodiments, the XRPD pattern of Form B comprises 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 °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 °2θ (e.g., 3.2, 6.5, 13.4, 16.7, 17.7, and 18.6 °2θ)) using Cu Ka radiation.

[0086] In some embodiments, the XRPD pattern of Form B comprises 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 °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 °2θ (e.g., 3.2, 6.5, 13.4, 16.7, 17.7, and 18.6 °2θ)) using Cu Ka radiation.

[0087] In some embodiments, the XRPD pattern of Form B comprises 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 °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 °2θ (e.g., 3.2, 6.5, 13.4, 16.7, 17.7, and 18.6 °2θ)) using Cu Ka radiation.

[0088] In some embodiments, Form B is characterized by an XRPD pattern substantially similar to Figure 2 XRPD pattern shown.

[0089] In some embodiments, Form B is characterized by an XRPD pattern comprising peaks at the approximate locations shown in the table below. It should be understood that the values ​​in the table are approximate and are subject to instrumental and experimental variations.

[0090] Table 2: XRPD Peak Listing of Form B

[0091]

[0092] Differential Scanning Calorimeter (DSC) Characterization

[0093] In some embodiments, Form B of Compound No. 1 is characterized in that a DSC curve has 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))))))).

[0094] In some embodiments, Form B of Compound No. 1 is characterized by a DSC curve having endothermic peaks 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))))))).

[0095] In some embodiments, Form B of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 155° C. In some embodiments, Form B of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 176° C.

[0096] Thermogravimetric analysis (TGA) characterization

[0097] In some embodiments, Form B of Compound No. 1 exhibits an approximately 1-3% weight loss between 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))))))) and 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))))))) as measured by TGA.

[0098] In some embodiments, Form B of Compound No. 1 exhibits a weight loss of approximately 1.5% between about 35°C and about 150°C as measured by TGA.

[0099] Form C

[0100] X-ray powder diffraction (XRPD) characterization

[0101] In some embodiments, the morphological form is Form C of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0102] In some embodiments, the morphological form is Form C of Compound No. 1.

[0103] In some embodiments, the present disclosure provides a form of Compound No. 1 (“Form C”) characterized by an X-ray diffraction (“XRPD”) pattern comprising peaks at 16.1±0.2, 16.7±0.2, and 19.1±0.2°2θ (e.g., 16.1±0.1, 16.7±0.1, and 19.1±0.1°2θ (e.g., 16.1, 16.7, and 19.1°2θ)) using Cu Ka radiation.

[0104] 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° 2θ (e.g., 4.0±0.1, 12.6±0.1, and 14.1±0.1° 2θ (e.g., 4.0, 12.6, and 14.1° 2θ)) using Cu Ka radiation.

[0105] 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° 2θ (e.g., 4.0±0.1, 12.6±0.1, and 14.1±0.1° 2θ (e.g., 4.0, 12.6, and 14.1° 2θ)) using Cu Ka radiation.

[0106] 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° 2θ (e.g., 4.0±0.1, 12.6±0.1, and 14.1±0.1° 2θ (e.g., 4.0, 12.6, and 14.1° 2θ)) using Cu Ka radiation.

[0107] In some aspects, the present disclosure provides a form of Compound No. 1 (“Form C”) characterized in that an X-ray diffraction (“XRPD”) pattern comprises 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°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°2θ (e.g., 4.0, 12.6, 14.1, 16.1, 16.7, and 19.1°2θ)) using Cu Ka radiation.

[0108] In some embodiments, the XRPD pattern of Form C comprises 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 °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 °2θ (e.g., 4.0, 12.6, 14.1, 16.1, 16.7, and 19.1 °2θ)) using Cu Ka radiation.

[0109] In some embodiments, the XRPD pattern of Form C comprises 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 °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 °2θ (e.g., 4.0, 12.6, 14.1, 16.1, 16.7, and 19.1 °2θ)) using Cu Ka radiation.

[0110] In some embodiments, the XRPD pattern of Form C comprises 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 °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 °2θ (e.g., 4.0, 12.6, 14.1, 16.1, 16.7, and 19.1 °2θ)) using Cu Ka radiation.

[0111] In some embodiments, Form C is characterized by an XRPD pattern substantially similar to Figure 3 XRPD pattern shown.

[0112] In some embodiments, Form C is characterized by an XRPD pattern comprising peaks at the approximate locations shown in the table below. It should be understood that the values ​​in the table are approximate and are subject to instrumental and experimental variations.

[0113] Table 3: XRPD Peak Listing of Form C

[0114]

[0115]

[0116] Differential Scanning Calorimeter (DSC) Characterization

[0117] 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))))))).

[0118] In some embodiments, Form C of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 181 °C.

[0119] Thermogravimetric analysis (TGA) characterization

[0120] In some embodiments, Form C of Compound No. 1 exhibits an approximately 1-3% weight loss between 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))))))) and 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)))))))) as measured by TGA.

[0121] In some embodiments, Form C of Compound No. 1 exhibits a weight loss of approximately 1.3% between about 28°C and about 170°C as measured by TGA.

[0122] Form D

[0123] X-ray powder diffraction (XRPD) characterization

[0124] In some embodiments, the morphological form is Form D of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0125] In some embodiments, the morphological form is Form D of the dioxane solvate of Compound No. 1.

[0126] In some embodiments, the morphological form is Form D of Compound No. 1.

[0127] In some embodiments, the disclosure provides a form of Compound No. 1 ("Form D") characterized by an X-ray diffraction ("XRPD") pattern comprising peaks at 15.3±0.2, 19.3±0.2, and 23.5±0.2°2θ (e.g., 5.3±0.1, 19.3±0.1, and 23.5±0.1°2θ (e.g., 5.3, 19.3, and 23.5°2θ)) using Cu Ka radiation.

[0128] 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° 2θ (e.g., 5.4±0.1, 9.7±0.1, and 18.8±0.1° 2θ (e.g., 5.4, 9.7, and 18.8° 2θ)) using Cu Ka radiation.

[0129] 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° 2θ (e.g., 5.4±0.1, 9.7±0.1, and 18.8±0.1° 2θ (e.g., 5.4, 9.7, and 18.8° 2θ)) using Cu Ka radiation.

[0130] 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° 2θ (e.g., 5.4±0.1, 9.7±0.1, and 18.8±0.1° 2θ (e.g., 5.4, 9.7, and 18.8° 2θ)) using Cu Ka radiation.

[0131] In some aspects, the present disclosure provides a form of Compound No. 1 (“Form D”) characterized in that an X-ray diffraction (“XRPD”) pattern comprises 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°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°2θ (e.g., 5.4, 9.7, 15.3, 18.8, 19.3, and 23.5°2θ)) using Cu Ka radiation.

[0132] In some embodiments, the XRPD pattern of Form D comprises 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 °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 °2θ (e.g., 5.4, 9.7, 15.3, 18.8, 19.3, and 23.5 °2θ)) using Cu Ka radiation.

[0133] In some embodiments, the XRPD pattern of Form D comprises 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 °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 °2θ (e.g., 5.4, 9.7, 15.3, 18.8, 19.3, and 23.5 °2θ)) using Cu Ka radiation.

[0134] In some embodiments, the XRPD pattern of Form D comprises 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 °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 °2θ (e.g., 5.4, 9.7, 15.3, 18.8, 19.3, and 23.5 °2θ)) using Cu Ka radiation.

[0135] In some embodiments, Form D is characterized by an XRPD pattern substantially similar to Figure 4 XRPD pattern shown.

[0136] In some embodiments, Form D is characterized by an XRPD pattern comprising peaks at the approximate locations shown in the table below. It should be understood that the values ​​in the table are approximate and are subject to instrumental and experimental variations.

[0137] Table 4: XRPD Peak Listing of Form D

[0138]

[0139]

[0140] Differential Scanning Calorimeter (DSC) Characterization

[0141] In some embodiments, Form D of Compound No. 1 is characterized in that a DSC curve has 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))))))

[0142] In some embodiments, Form D of Compound No. 1 is characterized in that a DSC curve has 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))))))

[0143] 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))))))).

[0144] In some embodiments, Form D of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 128° C. In some embodiments, Form D of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 149° C. In some embodiments, Form D of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 175° C.

[0145] Thermogravimetric analysis (TGA) characterization

[0146] In some embodiments, Form D of Compound No. 1 exhibits an approximately 12%-15% weight loss between 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))))))) and about 185±20°C (e.g., 185±10°C (e.g., 185±5°C (e.g., 185±4°C (e.g., 185±3°C (e.g., 185±2°C (e.g., 185±1°C (e.g., 185±0.5°C))))))) as measured by TGA.

[0147] In some embodiments, Form D of Compound No. 1 exhibits a weight loss of approximately 13.8% between about 33°C and about 185°C as measured by TGA.

[0148] Form E

[0149] X-ray powder diffraction (XRPD) characterization

[0150] In some embodiments, the morphological form is Form E of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0151] In some embodiments, the morphological form is Form E of Compound No. 1.

[0152] In some embodiments, the present disclosure provides a form of Compound No. 1 (“Form E”) characterized in that an X-ray diffraction (“XRPD”) pattern comprises peaks at 7.4±0.2, 15.8±0.2, and 16.3±0.2°2θ (e.g., 7.4±0.1, 15.8±0.1, and 16.3±0.1°2θ (e.g., 7.4, 15.8, and 16.3°2θ)) using Cu Ka radiation.

[0153] 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° 2θ (e.g., 13.3±0.1, 19.2±0.1, and 22.4±0.1° 2θ (e.g., 13.3, 19.2, and 22.4° 2θ)) using Cu Ka radiation.

[0154] 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° 2θ (e.g., 13.3±0.1, 19.2±0.1, and 22.4±0.1° 2θ (e.g., 13.3, 19.2, and 22.4° 2θ)) using Cu Ka radiation.

[0155] 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° 2θ (e.g., 13.3±0.1, 19.2±0.1, and 22.4±0.1° 2θ (e.g., 13.3, 19.2, and 22.4° 2θ)) using Cu Ka radiation.

[0156] In some aspects, the present disclosure provides a form of Compound No. 1 (“Form E”) characterized in that an X-ray diffraction (“XRPD”) pattern comprises 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°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°2θ (e.g., 7.4, 13.3, 15.8, 16.3, 19.2, and 22.4°2θ)) using Cu Ka radiation.

[0157] In some embodiments, the XRPD pattern of Form E comprises 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° 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° 2θ (e.g., 7.4, 13.3, 15.8, 16.3, 19.2, and 22.4° 2θ)) using Cu Ka radiation.

[0158] In some embodiments, the XRPD pattern of Form E comprises 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 °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 °2θ (e.g., 7.4, 13.3, 15.8, 16.3, 19.2, and 22.4 °2θ)) using Cu Ka radiation.

[0159] In some embodiments, the XRPD pattern of Form E comprises 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 °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 °2θ (e.g., 7.4, 13.3, 15.8, 16.3, 19.2, and 22.4 °2θ)) using Cu Ka radiation.

[0160] In some embodiments, Form E is characterized by an XRPD pattern substantially similar to Figure 5 XRPD pattern shown.

[0161] In some embodiments, Form E is characterized by an XRPD pattern comprising peaks at the approximate locations shown in the table below. It should be understood that the values ​​in the table are approximate and are subject to instrumental and experimental variations.

[0162] Table 5: XRPD Peak Listing of Form E

[0163]

[0164]

[0165] Differential Scanning Calorimeter (DSC) Characterization

[0166] 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))))))).

[0167] In some embodiments, Form E of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 173°C.

[0168] Thermogravimetric analysis (TGA) characterization

[0169] In some embodiments, Form E of Compound No. 1 exhibits an approximately 1-3% weight loss between 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))))))) and 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)))))))) as measured by TGA.

[0170] In some embodiments, Form E of Compound No. 1 exhibits a weight loss of approximately 1.3% between about 34°C and about 165°C as measured by TGA.

[0171] Form F

[0172] X-ray powder diffraction (XRPD) characterization

[0173] In some embodiments, the morphological form is Form F of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0174] In some embodiments, the morphological form is Form F of a hydrate of Compound No. 1.

[0175] In some embodiments, the morphological form is Form F of Compound No. 1.

[0176] In some embodiments, the present disclosure provides a form of Compound No. 1 ("Form F") characterized by an X-ray diffraction ("XRPD") pattern comprising peaks at 5.5±0.2, 16.4±0.2, and 21.9±0.2°2θ (e.g., 5.5±0.1, 16.4±0.1, and 21.9±0.1°2θ (e.g., 5.5, 16.4, and 21.9°2θ)) using Cu Ka radiation.

[0177] 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° 2θ (e.g., 7.2±0.1, 14.5±0.1, and 15.2±0.1° 2θ (e.g., 7.2, 14.5, and 15.2° 2θ)) using Cu Ka radiation.

[0178] 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° 2θ (e.g., 7.2±0.1, 14.5±0.1, and 15.2±0.1° 2θ (e.g., 7.2, 14.5, and 15.2° 2θ)) using Cu Ka radiation.

[0179] 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° 2θ (e.g., 7.2±0.1, 14.5±0.1, and 15.2±0.1° 2θ (e.g., 7.2, 14.5, and 15.2° 2θ)) using Cu Ka radiation.

[0180] In some aspects, the present disclosure provides a form of Compound No. 1 (“Form F”) characterized in that an X-ray diffraction (“XRPD”) pattern comprises 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 °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 °2θ (e.g., 5.5, 7.2, 14.5, 15.2, 16.4, and 21.9 °2θ)) using Cu Ka radiation.

[0181] In some embodiments, the XRPD pattern of Form F comprises 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 °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 °2θ (e.g., 5.5, 7.2, 14.5, 15.2, 16.4, and 21.9 °2θ)) using Cu Ka radiation.

[0182] In some embodiments, the XRPD pattern of Form F comprises 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 °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 °2θ (e.g., 5.5, 7.2, 14.5, 15.2, 16.4, and 21.9 °2θ)) using Cu Ka radiation.

[0183] In some embodiments, the XRPD pattern of Form F comprises 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 °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 °2θ (e.g., 5.5, 7.2, 14.5, 15.2, 16.4, and 21.9 °2θ)) using Cu Ka radiation.

[0184] In some embodiments, Form F is characterized by an XRPD pattern substantially similar to Figure 6 XRPD pattern shown.

[0185] In some embodiments, Form F is characterized by an XRPD pattern comprising peaks at the approximate locations shown in the table below. It should be understood that the values ​​in the table are approximate and are subject to instrumental and experimental variations.

[0186] Table 6: XRPD Peak Listing of Form F

[0187]

[0188]

[0189] Differential Scanning Calorimeter (DSC) Characterization

[0190] In some embodiments, Form F of Compound No. 1 is characterized in that a DSC curve has at least one endothermic peak selected from 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))))))

[0191] In some embodiments, Form F of Compound No. 1 is characterized by a DSC curve having at least two endothermic peaks selected from 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))))))

[0192] In some embodiments, Form F of Compound No. 1 is characterized by a DSC curve having at least three endothermic peaks selected from 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))))))

[0193] In some embodiments, Form F of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 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)))))))

[0194] In some embodiments, Form F of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 48°C. In some embodiments, Form F of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 80°C. In some embodiments, Form F of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 144°C. In some embodiments, Form F of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 146°C. In some embodiments, Form F of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 174°C.

[0195] Thermogravimetric analysis (TGA) characterization

[0196] In some embodiments, Form F of Compound No. 1 exhibits an approximately 2-5% weight loss between 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))))))) and 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))))))) as measured by TGA.

[0197] In some embodiments, Form F of Compound No. 1 exhibits a weight loss of approximately 3.8% between about 33°C and about 55°C as measured by TGA.

[0198] In some embodiments, Form F of Compound No. 1 exhibits an approximately 1-4% weight loss between 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))))))) and 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)))))))) as measured by TGA.

[0199] In some embodiments, Form F of Compound No. 1 exhibits a weight loss of approximately 2.7% between about 55°C and about 100°C as measured by TGA.

[0200] In some embodiments, Form F of Compound No. 1 exhibits an approximately 2-8% weight loss between 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))))))) and 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))))))) as measured by TGA.

[0201] In some embodiments, Form F of Compound No. 1 exhibits a weight loss of approximately 6.5% between about 33°C and about 100°C as measured by TGA.

[0202] In some embodiments, Form F of Compound No. 1 exhibits a weight loss of approximately 3.7% between about 33°C and about 100°C as measured by TGA.

[0203] Form G

[0204] X-ray powder diffraction (XRPD) characterization

[0205] In some embodiments, the morphological form is Form G of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0206] In some embodiments, the morphological form is Form G of Compound No. 1.

[0207] In some embodiments, the present disclosure provides a form of Compound No. 1 (“Form G”) characterized in that an X-ray diffraction (“XRPD”) pattern comprises peaks at 4.0±0.2, 5.3±0.2, and 16.0±0.2°2θ (e.g., 4.0±0.1, 5.3±0.1, and 16.0±0.1°2θ (e.g., 4.0, 5.3, and 16.0°2θ)) using Cu Ka radiation.

[0208] 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° 2θ (e.g., 7.1±0.1, 16.7±0.1, and 19.2±0.1° 2θ (e.g., 7.1, 16.7, and 19.2° 2θ)) using Cu Ka radiation.

[0209] 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° 2θ (e.g., 7.1±0.1, 16.7±0.1, and 19.2±0.1° 2θ (e.g., 7.1, 16.7, and 19.2° 2θ)) using Cu Ka radiation.

[0210] 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° 2θ (e.g., 7.1±0.1, 16.7±0.1, and 19.2±0.1° 2θ (e.g., 7.1, 16.7, and 19.2° 2θ)) using Cu Ka radiation.

[0211] In some aspects, the present disclosure provides a form of Compound No. 1 (“Form G”), characterized in that an X-ray diffraction (“XRPD”) pattern comprises 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°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°2θ (e.g., 4.0, 5.3, 7.1, 16.0, 16.7, and 19.2°2θ)) using Cu Ka radiation.

[0212] In some embodiments, the XRPD pattern of Form G comprises 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 °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 °2θ (e.g., 4.0, 5.3, 7.1, 16.0, 16.7, and 19.2 °2θ)) using Cu Ka radiation.

[0213] In some embodiments, the XRPD pattern of Form G comprises 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 °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 °2θ (e.g., 4.0, 5.3, 7.1, 16.0, 16.7, and 19.2 °2θ)) using Cu Ka radiation.

[0214] In some embodiments, the XRPD pattern of Form G comprises 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 °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 °2θ (e.g., 4.0, 5.3, 7.1, 16.0, 16.7, and 19.2 °2θ)) using Cu Ka radiation.

[0215] In some embodiments, Form G is characterized by an XRPD pattern substantially similar to Figure 7 XRPD pattern shown.

[0216] In some embodiments, Form G is characterized by an XRPD pattern comprising peaks at the approximate locations shown in the table below. It should be understood that the values ​​in the table are approximate and are subject to instrumental and experimental variations.

[0217] Table 7: XRPD Peak Listing of Form G

[0218]

[0219] Differential Scanning Calorimeter (DSC) Characterization

[0220] In some embodiments, Form G of Compound No. 1 is characterized in that a DSC curve has 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))))))

[0221] In some embodiments, Form G of Compound No. 1 is characterized in that a DSC curve has 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))))))).

[0222] In some embodiments, Form G of Compound No. 1 is characterized by a DSC curve having an endothermic peak 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))))))).

[0223] In some embodiments, Form G of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 34° C. In some embodiments, Form G of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 175° C. In some embodiments, Form G of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 182° C.

[0224] Thermogravimetric analysis (TGA) characterization

[0225] In some embodiments, Form G of Compound No. 1 exhibits an approximately 2-5% weight loss between 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))))))) and 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))))))) as measured by TGA.

[0226] In some embodiments, Form G of Compound No. 1 exhibits a weight loss of approximately 3.4% between about 33°C and about 100°C as measured by TGA.

[0227] Form H

[0228] X-ray powder diffraction (XRPD) characterization

[0229] In some embodiments, the morphological form is Form H of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0230] In some embodiments, the morphological form is Form H of Compound No. 1.

[0231] In some embodiments, the present disclosure provides a form of Compound No. 1 ("Form H") characterized by an X-ray diffraction ("XRPD") pattern comprising peaks at 4.6±0.2, 13.8±0.2, and 17.0±0.2°2θ (e.g., 4.6±0.1, 13.8±0.1, and 17.0±0.1°2θ (e.g., 4.6, 13.8, and 17.0°2θ)) using Cu Ka radiation.

[0232] 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° 2θ (e.g., 5.6±0.1, 8.6±0.1, and 17.8±0.1° 2θ (e.g., 5.6, 8.6, and 17.8° 2θ)) using Cu Ka radiation.

[0233] 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° 2θ (e.g., 5.6±0.1, 8.6±0.1, and 17.8±0.1° 2θ (e.g., 5.6, 8.6, and 17.8° 2θ)) using Cu Ka radiation.

[0234] 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° 2θ (e.g., 5.6±0.1, 8.6±0.1, and 17.8±0.1° 2θ (e.g., 5.6, 8.6, and 17.8° 2θ)) using Cu Ka radiation.

[0235] In some aspects, the present disclosure provides a form of Compound No. 1 (“Form H”) characterized in that an X-ray diffraction (“XRPD”) pattern comprises 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°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°2θ (e.g., 4.6, 5.6, 8.6, 13.8, 17.0, and 17.8°2θ)) using Cu Kα radiation.

[0236] In some embodiments, the XRPD pattern of Form H comprises 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 °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 °2θ (e.g., 4.6, 5.6, 8.6, 13.8, 17.0, and 17.8 °2θ)) using Cu Ka radiation.

[0237] In some embodiments, the XRPD pattern of Form H comprises 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 °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 °2θ (e.g., 4.6, 5.6, 8.6, 13.8, 17.0, and 17.8 °2θ)) using Cu Ka radiation.

[0238] In some embodiments, the XRPD pattern of Form H comprises 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 °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 °2θ (e.g., 4.6, 5.6, 8.6, 13.8, 17.0, and 17.8 °2θ)) using Cu Ka radiation.

[0239] In some embodiments, the present disclosure provides a form of Compound No. 1 ("Form H") characterized by an XRPD pattern substantially similar to Figure 8 XRPD pattern shown.

[0240] In some embodiments, Form H is characterized by an XRPD pattern comprising peaks at the approximate locations shown in the table below. It should be understood that the values ​​in the table are approximate and are subject to instrumental and experimental variations.

[0241] Table 8: XRPD Peak Listing of Form H

[0242]

[0243]

[0244] Differential Scanning Calorimeter (DSC) Characterization

[0245] In some aspects, the present disclosure provides a form of Compound No. 1 ("Form H"), characterized in that a DSC curve has 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))))))).

[0246] In some embodiments, Form H of Compound No. 1 is characterized by a DSC curve having endothermic peaks 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))))))).

[0247] In some embodiments, Form H of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 62° C. In some embodiments, Form H of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 153° C.

[0248] Form I

[0249] X-ray powder diffraction (XRPD) characterization

[0250] In some embodiments, the morphological form is Form I of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0251] In some embodiments, the morphological form is Form I of the methanol solvate of Compound No. 1.

[0252] In some embodiments, the morphological form is Form I of Compound No. 1.

[0253] In some embodiments, the present disclosure provides a form of Compound No. 1 ("Form I") characterized by an X-ray diffraction ("XRPD") pattern comprising peaks at 5.1±0.2, 20.4±0.2, and 21.5±0.2°2θ (e.g., 5.1±0.1, 20.4±0.1, and 21.5±0.1°2θ (e.g., 5.1, 20.4, and 21.5°2θ)) using Cu Ka radiation.

[0254] 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° 2θ (e.g., 17.0±0.1, 22.3±0.1, and 25.5±0.1° 2θ (e.g., 17.0, 22.3, and 25.5° 2θ)) using Cu Ka radiation.

[0255] 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° 2θ (e.g., 17.0±0.1, 22.3±0.1, and 25.5±0.1° 2θ (e.g., 17.0, 22.3, and 25.5° 2θ)) using Cu Ka radiation.

[0256] 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° 2θ (e.g., 17.0±0.1, 22.3±0.1, and 25.5±0.1° 2θ (e.g., 17.0, 22.3, and 25.5° 2θ)) using Cu Ka radiation.

[0257] In some aspects, the present disclosure provides a form of Compound No. 1 ("Form I") characterized in that an X-ray diffraction ("XRPD") pattern comprises 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°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°2θ (e.g., 5.1, 17.0, 20.4, 21.5, 22.3, and 25.5°2θ)) using Cu Ka radiation.

[0258] In some embodiments, the XRPD pattern of Form I comprises 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 °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 °2θ (e.g., 5.1, 17.0, 20.4, 21.5, 22.3, and 25.5 °2θ)) using Cu Ka radiation.

[0259] In some embodiments, the XRPD pattern of Form I comprises 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 °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 °2θ (e.g., 5.1, 17.0, 20.4, 21.5, 22.3, and 25.5 °2θ)) using Cu Ka radiation.

[0260] In some embodiments, the XRPD pattern of Form I comprises 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 °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 °2θ (e.g., 5.1, 17.0, 20.4, 21.5, 22.3, and 25.5 °2θ)) using Cu Ka radiation.

[0261] In some embodiments, Form I is characterized by an XRPD pattern substantially similar to Fig. 9 XRPD pattern shown.

[0262] In some embodiments, Form I is characterized by an XRPD pattern comprising peaks at the approximate locations shown in the table below. It should be understood that the values ​​in the table are approximate and are subject to instrumental and experimental variations.

[0263] Table 9: XRPD Peak Listing of Form I

[0264]

[0265]

[0266] Form J

[0267] In some embodiments, the morphological form is Form J of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0268] In some embodiments, the morphological form is Form J of the hydrate of Compound No. 1.

[0269] In some embodiments, the morphological form is Form J of Compound No. 1.

[0270] In some embodiments, the present disclosure provides a form of Compound No. 1 ("Form J") characterized by an X-ray diffraction ("XRPD") pattern comprising peaks at 4.5±0.2, 17.9±0.2, and 22.5±0.2°2θ (e.g., 4.5±0.1, 17.9±0.1, and 22.5±0.1°2θ (e.g., 4.5, 17.9, and 22.5°2θ)) using Cu Ka radiation.

[0271] 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° 2θ (e.g., 5.1±0.1, 10.4±0.1, and 16.0±0.1° 2θ (e.g., 5.1, 10.4, and 16.0° 2θ)) using Cu Ka radiation.

[0272] 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° 2θ (e.g., 5.1±0.1, 10.4±0.1, and 16.0±0.1° 2θ (e.g., 5.1, 10.4, and 16.0° 2θ)) using Cu Ka radiation.

[0273] 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° 2θ (e.g., 5.1±0.1, 10.4±0.1, and 16.0±0.1° 2θ (e.g., 5.1, 10.4, and 16.0° 2θ)) using Cu Ka radiation.

[0274] In some aspects, the present disclosure provides a form of Compound No. 1 (“Form J”) characterized in that an X-ray diffraction (“XRPD”) pattern comprises 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°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°2θ (e.g., 4.5, 5.1, 10.4, 16.0, 17.9, and 22.5°2θ)) using Cu Ka radiation.

[0275] In some embodiments, the XRPD pattern of Form J comprises 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 °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 °2θ (e.g., 4.5, 5.1, 10.4, 16.0, 17.9, and 22.5 °2θ)) using Cu Ka radiation.

[0276] In some embodiments, the XRPD pattern of Form J comprises 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 °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 °2θ (e.g., 4.5, 5.1, 10.4, 16.0, 17.9, and 22.5 °2θ)) using Cu Ka radiation.

[0277] In some embodiments, the XRPD pattern of Form J comprises 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 °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 °2θ (e.g., 4.5, 5.1, 10.4, 16.0, 17.9, and 22.5 °2θ)) using Cu Ka radiation.

[0278] In some embodiments, Form J is characterized by an XRPD pattern substantially similar to Fig.10 XRPD pattern shown.

[0279] In some embodiments, Form J is characterized by an XRPD pattern comprising peaks at the approximate locations shown in the table below. It should be understood that the values ​​in the table are approximate and are subject to instrumental and experimental variations.

[0280] Table 10: XRPD Peak Listing of Form J

[0281]

[0282]

[0283] Differential Scanning Calorimeter (DSC) Characterization

[0284] In some embodiments, Form J of Compound No. 1 is characterized in that a DSC curve has 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))))))).

[0285] In some embodiments, Form J of Compound No. 1 is characterized by a DSC curve having endothermic peaks 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))))))).

[0286] In some embodiments, Form J of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 137° C. In some embodiments, Form J of Compound No. 1 is characterized by a DSC curve having an endothermic peak at 166° C.

[0287] Thermogravimetric analysis (TGA) characterization

[0288] In some embodiments, Form J of Compound No. 1 exhibits an approximately 1-2% weight loss between 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))))))) and 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))))))) as measured by TGA.

[0289] In some embodiments, Form J of Compound No. 1 exhibits a weight loss of approximately 1.1% between about 33°C and about 75°C as measured by TGA.

[0290] In some embodiments, Form J of Compound No. 1 exhibits an approximately 6%-8% weight loss between 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)))))) and 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))))))) as measured by TGA.

[0291] In some embodiments, Form J of Compound No. 1 exhibits a weight loss of about 7.0% between about 75°C and about 175°C as measured by TGA.

[0292] In some embodiments, Form J of Compound No. 1 exhibits an approximately 7%-10% weight loss between 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)))))) and 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))))))) as measured by TGA.

[0293] In some embodiments, Form J of Compound No. 1 exhibits a weight loss of approximately 8.2% between about 33°C and about 175°C as measured by TGA.

[0294] Form K

[0295] X-ray powder diffraction (XRPD) characterization

[0296] In some embodiments, the morphological form is Form K of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0297] In some embodiments, the morphological form is Form K of Compound No. 1.

[0298] In some embodiments, the present disclosure provides a form of Compound No. 1 ("Form K") characterized in that an X-ray diffraction ("XRPD") pattern comprises peaks at 5.2±0.2, 17.0±0.2, and 20.5±0.2°2θ (e.g., 5.2±0.1, 17.0±0.1, and 20.5±0.1°2θ (e.g., 5.2, 17.0, and 20.5°2θ)) using Cu Ka radiation.

[0299] 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° 2θ (e.g., 6.8±0.1, 21.6±0.1, and 22.4±0.1° 2θ (e.g., 6.8, 21.6, and 22.4° 2θ)) using Cu Ka radiation.

[0300] 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° 2θ (e.g., 6.8±0.1, 21.6±0.1, and 22.4±0.1° 2θ (e.g., 6.8, 21.6, and 22.4° 2θ)) using Cu Ka radiation.

[0301] 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° 2θ (e.g., 6.8±0.1, 21.6±0.1, and 22.4±0.1° 2θ (e.g., 6.8, 21.6, and 22.4° 2θ)) using Cu Ka radiation.

[0302] In some aspects, the present disclosure provides a form of Compound No. 1 (“Form K”), characterized in that an X-ray diffraction (“XRPD”) pattern comprises 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°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°2θ (e.g., 5.2, 6.8, 17.0, 20.5, 21.6, and 22.4°2θ)) using Cu Ka radiation.

[0303] In some embodiments, the XRPD pattern of Form K comprises 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 °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 °2θ (e.g., 5.2, 6.8, 17.0, 20.5, 21.6, and 22.4 °2θ)) using Cu Ka radiation.

[0304] In some embodiments, the XRPD pattern of Form K comprises 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 °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 °2θ (e.g., 5.2, 6.8, 17.0, 20.5, 21.6, and 22.4 °2θ)) using Cu Ka radiation.

[0305] In some embodiments, the XRPD pattern of Form K comprises 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 °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 °2θ (e.g., 5.2, 6.8, 17.0, 20.5, 21.6, and 22.4 °2θ)) using Cu Ka radiation.

[0306] In some embodiments, Form K is characterized by an XRPD pattern substantially similar to Fig.11 XRPD pattern shown.

[0307] In some embodiments, Form K is characterized by an XRPD pattern comprising peaks at the approximate locations shown in the table below. It should be understood that the values ​​in the table are approximate and are subject to instrumental and experimental variations.

[0308] Table 11: XRPD Peak Listing of Form K

[0309]

[0310]

[0311] Form L

[0312] X-ray powder diffraction (XRPD) characterization

[0313] In some embodiments, the morphological form is Form L of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0314] In some embodiments, the morphological form is Form L of Compound No. 1.

[0315] In some embodiments, the present disclosure provides a form of Compound No. 1 ("Form L") characterized in that an X-ray diffraction ("XRPD") pattern comprises peaks at 5.4±0.2, 7.8±0.2, and 19.3±0.2°2θ (e.g., 5.4±0.1, 7.8±0.1, and 19.3±0.1°2θ (e.g., 5.4, 7.8, and 19.3°2θ)) using Cu Ka radiation.

[0316] 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 °2θ (e.g., 14.8±0.1, 15.3±0.1, and 16.6±0.1 °2θ (e.g., 14.8, 15.3, and 16.6 °2θ)) using Cu Ka radiation.

[0317] 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° 2θ (e.g., 14.8±0.1, 15.3±0.1, and 16.6±0.1° 2θ (e.g., 14.8, 15.3, and 16.6° 2θ)) using Cu Ka radiation.

[0318] 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° 2θ (e.g., 14.8±0.1, 15.3±0.1, and 16.6±0.1° 2θ (e.g., 14.8, 15.3, and 16.6° 2θ)) using Cu Ka radiation.

[0319] In some aspects, the present disclosure provides a form of Compound No. 1 (“Form L”), characterized in that an X-ray diffraction (“XRPD”) pattern comprises 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°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°2θ (e.g., 5.4, 7.8, 14.8, 15.3, 16.6, and 19.3°2θ)) using Cu Ka radiation.

[0320] In some embodiments, the XRPD pattern of Form L comprises 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 °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 °2θ (e.g., 5.4, 7.8, 14.8, 15.3, 16.6, and 19.3 °2θ)) using Cu Ka radiation.

[0321] In some embodiments, the XRPD pattern of Form L comprises 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 °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 °2θ (e.g., 5.4, 7.8, 14.8, 15.3, 16.6, and 19.3 °2θ)) using Cu Ka radiation.

[0322] In some embodiments, the XRPD pattern of Form L comprises 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 °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 °2θ (e.g., 5.4, 7.8, 14.8, 15.3, 16.6, and 19.3 °2θ)) using Cu Ka radiation.

[0323] In some embodiments, Form L is characterized by an XRPD pattern substantially similar to Fig.12 XRPD pattern shown.

[0324] In some embodiments, Form L is characterized by an XRPD pattern comprising peaks at the approximate locations shown in the table below. It should be understood that the values ​​in the table are approximate and are subject to instrumental and experimental variations.

[0325] Table 12: XRPD Peak Listing of Form L

[0326]

[0327]

[0328] Process for preparing the crystalline form

[0329] In some aspects, the disclosure features a method of preparing a crystalline form of Compound No. 1 or a pharmaceutically acceptable salt thereof.

[0330] In some aspects, the present disclosure provides a method of preparing a crystalline form of Compound No. 1 or a pharmaceutically acceptable salt thereof, comprising one or more steps as described herein.

[0331] In some aspects, the present disclosure provides a compound that can be obtained by the method for preparing a crystalline form of Compound No. 1 or a pharmaceutically acceptable salt thereof, or obtained by the method, or directly obtained by the method.

[0332] The crystalline form of Compound No. 1 or a pharmaceutically acceptable salt thereof can be prepared by any suitable technique known in the art. Specific processes for preparing these compounds are further described in the accompanying Examples.

[0333] Pharmaceutical composition

[0334] In some aspects, the disclosure features a pharmaceutical composition comprising a morphological form of Compound No. 1 described herein, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0335] The pharmaceutical composition comprising the active compound of the present disclosure can be manufactured in a generally known manner, for example, by conventional mixing, dissolving, granulating, making dragees, grinding, emulsifying, encapsulating, embedding or lyophilizing processes. The pharmaceutical composition can be prepared in a conventional manner using one or more pharmaceutically acceptable carriers, the carriers including excipients and / or adjuvants, which contribute to the active compound being processed into pharmaceutically usable preparations. Of course, suitable preparations depend on the selected route of administration.

[0336] 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. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL TM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be a fluid that is easily injectable to some extent. It must be stable under the conditions of production and storage, and must prevent the contaminating effects of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.) and suitable mixtures thereof. Suitable fluidity can be maintained by, for example, using a coating such as lecithin, by maintaining the desired particle size in the case of a dispersion, and by using a surfactant. Protection against microbial effects can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it will be preferred to include isotonic agents, such as sugars, polyols such as mannitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of injectable compositions can be achieved by including agents that delay absorption (e.g., aluminum monostearate and gelatin) in the composition.

[0337] Sterile injectable solutions can be prepared by incorporating the required amount of the active compound into an appropriate solvent containing one or a combination of the above-listed ingredients, followed by filtration sterilization. Typically, dispersions are prepared by incorporating the active compound into a sterile carrier containing a basic dispersion medium and other ingredients required from the above-listed ingredients. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation are vacuum drying and freeze drying, which produce a powder of the active ingredient plus any additional desired ingredients from its previously sterile filtered solution.

[0338] Oral compositions typically include an inert diluent or an edible pharmaceutically acceptable carrier. They can be encapsulated in a gelatin capsule or compressed into a tablet. For the purpose of oral therapeutic administration, the active compound can be incorporated with an excipient and used in the form of a tablet, lozenge or capsule. Liquid carriers can also be used to prepare oral compositions for use as mouthwashes, wherein the compound in the liquid carrier is orally administered, and the mouth is rinsed and spit out or swallowed. Pharmaceutically compatible binders and / or auxiliary materials can be included as part of the composition. Tablets, pills, capsules, lozenges, etc. can contain any of the following ingredients or compounds of similar nature: binders, such as microcrystalline cellulose, tragacanth or gelatin; excipients such as starch or lactose, disintegrants such as alginic acid, Primogel or corn starch; lubricants such as magnesium stearate or Sterotes; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as mint, methyl salicylate or orange flavoring.

[0339] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from a pressured container or dispenser which contains a suitable propellant, eg, a gas such as carbon dioxide, or a nebulizer.

[0340] Systemic administration can also be carried out by transmucosal or transdermal means. For transmucosal or transdermal administration, a penetrant suitable for the barrier to be penetrated is used in the formulation. Such penetrants are generally known in the art and include, for example, detergents, bile salts and fusidic acid derivatives for transmucosal administration. Transmucosal administration can be achieved by using nasal sprays or suppositories. For transdermal administration, the active compound is formulated into an ointment, salves, gel or cream, as generally known in the art.

[0341] The active compound can be prepared with a pharmaceutically acceptable carrier that will protect the compound from rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such formulations will be apparent to those skilled in the art.

[0342] It can be particularly advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form, as used herein, refers to physically discrete units suitable as unitary dosages for subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect together with the required pharmaceutical carrier. The specifications for the dosage unit forms of the present disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the specific therapeutic effect to be achieved.

[0343] In therapeutic applications, the dosage of the pharmaceutical composition used according to the present disclosure varies according to the agent, the age, weight and clinical condition of the patient receiving the therapy, and the experience and judgment of the clinician or practitioner administering the therapy, as well as other factors that affect the selected dosage. In general, the dosage should be sufficient to cause a reduction in, and preferably a regression of, the symptoms of the disease, and preferably also a complete regression of the disease.

[0344] It will be understood that the pharmaceutical compositions may be included in a container, pack, or dispenser together with instructions for administration.

[0345] How to use

[0346] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject, the method comprising administering to the subject a pharmaceutically effective amount of a form of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0347] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject, comprising administering to the subject a pharmaceutically 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 pharmaceutically acceptable salt thereof.

[0348] In some aspects, the present disclosure provides a form of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof for use in treating or preventing cancer in a subject.

[0349] In some aspects, the present 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 pharmaceutically acceptable salt thereof for use in treating or preventing cancer in a subject.

[0350] In some aspects, the present disclosure provides a use of a form of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing cancer in a subject.

[0351] In some aspects, the present disclosure provides 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 pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing cancer in a subject.

[0352] In some embodiments, Form A of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof is administered.

[0353] In some embodiments, Form B of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof is administered.

[0354] In some embodiments, Form C of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof is administered.

[0355] In some embodiments, Form D of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof is administered.

[0356] In some embodiments, Form E of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof is administered.

[0357] In some embodiments, Form F of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof is administered.

[0358] In some embodiments, Form G of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof is administered.

[0359] In some embodiments, Form H of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof is administered.

[0360] In some embodiments, Form I of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof is administered.

[0361] In some embodiments, Form J of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof is administered.

[0362] In some embodiments, Form K of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof is administered.

[0363] In some embodiments, Form L of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof is administered.

[0364] Suitable subjects and diseases

[0365] In some embodiments, the subject is a mammal.

[0366] In some embodiments, the subject is a human.

[0367] In some embodiments, the subject is a mouse.

[0368] The compounds of the present disclosure inhibit or modulate the activity of receptor tyrosine kinases, specifically extracellular mutants of ErbB-receptors, such as but not limited to EGFR-Viii, EGFR-Vii, EGFR-Vvi, EGFR-A289V and EGFR-G598V and HER2-S310F. Therefore, the compounds and compositions of the present disclosure can be used as drugs, i.e., as drugs in therapy, more specifically for preventing or treating cancer, as described in detail below. Therefore, in another aspect, the present disclosure provides a method for preventing or treating a mammal, such as a human, suffering from cancer, as described in detail below.

[0369] The term "prevention" or "preventing" refers to reducing or eliminating the 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, such as a human.

[0370] The term "treatment" or "treatment" is intended to encompass both therapy and cure. Such treatment includes the step of administering to the mammal, such as a human, 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).

[0371] Therefore, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition thereof, for preventing or treating cancer in a mammal, such as a human, as described in detail below.

[0372] In some aspects, the disclosure relates to a method of inhibiting an oncogenic variant of an ErbB receptor (eg, an oncogenic variant of EGFR), the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein.

[0373] In some aspects, the disclosure relates to a method of inhibiting an oncogenic variant of an ErbB receptor (eg, an oncogenic variant of EGFR), the method comprising administering to a subject in need thereof a composition described herein.

[0374] In some aspects, the disclosure relates 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.

[0375] In some aspects, the present disclosure relates to a method of preventing or treating cancer, comprising administering a composition described herein to a subject in need thereof.

[0376] In some aspects, the disclosure relates to compounds described herein for use in inhibiting oncogenic variants of ErbB receptors (eg, oncogenic variants of EGFR).

[0377] In some aspects, the disclosure relates to compounds described herein for use in preventing or treating cancer.

[0378] In some aspects, the disclosure relates to the compositions described herein for inhibiting oncogenic variants of ErbB receptors (eg, oncogenic variants of EGFR).

[0379] In some aspects, the disclosure relates to the compositions described herein for use in preventing or treating cancer.

[0380] In some aspects, the disclosure relates to the use of a compound described herein in the manufacture of a medicament for inhibiting an oncogenic variant of an ErbB receptor (eg, an oncogenic variant of EGFR).

[0381] In some aspects, the disclosure relates to the use of the compounds described herein for the manufacture of a medicament for the prevention or treatment of cancer.

[0382] In some embodiments, the compound is selected from the compounds described in Tables 1 and 2, pharmaceutically acceptable salts thereof, and stereoisomers thereof.

[0383] In some embodiments, the compound is selected from the compounds described in Tables 1 and 2 and pharmaceutically acceptable salts thereof.

[0384] In some embodiments, the compound is selected from the compounds described in Tables 1 and 2.

[0385] In some embodiments, the cancer is a solid tumor.

[0386] 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.

[0387] In some embodiments, the cancer is glioblastoma (GBM) or any subtype thereof.

[0388] In some embodiments, the cancer is glioblastoma.

[0389] In some embodiments, the cancer or tumor or cell thereof expresses an oncogenic variant of an ErbB receptor.

[0390] In some embodiments, the oncogenic variant of the ErbB receptor comprises an allosteric mutation.

[0391] In some embodiments, the oncogenic variant of the ErbB receptor is an allosteric variant of the ErbB receptor.

[0392] In some embodiments, the ErbB receptor is an epidermal growth factor receptor (EGFR) or a human epidermal growth factor receptor 2 (HER2) receptor.

[0393] In some embodiments, the ErbB receptor is epidermal growth factor receptor (EGFR).

[0394] In some embodiments, the ErbB receptor is a HER2 receptor.

[0395] In some embodiments, the cancer or tumor or cell thereof expresses an oncogenic variant of epidermal growth factor receptor (EGFR).

[0396] In some embodiments, the oncogenic variant of EGFR is an allosteric variant of EGFR.

[0397] In some embodiments, the oncogenic variant of EGFR comprises an allosteric mutation.

[0398] In some embodiments, the cancer or tumor or cell thereof expresses an oncogenic variant of the HER2 receptor.

[0399] In some embodiments, the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor.

[0400] In some embodiments, the oncogenic variant of the HER2 receptor comprises an allosteric mutation.

[0401] In some embodiments, the oncogenic variant of EGFR includes an EGFR variant III (EGFR-Viii) mutation.

[0402] In some embodiments, the oncogenic variant of EGFR includes an EGFR variant II (EGFR-Vii) mutation.

[0403] In some embodiments, the oncogenic variant of EGFR includes an EGFR variant VI (EGFR-Vvi) mutation.

[0404] 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.

[0405] In some embodiments, the oncogenic variant of EGFR comprises a substitution of glycine (G) with valine (V) at position 598 of SEQ ID NO:1.

[0406] In some embodiments, the cancer or its tumor or cell expresses an oncogenic variant of EGFR, and wherein the oncogenic variant of EGFR is an allosteric variant of EGFR, the oncogenic variant of EGFR includes a modification of the EGFR structure, wherein the oncogenic variant of EGFR is capable of forming a covalently linked dimer, wherein the covalently linked dimer is constitutively active, and wherein the covalently linked dimer enhances the activity of EGFR when in contact with a type I ErbB inhibitor. In some embodiments, the modification of the EGFR structure includes one or more modifications 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 includes a mutation, a splicing event, a post-translational process, a conformational change, or any combination thereof. In some embodiments, the modification of the EGFR structure occurs in the first cysteine-rich (CR1) region and / or the second cysteine-rich (CR2) region of EGFR. In some embodiments, the first cysteine-rich (CR1) region and / or the second cysteine-rich (CR2) region of EGFR include amino acid residues T211-R334 and / or C526-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 region and / or CR2 region. In some embodiments, the oncogenic variants of EGFR remove the physical barrier to disulfide bond formation within the CR1 region and / or CR2 region. In some embodiments, the oncogenic variants of EGFR include one or more free or unpaired cysteine ​​(C) residues located at the dimer interface of EGFR. In some embodiments, the oncogenic variants of EGFR include one or more free or unpaired cysteine ​​(C) residues at a site selected from the group consisting of: C190-C199, C194-C207, C215-C223, C219 according to SEQ ID NO: 1. - C231, C232-C240, C236-C248, C251-C260, C264-C291, C295-C307, C311-C326, C329-C333, C506-C515, C510-C523, C526-C535, C539 - C555, C558 - In some embodiments, the modification occurs within 10 angstroms or less of an intramolecular disulfide bond at a site selected from the group consisting of: C190-C199, C194-C207, C215-C223, C219-C231, C232-C240, C236-C248, C251-C260, C264-C273 according to SEQ ID NO: 1.- C291, C295-C307, C311-C326, C329-C333, C506-C515, C510 - C523, C526 - C535, C539-C555, C558-C571, C562-C579, C582-C591, C595-C617, C620 - C628 and C624 - C636.

[0407] In some embodiments, the cancer or tumor or cell thereof expresses an oncogenic variant of EGFR, and 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 comprising one or more amino acids encoding an adenosine triphosphate (ATP) binding site. In some embodiments, the ATP binding site comprises amino acids E746 to A750 of SEQ ID NO: 1. In some embodiments, the ATP binding site or its deletion or substitution comprises K858 of SEQ ID NO: 1. In some embodiments, the deletion comprises K858 of SEQ ID NO: 1. In some embodiments, arginine (R) replaces lysine (K) at position 858 of SEQ ID NO: 1 (K858R).

[0408] In some embodiments, the cancer or its tumor or cell expresses an oncogenic variant of EGFR, and wherein the oncogenic variant of EGFR is an allosteric variant of EGFR, and the nucleotide sequence encoding the oncogenic variant of EGFR includes an insertion within the sequence encoding exon 20 or a portion thereof. In some embodiments, the sequence encoding exon 20 or a portion thereof includes a sequence encoding KEILDEAYVMASVDNPHVCAR (SEQ ID NO: 7). In some embodiments, the sequence encoding exon 20 or a portion thereof includes a sequence encoding a C-helix, the end of a C-helix, or a loop following a C-helix. In some embodiments, the insertion includes the amino acid sequence of ASV, SVD, NPH, or FQEA. In some embodiments, the sequence encoding exon 20 or a portion thereof includes one or more of the following: (a) the amino acid sequence ASV inserted between positions V769 and D770 of SEQ ID NO: 1; (b) the amino acid sequence SVD inserted between positions D770 and N771 of SEQ ID NO: 1; (c) the amino acid sequence NPH inserted between positions H773 and V774 of SEQ ID NO: 1; (d) the amino acid sequence FQEA inserted between positions A763 and Y764 of SEQ ID NO: 1; (e) the amino acid sequence PH inserted between positions H773 and V774 of SEQ ID NO: 1; (f) the amino acid G inserted between positions D770 and N771 of SEQ ID NO: 1; (g) the amino acid H inserted between positions H773 and V774 of SEQ ID NO: 1; (h) the amino acid sequence HV inserted between positions V774 and C775 of SEQ ID NO: 1; (i) the amino acid sequence FQEA inserted between positions A763 and Y764 of SEQ ID NO: 1; The amino acid sequence AH between positions H773 and V774 of SEQ ID NO:1; (j) the amino acid sequence SVA inserted between positions A767 and S768 of SEQ ID NO:1; (k) the amino acid sequence GYN substituted for DN between positions 770 and 771 of SEQ ID NO:1; (i) the amino acid H inserted between positions N771 and P772 of SEQ ID NO:1; (m) the amino acid Y inserted between positions H773 and V774 of SEQ ID NO:1; (n) the amino acid sequence PHVC inserted between positions C775 and R776 of SEQ ID NO:1; (o) the amino acid sequence YNPY substituted for H at position 773 of SEQ ID NO:1; (p) the amino acid sequence DNP inserted between positions P772 and H773 of SEQ ID NO:1; (q) the amino acid sequence VDS inserted between positions S768 and V769 of SEQ ID NO:1;(r) the amino acid H inserted between positions D770 and N771 of SEQ ID NO:1; (s) the amino acid N inserted between positions N771 and P772 of SEQ ID NO:1; (t) the amino acid sequence PNP inserted between positions P772 and H773 of SEQ ID NO:1; (u) the amino acid sequence GSVDN substituted for DN between positions 770 and 771 of SEQ ID NO:1; (v) the amino acid sequence GYP substituted for NP between positions 771 and 772 of SEQ ID NO:1; (w) the amino acid G inserted between positions N771 and P772 of SEQ ID NO:1; (x) the amino acid sequence GNP inserted between positions P772 and H773 of SEQ ID NO:1; (y) the amino acid sequence GSV inserted between positions V769 and D770 of SEQ ID NO:1; (z) the amino acid sequence GNPHVC substituted for VC between positions 774 and 775 of SEQ ID NO:1; (aa) the amino acid sequence GNPHVC inserted between positions 775 and 776 of SEQ ID NO:1; the amino acid sequence LQEA between positions A763 and Y764 of SEQ ID NO:1; (bb) the amino acid sequence GL inserted between positions D770 and N771 of SEQ ID NO:1; (cc) the amino acid Y inserted between positions D770 and N771 of SEQ ID NO:1; (dd) the amino acid sequence NPY inserted between positions H773 and V774 of SEQ ID NO:1; (ee) the amino acid sequence TH inserted between positions H773 and V774 of SEQ ID NO:1; (ff) the amino acid sequence KGP replacing P between positions 771 and 772 of SEQ ID NO:1; (gg) the amino acid sequence SVDNP replacing NP between positions 771 and 772 of SEQ ID NO:1; (hh) the amino acid sequence NN inserted between positions N771 and P772 of SEQ ID NO:1; (ii) the amino acid T inserted between positions N771 and P772 of SEQ ID NO:1; and (jj) the amino acid sequence TH inserted between positions H773 and V774 of SEQ ID NO:1. The amino acid sequence STLASV replaces SV between positions 768 and 769 of NO:1.

[0409] In some embodiments, the cancer or tumor or cell thereof expresses an oncogenic variant of EGFR, and wherein the oncogenic variant of EGFR is an allosteric variant of EGFR, and the oncogenic variant of EGFR includes EGFR-Vii, EGFR-Vvi, EGFR-R222C, EGFR-R252C, EGFR-R252P, EGFR-R256Y, EGFR-T263P, EGFR-Y270C, EGFR-A289T, EGFR-A289V, EGFR-A289 D. EGFR-H304Y, EGFR-G331R, EGFR-P596S, EGFR-P596L, EGFR-P596R, EGFR-G598V, EGFR-G598A, EGFR-G614D, E GFR-C620Y, EGFR-C614W, EGFR-C628F, EGFR-C628Y, EGFR-C636Y, EGFR-G645C, EGFR-Δ660, EGFR-Δ768, or any combination thereof.

[0410] In some embodiments, the cancer or tumor or cell thereof expresses one or more of the following: (a) a wild-type human epidermal growth factor receptor 2 (HER2) receptor or an oncogenic variant of the HER-2 receptor.

[0411] In some embodiments, the cancer or tumor or cell thereof expresses a wild-type HER-2 receptor comprising the amino acid sequence of SEQ ID NO: 2, 3, 4, 5 or 6.

[0412] In some embodiments, the cancer or tumor or cell thereof expresses an oncogenic variant of the HER-2 receptor, and the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor.

[0413] In some embodiments, the cancer or tumor or cell thereof expresses an oncogenic variant of a HER-2 receptor, and wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of the HER2 receptor comprising a phenylalanine (F) substituted for the serine (S) at position 310 of SEQ ID NO: 2 or 5.

[0414] In some embodiments, the cancer or tumor or cell thereof expresses an oncogenic variant of the HER-2 receptor, and wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of the HER2 receptor comprising a tyrosine (Y) replacing the serine (S) at position 310 of SEQ ID NO: 2 or 5.

[0415] In some embodiments, the cancer or tumor or cell thereof expresses an oncogenic variant of a HER-2 receptor, and wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of the HER2 receptor comprising a glutamine (Q) replacing the arginine (R) at position 678 of SEQ ID NO: 2 or 5.

[0416] In some embodiments, the cancer or tumor or cell thereof expresses an oncogenic variant of a HER-2 receptor, and wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of the HER2 receptor comprising a leucine (L) replacing a valine (V) at position 777 of SEQ ID NO: 2 or 5.

[0417] In some embodiments, the cancer or tumor or cell thereof expresses an oncogenic variant of a HER-2 receptor, and wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of the HER2 receptor comprising a methionine (M) replacing a valine (V) at position 777 of SEQ ID NO: 2 or 5.

[0418] In some embodiments, the cancer or tumor or cell thereof expresses an oncogenic variant of the HER-2 receptor, and wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of the HER2 receptor comprising an isoleucine (I) replacing a valine (V) at position 842 of SEQ ID NO: 2 or 5.

[0419] In some embodiments, the cancer or tumor or cell thereof expresses an oncogenic variant of a HER-2 receptor, and wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of the HER2 receptor comprising an alanine (A) replacing a leucine (L) at position 755 of SEQ ID NO: 2 or 5.

[0420] In some embodiments, the cancer or tumor or cell thereof expresses an oncogenic variant of a HER-2 receptor, and wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of the HER2 receptor comprising a proline (P) replacing a leucine (L) at position 755 of SEQ ID NO: 2 or 5.

[0421] In some embodiments, the cancer or tumor or cell thereof expresses an oncogenic variant of a HER-2 receptor, and wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, the oncogenic variant of the HER2 receptor comprising a serine (S) replacing a leucine (L) at position 755 of SEQ ID NO: 2 or 5.

[0422] In some embodiments, the cancer or its tumor or cell expresses an oncogenic variant of the HER-2 receptor, and 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 includes an insertion within the sequence encoding exon 20 or a portion thereof. In some embodiments, the sequence encoding exon 20 or a portion thereof includes a sequence encoding KEILDEAYVMAGVGSPYVSR (SEQ ID NO: 8). In some embodiments, the sequence encoding exon 20 or a portion thereof includes a sequence encoding a C-helix, the end of a C-helix, or a loop following a C-helix. In some embodiments, the insertion includes the amino acid sequence of GSP or YVMA. In some embodiments, the sequence encoding exon 20 or a portion thereof includes one or more of the following: (a) the amino acid sequence YVMA inserted between positions A775 and G776 of SEQ ID NO: 2; (b) the amino acid sequence GSP inserted between positions P780 and Y781 of SEQ ID NO: 2; (c) the amino acid sequence YVMA inserted between positions A771 and Y772 of SEQ ID NO: 2; (d) the amino acid sequence YVMA inserted between positions A775 and G776 of SEQ ID NO: 2; (e) the amino acid V inserted between positions V777 and G778 of SEQ ID NO: 2; (f) the amino acid V inserted between positions V777 and G778 of SEQ ID NO: 2; (g) the amino acid sequence AVGCV replacing GV between positions 776 and 777 of SEQ ID NO: 2; (h) the amino acid sequence LC replacing G between positions 776 of SEQ ID NO: 2; (i) the amino acid sequence LC replacing G between positions 776 of SEQ ID NO: 2; NO:2 between positions 776 and 777 with the amino acid sequence LCV replacing G; (j) the amino acid sequence GSP inserted between positions V777 and G778 of SEQ ID NO:2; (k) the amino acid sequence PS replacing LRE between positions 755 and 757 of SEQ ID NO:2; (i) the amino acid sequence CPGSP replacing SP between positions 779 and 780 of SEQ ID NO:2; (m) the amino acid C inserted between positions V777 and G778 of SEQ ID NO:2; (n) the amino acid sequence VVMA replacing AG between positions 775 and 776 of SEQ ID NO:2; (o) the amino acid sequence VV replacing G at position 776 of SEQ ID NO:2; (p) the amino acid sequence AVCV replacing GV between positions 776 and 777 of SEQ ID NO:2; (q) the amino acid sequence VCV replacing GV between positions 776 and 777 of SEQ ID NO:2;(r) amino acid G inserted between positions G778 and S779 of SEQ ID NO:2; (s) substitution of LRE with the amino acid sequence PK between positions 755 and 757 of SEQ ID NO:2; (t) amino acid V inserted between positions A775 and G776 of SEQ ID NO:2; (u) amino acid sequence YAMA inserted between positions A775 and G776 of SEQ ID NO:2; (v) substitution of G with the amino acid sequence CV at position 776 of SEQ ID NO:2; (w) substitution of GVG with the amino acid sequence AVCGG between positions 776 and 778 of SEQ ID NO:2; (x) substitution of GVG with the amino acid sequence CVCG between positions 776 and 778 of SEQ ID NO:2; (y) substitution of GVG with the amino acid sequence VVVG between positions 776 and 778 of SEQ ID NO:2; (z) substitution of GVGS with the amino acid sequence SVGG between positions 776 and 779 of SEQ ID NO:2; (aa) substitution of GVGS with the amino acid sequence SVGG at positions 776 and 779 of SEQ ID NO:2; NO:2 between positions 776 and 779 by replacing GVGS with the amino acid sequence VVGES; (bb) by replacing GV with the amino acid sequence AVGSGV between positions 776 and 777 of SEQ ID NO:2; (cc) by replacing GV with the amino acid sequence CVC between positions 776 and 777 of SEQ ID NO:2; (dd) by replacing GV with the amino acid sequence HVC between positions 776 and 777 of SEQ ID NO:2; (ee) by replacing GV with the amino acid sequence VAAGV between positions 776 and 777 of SEQ ID NO:2; (ff) by replacing GV with the amino acid sequence VAGV between positions 776 and 777 of SEQ ID NO:2; (gg) by replacing GV with the amino acid sequence VVV between positions 776 and 777 of SEQ ID NO:2; (hh) by inserting the amino acid sequence FPG between positions G778 and S779 of SEQ ID NO:2; (ii) by inserting the amino acid sequence FPG between positions G778 and S779 of SEQ ID NO:2; The amino acid sequence GS is inserted between positions S779 and P780 of SEQ ID NO:2; (ij) the amino acid sequence VPS is substituted for VLRE between positions 754 and 757 of SEQ ID NO:2; (kk) the amino acid E is inserted between positions V777 and G778 of SEQ ID NO:2; (ll) the amino acid sequence MAGV is inserted between positions V777 and G778 of SEQ ID NO:2; (mm) the amino acid S is inserted between positions V777 and G778 of SEQ ID NO:2; (nn) the amino acid sequence SCV is inserted between positions V777 and G778 of SEQ ID NO:2;and (oo) the amino acid sequence LMAY inserted between positions Y772 and V773 of SEQ ID NO: 2. ;

[0423] In some embodiments, the cancer or its tumor or cell expresses an oncogenic variant of the HER-2 receptor, and wherein the oncogenic variant of the HER2 receptor is an allosteric variant of the HER2 receptor, and the oncogenic variant of the HER2 receptor includes HER2-Δ16, HER2-C311R, HER2-S310F, p95-HER2-M611 or any combination thereof.

[0424] In some embodiments, the cancer or its tumor or cell expresses 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-A16).

[0425] In some embodiments, the cancer, tumor or cell thereof expresses an oncogenic variant of EGFR, wherein the sequence encoding the oncogenic variant of EGFR comprises a deletion of exon 20 or a portion thereof, and wherein the cancer, tumor or cell thereof does not comprise a second oncogenic variant in a sequence other than EGFR exon 20. In some embodiments, the second oncogenic variant comprises a sequence encoding one or more of the EGFR kinase domain (KD), BRAF, NTRK, and KRAS.

[0426] In some embodiments, the cancer, tumor or cell thereof expresses an oncogenic variant of EGFR, wherein the sequence encoding the oncogenic variant of EGFR comprises a deletion of exon 20 or a portion thereof, and wherein the cancer, tumor or cell thereof does not comprise markers indicative of responsiveness to immunotherapy.

[0427] In some embodiments, the oncogenic variant (eg, allosteric variant) or the oncogenic mutation (eg, allosteric mutation) is detected by a Food and Drug Administration (FDA) approved diagnostic test.

[0428] In some embodiments, the subject is treated with a therapeutic agent other than a Compound of the Disclosure prior to treatment with a Compound of the Disclosure.

[0429] In some embodiments, the cancer or its tumor or cell is insensitive or resistant to treatment with a therapeutic agent different from a compound of the present disclosure. In some embodiments, the cancer or its tumor or cell is insensitive or resistant to treatment with a type I inhibitor. In some embodiments, the cancer or its tumor or cell is insensitive or resistant to treatment with one or more of the following: gefitinib, erlotinib, afatinib, osimertinib, naxituzumab, crizotinib, alectinib, ceritinib, dabrafenib, trametinib, afatinib, saputinib, dacomitinib, canertinib, dacomitinib, WZ4002, WZ8040, WZ3146, CO-1686 and AZD9291.

[0430] In some embodiments, the subject has an adverse reaction to treatment with a therapeutic agent different from a 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 the following: gefitinib, erlotinib, afatinib, osimertinib, nacitozumab, crizotinib, alectinib, ceritinib, dabrafenib, trametinib, afatinib, sabutinib, dacomitinib, canertinib, pelitinib, WZ4002, WZ8040, WZ3146, CO-1686 and AZD9291. In some embodiments, the adverse reaction is the activation of an oncogenic variant of EGFR, and wherein the oncogenic variant includes a mutation in the extracellular domain of the receptor. In some embodiments, the adverse reaction is the activation of an oncogenic variant of a HER-2 receptor, and wherein the oncogenic variant includes a mutation in the extracellular domain of the receptor.

[0431] In some embodiments, the method further comprises administering to a subject in need thereof 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.

[0432] In some embodiments, the method further comprises administering to a subject in need thereof 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.

[0433] 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.

[0434] 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.

[0435] In some embodiments, a therapeutically effective amount reduces the severity of a sign or symptom of cancer.

[0436] In some embodiments, the signs of cancer include tumor grade, and wherein the reduction in severity of the signs includes a reduction in tumor grade.

[0437] In some embodiments, the signs of cancer include tumor metastasis, and wherein the reduction in severity of the signs includes elimination of metastasis or a reduction in the rate or extent of metastasis.

[0438] In some embodiments, the signs of cancer include tumor volume, and wherein the reduction in severity of the signs includes elimination of the tumor or a reduction in volume.

[0439] In some embodiments, the symptoms of cancer include pain, and wherein the reduction in severity of the symptoms includes the elimination or alleviation of pain.

[0440] In some embodiments, the therapeutically effective amount induces remission.

[0441] In some embodiments, a therapeutically effective amount improves the subject's prognosis.

[0442] Such use (or prevention or treatment method) of a subject comprises administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject in need of such prevention or treatment by targeting allosteric variants and / or oncogenic variants of EGFR and HER-2 receptors.

[0443] definition

[0444] It should be understood that the compounds described herein include the compounds themselves, as well as their salts and their solvates, if applicable. For example, a salt can be formed between an anion on a substituted benzene compound and a positively charged group (e.g., amino). Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, mesylate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, toluenesulfonate, salicylate, lactate, naphthylidenesulfonate, and acetate (e.g., trifluoroacetate).

[0445] Unless otherwise expressly indicated, the terms "approximately" and "approximately" are synonymous. In some embodiments, "approximately" and "approximately" refer to the amount, value, dosage or duration ± 20%, ± 15%, ± 10%, ± 8%, ± 6%, ± 5%, ± 4%, ± 2%, ± 1% or ± 0.5% of the narrated amount. In some embodiments, "approximately" and "approximately" refer to the listed amount or duration ± 10%, ± 8%, ± 6%, ± 5%, ± 4% or ± 2%. In some embodiments, "approximately" and "approximately" refer to the listed amount, value, dosage or duration ± 5%. In some embodiments, "approximately" and "approximately" refer to the listed amount, value, dosage or duration ± 2%. In some embodiments, "approximately" and "approximately" refer to the listed amount, value, dosage or duration ± 1%.

[0446] As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Similarly, salts can also be formed between cations and negatively charged groups (e.g., carboxylates) on substituted benzene compounds. Suitable cations include sodium ions, potassium ions, magnesium ions, calcium ions, and ammonium cations, such as tetramethylammonium ions. Substituted benzene compounds also include those salts containing quaternary nitrogen atoms.

[0447] It should be understood that the compounds of the present disclosure (e.g., salts of compounds) can exist in hydrated or non-hydrated (anhydrous) forms, 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.

[0448] As used herein, the expressions "one or more of A, B or C", "one or more A, B or C", "one or more of A, B and C", "one or more A, B and C", "selected from the group consisting of A, B and C", "selected from A, B and C", etc. are used interchangeably and all refer to selected from the group consisting of A, B and / or C, that is, one or more A, one or more B, one or more C or any combination thereof, unless otherwise specified.

[0449] It should be understood that throughout the specification, when a composition is described as having, containing or including a specific component, it is contemplated that the composition is also substantially composed of or composed of the component. Similarly, when a method or process is described as having, containing or including a specific process step, the process is also substantially composed of or composed of the processing step. Further, it should be understood that as long as the disclosure remains operable, the order of steps or the order in which certain actions are performed is insignificant. In addition, two or more steps or actions can be performed simultaneously.

[0450] It should be understood that the compounds of the present disclosure can be prepared in various ways using commercially available starting materials, compounds known in the literature or from readily prepared intermediates, by employing standard synthetic methods and procedures known to those skilled in the art or which will be apparent to the skilled artisan in view of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and for functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the art. Although not limited to any one or several sources, classic texts such as Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 5th edition, John Wiley & Sons: New York, 2001; Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishing Company, (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999; Synthesis, John Wiley & Sons, Inc. (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley & Sons, Inc. (1995) are useful and recognized reference textbooks on organic synthesis known to those skilled in the art.

[0451] It should be understood that, unless otherwise stated, any description of a method of treatment or prevention encompasses the use of a crystalline form of Compound No. 1 or a pharmaceutically acceptable salt thereof to provide such treatment or prevention as described herein. It should be further understood that, unless otherwise stated, any description of a method of treatment or prevention encompasses the use of a crystalline form of Compound No. 1 or a pharmaceutically 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.

[0452] It should be understood that, unless otherwise stated, any description of a method of treatment encompasses the use of a crystalline form of Compound No. 1 or a pharmaceutically acceptable salt thereof to provide such treatment as described herein. It should be further understood that, unless otherwise stated, any description of a method of treatment encompasses the use of a crystalline form of Compound No. 1 or a pharmaceutically 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.

[0453] As used herein, the term "subject" refers to a subject who has a disease or has an increased risk of developing the disease. "Subject" includes mammals. The mammal can 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 can also be a bird or poultry. In one embodiment, the mammal is a human.

[0454] In some embodiments, the term "subject in need thereof" may be a subject that has previously been diagnosed or identified as suffering from a disease or condition disclosed herein. A subject in need thereof may also be a subject suffering from a disease or condition disclosed herein. Alternatively, a subject in need thereof may be a subject with an increased risk of developing a class disease or condition relative to the general population (i.e., a subject that is prone to developing such a condition relative to the general population). A subject in need thereof may suffer from a refractory or drug-resistant disease or condition disclosed herein (i.e., a disease or condition disclosed herein that is unresponsive or not yet responsive to treatment). A subject in need thereof may be resistant at the beginning of treatment, or may become resistant during treatment. In some embodiments, a subject in need thereof has received all known effective therapies for a disease or condition disclosed herein but has failed to treat. In some embodiments, a subject in need thereof has received at least one previous therapy.

[0455] As used herein, the term "treating or treating" describes 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 pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder. The term "treatment" may also include treatment of in vitro cells or animal models.

[0456] It will be appreciated that the crystalline form of Compound No. 1 or a pharmaceutically acceptable salt thereof can be or may also be used to prevent related diseases, conditions or disorders, or to identify suitable candidates for such purposes.

[0457] As used herein, the terms "preventing or preventing" or "protecting against" describe the reduction or elimination of the onset of symptoms or complications of such disease, condition or disorder.

[0458] It should be understood that "solubility" or "solubility grade" refers to the property of a polymorph disclosed herein (e.g., Form A, B, C, D, E, F, G, H, I, J, K or L) to dissolve in a liquid solvent and form a uniform solution. In some embodiments, solubility is expressed as a concentration, expressed by the mass of the solute per unit volume of solvent (e.g., g solute per kg solvent, g per dL (100 mL), mg / ml, etc.), molar concentration, mass molar concentration, molar fraction, or other similar descriptions of concentration. It will be understood by those skilled in the art that the maximum equilibrium amount of solute that can be dissolved per unit amount of solvent is the solubility of the solute in the solvent under specified conditions, including temperature, pressure, pH, and the nature of the solvent.

[0459] As used herein, "stable" refers to a polymorph that maintains purity, appearance, and / or analytical parameters within a defined time and temperature compared to an isolated polymorph. In some embodiments, a "stable" polymorph exhibits less than about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1% impurities within a set time period (e.g., 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, one week, two weeks, three weeks, one month, two months, three months, or four months).

[0460] As used herein, the term "pharmaceutical composition" is a preparation containing a compound of the present disclosure, which is in a form suitable for application to a subject. In one embodiment, the pharmaceutical composition is in bulk or unit dosage form. The unit dosage form is any one of a variety of forms, including, for example, a single pump or vial on a capsule, an intravenous bag, a tablet, an aerosol inhaler. The amount of active ingredient (e.g., a preparation of a disclosed compound or its salt, hydrate, solvate or isomer) in a unit dose of the composition is an effective amount and varies according to the specific treatment involved. It will be appreciated by those skilled in the art that it is sometimes necessary to make routine changes to the dosage according to the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, oral, sublingual, intrapleural, intrathecal, intranasal, etc. The dosage forms for topical or transdermal administration of the compounds disclosed herein 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 pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that are required.

[0461] As used herein, the term "pharmaceutically acceptable" refers to those compounds, anions, cations, materials, compositions, carriers and / or dosage forms which 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 problems or complications commensurate with a reasonable benefit / risk ratio.

[0462] As used herein, the term "pharmaceutically acceptable excipient" refers to an excipient that can be used to prepare a pharmaceutical composition that is generally safe, non-toxic, and biologically or otherwise desirable, and includes excipients that are acceptable for veterinary use and human pharmaceutical use. "Pharmaceutically acceptable excipient" as used in the specification and claims includes one and more than one such excipient.

[0463] As used herein, the term "therapeutically effective amount" refers to an amount of a pharmaceutical agent that is used to treat, improve or prevent an established disease or condition, or that exhibits a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend on the subject's weight, size, and health; the nature and extent of the condition; and the combination of treatments or therapies selected for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician.

[0464] It is to be understood that for the compounds of the present disclosure which are capable of further forming salts, all such forms are also contemplated within the scope of the claimed disclosure.

[0465] 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 preparing an acid or base salt thereof. In some embodiments, a 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 acid salts or organic acid salts of basic residues such as amines, alkali salts or organic salts of acidic residues such as carboxylic acids, and the like. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, non-toxic salts derived from inorganic and organic acids selected from the group consisting of 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, glycolamidophenylarsonic acid, hexylresorcinic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, Acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, lauryl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, sulfamic acid, para-aminobenzenesulfonic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid and common amino acids, for example, glycine, alanine, phenylalanine, arginine, etc.

[0466] Other examples of pharmaceutically 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, tert-butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when acidic protons present in the parent compound are replaced by metal ions such as alkali metal ions, alkaline earth ions, or aluminum ions; or coordinated with organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In salt form, it is understood that 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.

[0467] It should be understood that all references to pharmaceutically acceptable salts include solvent added forms (solvates) or crystal forms (polymorphs) as defined herein, of the same salt.

[0468] The compound or its pharmaceutically acceptable salt is administered orally, nasally, transdermally, pulmonary, inhaled, buccal, 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.

[0469] The dosage regimen using the compound is selected based on a variety of factors, including the type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the patient's renal or liver function; and the specific compound or salt thereof employed. A generally skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progression of the patient.

[0470] Techniques for formulating and administering the disclosed compounds of the present disclosure can be found in Remington: The Science and Practice of Pharmacy, 19th ed., Mack Publishing Co., Easton, PA (1995). In an embodiment, the compounds described herein and pharmaceutically acceptable salts thereof are used in combination with a pharmaceutically acceptable carrier or diluent in a pharmaceutical formulation. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compound will be present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the range described herein.

[0471] Unless otherwise indicated, all percentages and ratios used herein are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methods useful in practicing the present disclosure. The examples do not limit the disclosure claimed. Based on the present disclosure, the technician can identify and adopt other components and methods that can be used to practice the present disclosure.

[0472] All publications and patent documents cited herein are incorporated herein by reference, as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. The citation of publications and patent documents is not intended as an admission that any content is relevant prior art, nor does it constitute any admission about its content or date. Now that the present disclosure has been described by written specification, those skilled in the art will recognize that the present disclosure can be practiced in various embodiments, and the foregoing description and the following examples are for the purpose of illustrating, not limiting, the following claims.

[0473] Exemplary embodiments

[0474] Embodiment 1. A morphological form of Compound No. 1, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0475] Embodiment 2. The morphological form of Embodiment 1, wherein the morphological form is a crystalline form.

[0476] Embodiment 3. The morphological form of Embodiment 1 or 2, wherein the morphological form is Form A, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0477] Embodiment 4. The morphological 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°2θ (e.g., 4.8±0.1, 5.6±0.1, and 17.6±0.1°2θ (e.g., 4.8, 5.6, and 17.6°2θ)) using Cu Ka radiation.

[0478] Embodiment 5. A morphological form according to 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°2θ (e.g., 9.6±0.1, 20.0±0.1, and 24.6±0.1°2θ (e.g., 9.6, 20.0, and 24.6°2θ) using Cu Ka radiation.

[0479] Embodiment 6. The morphological 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 °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 °2θ (e.g., 4.8, 5.6, 9.6, 17.6, 20.0, and 24.6 °2θ)) using Cu Ka radiation.

[0480] Embodiment 7. The morphological form of Embodiment 3, wherein Form A is characterized by an XRPD pattern substantially similar to Figure 1 XRPD pattern shown.

[0481] Embodiment 8. The morphological form of Embodiment 3, wherein Form A is characterized by a DSC curve having a value selected from 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±5, and 170±5°C). 6±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))))))) at least one endothermic peak.

[0482] Embodiment 9. The morphological form of Embodiment 1 or 2, wherein the morphological form is Form B, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0483] Embodiment 10. The morphological 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° 2θ (e.g., 6.5±0.1, 16.7±0.1, and 18.6±0.1° 2θ (e.g., 6.5, 16.7, and 18.6° 2θ)) using Cu Ka radiation.

[0484] Embodiment 11. A morphological form according to 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°2θ (e.g., 3.2±0.1, 13.4±0.1, and 17.7±0.1°2θ (e.g., 3.2, 13.4, and 17.7°2θ)) using Cu Ka radiation.

[0485] Embodiment 12. The morphological 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 °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 °2θ (e.g., 3.2, 6.5, 13.4, 16.7, 17.7, and 18.6 °2θ)) using Cu Ka radiation.

[0486] Embodiment 13. The morphological form of embodiment 9, wherein Form B is characterized by an XRPD pattern substantially similar to Figure 2 XRPD pattern shown.

[0487] Embodiment 14. A morphological form according to Embodiment 9, wherein the form 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))))))).

[0488] Embodiment 15. The morphological form of Embodiment 1 or 2, wherein the morphological form is Form C, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0489] Embodiment 16. The morphological 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° 2θ (e.g., 16.1±0.1, 16.7±0.1, and 19.1±0.1° 2θ (e.g., 16.1, 16.7, and 19.1° 2θ)) using Cu Ka radiation.

[0490] Embodiment 17. A morphological form according to 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°2θ (e.g., 4.0±0.1, 12.6±0.1, and 14.1±0.1°2θ (e.g., 4.0, 12.6, and 14.1°2θ) using Cu Ka radiation.

[0491] Embodiment 18. The morphological 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 °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 °2θ (e.g., 4.0, 12.6, 14.1, 16.1, 16.7, and 19.1 °2θ)) using Cu Ka radiation.

[0492] Embodiment 19. The morphological form of Embodiment 15, wherein Form C is characterized by an XRPD pattern substantially similar to Figure 3 XRPD pattern shown.

[0493] Embodiment 20. A morphological form according to 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))))))).

[0494] Embodiment 21. The morphological form of Embodiment 1 or 2, wherein the morphological form is Form D, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0495] Embodiment 22. A morphological form according to 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°2θ (e.g., 5.3±0.1, 19.3±0.1, and 23.5±0.1°2θ (e.g., 5.3, 19.3, and 23.5°29)) using Cu Ka radiation.

[0496] Embodiment 23. A morphological form according to 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°2θ (e.g., 5.4±0.1, 9.7±0.1, and 18.8±0.1°2θ (e.g., 5.4, 9.7, and 18.8°2θ) using Cu Ka radiation.

[0497] Embodiment 24. The morphological 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°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°2θ (e.g., 5.4, 9.7, 15.3, 18.8, 19.3, and 23.5°2θ)) using Cu Ka radiation.

[0498] Embodiment 25. The morphological form of Embodiment 21, wherein Form D is characterized by an XRPD pattern substantially similar to Figure 4 XRPD pattern shown.

[0499] Embodiment 26. A morphological form according to 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))))))

[0500] Embodiment 27. The morphological form of Embodiment 1 or 2, wherein the morphological form is Form E, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0501] Embodiment 28. A morphological form according to 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°2θ (e.g., 7.4±0.1, 15.8±0.1, and 16.3±0.1°2θ (e.g., 7.4, 15.8, and 16.3°2θ)) using Cu Ka radiation.

[0502] Embodiment 29. A morphological form according to 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°2θ (e.g., 13.3±0.1, 19.2±0.1, and 22.4±0.1°2θ (e.g., 13.3, 19.2, and 22.4°2θ) using Cu Ka radiation.

[0503] Embodiment 30. The morphological 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 °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 °2θ (e.g., 7.4, 13.3, 15.8, 16.3, 19.2, and 22.4 °2θ)) using Cu Ka radiation.

[0504] Embodiment 31. The morphological form of Embodiment 27, wherein Form E is characterized by an XRPD pattern substantially similar to Figure 5 XRPD pattern shown.

[0505] Embodiment 32. A morphological form according to 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))))))).

[0506] Embodiment 33. The morphological form of Embodiment 1 or 2, wherein the morphological form is Form F, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0507] Embodiment 34. A morphological form according to 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°2θ (e.g., 5.5±0.1, 16.4±0.1, and 21.9±0.1°2θ (e.g., 5.5, 16.4, and 21.9°2θ)) using Cu Ka radiation.

[0508] Embodiment 35. A morphological form according to 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°2θ (e.g., 7.2±0.1, 14.5±0.1, and 15.2±0.1°2θ (e.g., 7.2, 14.5, and 15.2°2θ) using Cu Ka radiation.

[0509] Embodiment 36. The morphological 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 °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 °2θ (e.g., 5.5, 7.2, 14.5, 15.2, 16.4, and 21.9 °2θ)) using Cu Ka radiation.

[0510] Embodiment 37. The morphological form of Embodiment 33, wherein Form F is characterized by an XRPD pattern substantially similar to Figure 6 XRPD pattern shown.

[0511] Embodiment 38. The morphological form of Embodiment 33, wherein Form F is characterized by a DSC curve having a value selected from 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, 1 At least one endothermic peak of 46±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)))))))

[0512] Embodiment 39. The morphological form of Embodiment 1 or 2, wherein the morphological form is Form G, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0513] Embodiment 40. The morphological 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°2θ (e.g., 4.0±0.1, 5.3±0.1, and 16.0±0.1°2θ (e.g., 4.0, 5.3, and 16.0°2θ)) using Cu Ka radiation.

[0514] Embodiment 41. A morphological form according to 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°2θ (e.g., 7.1±0.1, 16.7±0.1, and 19.2±0.1°2θ (e.g., 7.1, 16.7, and 19.2°2θ) using Cu Ka radiation.

[0515] Embodiment 42. The morphological 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°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°2θ (e.g., 4.0, 5.3, 7.1, 16.0, 16.7, and 19.2°2θ)) using Cu Ka radiation.

[0516] Embodiment 43. The morphological form of Embodiment 39, wherein Form G is characterized by an XRPD pattern substantially similar to Figure 7 XRPD pattern shown.

[0517] Embodiment 44. A morphological form according to 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))))))

[0518] Embodiment 45. The morphological form of Embodiment 1 or 2, wherein the morphological form is Form H, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0519] Embodiment 46. The morphological 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°2θ (e.g., 4.6±0.1, 13.8±0.1, and 17.0±0.1°2θ (e.g., 4.6, 13.8, and 17.0°2θ)) using Cu Ka radiation.

[0520] Embodiment 47. A morphological form according to 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°2θ (e.g., 5.6±0.1, 8.6±0.1, and 17.8±0.1°2θ (e.g., 5.6, 8.6, and 17.8°2θ) using Cu Ka radiation.

[0521] Embodiment 48. The morphological 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 °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 °2θ (e.g., 4.6, 5.6, 8.6, 13.8, 17.0, and 17.8 °2θ)) using Cu Ka radiation.

[0522] Embodiment 49. The morphological form of Embodiment 45, wherein Form H is characterized by an XRPD pattern substantially similar to Figure 8 XRPD pattern shown.

[0523] Embodiment 50. A morphological form according to 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))))))

[0524] Embodiment 51. The morphological form of Embodiment 1 or 2, wherein the morphological form is Form I, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0525] Embodiment 52. A morphological form according to 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°2θ (e.g., 5.1±0.1, 20.4±0.1, and 21.5±0.1°2θ (e.g., 5.1, 20.4, and 21.5°2θ)) using Cu Ka radiation.

[0526] Embodiment 53. A morphological form according to 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°2θ (e.g., 17.0±0.1, 22.3±0.1, and 25.5±0.1°2θ (e.g., 17.0, 22.3, and 25.5°2θ) using Cu Ka radiation.

[0527] Embodiment 54. The morphological 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 °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 °2θ (e.g., 5.1, 17.0, 20.4, 21.5, 22.3, and 25.5 °2θ)) using Cu Ka radiation.

[0528] Embodiment 55. The morphological form of Embodiment 51, wherein Form I is characterized by an XRPD pattern substantially similar to Fig. 9 XRPD pattern shown.

[0529] Embodiment 56. The morphological form of Embodiment 1 or 2, wherein the morphological form is Form J, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0530] Embodiment 57. A morphological form according to 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°2θ (e.g., 4.5±0.1, 17.9±0.1, and 22.5±0.1°2θ (e.g., 4.5, 17.9, and 22.5°2θ)) using Cu Ka radiation.

[0531] Embodiment 58. A morphological form according to 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°2θ (e.g., 5.1±0.1, 10.4±0.1, and 16.0±0.1°2θ (e.g., 5.1, 10.4, and 16.0°2θ) using Cu Ka radiation.

[0532] Embodiment 59. The morphological 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°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°2θ (e.g., 4.5, 5.1, 10.4, 16.0, 17.9, and 22.5°2θ)) using Cu Ka radiation.

[0533] Embodiment 60. The morphological form of embodiment 59, wherein Form J is characterized by an XRPD pattern substantially similar to Fig.10 XRPD pattern shown.

[0534] Embodiment 61. A morphological form according to 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))))))

[0535] Embodiment 62. The morphological form of Embodiment 1 or 2, wherein the morphological form is Form K, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0536] Embodiment 63. A morphological form according to 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°2θ (e.g., 5.2±0.1, 17.0±0.1, and 20.5±0.1°2θ (e.g., 5.2, 17.0, and 20.5°2θ)) using Cu Ka radiation.

[0537] Embodiment 64. A morphological form according to 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°2θ (e.g., 6.8±0.1, 21.6±0.1, and 22.4±0.1°2θ (e.g., 6.8, 21.6, and 22.4°2θ)) using Cu Ka radiation.

[0538] Embodiment 65. The morphological 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 °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 °2θ (e.g., 5.2, 6.8, 17.0, 20.5, 21.6, and 22.4 °2θ)) using Cu Ka radiation.

[0539] Embodiment 66. The morphological form of Embodiment 62, wherein Form K is characterized by an XRPD pattern substantially similar to Fig.11 XRPD pattern shown.

[0540] Embodiment 67. The morphological form of Embodiment 1 or 2, wherein the morphological form is Form L, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0541] Embodiment 68. A morphological form according to 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°2θ (e.g., 5.4±0.1, 7.8±0.1, and 19.3±0.1°2θ (e.g., 5.4, 7.8, and 19.3°2θ)) using Cu Ka radiation.

[0542] Embodiment 69. A morphological form according to 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°2θ (e.g., 14.8±0.1, 15.3±0.1, and 16.6±0.1°2θ (e.g., 14.8, 15.3, and 16.6°2θ) using Cu Ka radiation.

[0543] Embodiment 70. The morphological 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 °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 °2θ (e.g., 5.4, 7.8, 14.8, 15.3, 16.6, and 19.3 °2θ)) using Cu Ka radiation.

[0544] Embodiment 71. The morphological form of Embodiment 67, wherein Form L is characterized by an XRPD pattern substantially similar to Fig.12 XRPD pattern shown.

[0545] Embodiment 72. The morphological form according to any preceding embodiment, which is at least 90%, 95%, 96%, 97%, 98% or 99% pure.

[0546] Embodiment 73. A pharmaceutical composition comprising a therapeutically effective amount of any one of the morphological forms of any of the preceding embodiments or a combination thereof and a pharmaceutically acceptable excipient.

[0547] Embodiment 74. A method of inhibiting oncogenic variants of an ErbB receptor, comprising administering to a subject in need thereof a therapeutically effective amount of a morphological form according to any one of the preceding embodiments.

[0548] Embodiment 75. A method of inhibiting oncogenic variants of ErbB receptors, comprising administering to a subject in need thereof a pharmaceutical composition according to any one of the preceding embodiments.

[0549] Embodiment 76. A method of preventing or treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a morphological form according to any one of the preceding embodiments.

[0550] Embodiment 77. A method for preventing or treating cancer, comprising administering the pharmaceutical composition according to any one of the preceding embodiments to a subject in need thereof.

[0551] Embodiment 78. A method for preventing or treating cancer, comprising: i) identifying a subject candidate as a subject in need of said treatment when at least one oncogenic variant of an ErbB receptor is present in the subject; and ii) administering to the subject in need of said treatment a therapeutically effective amount of a morphological form according to any one of the preceding embodiments.

[0552] Embodiment 79. A method for preventing or treating cancer, comprising: i) identifying a subject candidate as a subject in need of said treatment when at least one oncogenic variant of an ErbB receptor is present in the subject; and ii) administering to the subject in need of said treatment a pharmaceutical composition according to any one of the preceding embodiments.

[0553] Embodiment 80. A method for preventing or treating cancer, comprising: i) identifying a subject candidate as a subject in need of said treatment when 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 said treatment a therapeutically effective amount of a morphological form according to any one of the preceding embodiments.

[0554] Embodiment 81. A method for preventing or treating cancer, comprising: i) identifying a subject candidate as a subject in need of said treatment when 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 said treatment a pharmaceutical composition according to any one of the preceding embodiments.

[0555] Embodiment 82. A method for preventing or treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a morphological form according to any one of the preceding embodiments, upon identifying the presence of at least one oncogenic variant of an ErbB receptor in the subject.

[0556] Embodiment 83. A method of preventing or treating cancer, comprising administering to a subject in need thereof a morphological form according to any one of the preceding embodiments, upon identifying the presence of at least one oncogenic variant of an ErbB receptor in the subject.

[0557] Embodiment 84. A method of preventing or treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a morphological form according to any one of the preceding embodiments when at least one oncogenic variant of an ErbB receptor is identified in a biological sample from the subject.

[0558] Embodiment 85. A method of preventing or treating cancer, comprising administering to a subject in need thereof a pharmaceutical composition according to any one of the preceding embodiments when at least one oncogenic variant of an ErbB receptor is identified in a biological sample from the subject.

[0559] Embodiment 86. A morphological form according to any of the preceding embodiments for use in inhibiting oncogenic variants of ErbB receptors.

[0560] Embodiment 87. A pharmaceutical composition according to any of the preceding embodiments, for inhibiting oncogenic variants of ErbB receptors.

[0561] Embodiment 88. A morphological form according to any of the preceding embodiments for use in preventing or treating cancer.

[0562] Embodiment 89. A pharmaceutical composition according to any one of the preceding embodiments, for use in preventing or treating cancer.

[0563] Embodiment 90. The morphological form according to any of the preceding embodiments, for use in preventing or treating cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor is present in the subject.

[0564] Embodiment 91. A pharmaceutical composition according to any one of the preceding embodiments, for use in preventing or treating cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor is present in the subject.

[0565] Embodiment 92. The morphological form according to any of the preceding embodiments, for use in preventing or treating cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor is present in a biological sample from the subject.

[0566] Embodiment 93. A pharmaceutical composition according to any one of the preceding embodiments, for use in preventing or treating cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor is present in a biological sample from the subject.

[0567] Embodiment 94. Use of a morphological form according to any of the preceding embodiments for the manufacture of a medicament for inhibiting oncogenic variants of an ErbB receptor.

[0568] Embodiment 95. Use of a morphological form according to any of the preceding embodiments in the manufacture of a medicament for the prevention or treatment of cancer.

[0569] Embodiment 96. The morphological form, pharmaceutical composition, method or use according to any one of the preceding embodiments, wherein the cancer is a solid tumor.

[0570] Embodiment 97. A morphological form, pharmaceutical composition, method or use according to any 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.

[0571] Embodiment 98. A morphological form, pharmaceutical composition, method or use according to any of the preceding embodiments, wherein the cancer is glioblastoma (GBM) or any subtype thereof.

[0572] Embodiment 99. A morphological form, pharmaceutical composition, method or use according to any one of the preceding embodiments, wherein the cancer is glioblastoma.

[0573] Embodiment 100. A morphological form, pharmaceutical composition, method or use according to any of the preceding embodiments, wherein the cancer or tumor or cell thereof expresses an oncogenic variant of the epidermal growth factor receptor (EGFR).

[0574] Embodiment 101. A morphological form, pharmaceutical composition, method or use according to any of the preceding embodiments, wherein the oncogenic variant is an oncogenic variant in an ErbB receptor.

[0575] Embodiment 102. The morphological form, pharmaceutical composition, method or use according to any of the preceding embodiments, wherein the oncogenic variant in the ErbB receptor is an allosteric variant.

[0576] Embodiment 103. A morphological form, pharmaceutical composition, method or use according to any of the preceding embodiments, wherein the oncogenic variant is an oncogenic variant in the epidermal growth factor receptor (EGFR).

[0577] Embodiment 104. The morphological form, pharmaceutical composition, method or use according to any of the preceding embodiments, wherein the oncogenic variant of EGFR is an allosteric variant.

[0578] Embodiment 105. A morphological form, a pharmaceutical composition, a method or a use according to any of the preceding embodiments, wherein the oncogenic variant is an oncogenic variant of the HER2 receptor.

[0579] Embodiment 106. A morphological form, pharmaceutical composition, method or use according to any of the preceding embodiments, wherein the oncogenic variant in the HER2 receptor is an allosteric variant.

[0580] Embodiment 107. The morphological form, pharmaceutical composition, method or use according to any of the preceding embodiments, wherein the oncogenic variant is an oncogenic variant in the HER-4 receptor.

[0581] Embodiment 108. The morphological form, pharmaceutical composition, method or use according to any of the preceding embodiments, wherein the subject or cancer is insensitive or resistant to treatment with one or more of gefitinib, erlotinib, afatinib, osimertinib and necrotizumab.

[0582] Embodiment 109. A morphological form, pharmaceutical composition, method or use according to any of the preceding embodiments, wherein the sequence encoding an oncogenic variant of EGFR comprises a deletion of exon 20 or a portion thereof, and wherein the cancer, its tumor or cell does not include an oncogenic variation in the sequence encoding one or more of the EGFR kinase domain (KD), BRAF, NTRK and KRAS, or wherein.

[0583] Embodiment 110. A morphological form, pharmaceutical composition, method or use according to any of the preceding embodiments, wherein the sequence encoding the oncogenic variant of EGFR comprises a deletion of exon 20 or a portion thereof, and wherein the cancer, its tumor or cells do not comprise markers indicative of responsiveness to immunotherapy.

[0584] Embodiment 111. The morphological form, pharmaceutical composition, method or use according to any of the preceding embodiments, wherein the oncogenic variant or oncogenic mutation is detected by a diagnostic test approved by the Food and Drug Administration (FDA).

[0585] Embodiment 112. The morphological form, pharmaceutical composition, method or use according to any of the preceding embodiments, wherein the subject has an adverse reaction to treatment with a Type I inhibitor.

[0586] Embodiment 113. The morphological form, pharmaceutical composition, method or use according to any of the preceding embodiments, wherein the individual has an adverse reaction to treatment with one or more of the following: gefitinib, erlotinib, afatinib, osimertinib, naximol, crizotinib, alectinib, ceritinib, dabrafenib, trametinib, afatinib, sabutinib, dacomitinib, canertinib, pelitinib, WZ4002, WZ8040, WZ3146, CO-1686 and AZD9291.

[0587] Example

[0588] It should be understood that the experimental values ​​described in this application are approximate and are subject to instrumental variations.

[0589] X-ray powder diffractometer (XRPD) was used to perform XRPD analysis using a Bruker D8 Advance X-ray powder diffractometer. The analysis was performed using the parameters described below.

[0590]

[0591] Differential Scanning Calorimetry (DSC): DSC was performed using a TA Discover 2500. The analysis was performed using the parameters described below.

[0592]

[0593]

[0594] Thermogravimetric analysis (TGA): TGA analysis was performed using a Discover 5500. The analysis was performed using the parameters described below.

[0595]

[0596] Dynamic Vapor Sorption (DVS): DVS analysis was performed using Intrinsic. The analysis was performed using the parameters described below.

[0597]

[0598] Karl Fischer Analysis: Karl Fischer analysis was performed using the coulometric method using a Mettler Toledo Coulometric KF titrator C30.

[0599] Polarized light microscopy (PLM): PLM analysis was performed using a BX53LED OLYMPUS using crossed polarizers with added silicone oil.

[0600] Nuclear Magnetic Resonance (NMR): NMR analyses were performed using a Bruker Avance-AV 400M at a frequency of 400 MHz, a 5 mm PABBO BB-1 H / D probe, 8 scans, a temperature of 297.6 K and a relaxation delay of 1 s.

[0601] 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.

[0602]

[0603] Example 1. Preparation of crystalline form

[0604] The crystalline forms of the present disclosure can be prepared according to one or more of the schemes as described herein.

[0605] Protocol 1: Equilibrate with solvent for 2 weeks at 25° C. About 20 mg of Form A was equilibrated in a suitable amount of solvent with a stirring plate at 25° C. for 2 weeks. The obtained suspension was filtered.

[0606] Protocol 2: Equilibrate with solvent for 1 week at 50° C. Equilibrate about 30 mg of Form A in a suitable amount of solvent with a stirring plate at 50° C. for 1 week. Filter the obtained suspension.

[0607] Scheme 3, Equilibration with solvent under temperature cycling. About 30 mg of Form A was equilibrated in a suitable amount of solvent under temperature cycling from 5°C to 50°C with a heating / cooling rate of 0.2°C / min for 10 cycles.

[0608] Scheme 4, crystallization by slow evaporation at room temperature. About 10 mg of Form A is dissolved in a suitable amount of solvent. The obtained solution is filtered through a 0.45 μm nylon filter. The filtered solution is then slowly evaporated under ambient conditions.

[0609] Scheme 5: Crystallization by rapid evaporation under a stream of nitrogen. About 10 mg of Form A is dissolved in a suitable amount of solvent. The obtained solution is filtered through a 0.45 μm nylon filter. The filtered solution is then rapidly evaporated under a stream of nitrogen.

[0610] Scheme 6: Crystallization from hot saturated solution by slow cooling. About 20 mg of Form A was dissolved in a minimum amount of the selected solvent at 50°C. The obtained 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.

[0611] Scheme 7, crystallization from hot saturated solution by rapid cooling. At 50°C, about 20 mg of Form A is dissolved in a minimum amount of selected solvent. The obtained solution is filtered through a 0.45 μm nylon filter. The filtered solution is then placed under a 5 ratio and stirred at a rate of 400 rpm. The precipitate is collected by filtration.

[0612] Scheme 8: Precipitation by adding antisolvent. Dissolve approximately 20 mg of Form A in a minimal amount of good solvent. Filter the solution. Slowly add antisolvent to the filtered solution. Collect the precipitate by filtration. When a turbid sample is obtained from the antisolvent experiment, perform a slow evaporation experiment at 25 °C.

[0613] Scheme 9: Variable relative humidity experiments. Form F was studied by variable humidity XRPD experiments. At 0% RH, Form F converted to a new crystalline form, designated Form L. Form L reverted to Form F at >10% RH. This indicates that Form L is a metastable anhydrate and is only stable at about 0% RH. See Example 8 for more details.

[0614] Preparation of Crystalline Forms. The disclosed forms may be prepared by one or more of the schemes shown in Table A below.

[0615] Table A

[0616]

[0617]

[0618] Example 2. Preparation of Anhydrate Form C

[0619] Preparation of Form C seed crystals. About 20 mg of Form A of Compound No. 1 was equilibrated in a suitable amount of solvent at 25° C. with a stirring plate for 2 weeks. The obtained suspension was filtered.

[0620] Preparation of anhydrous form C. About 300 mg of form A of compound No. 1 was weighed into a 40 mL bottle. 3 mL of acetone was added to the bottle. The obtained suspension was stirred at a rate of 300 rpm at 25 ° C. About 3 mg of form C seeds were added to the suspension. After the precipitate was formed, another 8 mL of acetone was added to the bottle. The suspension was kept stirring at a rate of 400 rpm at 25 ° C for 48 hours. The obtained suspension was taken out and the solid was separated by centrifugation. The solid was dried under vacuum at 30 ° C for 1 hour. About 240 mg of free base form C was obtained as a brown powder with a yield of 80%. This batch shows high crystallinity (see, e.g. Figure 3 ).

[0621] Example 3. Preparation of Hydrate Form F

[0622] Preparation of Form F seed crystals. About 30 mg of Form A of Compound No. 1 was equilibrated in a suitable amount of MeOH / H2O (v:v=7:3) at a heating / cooling rate of 0.2°C / min under temperature cycling between 5°C and 50°C for 10 cycles.

[0623] Preparation of anhydrous form F. About 300 mg of form A of compound No. 1 was added to a 20 mL bottle. Then 2 mL of MeOH:H2O (v:v=7:3) was added to the bottle. The obtained suspension was stirred at a rate of 400 rpm at 25°C. About 3 mg of form F seeds were added to the suspension. After the 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 a rate of 400 rpm at 25°C for 1 week. The obtained suspension was taken out and the solid was separated by centrifugation. The solid was dried under vacuum at 25°C for 14 hours. About 175 mg of form F was obtained as a brown powder with a yield of 58%, and was characterized by XRPD accordingly ( Figure 6 ).

[0624] Example 4. Competitive equilibrium experiment

[0625] Competitive equilibrium experiments were performed to determine the thermodynamic relationships of the anhydrous polymorphs. The experiments were performed at 25°C in 5 solvent systems as shown in Table B below.

[0626] Table B

[0627] form Solvents Remark Form B and Form C MeCN Get Form C Form B and Form C acetone Get Form C Form E and Form C EtOH Get Form C Form E and Form C EA Get Form C Form E and Form C Toluene Get Form E Form B, Form C and Form J MeOH Get Form G

[0628] Example 5. Bulk stability

[0629] Anhydrous Form C and Hydrate Form F were placed under three accelerated conditions for two weeks and four weeks. The solid obtained after bulk stability study was characterized by XRPD and HPLC. As shown in Table C-1 below, Form C and Form F do not change form under various storage conditions and time.

[0630] Table C-1

[0631]

[0632] The stability of the anhydrate Form C was analyzed after one month as shown in Table C-2 below.

[0633] Table C-2

[0634]

[0635]

[0636] "NT" means parameter not tested; "-" means value is below reported level

[0637] Example 6. Solubility study

[0638] 2.01mg of free alkali form C (equal to 2mg free alkali after correction for water content) is weighed into a 2mL vial. 2.09mg of free alkali form F (equal to 2mg free alkali after correction for water content) is weighed into a 2mL vial. 1mL of aqueous medium is added respectively. These suspensions are stirred at 37 ℃ with a speed of 400rpm. Take out these suspensions after 2 hours and 24 hours, then centrifuge for 5 minutes at 14,000rpm. Analyze supernatant by HPLC. Test the pH of supernatant.

[0639] As shown in Table D, Form C and Form F show pH-dependent solubility and similar solubility profiles in these aqueous media. They show good solubility (>2 mg / mL) in pH 1.0 HCl solution, pH 4.5 acetate buffer (50 mM), and SGF. They show low solubility (about 20 μg / mL) in pH 6.8 phosphate buffer (50 mM) and show (<10 μg / mL) in pure water. Both of them degrade in FeSSIF-v1 and FaSSIF-v1.

[0640] Table D

[0641]

[0642] "*" Samples were turbid in pH 4.5 acetate buffer.

[0643] Example 7. Hygroscopicity studies of Form C and Form F

[0644] The hygroscopicity of Form C and Form F was examined. See, e.g., Table E.

[0645] Table E

[0646]

[0647] Example 8. Variable Relative Humidity Experiments with Form F

[0648] Form F was studied by variable humidity XRPD experiments. See, e.g., Table F. At 0% RH, Form F converted to a new crystalline form, designated Form L. Form L reverted to Form F at >10% RH. This suggests that Form L is a metastable anhydrate and is only stable near 0% RH.

[0649] Table F

[0650]

[0651]

[0652] Equivalent form

[0653] It should be understood that the present invention may be embodied in other specific forms without departing from the spirit or essential features of the present invention. Therefore, the foregoing embodiments should be considered illustrative in all respects, rather than limiting the present invention described herein. Therefore, the scope of the present invention is indicated by the appended claims rather than the foregoing description, and all changes falling within the equivalent meaning and scope of the claims are intended to be included therein.

Claims

1. A morphological form of compound No. 1: Its solvate, its hydrate or its pharmaceutically acceptable salt.

2. The morphological form of claim 1, wherein the morphological form is a crystalline form.

3. The morphological form according to claim 1 or 2, wherein the morphological form is Form A, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and characterized in that The X-ray diffraction ("XRPD") pattern comprises 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 °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 °2θ (e.g., 4.8, 5.6, 9.6, 17.6, 20.0, and 24.6 °2θ)) using Cu Ka radiation, and is characterized in that the DSC curve has a peak selected from 76±20, 141±20, 156±20, and 170±20 °C (e.g., 76±1 0, 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))))))) at least one endothermic peak.

4. The morphological form according to claim 1 or 2, wherein the morphological form is Form B, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and characterized in that 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 °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 °2θ (e.g., 3.2, 6.5, 13.4, 16.7, 17.7, and 18.6 °2θ)) using Cu Ka radiation, and It is characterized in that the DSC curve has 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))))))).

5. The morphological form of claim 1 or 2, wherein the morphological form is Form C, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and characterized in that The X-ray diffraction ("XRPD") pattern comprises a 2θ 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 °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 °2θ (e.g., 4.0, 12.6, 14.1±0.1, 16.1±0.1, 16.7±0.1, and 19.1±0.1 °2θ (e.g., 4.0, 12.6, 14.1±0.1, 1, 16.1, 16.7 and 19.1 ° 2θ)), and is characterized in that the DSC curve has 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))))))).

6. The morphological form of claim 1 or 2, wherein the morphological form is Form D, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and characterized in that The X-ray diffraction ("XRPD") pattern comprises 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° 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° 2θ (e.g., 5.4, 9.7, 15.3, 18.8, 19.3, and 23.5° 2θ)) using Cu Ka radiation, and is characterized in that the DSC curve has a peak value selected from 128±20, 149±2 0 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))))))) at least one endothermic peak.

7. The morphological form of claim 1 or 2, wherein the morphological form is Form E, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and characterized in that The X-ray diffraction ("XRPD") pattern comprises a 2θ 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 °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 °2θ (e.g., 7.4, 13.3, 15.8±0.2, 16.3±0.2, 19.2±0.2, and 22.4±0.2 °2θ (e.g., 7.4, 13.3, 15.8±0.1, 8, 16.3, 19.2 and 22.4 ° 2θ)), and is characterized in that the DSC curve has 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))))))).

8. The morphological form of claim 1 or 2, wherein the morphological form is Form F, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and characterized in that The X-ray diffraction ("XRPD") pattern comprises 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 °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 °2θ (e.g., 5.5, 7.2, 14.5, 15.2, 16.4, and 21.9 °2θ)) using Cu Ka radiation, and is characterized in that the DSC curve has a peak selected from 48±20, 80±20, 146±20, and 174±20 °C (e.g., At least one endothermic peak of 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))))))) 9. The morphological form of claim 1 or 2, wherein the morphological form is Form G, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and characterized in that The X-ray diffraction ("XRPD") pattern comprises 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 °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 °2θ (e.g., 4.0, 5.3, 7.1, 16.0, 16.7, and 19.2 °2θ)) using Cu Ka radiation, and is characterized in that the DSC curve has a 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))))))) at least one endothermic peak.

10. The morphological form of claim 1 or 2, wherein the morphological form is Form H, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and characterized in that The X-ray diffraction ("XRPD") pattern comprises 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 °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 °2θ (e.g., 4.6, 5.6, 8.6, 13.8, 17.0, and 17.8 °2θ)) using Cu Ka radiation , and characterized in that the DSC curve has 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))))))) 11. The morphological form of claim 1 or 2, wherein the morphological form is Form I, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and characterized in that The X-ray diffraction ("XRPD") pattern comprises 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 °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 °2θ (e.g., 5.1, 17.0, 20.4, 21.5, 22.3, and 25.5 °2θ)) using Cu Ka radiation.

12. The morphological form of claim 1 or 2, wherein the morphological form is Form J, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and characterized in that 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° 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° 2θ (e.g., 4.5, 5.1, 10.4, 16.0, 17.9, and 22.5° 2θ)) using Cu Ka radiation, and It is characterized in that the DSC curve has 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))))))).

13. The morphological form of claim 1 or 2, wherein the morphological form is Form K, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and characterized in that The X-ray diffraction ("XRPD") pattern comprises 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 °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 °2θ (e.g., 5.2, 6.8, 17.0, 20.5, 21.6, and 22.4 °2θ)) using Cu Ka radiation.

14. The morphological form of claim 1 or 2, wherein the morphological form is Form L, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and characterized in that The x-ray diffraction ("XRPD") pattern comprises 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 °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 °2θ (e.g., 5.4, 7.8, 14.8, 15.3, 16.6, and 19.3 °2θ)) using Cu Ka radiation.

15. The morphological form of any of the preceding claims which is at least 90%, 95%, 96%, 97%, 98% or 99% pure.

16. A pharmaceutical composition comprising a therapeutically effective amount of any one or combination of the morphological forms according to any preceding claim and a pharmaceutically acceptable excipient.

17. A method of inhibiting oncogenic variants of ErbB receptors comprising administering to a subject in need thereof a therapeutically effective amount of a morphological form or a pharmaceutical composition according to any one of the preceding claims.

18. A method of preventing or treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of the morphological form or pharmaceutical composition according to any one of the preceding claims.

19. A method for preventing or treating cancer, comprising: i) identifying the subject candidate as a subject in need of said treatment when at least one oncogenic variant of an ErbB receptor is present in the subject or in a biological sample from said subject; and ii) administering to said subject in need of said treatment a therapeutically effective amount of a morphological form or a pharmaceutical composition according to any one of the preceding claims.

20. A method of preventing or treating cancer comprising administering to a subject in need thereof a morphological form or a pharmaceutical composition according to any one of the preceding claims upon identification of the presence of at least one oncogenic variant of an ErbB receptor in the subject or in a biological sample from the subject.

21. The morphological form or pharmaceutical composition according to any one of the preceding claims for use in inhibiting oncogenic variants of ErbB receptors.

22. The morphological form or pharmaceutical composition according to any one of the preceding claims for use in the prevention or treatment of cancer.

23. The morphological form or pharmaceutical composition according to any of the preceding claims for use in preventing or treating cancer in a subject, wherein at least one oncogenic variant of an ErbB receptor is present in the subject or in a biological sample from the subject.

24. Use of a morphological form according to any one of the preceding claims in the manufacture of a medicament for inhibiting oncogenic variants of ErbB receptors.

25. Use of a morphological form according to any one of the preceding claims in the manufacture of a medicament for the prevention or treatment of cancer.

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

27. The morphological form, pharmaceutical composition, method or use according to any one of the preceding claims, wherein the cancer or tumor or cell thereof expresses an oncogenic variant of the epidermal growth factor receptor (EGFR).

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

29. The morphological form, pharmaceutical composition, method or use of any of the preceding claims, wherein the subject or the cancer is insensitive or resistant to treatment with one or more of gefinitinib, erlotinib, afatinib, osimertinib and necitumumab.

30. A morphological form, pharmaceutical composition, method or use according to any of the preceding claims, wherein the sequence encoding the oncogenic variant of the EGFR comprises a deletion of exon 20 or a portion thereof, and wherein the cancer, or a tumor or cell thereof, does not comprise an oncogenic variation or a marker indicative of responsiveness to immunotherapy in the sequence encoding one or more of the EGFR kinase domain (KD), BRAF, NTRK and KRAS.

31. The morphological form, pharmaceutical composition, method or use according to any one of the preceding claims, wherein the oncogenic variant or oncogenic mutation is detected by a diagnostic test approved by the Food and Drug Administration (FDA).

32. The morphological form, pharmaceutical composition, method or use according to any one of the preceding claims, wherein the subject has an adverse reaction to treatment with a Type I inhibitor.

33. The morphological form, pharmaceutical composition, method or use of any of the preceding claims, wherein the subject has an adverse reaction to treatment with one or more of gefitinib, erlotinib, afatinib, osimertinib, naximol, crizotinib, alectinib, ceritinib, dabrafenib, trametinib, afatinib, sapitinib, dacomitinib, canertinib, dacomitinib, WZ4002, WZ8040, WZ3146, CO-1686 and AZD9291.

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