Crystalline forms of HER2 inhibitors

Abstract

The present invention relates to crystalline forms of HER2 inhibitors, to processes for their preparation, to pharmaceutical compositions comprising them and to their use, in particular for the treatment and / or prophylaxis of cancer and for the preparation of solid dispersions of such HER2 inhibitors.

Description

Technical Field

[0001] The present invention relates to a crystalline form of N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazino[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide. Background Art

[0002] N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]-diazino[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide (also referred to herein as Compound (1) or zongertinib) is a HER2 (ErbB2) inhibitor as set forth in WO 2021 / 213800. Zongertinib is a potent and selective tyrosine kinase inhibitor of wild-type and mutant HER2, which does not affect wild-type epidermal growth factor receptor (EGFR). Thus, it can be used for treating and / or preventing diseases and / or conditions, particularly tumors and / or hyperproliferative diseases (such as cancer), in which inhibition of wild-type and / or mutant HER2 provides a therapeutic benefit.

[0003] Different solid forms of an active pharmaceutical ingredient (API) generally have different properties. Differences in the physicochemical properties of the solid forms play a key role in the improvement of pharmaceutical compositions. For example, due to an improved solid form of the API, pharmaceutical formulations with improved dissolution characteristics or with improved stability or shelf life become available. The handling or disposal of the API can also be improved during the formulation process. The new solid form of the API can thus have desirable handling properties. Compared with other solid forms, it is easy to handle, more suitable for storage and / or allows more preferred purification.

[0004] For example, the tendency of the API to absorb water from the environment can negatively affect the pharmaceutical behavior and quality of formulations comprising the API. Water absorption can, for example, cause chemical degradation (e.g., via hydrolysis), trigger physical form changes (e.g., via hydrate formation), result in changes in dissolution behavior and affect powder properties (such as flowability, compressibility, tableting, compression behavior, etc.). In addition, the sudden appearance or disappearance of metastable polymorphs can present problems in drug development. Similarly, serious consequences can occur if a phase transition occurs in a pharmaceutical dosage form (e.g., after storage).

[0005] Thus, compared with the solutions of the prior art, there is still a need to improve the physicochemical properties (e.g., thermal stability) of N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]-diazinopyrimidin-2-yl]piperidin-4-yl}prop-2-enamide. A specific objective of the present invention is (e.g.) to improve the physical and chemical stability of compound (1) under temperature and / or moisture stress. Another objective of the present invention is to improve the powder properties (e.g., crystallinity, hygroscopicity, and morphology) of compound (1). There is also a strong need to provide forms of compound (1) that exhibit low hygroscopicity and / or are thermodynamically stable to avoid phase transitions during drug processing or storage. Description of the Drawings

[0006] Figure 1 Shows the X-ray powder diffraction pattern (XRPD) of crystalline Form I of compound (1); the x-axis shows the scattering angle in °2θ, and the y-axis shows the intensity of the scattered X-ray beam (in counts per second (cps) of the detected photons).

[0007] Figure 2 Shows the X-ray powder diffraction pattern (XRPD) of crystalline Form III of compound (1); the x-axis shows the scattering angle in °2θ, and the y-axis shows the intensity of the scattered X-ray beam (in counts per second (cps) of the detected photons).

[0008] Figure 3 Shows the X-ray powder diffraction pattern (XRPD) of crystalline Form IV of compound (1); the x-axis shows the scattering angle in °2θ, and the y-axis shows the intensity of the scattered X-ray beam (in counts per second (cps) of the detected photons).

[0009] Figure 4 Shows the overlay of the X-ray powder diffraction patterns (XRPD) of Form I (bottom), Form III (middle), and Form IV (top) of compound (1);

[0010] Figure 5 a shows the background Raman spectra;

[0011] Figure 5 b shows the Raman spectrum of crystalline Form I of compound (1);

[0012] Figure 5 c shows the Raman spectrum of crystalline Form III of compound (1);

[0013] Figure 5 d shows the Raman spectrum of crystalline Form IV of compound (1);

[0014] Figure 6 DSC curve showing crystalline Form I of compound (1);

[0015] Figure 7 DSC curve showing crystalline Form III of compound (1);

[0016] Figure 8 DSC curve showing crystalline Form IV of compound (1);

[0017] Figure 9 TGA curve showing crystalline Form I of compound (1);

[0018] Figure 10 TGA curve showing crystalline Form III of compound (1);

[0019] Figure 11 TGA curve showing crystalline Form IV of compound (1);

[0020] Figure 12 DVS adsorption and desorption isotherms showing crystalline Form I of compound (1);

[0021] Figure 13 Overlay of X-ray powder diffraction patterns (XRPD) of crystalline Form I measured before (bottom) and after (top) the DVS experiment described in Example 3.5;

[0022] Figure 14 DVS adsorption and desorption isotherms showing crystalline Form III of compound (1);

[0023] Figure 15 DVS adsorption and desorption isotherms showing crystalline Form IV of compound (1);

[0024] Figure 16 SEM image of crystalline Form I of compound (1) (Magnification: ×2000; Scale bar: 30 μm);

[0025] Figure 17 SEM image of crystalline Form III of compound (1) (Magnification: ×1000; Scale bar: 80 μm);

[0026] Figure 18 SEM image of crystalline Form IV of compound (1) (Magnification: ×440; Scale bar: 100 μm);

[0027] Figure 19 Overlay of the diffraction pattern of Form IV calculated from SXRD data (bottom) with two experimental diffraction patterns of a reference Form IV sample (middle and top);

[0028] Figure 20 Superposition of powder X-ray diffraction patterns of Form III of Compound (1) under different stress conditions: from bottom to top, reference Form III sample, Form III stressed at 90 °C / 78% RH for 21 days, Form III stressed at 90 °C / 3% RH for 21 days, reference Form III sample;

[0029] Figure 21 Superposition of powder X-ray diffraction patterns of Form IV of Compound (1) under different stress conditions: from bottom to top, reference Form IV sample, Form IV stressed at 90 °C / 78% RH for 21 days, Form IV stressed at 90 °C / 3% RH for 21 days, reference Form IV sample;

[0030] Figure 22 Superposition of powder X-ray diffraction patterns of Form I of Compound (1) before (bottom curve) and after (top curve) being stressed at 150 °C for 6 hours.

[0031] Figure 23 Superposition of powder X-ray diffraction patterns of Form II of Compound (1) before (bottom curve) and after (top curve) vacuum drying at 40 °C, which causes a phase transition from Form II to Form V.

[0032] Figure 24 Superposition of powder X-ray diffraction patterns of Form VI of Compound (1) before (bottom curve) and after (top curve) being stressed at 120 °C for 1 hour, which causes a phase transition from Form VI to amorphous Compound (1).

[0033] Figure 25 Superposition of powder X-ray diffraction patterns of various crystalline forms of Compound (1): from bottom to top, Form III, Form I, Form II, Form V, Form IV, Form VI, Form VII.

[0034] Figure 26 X-ray powder diffraction pattern (XRPD) of the spray-dried amorphous solid dispersion of Compound (1) with 75 wt% HPMCAS-M (top curve) and 50 wt% HPMCAS-M (bottom curve) obtained from Example 6 herein, compared with the XRPD of crystalline Compound (1).

[0035] Figure 27 X-ray powder diffraction pattern (XRPD) of the spray-dried amorphous solid dispersion of Compound (1) with 75 wt% PVP-VA (top curve) and 50 wt% PVP-VA (bottom curve) obtained from Example 6 herein, compared with the XRPD of crystalline Compound (1).

[0036] Figure 28 Shows the X-ray powder diffraction pattern (XRPD) of the spray-dried amorphous solid dispersion of compound (1) having 75 wt% L100 (top curve) and 50 wt% L100 (bottom curve) compared to the XRPD of crystalline compound (1) obtained from Example 6 herein.

[0037] Figure 29 Shows the X-ray powder diffraction pattern (XRPD) of the spray-dried amorphous solid dispersion of compound (1) having 75 wt% HPMCHME 15LV (top curve) and 50 wt% HPMC HME 15LV (bottom curve) compared to the XRPD of crystalline compound (1) obtained from Example 6 herein. SUMMARY OF THE INVENTION

[0038] According to a first aspect, different crystalline forms of compound (1) as shown below are provided:

[0039]

[0040] As yet another aspect, methods for producing the crystalline forms of compound (1) as shown above are provided. The crystalline forms of compound (1) obtainable by or via these methods represent further aspects of the present invention.

[0041] As still further aspects, uses and methods for treating and / or preventing tumors and / or hyperproliferative diseases (specifically cancer) using the crystalline forms of compound (1) are provided.

[0042] As another aspect, pharmaceutical compositions comprising the crystalline forms of compound (1) are provided.

[0043] Also provided herein is the use of these crystalline forms of compound (1) for preparing solid dispersions of compound (1). Also provided is a procedure for preparing solid dispersions of compound (1) using the crystalline forms of compound (1). DETAILED DESCRIPTION

[0044] The object of the present invention is to improve the physicochemical properties (e.g., thermal stability) of compound (1), wherein compound (1) has the following structure:

[0045]

[0046] Compared with other solid forms, the crystalline forms I, III, and IV as defined herein have one or more improved properties in terms of chemical stability, physical stability, melting point, moisture absorption, morphology, solubility, crystallinity, flowability, bulk density, compressibility, and wettability. Specifically, it has been found that the crystalline forms I, III, and IV improve the physical and chemical stability of compound (1) under temperature and / or moisture stress, thus allowing its stable storage.

[0047] For example, no irreversible phase change occurred during the DVS experiments of Form I, Form III, and Form IV (see Example 3.5). Additionally, Form I is polymorphically stable when subjected to temperature stress (see Example 4.2). Accelerated stress stability studies conducted on Form III and Form IV showed that no form underwent a phase change even under extreme storage conditions of 90 °C / 3% RH and 90 °C / 78% RH (see Example 4.1).

[0048] Form I contains a higher content of residual solvents (including water) and has a lower melting point compared to Forms III and IV. Form I can be converted to Form III and / or Form IV, for example, under competitive slurry conditions.

[0049] Compared with Form I, Forms III and IV can allow for higher storage stability of compound (1), which is important for maintaining the quality of the compound over time.

[0050] Forms III and IV have extremely similar melting points. Solid-state stability data indicate that they are both stable crystalline forms. Forms III and IV are not easily interconvertible under competitive slurry conditions.

[0051] Any one or a mixture of the crystalline forms I, III, and IV described herein can be advantageously used to prepare solid dispersions comprising compound (1) and a pharmaceutically acceptable dispersion carrier. Thus, the identity of the crystalline form - whether it is Form I, III, or IV - is not critical for the formulation process of compound (1) into a solid dispersion. For example, Forms III and IV showed comparable dissolution properties in the solvent system for preparing the solid dispersion.

[0052] It has been found that the crystalline forms I, III, and IV as defined herein exhibit improved thermal stability compared to the amorphous form of compound (1), which directly affects the quality of the material and its preservation during storage. In addition, the separation of the crystalline forms I, III, and / or IV (e.g., involving solid / liquid separation) is generally not only easier on a production scale but also allows for excellent control of the chemical purity of materials that rely on a well-defined crystal lattice. It also opens up opportunities for particle modification via research and development / optimization of crystallization procedures and / or milling protocols.

[0053] Accordingly, the polymorphic forms of the present invention surprisingly exhibit significantly advantageous physicochemical properties, which permit the stable manufacture and storage of compound (1) and the reliable manufacture of safe and effective pharmaceutical products containing compound (1).

[0054] The expressions “crystalline form”, “polymorphic form” and “polymorph” are used interchangeably herein and refer to a crystalline solid-phase chemical composition, which is a single chemical entity (e.g., compound X) or a multi-component composition (e.g., a salt or solvate (e.g., X a Y b Z c ))), each having a unique crystal lattice (periodic arrangement of molecules) and showing different X-ray diffraction patterns. When referring to the crystalline forms of compound (1) as shown below, any one of crystalline forms I, III and IV means including the respective broader aspects or definitions and each of its embodiments.

[0055] The term “solid form” as used herein refers to any crystalline and / or amorphous phase of a compound (e.g., compound (1)).

[0056] The crystalline forms of compound (1) of the present invention can be characterized by analytical methods for characterizing solids well-known in the pharmaceutical industry. These methods include (but are not limited to) XRPD, ssNMR, FTIR spectroscopy, Raman spectroscopy, DSC, TGA and GMS. The crystalline forms of compound (1) of the present invention can be characterized by one of the above analytical methods or by combining two or more of them. Specifically, the crystalline forms of compound (1) of the present invention can be characterized by any one of the following embodiments or by combining two or more of the following embodiments. As used in the present invention, “Cu-Kα radiation” includes Cu-Kα1 radiation and Cu-Kα1,2 radiation, where Cu-Kα1 radiation has a wavelength of and Cu-Kα1,2 radiation has an average wavelength of.

[0057] The term “compound (1)” as used herein refers to the compound defined as follows:

[0058]

[0059] The IUPAC name of compound (1) is N-{1-[8-({3-methyl-4-[(1-methyl-1H-1,3-benzodiazol-5-yl)oxy]phenyl}amino)-[1,3]diazino[5,4-d]pyrimidin-2-yl]piperidin-4-yl}prop-2-enamide. In the event of a discrepancy between the IUPAC name and the depicted formula, the formula shall prevail. Compound (1) was disclosed as Example Compound I-01 in WO 2021 / 213800. Compound (1) is also known as zogotinib. WO 2021 / 213800 describes [1,3]diazino[5,4-d]pyrimidines (such as compound (1)) as HER2 inhibitors and provides the synthetic procedures for compound (1). The properties of compound (1) and evidence of its inhibitory effect on HER2 wild type and YVMA kinase activity (without affecting EGFR) are also disclosed in WO 2021 / 213800, which is incorporated herein by reference.

[0060] Form IV

[0061] According to a first aspect, there is provided a crystalline form which is also referred to as Form IV in the context of the present invention. According to Form IV of the present invention, there is provided a crystalline form of compound (1):

[0062]

[0063] which is characterized in that:

[0064] (a) when measured using CuKα radiation having a or wavelength in the temperature range of 20 to 30 °C, the powder X-ray diffraction pattern comprises peaks at the following 2θ values: (5.9 ± 0.2)°, (11.7 ± 0.2)° and (16.7 ± 0.2)°; and / or

[0065] (b) when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the Raman spectrum comprises a peak at any of the following wavenumbers expressed as cm -1 : 640 ± 2 and / or 831 ± 2.

[0066] According to one embodiment of Form IV, when measured using CuKα radiation having a or wavelength in the temperature range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern comprising peaks at the following 2θ values: (5.9 ± 0.2)°, (11.7 ± 0.2)° and (16.7 ± 0.2)°.

[0067] According to yet another embodiment of Form IV, when using a or When measured within a temperature range of 20 to 30 °C using CuKα radiation having a wavelength of

[0068] According to yet another embodiment of Form IV, when using or When measured within a temperature range of 20 to 30 °C using CuKα radiation having a wavelength of

[0069] According to yet another embodiment of Form IV, when using or When measured within a temperature range of 20 to 30 °C using CuKα radiation having a wavelength of

[0070] According to yet another embodiment of Form IV, when using or When measured within a temperature range of 20 to 30 °C using CuKα radiation having a wavelength of

[0071] According to yet another embodiment of Form IV, when using or When measured within a temperature range of 20 to 30 °C using CuKα radiation having a wavelength of

[0072] According to yet another embodiment of Form IV, when using or When measured in the temperature range of 20 to 30 °C using CuKα radiation having a wavelength of, the crystalline form has a powder X-ray diffraction pattern including peaks at the following 2θ values: (5.9 ± 0.2)°, (11.5 ± 0.2)°, (11.7 ± 0.2)°, (14.7 ± 0.2)°, (16.7 ± 0.2)°, (18.8 ± 0.2)°, (19.2 ± 0.2)°, (24.3 ± 0.2)°, and (25.8 ± 0.2)°.

[0073] According to yet another embodiment of Form IV, when using CuKα radiation having a or wavelength and measured in the temperature range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern including peaks at the following 2θ values: (5.9 ± 0.1)°, (11.5 ± 0.1)°, (11.7 ± 0.1)°, (14.7 ± 0.1)°, (16.7 ± 0.1)°, (18.8 ± 0.1)°, (19.2 ± 0.1)°, (24.3 ± 0.1)°, and (25.8 ± 0.1)°.

[0074] According to yet another embodiment of Form IV, when using CuKα radiation having a or wavelength and measured in the temperature range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern including peaks at the following 2θ values: (5.9 ± 0.2)°, (11.5 ± 0.2)°, (11.7 ± 0.2)°, (14.7 ± 0.2)°, (16.7 ± 0.2)°, (18.8 ± 0.2)°, (19.2 ± 0.2)°, (21.3 ± 0.2)°, (24.3 ± 0.2)°, and (25.8 ± 0.2)°.

[0075] According to yet another embodiment of Form IV, when using CuKα radiation having a or wavelength and measured in the temperature range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern including peaks at the following 2θ values: (5.9 ± 0.1)°, (11.5 ± 0.1)°, (11.7 ± 0.1)°, (14.7 ± 0.1)°, (16.7 ± 0.1)°, (18.8 ± 0.1)°, (19.2 ± 0.1)°, (21.3 ± 0.1)°, (24.3 ± 0.1)°, and (25.8 ± 0.1)°.

[0076] According to yet another embodiment of Form IV, when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a powder X-ray diffraction pattern including peaks at the following expressed in cm -1Raman spectra of peaks at any of the wavenumbers: 640 ± 2 and / or 831 ± 2.

[0077] According to yet another embodiment of Form IV, when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum comprising peaks at the wavenumbers expressed below as cm -1 : 640 ± 2.

[0078] According to yet another embodiment of Form IV, when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum comprising peaks at the wavenumbers expressed below as cm -1 : 831 ± 2.

[0079] According to yet another embodiment of Form IV, when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum comprising peaks at the wavenumbers expressed below as cm -1 : 640 ± 2 and 831 ± 2.

[0080] According to yet another embodiment of Form IV, when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum comprising peaks at the wavenumbers expressed below as cm -1 : 238 ± 2, 640 ± 2 and 831 ± 2.

[0081] According to yet another embodiment of Form IV, when using CuKα radiation having or wavelength and measured in the temperature range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern comprising peaks at the following 2θ values: (5.9 ± 0.2)°, (11.7 ± 0.2)° and (16.7 ± 0.2)°, and when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum comprising peaks at any of the wavenumbers expressed below as cm -1 : 640 ± 2 and / or 831 ± 2.

[0082] According to yet another embodiment of Form IV, when using CuKα radiation having or wavelength and measured in the temperature range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern comprising peaks at the following 2θ values: (5.9 ± 0.2)°, (11.7 ± 0.2)° and (16.7 ± 0.2)°, and when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum comprising peaks at the wavenumbers expressed below as cm -1Raman spectra of the peaks at any of the wavenumbers: 640 ± 1 and / or 831 ± 1.

[0083] According to yet another embodiment of Form IV, when measured using CuKα radiation having a or wavelength in the temperature range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern comprising peaks at the following 2θ values: (5.9 ± 0.1)°, (11.7 ± 0.1)°, and (16.7 ± 0.1)°, and when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum comprising peaks at any of the wavenumbers expressed as cm -1 : 640 ± 2 and / or 831 ± 2.

[0084] According to yet another embodiment of Form IV, when measured using CuKα radiation having a or wavelength in the temperature range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern comprising peaks at the following 2θ values: (5.9 ± 0.2)°, (11.7 ± 0.2)°, and (16.7 ± 0.2)°, and when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum comprising peaks at the wavenumber expressed as cm -1 : 640 ± 2 and 831 ± 2.

[0085] According to yet another embodiment of Form IV, when measured using CuKα radiation having a or wavelength in the temperature range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern comprising peaks at the following 2θ values: (5.9 ± 0.2)°, (11.7 ± 0.2)°, and (16.7 ± 0.2)°, and when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum comprising peaks at the wavenumber expressed as cm -1 : 640 ± 2 or 831 ± 2.

[0086] According to yet another embodiment of Form IV, when measured using CuKα radiation having a or When measured within a temperature range of 20 to 30 °C using CuKα radiation having a wavelength of, the crystalline form has a powder X-ray diffraction pattern including peaks at the following 2θ values: (5.9 ± 0.2)°, (11.7 ± 0.2)°, (14.7 ± 0.2)°, (16.7 ± 0.2)°, (18.8 ± 0.2)°, and (19.2 ± 0.2)°, and when measured within a temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum including peaks at the following wave numbers expressed as cm -1 : 238 ± 2, 640 ± 2, and 831 ± 2.

[0087] According to yet another embodiment of Form IV, when using CuKα radiation having a wavelength of or and measured within a temperature range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern including peaks at the following 2θ values: (5.9 ± 0.2)°, (11.7 ± 0.2)°, (14.7 ± 0.2)°, (16.7 ± 0.2)°, (18.8 ± 0.2)°, and (19.2 ± 0.2)°, and when measured within a temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum including peaks at the following wave numbers expressed as cm -1 : 238 ± 1, 640 ± 1, and 831 ± 1.

[0088] According to yet another embodiment of Form IV, the crystalline form is in a substantially pure form.

[0089] As used herein, the term "substantially pure" when referring to a specified crystalline form of compound (1) means that the specified crystalline form contains less than about 20% (by weight) of residual components (such as its alternative polymorphic or isomorphic crystalline forms). Preferably, the substantially pure form of compound (1) contains less than about 10% (by weight) of alternative polymorphic or isomorphic crystalline forms, more preferably less than about 5% (by weight) (such as less than about 3% (by weight)) and most preferably less than about 1% (by weight) of alternative polymorphic or isomorphic crystalline forms.

[0090] As used herein, the term "isomorphic form" refers to forms having an overall identical crystal structure but with minor differences in unit cell dimensions (i.e., showing similar but not identical XRPD patterns). Due to the relatively small size of certain solvent molecules compared to the active compound, certain solvates can be isomorphic.

[0091] In a preferred embodiment of Form IV, the crystalline form has a TGA thermogram characterized by a weight loss of from about 243 °C (±5 °C) to about 580 °C (±5 °C). Preferably, the weight loss is measured at a heating rate of 20 °C / min. Additionally or alternatively, preferably, based on the weight of the crystalline form, the weight loss is about 50 wt%.

[0092] In a preferred embodiment of Form IV, the crystalline form has a TGA thermogram characterized by a weight loss of from about 420 °C (±5 °C) to about 455 °C (±5 °C). Preferably, the weight loss is measured at a heating rate of 20 °C / min. Additionally or alternatively, preferably, based on the weight of the crystalline form, the weight loss is about 50 wt%.

[0093] As used herein, the terms “about” and “approximately” mean within a statistically significant range of a value. The range can be within an order of magnitude, typically within 10% of a given value or range, more typically 5%, and even more typically 1% or most typically 0.1%. Sometimes, the range can be within the typical experimental error of the standard method used to measure and / or determine a given value or range.

[0094] In another embodiment of Form IV, when heated from 25 °C to 244 °C at a rate of 20 °C / min, based on the weight of the crystalline form, the crystalline form has a TGA thermogram showing a weight loss of no greater than 2.0 wt%, preferably no greater than 1.5 wt%, and even more preferably no greater than 1.3 wt%.

[0095] According to yet another embodiment of Form IV, the crystalline form has a melting point between 220 °C and 240 °C. According to yet another embodiment of Form IV, the crystalline form has a melting point between 225 °C and 235 °C. According to yet another embodiment of Form IV, the crystalline form has a melting point of about 232 °C (±5 °C). In these embodiments, the melting point is preferably determined by differential scanning calorimetry (DSC), specifically at a heating rate of 10 °C / min.

[0096] In another embodiment of Form IV, when measured at a heating rate of 10 °C / min, the crystalline form is characterized by a DSC curve comprising an endothermic peak, preferably a single endothermic peak, having a peak starting at a temperature of (229 ± 2) °C, preferably (229 ± 1) °C (e.g., about 229 °C).

[0097] In yet another embodiment of Form IV, when measured at a heating rate of 10 °C / min, the crystalline form is characterized by a DSC curve comprising an endothermic peak, preferably a single endothermic peak, having a peak maximum at a temperature of (232 ± 2) °C, preferably (232 ± 1) °C (e.g., about 232 °C).

[0098] In yet another embodiment of Form IV, when measured using DVS in the relative humidity range of 0 to 90% and at a temperature of (25.0 ± 1.0) °C, the crystalline form is characterized by showing a mass change of not more than 2.0 wt%, preferably not more than 1.0 wt%, most preferably not more than 0.5 wt% based on the weight of the crystalline form.

[0099] In yet another embodiment of Form IV, when measured using DVS in the relative humidity range of 0 to 80% and at a temperature of (25.0 ± 1.0) °C, the crystalline form is characterized by showing a mass change of not more than 2.0 wt%, preferably not more than 1.0 wt%, most preferably not more than 0.5 wt% (e.g., not more than 0.4 wt%) based on the weight of the crystalline form.

[0100] In one embodiment of Form IV, the crystalline form is anhydrous. As used herein, the term "anhydrous" or "anhydrate" refers to a crystalline solid that does not cooperate with or accommodate water in its crystal structure. The anhydrous form may still contain residual water, which is not part of the crystal structure but may be adsorbed on the surface of the crystal or absorbed in the disordered regions of the crystal. Generally, the anhydrous form does not contain more than 2.0 wt%, preferably not more than 1.0 wt%, and most preferably not more than 0.5 wt% of water based on the weight of the crystalline form.

[0101] In yet another embodiment of Form IV, the crystalline form is slightly hygroscopic. As used herein, the term "slightly hygroscopic" refers to a compound that shows a water absorption rate of at most 2 wt% based on the weight of the compound during the adsorption cycle when measured using DVS in the relative humidity range of 0 to 90% and at a temperature of (25.0 ± 1.0) °C.

[0102] In yet another embodiment of Form IV, the crystalline form is characterized by showing a triclinic unit cell with the space group P-1. Preferably, the unit cell has approximately the following parameters:

[0103]

[0104]

[0105]

[0106] α = 91.327(6)°

[0107] β = 102.462(7)°

[0108] γ = 114.987(8)°

[0109] It was measured by single crystal x-ray diffraction using CuKα radiation with a wavelength of at 283 - 303K.

[0110] In a preferred embodiment, the present invention relates to a composition comprising crystalline form IV as defined herein, wherein the crystalline form of compound (1) is present in an amount of at least about 50% (w / w), 60% (w / w), 65% (w / w), 67% (w / w), 70% (w / w), 75% (w / w), 80% (w / w) or 82% (w / w), preferably at least about 85% (w / w) or 88% (w / w), more preferably at least about 90% (w / w) (including at least about 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% (w / w) and also including equal to about 100% (w / w)) based on the weight of the composition. The remaining material may include other solid forms of compound (1) (e.g., amorphous compound (1)) and / or reaction impurities and / or processing impurities resulting from the preparation of the composition, but does not include any pharmaceutically acceptable excipients. Preferably, the remaining material is amorphous compound (1).

[0111] According to another aspect, there is provided a procedure for preparing a crystalline form of compound (1), wherein compound (1) is as follows:

[0112]

[0113] wherein the procedure comprises the following steps:

[0114] i) Dissolve compound (1) in at least one organic solvent under heating;

[0115] ii) Cool the solution obtained in step (i), wherein a crystalline form of compound (1) is formed; and

[0116] iii) Isolate at least a portion of the crystalline form of compound (1) obtained in step (ii).

[0117] Preferably, according to this procedure, crystalline form IV as defined herein is formed at least in part, especially selectively.

[0118] According to this method and according to step i), compound (1) is dissolved in at least one organic solvent under heating. Thus, one or more solvents can be used. Particularly preferably, the solvent is an alcohol or a solvent mixture comprising an alcohol. Even more preferably, the solvent is n-butanol or a solvent mixture comprising n-butanol. Dissolution can be exemplified by stirring the mixture at a temperature equal to or higher than 75 °C (e.g., at about 90 °C).

[0119] According to step ii), the mixture is cooled using an appropriate cooling rate. For example, it is possible to first cool slowly at a cooling rate of less than 1 °C / min (e.g., less than 0.5 °C / min, e.g., about 0.2 °C / min), and optionally subsequently cool rapidly at a higher cooling rate than the slow cooling (e.g.,) to room temperature (e.g., to about 20 °C). By means of cooling, crystalline Form IV is formed.

[0120] Finally, the resulting crystalline form can be separated according to step iii). This can be achieved by common procedures. According to one embodiment, the crystals can be preferably filtered and washed.

[0121] As yet another example, crystalline Form IV can also be formed in the presence of a seed crystal (e.g., using a seed crystal of crystalline Form III that has already been formed).

[0122] Therefore, to dissolve compound (1), a mixture of an alcohol and another organic solvent can be used. As an example of the organic solvent, anisole can be used, which can be used in an amount suitable for dissolving compound (1). For example, a mixture of anisole and n-butanol can be used in a volume ratio of approximately 1:1.

[0123] Then the alcohol can be removed at least partially by distillation. The resulting mixture with a seed crystal of crystalline Form III can be provided and maintained at a temperature equal to or higher than 100 °C. Then the mixture can be cooled to room temperature and the resulting solid in the form of crystalline Form IV can be separated out.

[0124] According to another aspect, there is provided a crystalline form obtainable or obtained by or by the following:

[0125] i) dissolving compound (1) in at least one organic solvent under heating; and

[0126] ii) cooling the solution obtained in step (i), wherein a crystalline form of compound (1) is formed.

[0127] In the embodiments where the crystalline form is obtained or obtainable herein, steps (i) and (ii) can be carried out as detailed above.

[0128] Crystalline forms obtainable by or by a process according to aspects of Form IV and its preferred embodiments set forth in this section are another object of the present invention. Preferably, the crystalline form is characterized by having a powder X-ray diffraction pattern comprising peaks as defined above for Form IV and / or a Raman spectrum comprising peaks at wavenumbers as defined above for Form IV. Preferably, the crystalline form corresponds to Form IV in its broadest form as defined herein or in any one of the embodiments.

[0129] Form III

[0130] According to another aspect, there is provided a crystalline form also referred to as Form III in the sense of the present invention. According to Form III of the present invention, there is provided a crystalline form of compound (1):

[0131]

[0132] which is characterized in that:

[0133] (a) when measured using CuKα radiation having a wavelength of or in the temperature range of 20 to 30 °C, the powder X-ray diffraction pattern comprises peaks at the following 2θ values: (6.2 ± 0.2)°, (9.5 ± 0.2)°, (11.4 ± 0.2)°, (12.4 ± 0.2)° and (16.2 ± 0.2)°; or

[0134] (b) when measured using CuKα radiation having a wavelength of or in the temperature range of 20 to 30 °C, the powder X-ray diffraction pattern comprises peaks at the following 2θ values: (6.2 ± 0.1)°, (9.5 ± 0.1)°, (11.4 ± 0.1)° and (12.4 ± 0.1)°; or

[0135] (c) when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the Raman spectrum comprises peaks at any of the following wavenumbers expressed as cm -1 : 1310 ± 2 and / or 1400 ± 2; or

[0136] (d) when using a wavelength of or When measured within a temperature range of 20 to 30 °C using CuKα radiation having a wavelength of -1 , the powder X-ray diffraction pattern includes peaks at the following 2θ values: (6.2 ± 0.2)°, (9.5 ± 0.2)°, (11.4 ± 0.2)°, (12.4 ± 0.2)°, and (16.2 ± 0.2)°, and when measured within a temperature range of 20 to 30 °C and at a wavelength of 785 nm, the Raman spectrum includes peaks at any of the following wavenumbers expressed in cm

[0137] (e) When using CuKα radiation having a wavelength of or and measured within a temperature range of 20 to 30 °C, the powder X-ray diffraction pattern includes peaks at the following 2θ values: (6.2 ± 0.1)°, (9.5 ± 0.1)°, (11.4 ± 0.1)°, and (12.4 ± 0.1)°, and when measured within a temperature range of 20 to 30 °C and at a wavelength of 785 nm, the Raman spectrum includes peaks at any of the following wavenumbers expressed in cm -1 : 1310 ± 2 and / or 1400 ± 2.

[0138] According to one embodiment of Form III, when measured within a temperature range of 20 to 30 °C using CuKα radiation having a wavelength of or , the crystalline form has a powder X-ray diffraction pattern that includes peaks at the following 2θ values: (6.2 ± 0.2)°, (9.5 ± 0.2)°, (11.4 ± 0.2)°, (12.4 ± 0.2)°, and (16.2 ± 0.2)°.

[0139] According to yet another embodiment of Form III, when measured within a temperature range of 20 to 30 °C using CuKα radiation having a wavelength of or , the crystalline form has a powder X-ray diffraction pattern that includes peaks at the following 2θ values: (6.2 ± 0.1)°, (9.5 ± 0.1)°, (11.4 ± 0.1)°, and (12.4 ± 0.1)°.

[0140] According to yet another embodiment of Form III, when measured within a temperature range of 20 to 30 °C using CuKα radiation having a wavelength of or , the crystalline form has a powder X-ray diffraction pattern that includes peaks at the following 2θ values: (6.2 ± 0.1)°, (9.5 ± 0.1)°, (11.4 ± 0.1)°, (12.4 ± 0.1)°, and (16.2 ± 0.1)°.

[0141] According to one embodiment of Form III, when measured using CuKα radiation having a wavelength of or in the temperature range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern comprising peaks at the following 2θ values: (6.2 ± 0.2)°, (9.5 ± 0.2)°, (11.4 ± 0.2)°, (12.4 ± 0.2)°, (15.4 ± 0.2)°, and (16.2 ± 0.2)°.

[0142] According to yet another embodiment of Form III, when measured using CuKα radiation having a wavelength of or in the temperature range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern comprising peaks at the following 2θ values: (6.2 ± 0.1)°, (9.5 ± 0.1)°, (11.4 ± 0.1)°, (12.4 ± 0.1)°, (15.4 ± 0.1)°, and (16.2 ± 0.1)°.

[0143] According to yet another embodiment of Form III, when measured using CuKα radiation having a wavelength of or in the temperature range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern comprising peaks at the following 2θ values: (6.2 ± 0.2)°, (9.5 ± 0.2)°, (11.4 ± 0.2)°, (12.4 ± 0.2)°, (16.2 ± 0.1)°, and (18.3 ± 0.2)°.

[0144] According to yet another embodiment of Form III, when measured using CuKα radiation having a wavelength of or in the temperature range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern comprising peaks at the following 2θ values: (6.2 ± 0.1)°, (9.5 ± 0.1)°, (11.4 ± 0.1)°, (12.4 ± 0.1)°, (16.2 ± 0.1)°, and (18.3 ± 0.1)°.

[0145] According to yet another embodiment of Form III, when measured using CuKα radiation having a wavelength of or When measured within the temperature range of 20 to 30 °C using CuKα radiation with a wavelength of, the crystalline form has a powder X-ray diffraction pattern including peaks at the following 2θ values: (6.2 ± 0.2)°, (9.5 ± 0.2)°, (11.4 ± 0.2)°, (12.4 ± 0.2)°, (13.5 ± 0.2)°, (13.8 ± 0.2)°, (16.2 ± 0.2)°, and (18.3 ± 0.2)°.

[0146] According to yet another embodiment of Form III, when using CuKα radiation with a wavelength of or When measured within the temperature range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern including peaks at the following 2θ values: (6.2 ± 0.1)°, (9.5 ± 0.1)°, (11.4 ± 0.1)°, (12.4 ± 0.1)°, (13.5 ± 0.1)°, (13.8 ± 0.1)°, (16.2 ± 0.1)°, and (18.3 ± 0.1)°.

[0147] According to yet another embodiment of Form III, when using CuKα radiation with a wavelength of or When measured within the temperature range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern including peaks at the following 2θ values: (6.2 ± 0.2)°, (9.5 ± 0.2)°, (11.4 ± 0.2)°, (12.4 ± 0.2)°, (15.4 ± 0.2)°, (16.2 ± 0.2)°, and (18.3 ± 0.2)°.

[0148] According to yet another embodiment of Form III, when using CuKα radiation with a wavelength of or When measured within the temperature range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern including peaks at the following 2θ values: (6.2 ± 0.1)°, (9.5 ± 0.1)°, (11.4 ± 0.1)°, (12.4 ± 0.1)°, (15.4 ± 0.1)°, (16.2 ± 0.1)°, and (18.3 ± 0.1)°.

[0149] According to yet another embodiment of Form III, when using CuKα radiation with a wavelength of or When measured in the temperature range of 20 to 30 °C using CuKα radiation with a wavelength of, the crystalline form has a powder X-ray diffraction pattern including peaks at the following 2θ values: (6.2 ± 0.2)°, (9.5 ± 0.2)°, (11.4 ± 0.2)°, (12.4 ± 0.2)°, (13.5 ± 0.2)°, (13.8 ± 0.2)°, (14.0 ± 0.2)°, (15.4 ± 0.2)°, (16.2 ± 0.2)° and (18.3 ± 0.2)°.

[0150] According to a further embodiment of Form III, when using a or When measured in the temperature range of 20 to 30 °C using CuKα radiation with a wavelength of, the crystalline form has a powder X-ray diffraction pattern including peaks at the following 2θ values: (6.2 ± 0.1)°, (9.5 ± 0.1)°, (11.4 ± 0.1)°, (12.4 ± 0.1)°, (13.5 ± 0.1)°, (13.8 ± 0.1)°, (14.0 ± 0.1)°, (15.4 ± 0.1)°, (16.2 ± 0.1)° and (18.3 ± 0.1)°.

[0151] According to a further embodiment of Form III, when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum including peaks at any of the following wavenumbers expressed as cm -1 : 1310 ± 2 and / or 1400 ± 2.

[0152] According to a further embodiment of Form III, when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum including a peak at the following wavenumber expressed as cm -1 : 1310 ± 2.

[0153] According to a further embodiment of Form III, when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum including a peak at the following wavenumber expressed as cm -1 : 1400 ± 2.

[0154] According to a further embodiment of Form III, when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum including peaks at the following wavenumbers expressed as cm -1 : 1310 ± 2 and 1400 ± 2.

[0155] According to yet another embodiment of Form III, the crystalline form has a Raman spectrum that includes peaks at any of the wavenumbers expressed as cm -1 when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm: 1310 ± 2 and / or 1400 ± 2 and peaks at any of the wavenumbers expressed as cm -1 when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm: 485 ± 2, 610 ± 2 and / or 1029 ± 2.

[0156] According to yet another embodiment of Form III, when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum that includes peaks at the wavenumbers expressed as cm -1 : 485 ± 2, 610 ± 2, 1029 ± 2, 1310 ± 2 and 1400 ± 2.

[0157] According to yet another embodiment of Form III, when measured in the temperature range of 20 to 30 °C using CuKα radiation having a wavelength of or , the crystalline form has a powder X-ray diffraction pattern that includes peaks at the following 2θ values: (6.2 ± 0.2)°, (9.5 ± 0.2)°, (11.4 ± 0.2)°, (12.4 ± 0.2)° and (16.2 ± 0.2)°, and when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum that includes peaks at any of the wavenumbers expressed as cm -1 : 1310 ± 2 and / or 1400 ± 2.

[0158] According to yet another embodiment of Form III, when measured in the temperature range of 20 to 30 °C using CuKα radiation having a wavelength of or , the crystalline form has a powder X-ray diffraction pattern that includes peaks at the following 2θ values: (6.2 ± 0.2)°, (9.5 ± 0.2)°, (11.4 ± 0.2)°, (12.4 ± 0.2)°, (15.4 ± 0.2)° and (16.2 ± 0.2)°, and when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum that includes peaks at any of the wavenumbers expressed as cm -1 : 1310 ± 2 and / or 1400 ± 2.

[0159] According to yet another embodiment of Form III, when measured in the temperature range of 20 to 30 °C using CuKα radiation having a wavelength of or When measured at a temperature in the range of 20 to 30 °C using CuKα radiation with a wavelength of, the crystalline form has a powder X-ray diffraction pattern with peaks at the following 2θ values: (6.2 ± 0.2)°, (9.5 ± 0.2)°, (11.4 ± 0.2)°, (12.4 ± 0.2)°, and (16.2 ± 0.2)°, and when measured at a temperature in the range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum with peaks at the following wavenumbers expressed in cm -1 : 1310 ± 2 and 1400 ± 2.

[0160] According to yet another embodiment of Form III, when using CuKα radiation with a wavelength of or When measured at a temperature in the range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern with peaks at the following 2θ values: (6.2 ± 0.2)°, (9.5 ± 0.2)°, (11.4 ± 0.2)°, (12.4 ± 0.2)°, (15.4 ± 0.2)°, and (16.2 ± 0.2)°, and when measured at a temperature in the range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum with peaks at the following wavenumbers expressed in cm -1 : 1310 ± 2 and 1400 ± 2.

[0161] According to yet another embodiment of Form III, when using CuKα radiation with a wavelength of or When measured at a temperature in the range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern with peaks at the following 2θ values: (6.2 ± 0.2)°, (9.5 ± 0.2)°, (11.4 ± 0.2)°, (12.4 ± 0.2)°, and (16.2 ± 0.2)°, and when measured at a temperature in the range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum with peaks at the following wavenumbers expressed in cm -1 : 485 ± 2, 610 ± 2, 1029 ± 2, 1310 ± 2, and 1400 ± 2.

[0162] According to yet another embodiment of Form III, when using CuKα radiation with a wavelength of or When measured at a temperature in the range of 20 to 30 °C with CuKα radiation having a wavelength of, the crystalline form has a powder X-ray diffraction pattern including peaks at the following 2θ values: (6.2 ± 0.2)°, (9.5 ± 0.2)°, (11.4 ± 0.2)°, (12.4 ± 0.2)°, (15.4 ± 0.2)° and (16.2 ± 0.2)°, and when measured at a temperature in the range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum including peaks at the following wave numbers expressed as cm -1 : 485 ± 2, 610 ± 2, 1029 ± 2, 1310 ± 2 and 1400 ± 2.

[0163] According to yet another embodiment of Form III, when using CuKα radiation having a wavelength of or and measured at a temperature in the range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern including peaks at the following 2θ values: (6.2 ± 0.1)°, (9.5 ± 0.1)°, (11.4 ± 0.1)° and (12.4 ± 0.1)°, and when measured at a temperature in the range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum including peaks at any of the following wave numbers expressed as cm -1 : 1310 ± 2 and / or 1400 ± 2.

[0164] According to yet another embodiment of Form III, when using CuKα radiation having a wavelength of or and measured at a temperature in the range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern including peaks at the following 2θ values: (6.2 ± 0.1)°, (9.5 ± 0.1)°, (11.4 ± 0.1)° and (12.4 ± 0.1)°, and when measured at a temperature in the range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum including peaks at the following wave numbers expressed as cm -1 : 1310 ± 2 and 1400 ± 2.

[0165] According to yet another embodiment of Form III, when using CuKα radiation having a wavelength of or and measured at a temperature in the range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern including peaks at the following 2θ values: (6.2 ± 0.1)°, (9.5 ± 0.1)°, (11.4 ± 0.1)°, (12.4 ± 0.1)° and (16.2 ± 0.1)°, and when measured at a temperature in the range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum including peaks at the following wave numbers expressed as cm -1Raman spectra of the peaks at any of the wavenumbers: 1310 ± 2 and / or 1400 ± 2.

[0166] According to yet another embodiment of Form III, when measured using CuKα radiation having a or wavelength in the temperature range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern comprising peaks at the following 2θ values: (6.2 ± 0.1)°, (9.5 ± 0.1)°, (11.4 ± 0.1)°, (12.4 ± 0.1)°, (15.4 ± 0.1)°, and (16.2 ± 0.1)°, and when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum comprising peaks at any of the following wavenumbers expressed in cm -1 : 1310 ± 2 and / or 1400 ± 2.

[0167] According to yet another embodiment of Form III, when measured using CuKα radiation having a or wavelength in the temperature range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern comprising peaks at the following 2θ values: (6.2 ± 0.1)°, (9.5 ± 0.1)°, (11.4 ± 0.1)°, (12.4 ± 0.1)°, and (16.2 ± 0.1)°, and when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum comprising peaks at the following wavenumber expressed in cm -1 : 1310 ± 2 and 1400 ± 2.

[0168] According to yet another embodiment of Form III, when measured using CuKα radiation having a or wavelength in the temperature range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern comprising peaks at the following 2θ values: (6.2 ± 0.1)°, (9.5 ± 0.1)°, (11.4 ± 0.1)°, (12.4 ± 0.1)°, (15.4 ± 0.1)°, and (16.2 ± 0.1)°, and when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum comprising peaks at any of the following wavenumbers expressed in cm -1 : 1310 ± 2 and 1400 ± 2.

[0169] According to yet another embodiment of Form III, when measured using CuKα radiation having a or When measured at a temperature range of 20 to 30 °C using CuKα radiation with a wavelength of, the crystalline form has a powder X-ray diffraction pattern with peaks at the following 2θ values: (6.2 ± 0.1)°, (9.5 ± 0.1)°, (11.4 ± 0.1)°, and (12.4 ± 0.1)°, and when measured at a temperature range of 20 to 30 °C and a wavelength of 785 nm, the crystalline form has a Raman spectrum with peaks at the following wave numbers expressed as cm -1 : 485 ± 2, 610 ± 2, 1029 ± 2, 1310 ± 2, and 1400 ± 2.

[0170] According to yet another embodiment of Form III, when using CuKα radiation with a wavelength of or and measured at a temperature range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern with peaks at the following 2θ values: (6.2 ± 0.2)°, (9.5 ± 0.2)°, (11.4 ± 0.2)°, (12.4 ± 0.2)°, (15.4 ± 0.2)°, (16.2 ± 0.2)°, and (18.3 ± 0.2)°, and when measured at a temperature range of 20 to 30 °C and a wavelength of 785 nm, the crystalline form has a Raman spectrum with peaks at the following wave numbers expressed as cm -1 : 485 ± 2, 610 ± 2, 1029 ± 2, 1310 ± 2, and 1400 ± 2.

[0171] According to yet another embodiment of Form III, the crystalline form is in a substantially pure form.

[0172] In a preferred embodiment of Form III, the crystalline form has a TGA thermogram characterized by a mass loss of approximately 240 °C (±5 °C) to approximately 580 °C (±5 °C). Preferably, the mass loss is measured at a heating rate of 20 °C / min. Additionally or alternatively, preferably, based on the weight of the crystalline form, the mass loss is approximately 61 wt%.

[0173] In a preferred embodiment of Form III, the crystalline form has a TGA thermogram characterized by a mass loss of approximately 420 °C (±5 °C) to approximately 454 °C (±5 °C). Preferably, the mass loss is measured at a heating rate of 20 °C / min. Additionally or alternatively, preferably, based on the weight of the crystalline form, the mass loss is approximately 61 wt%.

[0174] In another embodiment of Form III, when heated from 25 °C to 240 °C at a rate of 20 °C / min, the crystalline form has a TGA thermogram showing a mass loss of not more than 2.0 wt%, preferably not more than 1.5 wt%, even more preferably not more than 1.1 wt% based on the weight of the crystalline form.

[0175] According to yet another embodiment of Form III, the crystalline form has a melting point between 220 °C and 240 °C. According to yet another embodiment of Form III, the crystalline form has a melting point between 225 °C and 230 °C. According to yet another embodiment of Form III, the crystalline form has a melting point of about 231 °C (±5 °C). In these embodiments, the melting point is preferably determined by differential scanning calorimetry (DSC), specifically at a heating rate of 10 °C / min.

[0176] In another embodiment of Form III, when measured at a heating rate of 10 °C / min, the crystalline form is characterized by a DSC curve comprising an endothermic peak, preferably a single endothermic peak, which has a peak starting at a temperature of (228 ± 2) °C, preferably (228 ± 1) °C (e.g., about 228 °C).

[0177] In yet another embodiment of Form III, when measured at a heating rate of 10 °C / min, the crystalline form is characterized by a DSC curve comprising an endothermic peak, preferably a single endothermic peak, which has a peak maximum at a temperature of (231 ± 2) °C, preferably (231 ± 1) °C (e.g., about 231 °C).

[0178] In yet another embodiment of Form III, when measured using DVS in the relative humidity range of 0 to 90% and at a temperature of (25.0 ± 1.0) °C, the crystalline form is characterized by showing a mass change of not more than 2.0 wt%, preferably not more than 1.7 wt% based on the weight of the crystalline form.

[0179] In yet another embodiment of Form III, when measured using DVS in the relative humidity range of 0 to 80% and at a temperature of (25.0 ± 1.0) °C, the crystalline form is characterized by showing a mass change of not more than 2.0 wt%, preferably not more than 1.5 wt%, most preferably not more than 1.2 wt% based on the weight of the crystalline form.

[0180] In one embodiment of Form III, the crystalline form is anhydrous.

[0181] In yet another embodiment of Form III, the crystalline form is slightly hygroscopic.

[0182] In a preferred embodiment, the present invention relates to a composition comprising crystalline Form III as defined herein, wherein the crystalline form of compound (1) is present in an amount of at least about 50% (w / w), 60% (w / w), 65% (w / w), 67% (w / w), 70% (w / w), 75% (w / w), 80% (w / w) or 82% (w / w), preferably at least about 85% (w / w) or 88% (w / w), more preferably at least about 90% (w / w) (including at least about 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% (w / w) and also including equal to about 100% (w / w)) based on the weight of the composition. The remaining material may include other solid forms of compound (1) (e.g., amorphous compound (1)) and / or reaction impurities and / or processing impurities resulting from the preparation of the composition, but does not include any pharmaceutically acceptable excipients. Preferably, the remaining material is amorphous compound (1).

[0183] According to another aspect, there is provided a procedure for preparing a crystalline form of compound (1), wherein compound (1) is as follows:

[0184]

[0185] wherein the procedure comprises the following steps:

[0186] i) providing a suspension of compound (1) in at least one organic solvent;

[0187] ii) agitating the suspension obtained in step (i) until a crystalline form of compound (1) is formed; and

[0188] iii) separating at least a portion of the crystalline form of compound (1) obtained in step (ii).

[0189] Preferably, according to this procedure, crystalline Form III as defined herein is formed at least in part, particularly selectively.

[0190] According to this method and according to step (i), compound (1) is preferably suspended or slurried in at least one organic solvent after heating. Accordingly, one or more organic solvents may be used. In a preferred embodiment in this regard, the at least one organic solvent is an alcohol or an ester. In a preferred embodiment in this regard, the at least one organic solvent is an ester. In a preferred embodiment in this regard, the at least one organic solvent is isopropyl alcohol or isopropyl acetate (IPAc). In a preferred embodiment in this regard, the at least one organic solvent is isopropyl acetate (IPAc). The suspension can be achieved, for example, by agitating the mixture at a temperature equal to or higher than 50°C (e.g., at about 70°C (±5°C)).

[0191] Agitation is carried out according to step (ii). In one embodiment in this regard, the agitation of step (ii) is carried out at a temperature of 18 °C - 75 °C and / or for 1 - 18 hours. In one embodiment in this regard, the agitation of step (ii) is carried out at a temperature of at least 50 °C and / or for at least 8 hours. In one alternative or additional preferred embodiment in this regard, the agitation of step (ii) is carried out at a temperature of 55 °C to 75 °C and / or for 10 to 18 hours. In one alternative embodiment in this regard, the agitation of step (ii) is carried out at a temperature of 18 °C to 30 °C and / or for 1 to 3 hours (e.g., about 2 hours).

[0192] During agitation, the slurry or suspension is cooled at an appropriate cooling rate. The cooling rate may preferably be reduced during the subsequent cooling phase. Generally, cooling can be carried out from the agitation temperature described above to room temperature. During cooling, solid crystalline Form III is formed.

[0193] The solid thus formed can then be separated. This can be achieved by common procedures. According to one embodiment, separation can be carried out by filtering the mixture.

[0194] According to one embodiment, the procedures described above may include an additional seeding step. Thus, seeds of crystalline Form III can preferably be added to the suspension at the start of agitation step (ii).

[0195] According to another aspect, there is provided a crystalline form obtainable or obtained by:

[0196] i) providing a suspension of compound (1) in at least one organic solvent; and

[0197] ii) agitating the suspension obtained in step (i) until a crystalline form of compound (1) is formed.

[0198] In the embodiments in which the crystalline form is obtained or obtainable herein, steps (i) and (ii) can be carried out as detailed above.

[0199] The crystalline form obtainable or obtained by the procedures according to the aspects of Form III and its preferred embodiments described in this section is another object of the present invention. Preferably, the crystalline form is characterized by having a powder X-ray diffraction pattern comprising peaks as defined above for Form III and / or a Raman spectrum comprising peaks at wavenumbers as defined above for Form III. Preferably, the crystalline form corresponds to Form III in its broadest form as defined herein or in any one of the embodiments.

[0200] Form I

[0201] According to another aspect, there is provided a crystalline form also referred to as Form I in the sense of the present invention. For Form I according to the present invention, there is provided a crystalline form of compound (1):

[0202]

[0203] which is characterized in that:

[0204] (a) when measured using CuKα radiation having a wavelength of or in the temperature range of 20 to 30 °C, the powder X-ray diffraction pattern includes peaks at the following 2θ values: (7.9 ± 0.2)° and (12.1 ± 0.2)°; and / or

[0205] (b) when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the Raman spectrum includes peaks at any of the following wavenumbers expressed as cm -1 : 1411 ± 2 and / or 1602 ± 2.

[0206] Alternatively, for Form I according to the present invention, there is provided a crystalline form of compound (1):

[0207]

[0208] which is characterized in that:

[0209] (a) when measured using CuKα radiation having a wavelength of or in the temperature range of 20 to 30 °C, the powder X-ray diffraction pattern includes peaks at the following 2θ values: (7.9 ± 0.2)° and (12.0 ± 0.2)°; and / or

[0210] (b) when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the Raman spectrum includes peaks at any of the following wavenumbers expressed as cm -1 : 1411 ± 2 and / or 1602 ± 2.

[0211] According to one embodiment of Form I, when measured using CuKα radiation having a wavelength of or in the temperature range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern including peaks at the following 2θ values: (7.9 ± 0.2)° and (12.1 ± 0.2)°.

[0212] According to one embodiment of Form I, when measured using CuKα radiation having a wavelength of or When measured within a temperature range of 20 to 30 °C using CuKα radiation having a wavelength of, the crystalline form has a powder X-ray diffraction pattern including peaks at the following 2θ values: (7.9 ± 0.2)° and (12.0 ± 0.2)°.

[0213] According to yet another embodiment of Form I, when using CuKα radiation having a wavelength of or and measured within a temperature range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern including peaks at the following 2θ values: (7.9 ± 0.1)° and (12.1 ± 0.1)°.

[0214] According to yet another embodiment of Form I, when using CuKα radiation having a wavelength of or and measured within a temperature range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern including peaks at the following 2θ values: (7.9 ± 0.1)° and (12.0 ± 0.1)°.

[0215] According to yet another embodiment of Form I, when using CuKα radiation having a wavelength of or and measured within a temperature range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern including peaks at the following 2θ values: (6.1 ± 0.2)°, (7.9 ± 0.2)°, (11.1 ± 0.2)°, (12.0 ± 0.2)°, (17.2 ± 0.2)°, and (17.9 ± 0.2)°.

[0216] According to yet another embodiment of Form I, when using CuKα radiation having a wavelength of or and measured within a temperature range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern including peaks at the following 2θ values: (6.1 ± 0.1)°, (7.9 ± 0.1)°, (11.1 ± 0.1)°, (12.0 ± 0.1)°, (17.2 ± 0.1)°, and (17.9 ± 0.1)°.

[0217] According to yet another embodiment of Form I, when using CuKα radiation having a wavelength of or When measured in the temperature range of 20 to 30 °C using CuKα radiation with a wavelength of

[0218] According to yet another embodiment of Form I, when using or When measured in the temperature range of 20 to 30 °C using CuKα radiation with a wavelength of

[0219] According to yet another embodiment of Form I, when using or When measured in the temperature range of 20 to 30 °C using CuKα radiation with a wavelength of

[0220] According to yet another embodiment of Form I, when using or When measured in the temperature range of 20 to 30 °C using CuKα radiation with a wavelength of

[0221] According to yet another embodiment of Form I, when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a powder X-ray diffraction pattern comprising peaks at the following 2θ values expressed in cm -1Raman spectrum of the peaks at any of the wavenumbers: 1411 ± 2 and / or 1602 ± 2.

[0222] According to yet another embodiment of Form I, when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum comprising peaks at the following wavenumbers expressed in cm -1 : 1411 ± 2.

[0223] According to yet another embodiment of Form I, when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum comprising peaks at the following wavenumbers expressed in cm -1 : 1602 ± 2.

[0224] According to yet another embodiment of Form I, when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum comprising peaks at the following wavenumbers expressed in cm -1 : 1411 ± 2 and 1602 ± 2.

[0225] According to yet another embodiment of Form I, when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum comprising peaks at the following wavenumbers expressed in cm -1 : 824 ± 2, 1411 ± 2 and 1602 ± 2.

[0226] According to yet another embodiment of Form I, when using CuKα radiation having a or wavelength and measuring in the temperature range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern comprising peaks at the following 2θ values: (7.9 ± 0.2)° and (12.1 ± 0.2)°, and when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum comprising peaks at any of the following wavenumbers expressed in cm -1 : 1411 ± 2 and / or 1602 ± 2.

[0227] According to yet another embodiment of Form I, when using CuKα radiation having a or wavelength and measuring in the temperature range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern comprising peaks at the following 2θ values: (7.9 ± 0.2)° and (12.0 ± 0.2)°, and when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum comprising peaks at any of the following wavenumbers expressed in cm -1 : 1411 ± 2 and / or 1602 ± 2.

[0228] According to yet another embodiment of Form I, when measured using CuKα radiation having a wavelength of or in the temperature range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern comprising peaks at the following 2θ values: (7.9 ± 0.1)° and (12.1 ± 0.1)°, and when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum comprising peaks at any of the following wave numbers expressed as cm -1 : 1411 ± 2 and / or 1602 ± 2.

[0229] According to yet another embodiment of Form I, when measured using CuKα radiation having a wavelength of or in the temperature range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern comprising peaks at the following 2θ values: (7.9 ± 0.1)° and (12.0 ± 0.1)°, and when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum comprising peaks at any of the following wave numbers expressed as cm -1 : 1411 ± 2 and / or 1602 ± 2.

[0230] According to yet another embodiment of Form I, when measured using CuKα radiation having a wavelength of or in the temperature range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern comprising peaks at the following 2θ values: (7.9 ± 0.2)° and (12.1 ± 0.2)°, and when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum comprising peaks at the following wave number expressed as cm -1 : 1411 ± 2 and 1602 ± 2.

[0231] According to yet another embodiment of Form I, when measured using CuKα radiation having a wavelength of or in the temperature range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern comprising peaks at the following 2θ values: (7.9 ± 0.2)° and (12.0 ± 0.2)°, and when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum comprising peaks at the following wave number expressed as cm -1 : 1411 ± 2 and 1602 ± 2.

[0232] According to yet another embodiment of Form I, when measured using or When measured in the temperature range of 20 to 30 °C with CuKα radiation of a wavelength of , the crystalline form has a powder X-ray diffraction pattern including peaks at the following 2θ values: (6.1 ± 0.2)°, (7.9 ± 0.2)°, (11.1 ± 0.2)°, (12.0 ± 0.2)°, (17.2 ± 0.2)°, and (17.9 ± 0.2)°, and when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum including peaks at the following wavenumbers expressed in cm -1 : 824 ± 2, 1411 ± 2, and 1602 ± 2.

[0233] According to yet another embodiment of Form I, the crystalline form is in a substantially pure form.

[0234] In a preferred embodiment of Form I, the crystalline form has a TGA thermogram characterized by a mass loss from about 100 °C (±5 °C) to about 580 °C (±5 °C). Preferably, the mass loss is measured at a heating rate of 20 °C / min. Additionally or alternatively, preferably, based on the weight of the crystalline form, the mass loss is about 48 wt%.

[0235] In a preferred embodiment of Form I, the crystalline form has a TGA thermogram characterized by a mass loss from about 419 °C (±5 °C) to about 463 °C (±5 °C). Preferably, the mass loss is measured at a heating rate of 20 °C / min. Additionally or alternatively, preferably, based on the weight of the crystalline form, the mass loss is about 48 wt%.

[0236] According to yet another embodiment of Form I, the crystalline form has a melting point between 160 °C and 180 °C. According to yet another embodiment of Form I, the crystalline form has a melting point between 165 °C and 175 °C. According to yet another embodiment of Form I, the crystalline form has a melting point of about 171 °C (±5 °C). In these embodiments, the melting point is preferably determined by differential scanning calorimetry (DSC), specifically at a heating rate of 10 °C / min.

[0237] In another embodiment of Form I, when measured at a heating rate of 10 °C / min, the crystalline form is characterized by a DSC curve including an endothermic peak having a peak starting at a temperature of (165 ± 2) °C, preferably (165 ± 1) °C (e.g., about 165 °C).

[0238] In another embodiment of Form I, when measured at a heating rate of 10 °C / min, the crystalline form is characterized by a DSC curve comprising an endothermic peak having a peak maximum at a temperature of (171 ± 2) °C, preferably (171 ± 1) °C (e.g., about 171 °C).

[0239] In a preferred embodiment, the present invention relates to a composition comprising crystalline Form I as defined herein, wherein the crystalline form of compound (1) is present in an amount of at least about 50% (w / w), 60% (w / w), 65% (w / w), 67% (w / w), 70% (w / w), 75% (w / w), 80% (w / w) or 82% (w / w), preferably at least about 85% (w / w) or 88% (w / w), more preferably at least about 90% (w / w) (including at least about 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% (w / w) and also including equal to about 100% (w / w)) based on the weight of the composition. The remaining material may include other solid forms of compound (1) (e.g., amorphous compound (1)) and / or reaction impurities and / or processing impurities resulting from the preparation of the composition, but does not include any pharmaceutically acceptable excipients. Preferably, the remaining material is amorphous compound (1).

[0240] According to another aspect, there is provided a procedure for preparing a crystalline form of compound (1), wherein compound (1) is as follows:

[0241]

[0242] wherein the procedure comprises the following steps:

[0243] i) dissolving compound (1) under heating in a mixture of solvents comprising at least one water-miscible organic solvent and water;

[0244] ii) cooling the solution obtained in step (i), wherein a crystalline form of compound (1) is formed; and

[0245] iii) separating at least a portion of the crystalline form of compound (1) obtained in step (ii).

[0246] Preferably, according to the procedure, crystalline Form I as defined herein is formed at least in part, particularly selectively.

[0247] According to this method and according to step i), compound (1) is dissolved under heating in at least one water-miscible organic solvent and water. In particular, preferably the water-miscible organic solvent includes an alcohol. Even more preferably, the water-miscible organic solvent includes isopropanol. The amount of the water-miscible organic solvent can be in the range equal to or less than 10% w / w H2O. Dissolution can be exemplified by stirring the mixture at a temperature equal to or higher than 75 °C (for example, at about 90 °C).

[0248] According to step ii), the mixture is cooled to a suitable temperature (for example, equal to or lower than 85 °C, illustratively to about 75 °C), and the solution is stirred. Optional seeding with crystalline form I can be carried out. Crystalline form I is formed by cooling, preferably to room temperature (for example, to about 20 °C).

[0249] Finally, the resulting crystalline form can be separated according to step iii). This can be achieved by common procedures. According to one embodiment, the crystals can be preferably filtered and washed.

[0250] As yet another example, crystalline form I can also be formed by dissolving compound (1) in a mixture of organic solvents including an alcohol and one or more other organic solvents. As an example, a mixture of dichloromethane, tetrahydrofuran, and methanol can be used. The mixture can be washed, for example, with brine. The mixture can then be distilled and diluted with an organic solvent (for example, tetrahydrofuran). The distillation and dilution can be repeated until the amounts of water and alcohol are each equal to or less than 1.0% w / w. After cooling and holding the mixture at room temperature (for example, at 20 °C), crystalline form I is formed. This can be separated, for example, by filtration.

[0251] According to another aspect, crystalline form I is obtained as set forth in steps 1 to 6 of Example 1.1 (presented below).

[0252] According to another aspect, crystalline form I is obtained as set forth in steps 1 to 5 of Example 1.2 (presented below).

[0253] According to another aspect, there is provided a crystalline form obtainable or obtained by:

[0254] i) dissolving compound (1) under heating in a mixture of solvents including at least one water-miscible organic solvent and water; and

[0255] ii) cooling the solution obtained in step (i), wherein a crystalline form of compound (1) is formed.

[0256] In embodiments in which the crystalline form is obtained or obtainable herein, steps (i) and (ii) can be carried out as detailed above.

[0257] Crystalline forms obtainable by or via the procedures described in this section with respect to the aspects of Form I and its preferred embodiments are another object of the present invention. Preferably, the crystalline form is characterized by having a powder X-ray diffraction pattern comprising peaks as defined above for Form I and / or a Raman spectrum comprising peaks at wavenumbers as defined above for Form I. Preferably, the crystalline form corresponds to Form I in its broadest form as defined herein or in any one of the embodiments.

[0258] Solid dispersion

[0259] All solid forms as described herein (individually or as a mixture) can be used to generate a solid dispersion. Accordingly, the present invention further provides the use of any one of crystalline Forms I, III, and IV in their broadest form as described above or in any one of the embodiments for producing a solid dispersion comprising Compound (1) and a pharmaceutically acceptable dispersion carrier. The present invention also provides the use of any one of crystalline Forms I, III, and IV (in their broadest form as described above or in any one of the embodiments) or a mixture thereof for producing a solid dispersion comprising Compound (1) and a pharmaceutically acceptable dispersion carrier. In the solid dispersion, preferably Compound (1) is amorphous. In other words, the solid dispersion preferably comprises Compound (1) in amorphous form.

[0260] The present invention also provides the use of any one of crystalline Forms I, III, and IV (in their broadest form as described above or in any one of the embodiments) or a mixture thereof for producing a solid dispersion consisting essentially of Compound (1) and a pharmaceutically acceptable dispersion carrier. As used herein, the expressions "consists essentially of" and "consisting essentially of" have the meaning given to them in the art. Specifically, it indicates that other components may be present, particularly those other components that do not substantially affect the properties of the individual dispersion, composition, or formulation. These other components may be, for example, residual solvents.

[0261] The present invention also provides the use of any one of crystalline Forms I, III, and IV (in their broadest form as described above or in any one of the embodiments) or a mixture thereof for producing a solid dispersion consisting of Compound (1) and a pharmaceutically acceptable dispersion carrier.

[0262] As used herein, the term "solid dispersion" refers to a solid-state system comprising at least two components, wherein preferably one component in amorphous form (such as Compound (1) or generally an active pharmaceutical ingredient (API)) is dispersed throughout the other component (such as a pharmaceutically acceptable solid dispersion carrier, specifically a dispersion polymer).

[0263] As used herein, the phrase "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human tissue without excessive toxicity, irritation, allergic response, or other problems or complications and commensurate with a reasonable benefit / risk ratio.

[0264] As used herein, the term "dispersion carrier" refers to a carrier component that allows an API (e.g., compound (1)) to be dispersed throughout it such that a solid dispersion can be formed. In an embodiment, compound (1) is dispersed at the molecular level in a pharmaceutically acceptable dispersion carrier.

[0265] In an embodiment, the pharmaceutically acceptable dispersion carrier is a polymer. Thus, in the uses and procedures described herein, the solid dispersion preferably comprises compound (1) or a pharmaceutically acceptable salt thereof as defined herein and a polymer. The polymeric dispersion carrier is also referred to as a "dispersion polymer". Polymers are widely used in solid dispersion formulations. Different polymeric carriers produce solid dispersions with various properties in terms of physical stability, phase behavior, and drug release rate and extent. Due to the complex nature, it is necessary to test the solid dispersion formulation carriers most suitable for a given API. The pharmaceutically acceptable dispersion polymer is preferably a neutral or acidic polymer.

[0266] In other embodiments, the pharmaceutically acceptable dispersion carrier is enteric-coated (acidic polymer) or non-enteric-coated (neutral polymer), preferably an enteric-coated polymer. In other embodiments, the polymer is enteric-coated or non-enteric-coated, preferably enteric-coated. The term "enteric polymer" refers to a pH-dependent acidic polymer that is insoluble or only slightly soluble at low pH (e.g., about pH 1 but not exceeding pH 3) but becomes soluble at higher pH (e.g., pH 5 and above). In certain embodiments, the pH-dependent polymer becomes soluble in the pH range of about pH 5 and above (e.g., about pH 6 to about pH 9, about pH 6 to about pH 8, about pH 5 to about pH 7, or about pH 5 to about pH 6), the acidity of which is generally lower than the gastric environment and roughly corresponds to the pH value in the small intestine. Examples of enteric polymers include (but are not limited to) methyl acrylate-methacrylic acid copolymer, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hydroxypropyl methylcellulose acetate succinate, HPMCAS), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymer ( L100), shellac, cellulose acetate trimellitate, sodium alginate, and zein. The term "non-enteric polymer" refers to a neutral polymer that does not exhibit pH-dependent solubility characteristics. Examples of non-enteric polymers include (but are not limited to) cellulose derivatives (such as methylcellulose (MC), ethylcellulose (EC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), hydroxypropylmethylcellulose (HPMC)), poly-vinyl-pyrrolidone (PVP), copovidone (such as polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA)), poly(ethylene glycol) PEG, starch derivatives (such as cyclodextrin), (which is an amphiphilic copolymer composed of polyethylene glycol, polyvinylcaprolactam, and polyvinyl acetate).

[0267] In an embodiment, the pharmaceutically acceptable dispersion carrier is a polymer, or more simply the polymer is selected from the group consisting of: hydroxypropylmethylcellulose and its esters, polyvinylpyrrolidone and its copolymers, and polymethacrylates and their copolymers. The pharmaceutically acceptable dispersion carrier may contain a mixture of two or more polymers.

[0268] In one embodiment, hydroxypropylmethylcellulose and its esters are selected from the group consisting of: hydroxypropylmethylcellulose acetate (HPMCA), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), methylcellulose, hydroxyethylmethylcellulose, hydroxyethylcellulose, hydroxyethylcellulose acetate, hydroxyethylethylcellulose, hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropylmethylcellulose phthalate (HPMCP), carboxymethylethylcellulose (CMEC), cellulose acetate phthalate (CAP), cellulose acetate succinate (CAS), hydroxypropylmethylcellulose acetate phthalate (HPMCAP), cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose acetate trimellitate (HPMCAT), and carboxymethylcellulose acetate phthalate (CMCAB). In one embodiment, hydroxypropylmethylcellulose and its esters are selected from the group consisting of: hydroxypropylmethylcellulose acetate succinate and hydroxypropylmethylcellulose, specifically the hot-melt extrusion grade hydroxypropylmethylcellulose.

[0269] In one embodiment, polyvinylpyrrolidone and its copolymers are selected from the group consisting of: polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), polyvinyl alcohol, polyvinyl alcohol-polyvinyl acetate copolymer, and polyvinylpyrrolidone (PVP). Polyvinylpyrrolidone (PVP) is also commonly referred to as polyvidone or povidone. In an embodiment, polyvinylpyrrolidone and its copolymers are polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA).

[0270] In one embodiment, the polymethacrylate and its copolymer are selected from the group consisting of: ethyl acrylate-methyl methacrylate copolymer, methyl methacrylate-methacrylic acid copolymer, and methyl methacrylate-methacrylic acid copolymer. The polymethacrylate and its copolymer are obtained (for example) under the trade name from Evonik Industries AG. The methyl methacrylate-methacrylic acid copolymer is obtained (for example) under the trade name L100. In certain embodiments, the polymethacrylate and its copolymer are methyl methacrylate-methacrylic acid copolymer.

[0271] In an embodiment, the pharmaceutically acceptable dispersion carrier is a polymer, or more simply the polymer is selected from the group consisting of: hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), methyl methacrylate-methacrylic acid copolymer (for example L100) and hot melt extrusion grade hydroxypropyl methylcellulose (HPMC HME).

[0272] In certain embodiments, the pharmaceutically acceptable dispersion carrier is hydroxypropyl methylcellulose acetate succinate (HPMCAS). HPMCAS is also known as hydroxypropyl methylcellulose acetate succinate. Hydroxypropyl methylcellulose acetate succinate (HPMCAS) can be obtained by introducing acetyl and succinyl groups onto the hydroxyl groups of the main chain of hydroxypropyl methylcellulose (HPMC) (also known as hydroxypropyl methylcellulose). This procedure can be carried out by known methods (for example, by treating HPMC with acetic anhydride and / or using succinic anhydride). Acetic anhydride and succinic anhydride can react with hydroxypropyl methylcellulose (HPMC) under specific controlled conditions to produce HPMCAS with different degrees of substitution of acetyl and succinyl groups.

[0273] Based on the content (wt%) of acetyl and succinyl groups in HPMCAS, HPMCAS can be obtained in several grades (L, M, and H) with different degrees of substitution of acetyl and succinyl groups. Any grade of HPMCAS can be used in the solid dispersions of the present invention. Preferably, HPMCAS of grade L, M, or H is used. In certain embodiments, the pharmaceutically acceptable dispersion carrier is HPMCAS grade L. In certain embodiments, the pharmaceutically acceptable dispersion carrier is HPMCAS grade M. HPMCAS grade M may include an acetyl content of 7-11 wt%, a succinyl content of 10-14 wt%, a methoxy content of 21-25 wt%, and a hydroxypropoxy content of 5-9 wt%. Preferably, HPMCAS grade M (HPMCAS-M) is soluble at pH ≥ 6. In certain embodiments, the pharmaceutically acceptable dispersion carrier is HPMCAS grade H. Preferably, particulate HPMCAS (HPMCAS-G) is used. HPMCAS-G can be used for any grade of HPMCAS, specifically grade G, to use HPMCAS-MG.

[0274] In certain embodiments, the pharmaceutically acceptable dispersion carrier is polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA). Polyvinylpyrrolidone-vinyl acetate copolymer is a linear, random copolymer that can be obtained by free radical polymerization of monomers with a ratio of vinyl acetate to vinylpyrrolidone varying from 70 / 30 to 30 / 70.

[0275] In certain embodiments, the pharmaceutically acceptable dispersion carrier is a methacrylic acid-methyl methacrylate copolymer (e.g., L100). As used herein, the terms "methylacrylic acid methyl methacrylate copolymer" and "methacrylic acid methyl methacrylate copolymer" are used interchangeably.

[0276] In certain embodiments, the pharmaceutically acceptable dispersion carrier is a hot melt extrusion grade hydroxypropyl methylcellulose (HPMC HME). HPMC HME refers to a modified grade of hydroxypropyl methylcellulose with a low glass transition temperature and melt viscosity, which can be used for preparing solid dispersions via hot melt extrusion. HPMC HME is a water-soluble amorphous polymer, usually provided in the form of a white to off-white powder, and three grades with different molecular weights can be obtained (HPMC HME 15LV, HPMC HME100LV, and HPMC HME 4M). Preferably, the one with a molecular weight (M) lower than 100 kDa is used.W ) of HPMC HME 15LV. More preferably, those having a molecular weight (M W ) of HPMC HME 100LV are used.

[0277] By preferably dispersing the crystalline form of compound (1) at the molecular level in, for example, a polymeric pharmaceutically acceptable dispersion carrier, the amorphous state of compound (1) can be obtained and maintained even when exposed to high temperature and / or humidity conditions, and the solid dispersion can reliably provide compound (1) in amorphous form. In embodiments of the solid dispersion, compound (1) is amorphous.

[0278] As used herein, the term "amorphous" refers to a condensed phase in which the molecules are randomly oriented and which is characterized by the absence of any microscopic order, where no diffraction peaks are found by XRPD; an amorphous solid system can be composed of a single chemical entity or can be a multi-component system with a non-stoichiometric composition containing, for example, APIs, polymers, and other excipients. Amorphous solids typically have a crystalline-like short-range molecular arrangement but no long-range molecular packing order as in crystalline solids. The solid state form of a solid can be determined, for example, by X-ray powder diffraction ("XRPD") or modulated differential scanning calorimetry ("mDSC").

[0279] In embodiments, the solid dispersion comprises, consists of, or consists essentially of amorphous compound (1) and a pharmaceutically acceptable dispersion carrier, wherein compound (1) is substantially in an amorphous solid state form. In certain embodiments, substantially amorphous solid state form means a solid dispersion comprising at least 80 wt% amorphous compound (1) based on the total weight of 100 wt% of compound (1). In certain embodiments, substantially amorphous solid state form means a solid dispersion comprising at least 85 wt% amorphous compound (1) based on the total weight of 100 wt% of compound (1). In certain embodiments, substantially amorphous solid state form means a solid dispersion comprising at least 90 wt% amorphous compound (1) based on the total weight of 100 wt% of compound (1). In certain embodiments, substantially amorphous solid state form means a solid dispersion comprising at least 95 wt% amorphous compound (1) based on the total weight of 100 wt% of compound (1). In certain embodiments, substantially amorphous solid state form means a solid dispersion comprising at least 96, 97, 98, or 99 wt% amorphous compound (1) based on the total weight of 100 wt% of compound (1). Thus, the solid dispersion can provide compound (1) in an amorphous or substantially amorphous state. The solid dispersion can thus be referred to as an amorphous solid dispersion. In embodiments, the solid dispersion is thus an amorphous solid dispersion.

[0280] In one embodiment, the solid dispersion comprises a predetermined amount of compound (1) or a pharmaceutically acceptable salt thereof. In this context, the predetermined amount refers to the initial amount of compound (1) or a pharmaceutically acceptable salt thereof used to prepare the solid dispersion.

[0281] In another embodiment, the solid dispersion comprises a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof.

[0282] The solid dispersions of the present invention can be prepared using any procedure known in the art for this purpose (such as, for example, as disclosed in S.V. Bhujbal et al., Acta Pharmaceutica Sinica B 2021; 11(8):2505e2536, which is incorporated herein by reference) starting from form I, III or IV (in the broadest form or in any embodiment or aspect thereof) or a mixture thereof as set forth herein. According to the present invention, the solid dispersion is generally prepared by dissolving the active substance and a pharmaceutically acceptable dispersion carrier in a solvent or a mixture of solvents to form a feed solution, and then removing the solvent from the feed solution (for example) by spray drying to form the solid dispersion.

[0283] Another aspect of the present invention is thus a procedure for preparing a solid dispersion as set forth herein, the procedure comprising the following steps:

[0284] a) providing a mixture of compound (1) and a pharmaceutically acceptable dispersion carrier and adding a solvent to obtain a solution or a suspension; and

[0285] b) removing the solvent from the solution or suspension to form a solid dispersion as set forth herein, wherein

[0286] in step a), compound (1) is provided in any of crystalline forms I, III, IV in the broadest form or in any embodiment as set forth above. Preferably, in step b), the solid dispersion comprises compound (1) in an amorphous form.

[0287] Another aspect of the present invention is thus a procedure for preparing a solid dispersion as set forth herein, the procedure comprising the following steps:

[0288] a) providing a mixture of compound (1) and a pharmaceutically acceptable dispersion carrier and adding a solvent to obtain a solution or a suspension; and

[0289] b) removing the solvent from the solution or suspension to form a solid dispersion as set forth herein, wherein

[0290] In step a), compound (1) is provided as any one of crystalline forms I, III, IV (in the broadest form or in any one of the embodiments as described above) or as a mixture thereof. Preferably, in step b), the solid dispersion comprises compound (1) in amorphous form.

[0291] The procedure may further comprise drying the solid dispersion obtained in step b).

[0292] The solid dispersion obtainable by or through the procedure is another aspect of the present invention.

[0293] In one embodiment, a procedure for preparing a solid dispersion as described herein is provided, the procedure comprising the following steps:

[0294] a) providing a solution or suspension comprising compound (1) or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable dispersion carrier, and at least one solvent; and

[0295] b) removing the solvent from the solution or suspension to form a solid dispersion as described herein; and

[0296] c) optionally, drying the solid dispersion obtained in b), wherein

[0297] In step a), compound (1) is provided as any one of crystalline forms I, III, IV (in the broadest form or in any one of the embodiments as described above) or as a mixture thereof.

[0298] The solution or suspension of step a) according to any one of the above procedures may be referred to as a feed solution.

[0299] In an embodiment, the removal of the solvent in step b) of the procedure as defined above is carried out by spray drying, freeze drying, rotary evaporation, distillation, drum drying, and / or vacuum drying. In a preferred embodiment, the removal of the solvent in step b) is carried out by spray drying. Preferably, in step b), the solid dispersion comprises compound (1) in amorphous form.

[0300] The term "spray drying" as used herein is used conventionally and widely and generally refers to any procedure involving atomizing a solution, suspension, slurry, or emulsion containing one or more components of the desired product into droplets by spraying and then rapidly evaporating the sprayed droplets into solid powder by hot air at a specific temperature and pressure. Spray drying is a procedure known to those skilled in the art.

[0301] Spray drying is typically carried out by dissolving the crystalline form of compound (1) and a pharmaceutically acceptable dispersion polymer in a solvent to prepare a feed solution. The feed solution can be aspirated into a drying chamber via an atomizer. The feed solution can be atomized by common methods known in the art (such as two-fluid ultrasonic nozzles, pressure nozzles, rotary nozzles, and two-fluid non-ultrasonic nozzles). Then, the solvent is removed in the drying chamber to form a solid dispersion. A typical drying chamber uses a hot gas (such as forced air, nitrogen, nitrogen-enriched air, or argon) to dry the particles. The size of the drying chamber can be adjusted to achieve particle properties or throughput.

[0302] Although preferably prepared by common spray drying techniques, other techniques known in the art can be used (such as melt extrusion, freeze drying, rotary evaporation, co-precipitation, dispersion technology (KSD), fluidized bed technology, drum drying, vacuum drying, or other solvent removal procedures).

[0303] The procedures described above for preparing the solid dispersions as set forth herein can include an additional step between steps a) and b), which is spraying the solution or suspension obtained in step a) onto an inert excipient core. This procedure belongs to fluidized bed technology, specifically fluidized bed granulation technology.

[0304] In one embodiment, a procedure for preparing a solid dispersion as set forth herein is provided, which includes the following steps:

[0305] (a) Providing a solution or suspension comprising compound (1) or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable dispersion carrier, and at least one solvent; and

[0306] (a’) Spraying the solution or suspension provided in (a) onto an inert excipient core; and

[0307] (b’) Removing the solvent from the inert excipient core; and

[0308] (c’) Optionally, drying the excipient core comprising the solid dispersion obtained in (c’), wherein in step a), compound (1) is provided as any one of crystalline forms I, III, IV (in the broadest form or in any one embodiment as described above) or as a mixture thereof.

[0309] The spraying in step (a’) can be carried out in a fluidized bed coater (such as top spraying, bottom spraying, Wurster, tangential, or side rotor spraying).

[0310] Any solvent or mixture of solvents that at least partially dissolves the crystalline compound (1) can be used. Examples of suitable solvents that can be used individually or as a mixture include water, alcohols (such as methanol (“MeOH”), ethanol (“EtOH”), n-propanol, isopropanol, and butanols (such as n-butanol, 2-butanol, isobutanol, and tert-butanol)), ketones (such as acetone, methyl ethyl ketone, and methyl isobutyl ketone), esters (such as methyl acetate, ethyl acetate, and propyl acetate, isopropyl acetate, n-butyl acetate, and isobutyl acetate), and various other solvents (such as dichloromethane (DCM), chloroform, tetrahydrofuran, acetonitrile, toluene, and 1,1,1-trichloroethane). In one embodiment, the solvent mentioned in any of the above procedures and their embodiments is selected from the group consisting of: water, alcohols, ketones, esters, dichloromethane, chloroform, tetrahydrofuran, acetonitrile, toluene, 1,1,1-trichloroethane, and mixtures thereof. In one embodiment, the solvent mentioned in any of the above procedures and their embodiments is selected from the group consisting of: alcohols (specifically methanol, ethanol, n-propanol, isopropanol, and butanols (such as n-butanol, 2-butanol, isobutyl alcohol, and tert-butanol)), ketones (specifically acetone, methyl ethyl ketone, and methyl isobutyl ketone), esters (specifically methyl acetate, ethyl acetate, and propyl acetate, isopropyl acetate, n-butyl acetate, and isobutyl acetate), dichloromethane (DCM), tetrahydrofuran, acetonitrile, toluene, and 1,1,1-trichloroethane. Mixtures of solvents and water can also be used.

[0311] In an embodiment, the solvent is a mixture of dichloromethane (DCM) and methanol (MeOH). The relative amounts of DCM and MeOH in the mixture can vary. Preferably, the mixture includes at least 25 wt% MeOH based on the total weight of 100 wt% of the mixture. In an embodiment, the mixture includes an excess of DCM. Still preferably, the weight:weight ratio of DCM:MeOH is in the range of 25:75 to 95:5 (w / w). Preferably, DCM and MeOH have a weight:weight ratio of approximately 25:75, 50:50, 70:30, 75:25, 80:20, 85:15, or 90:10. It has been advantageously found that a solvent mixture of DCM:MeOH having a ratio of approximately 90:10 (w / w) can achieve a higher spray drying throughput.

[0312] In an embodiment, based on the total weight of 100 wt% of the feed solution, the concentration of solids in the feed solution (specifically the suspension or solution as defined in step a) above) is in the range of about 1 to 20 wt%. Preferably, based on the total weight of 100 wt% of the feed solution, the concentration of solids in the feed solution is in the range of about 5 to 15 wt%, more preferably about 8 to 12 wt%. For example, based on the total weight of 100 wt% of the feed solution, the concentration of solids in the feed solution is about 8 wt% or 10 wt%.

[0313] After removal of the solvent by spray drying, the obtained solid dispersion is optionally subjected to a drying procedure to reduce the residual solvent content. In an embodiment, the drying is carried out at a temperature in the range of from about room temperature to 100 °C, preferably from about 30 to 60 °C, more preferably from about 35 to 45 °C. For example, the drying is carried out at a temperature of about 40 °C. In other embodiments, the drying is carried out at ambient pressure and / or under reduced pressure. For example, the drying is carried out at ambient pressure or at a pressure of about 900 mbar or less, more preferably about 100 mbar or less and most preferably about 50 mbar or less (e.g., about 20 mbar or less). In other embodiments, the drying is carried out for a period of time in the range of from about 6 to 72 hours, preferably from about 12 to 48 hours.

[0314] The pharmaceutical composition (e.g., tablets, preferably film-coated tablets) can be manufactured according to conventional methods known to those skilled in the art. In an embodiment, the manufacturing process may include the following steps: 1) manufacturing a solid dispersion, for example by spray drying as described herein, 2) performing dry granulation on the solid dispersion using one or more suitable excipients, 3) blending the granules with a suitable disintegrant and / or lubricant, and / or glidant, 4) compressing the blend into a tablet core and 5) optionally film-coating the tablet core.

[0315] In an embodiment of the process for preparing the solid dispersion, the crystalline form of compound (1) can be provided in an amount in the range of from 5 wt% to 95 wt% based on the total weight of 100 wt% of the solid dispersion. In an embodiment of the process for preparing the solid dispersion, the crystalline form of compound (1) can be provided in an amount in the range of from 25 wt% to 75 wt% based on the total weight of 100 wt% of the solid dispersion. In an embodiment, the pharmaceutically acceptable dispersion carrier can be provided in an amount in the range of from 5 wt% to 95 wt% based on the total weight of 100 wt% of the solid dispersion. In an embodiment, the pharmaceutically acceptable dispersion carrier can be provided in an amount in the range of from 25 wt% to 75 wt% based on the total weight of 100 wt% of the solid dispersion.

[0316] In an embodiment of the process for preparing a solid dispersion, the crystalline form of compound (1) can be provided in an amount in the range of 20 wt% to 50 wt% based on the total weight of the solid dispersion of 100 wt%. In an embodiment, the crystalline form of compound (1) can be provided in an amount in the range of 25 wt% to 50 wt% based on the total weight of the solid dispersion of 100 wt%. In an embodiment, the pharmaceutically acceptable dispersion carrier can be provided in an amount in the range of 50 wt% to 80 wt% based on the total weight of the solid dispersion of 100 wt%. In an embodiment, the pharmaceutically acceptable dispersion carrier can be provided in an amount in the range of 50 wt% to 80 wt% based on the total weight of the solid dispersion of 100 wt%. In an embodiment, the pharmaceutically acceptable dispersion carrier can be provided in an amount in the range of 50 wt% to 75 wt% based on the total weight of the solid dispersion of 100 wt%.

[0317] In an embodiment, compound (1) and the pharmaceutically acceptable dispersion carrier can be provided in approximately equal weight amounts. In an embodiment, approximately 50 wt% of compound (1) and approximately 50 wt% of the pharmaceutically acceptable dispersion carrier are provided.

[0318] In an embodiment, approximately 25 wt% or 50 wt% of compound (1) and approximately 75 wt% or 50 wt% of the pharmaceutically acceptable dispersion carrier are provided.

[0319] In an embodiment, in the process for preparing a solid dispersion, specifically in the solution or suspension of step a), the weight ratio of compound (1):pharmaceutically acceptable dispersion carrier is from about 1:4 to 4:1, preferably 1:3 to 3:1 (such as 1:1 to 1:3). In an embodiment, in the process for preparing a solid dispersion, specifically in the solution or suspension of step a), the weight ratio of compound (1) to the pharmaceutically acceptable dispersion carrier is about 1:1.

[0320] Use for the treatment and / or prophylaxis of tumours and / or hyperproliferative diseases

[0321] The crystalline forms I, III, IV in the broadest form or in any one of the embodiments as set out above can be used as medicaments. In particular, the crystalline forms I, III, IV in the broadest form or in any one of the embodiments as set out above can be used for the treatment and / or prophylaxis of tumours and / or hyperproliferative disorders, specifically in anticancer therapy.

[0322] Provided according to one aspect is crystalline Form I in the broadest form or in any one of the embodiments as described above for use as a medicament. Provided according to one aspect is crystalline Form III in the broadest form or in any one of the embodiments as described above for use as a medicament. Provided according to one aspect is crystalline Form IV in the broadest form or in any one of the embodiments as described above for use as a medicament. Provided according to one aspect is a mixture of crystalline Forms I, III and / or IV in the broadest form or in any one of the embodiments as described above for use as a medicament.

[0323] Provided according to one aspect is crystalline Form I in the broadest form or in any one of the embodiments as described above for use as an anti-cancer medicament. According to one aspect is crystalline Form III in the broadest form or in any one of the embodiments as described above for use as an anti-cancer medicament. According to one aspect is crystalline Form IV in the broadest form or in any one of the embodiments as described above for use as an anti-cancer medicament.

[0324] Provided in one embodiment is crystalline Form I, III or IV or a mixture thereof (in the broadest form or in any one of the embodiments) as described above for use in the treatment and / or prevention of a HER2-regulated disease or disorder, specifically a tumor and / or a hyperproliferative disease. Another aspect refers to crystalline Form I, III or IV (in the broadest form or in any one of the embodiments) or a mixture thereof as described above for use in a method for the treatment and / or prevention of a HER2-regulated disease or disorder, specifically a tumor or a hyperproliferative disease.

[0325] Yet another aspect refers to a method for the treatment and / or prevention of a HER2-regulated disease or disorder, specifically a tumor and / or a hyperproliferative disease, wherein the method comprises the step of administering crystalline Form I, III or IV (in the broadest form or in any one of the embodiments) or a mixture thereof as described above to a patient. In one embodiment, the method comprises administering a therapeutically effective amount of crystalline Form I, III or IV (in the broadest form or in any one of the embodiments) or a mixture thereof as described above to a human in need of such treatment.

[0326] A related aspect refers to the use of crystalline Form I, III or IV (in the broadest form or in any one of the embodiments) or a mixture thereof as described above for the manufacture of a medicament. One embodiment refers to the use of crystalline Form I, III or IV (in the broadest form or in any one of the embodiments) or a mixture thereof as described above for the manufacture of a medicament for the treatment and / or prevention of a HER2-regulated disease or disorder, specifically a tumor and / or a hyperproliferative disease.

[0327] In one aspect, there is provided crystalline Form I, III or IV as described above (in the broadest form or in any one of the embodiments) or a mixture thereof for treating and / or preventing a disease and / or condition in which inhibition of wild-type and / or mutant HER2 is therapeutically beneficial, specifically for treating and / or preventing a disease and / or condition in which inhibition of the HER2 exon 20 mutant protein is therapeutically beneficial. Examples of such diseases and / or conditions include (but are not limited to) tumors and / or hyperproliferative diseases (such as cancer).

[0328] One aspect refers to crystalline Form I, III or IV as described above (in the broadest form or in any one of the embodiments) or a mixture thereof for treating and / or preventing tumors and / or hyperproliferative diseases.

[0329] As used herein, the term "hyperproliferative disease" refers to a condition in which cell growth increases to an extent greater than normal. Hyperproliferative diseases include malignant diseases (such as cancer) and non-malignant diseases. In a preferred embodiment, the hyperproliferative disorder is cancer. As used herein, the term "tumor disease" refers to a disease or medical condition associated with cancer or a cancer indication. Cancer can be classified by the type of tissue from which the cancer originated (histological type) and the primary site or location in the body where the cancer first occurred.

[0330] In one embodiment, the tumor and / or hyperproliferative disease is cancer.

[0331] In one embodiment, there is provided crystalline Form I as described above (in the broadest form or in any one of the embodiments) for treating and / or preventing cancer. In one embodiment, there is provided crystalline Form III as described above (in the broadest form or in any one of the embodiments) for treating and / or preventing cancer. In one embodiment, there is provided crystalline Form IV as described above (in the broadest form or in any one of the embodiments) for treating and / or preventing cancer. In one embodiment, there is provided a mixture of crystalline Forms I, III and / or IV as described above (in the broadest form or in any one of the embodiments) for treating and / or preventing cancer.

[0332] Another aspect refers to crystalline Form I, III or IV as described above (in the broadest form or in any one of the embodiments) or a mixture thereof for a method of treating and / or preventing cancer.

[0333] Another aspect refers to a method for treating and / or preventing cancer, which method comprises the step of administering to a patient a crystalline form I, III or IV (in the broadest form or in any of the embodiments) as set forth above or a mixture thereof. In one embodiment, the method comprises administering to a human in need of such treatment a therapeutically effective amount of a crystalline form I, III or IV (in the broadest form or in any of the embodiments) as set forth above or a mixture thereof.

[0334] One embodiment refers to the use of a crystalline form I, III or IV (in the broadest form or in any of the embodiments) as set forth above or a mixture thereof for the manufacture of a medicament for treating and / or preventing cancer.

[0335] In an embodiment, the cancer is HER2-overexpressing, HER2-amplified and / or HER2-mutated cancer. In an embodiment, the cancer is HER2 exon 20-mutated cancer.

[0336] In an embodiment, the tumor and / or hyperproliferative disease is HER2-overexpressing, HER2-amplified and / or HER2-mutated cancer.

[0337] As used herein, "HER2-overexpressing" refers to a cancer in which the cells of the cancer or tumor exhibit HER2 at a level detectable by methods such as immunohistochemistry (e.g., IHC 2+ or IHC 3+) and / or analysis of ERBB2 messenger RNA.

[0338] As used herein, "HER2-amplified" refers to a cancer in which the cancer or tumor cells show more than 2, specifically more than 3, 4, 5, 6, 7, 8, 9 or 10, preferably more than 6, copies of the HER2 gene ERBB2.

[0339] HER2 expression, gene copy number and amplification can be measured (e.g.) by determining nucleic acid sequences (e.g., sequencing of genomic DNA or cDNA), measuring mRNA expression, measuring protein abundance or a combination thereof. HER2 testing methods include immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), chromogenic in situ hybridization (CISH), ELISA and RNA quantification using techniques such as RT-PCR, microarray analysis and next generation sequencing (NGS). The HER2 expression in or on the cancer sample cells can be compared with reference cells. The reference cells can be non-cancer cells obtained from the same subject as the sample cells. The reference cells can be non-cancer cells obtained from a different subject or a group of subjects.

[0340] When a cancer is HER2-overexpressing and / or HER2-amplified in or on the cells, the cancer can be referred to as "HER2-positive".

[0341] As used herein, "HER2 mutant" refers to a cancer having at least one mutation (i.e., a change in the nucleic acid sequence of the HER2 gene and / or a change in the amino acid sequence of the HER2 protein, including (but not limited to) those listed below). The mutation can be detected using any method known to those skilled in the art (e.g., molecular diagnostic methods), which include (but are not limited to) polymerase chain reaction (PCR), single-strand conformation polymorphism (SSCP), denaturing gradient gel electrophoresis (DGGE), heteroduplex analysis, restriction fragment length polymorphism analysis (RFLP), next-generation sequencing (NGS), and whole exome sequencing.

[0342] As used herein, "cancer having a HER2 exon 20 mutation" or "HER2 exon 20 mutant cancer" refers to a cancer or tumor cell having at least one HER2 exon 20 mutation including (but not limited to) the mutations listed below.

[0343] ERBB2 (HER2) exon 20 encodes a part of the kinase domain and encompasses amino acids 769 to 835. Each mutation, insertion, duplication, or deletion within this region is defined as an exon 20 mutation including the following mutations: p.A772_G773insMMAY, p.Y772_A775_dup(YVMA), p.A775_G776insYVMA, p.Y772insYVMA, p.M774delinsWLV, p.A775_G776insSVMA, p.A775_G776insVVMA, p.A775_G776insYVMS, p.A775_G776insC, p.A776_delinsVC, p.A776_delinsLC, p.A776_delinsVV, p.A776_delinsAVGC, p.A776_delinsIC, p.A776_V777delinsCVC, p.V777_insE, p.G778_P780dup(GSP), p.G776_delinsVC ("p." refers to the HER2 protein).

[0344] In addition, there are oncogenic HER2 mutations containing the following mutations in addition to exon 20: p.S310F, p.R678Q, p.L755S, p.L755A, p.L755P, p.S310Y, p.S310A, p.V842I, p.D769Y, p.D769H, p.R103Q, p.G1056S, p.I767M, p.L869R, p.L869R, p.T733I, p.T862A, p.V697L, p.V777L, p.V777M, p.R929W, p.D277H, p.D277Y, p.G660D (where "p." refers to the HER2 protein).

[0345] In an embodiment, the tumor and / or hyperproliferative disease or cancer is one (but not limited to) of the following cancers, tumors, or other proliferative diseases:

[0346] Cancers / tumors / carcinomas of the head and neck: such as tumors / carcinomas / cancers of the nasal cavity, paranasal sinuses, nasopharynx, oral cavity (including the lips, gums, alveolar ridge, retromolar area, floor of the mouth, tongue, hard palate, buccal mucosa), oropharynx (including the base of the tongue, tonsils, tonsillar pillars, soft palate, tonsillar fossa, pharyngeal wall), middle ear, larynx (including the epiglottic region, glottis, subglottis, vocal cords), hypopharynx, salivary glands (including minor salivary glands);

[0347] Cancers / tumors / carcinomas of the lung: such as non-small cell lung cancer (NSCLC) (squamous cell carcinoma, spindle cell carcinoma, adenocarcinoma, large cell carcinoma, clear cell carcinoma, bronchioloalveolar carcinoma), small cell lung cancer (SCLC) (oat cell carcinoma, intermediate cell carcinoma, combined oat cell carcinoma);

[0348] Sarcomas of the mediastinum: such as nerve tumors (including neurofibroma, schwannoma, malignant schwannoma, neuro sarcoma, ganglioneuroblastoma, ganglioneuroma, neurocytoma, pheochromocytoma, paraganglioma), germ cell tumors (including seminoma, teratoma, non-seminoma), thymic tumors (including thymoma, thymolipoma, thymic carcinoma, thymic carcinoid), mesenchymal tumors (including fibroma, fibrosarcoma, lipoma, liposarcoma, myxoma, mesothelioma, leiomyoma, leiomyosarcoma, rhabdomyosarcoma, xanthogranuloma, mesenchymoma, hemangioma, hemangioendothelioma, hemangiopericytoma, lymphangioma, lymphangiopericytoma, lymphangioleiomyoma);

[0349] Cancers / tumors / neoplasms of the gastrointestinal (GI) tract: such as those of the esophagus, stomach (gastric cancer), pancreas, liver and biliary system (including hepatocellular carcinoma (HCC) (e.g., pediatric HCC, fibrolamellar HCC, combined HCC, spindle cell HCC, clear cell HCC, giant cell HCC, carcinosarcoma HCC, sclerosing HCC), hepatoblastoma, cholangiocarcinoma, cholangiocellular carcinoma, cystadenocarcinoma of the liver, angiosarcoma, hemangioendothelioma, leiomyosarcoma, malignant schwannoma, fibrosarcoma, Klatskin tumor), gallbladder, extrahepatic bile duct, small intestine (including duodenum, jejunum, ileum), large intestine (including cecum, colon, rectum, anus; colorectal cancer, gastrointestinal stromal tumor (GIST)), urogenital system (including kidney (e.g., renal pelvis), renal cell carcinoma (RCC), nephroblastoma (Wilms' tumor), adrenomatoid tumor, Grawitz tumor; ureter; bladder (e.g., urachal carcinoma, urothelial carcinoma); urethra (e.g., terminal, bulbomembranous, prostatic); prostate (androgen-dependent, androgen-independent, castration-resistant, hormone-independent, hormone-refractory), penis), tumors / cancers / neoplasms of the appendix;

[0350] Cancers / tumors / neoplasms of the testis: such as seminoma, non-seminoma;

[0351] Gynecological cancers / tumors / neoplasms: such as those of the ovary, fallopian tube, peritoneum, cervix, vulva, vagina, uterine body (including endometrium, fundus);

[0352] Cancers / tumors / neoplasms of the breast: such as breast cancer (invasive ductal carcinoma, colloid carcinoma, invasive lobular carcinoma, tubular carcinoma, cystadenocarcinoma, papillary carcinoma, medullary carcinoma, mucinous carcinoma), hormone receptor-positive breast cancer (estrogen receptor-positive breast cancer, progesterone receptor-positive breast cancer), HER2-positive breast cancer, triple-negative breast cancer, Paget's disease of the breast;

[0353] Cancers / tumors / neoplasms of the endocrine system: such as those of the endocrine glands, thyroid (thyroid neoplasms / tumors: papillary, follicular, undifferentiated, medullary), parathyroid (parathyroid neoplasms / tumors), adrenal cortex (adrenal cortical neoplasms / tumors), pituitary gland (including prolactinoma, craniopharyngioma), thymus, adrenal gland, pineal gland, tumors / cancers / neoplasms of the carotid body, islet cell tumors, paraganglioma tumors, pancreatic endocrine tumors (PET; non-fluorine functional PET, PPoma, gastrinoma, insulinoma, VIPoma, glucagonoma, somatostatinoma, GRFoma, ACTHoma), carcinoid tumors;

[0354] Sarcomas of soft tissue: such as fibrosarcoma, fibrous histiocytoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, lymphangiosarcoma, Kaposi's sarcoma, glomus tumor, hemangiopericytoma, synovial sarcoma, giant cell tumor of tendon sheath, solitary fibrous tumor of pleura and peritoneum, diffuse mesothelioma, malignant peripheral nerve sheath tumor (MPNST), granular cell tumor, clear cell sarcoma, melanocytic schwannoma, plexosarcoma, neuroblastoma, ganglioneuroblastoma, neuroepithelioma, extraskeletal Ewing's sarcoma, paraganglioma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, mesenchymoma, alveolar soft part sarcoma, epithelioid sarcoma, extra-renal rhabdoid tumor, desmoplastic small round cell tumor;

[0355] Sarcomas of bone: such as myeloma, reticulum cell sarcoma, chondrosarcoma (including central type, peripheral type, clear cell, mesenchymal chondrosarcoma), osteosarcoma (including extraperiosteal, periosteal, high grade surface, small cell, radiation-induced osteosarcoma, Paget's sarcoma), Ewing's tumor, malignant giant cell tumor, ameloblastoma, (fibrous) histiocytoma, fibrosarcoma, chordoma, small round cell sarcoma, hemangioendothelioma, hemangiopericytoma, osteochondroma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, chondroblastoma;

[0356] Mesothelioma: such as pleural mesothelioma, peritoneal mesothelioma;

[0357] Cancers of the skin: such as basal cell carcinoma, squamous cell carcinoma, Merkel's cell carcinoma, melanoma (including cutaneous, superficial spreading, lentigo maligna, acral lentiginous, nodular, uveal melanoma), actinic keratosis, carcinoma of eyelid;

[0358] Neoplasms of the central nervous system and brain: such as astrocytoma (cerebral, cerebellar, diffuse, fibrillary, undifferentiated, pilocytic, protoplasmic, gemistocytic), glioblastoma, glioma, oligodendroglioma, oligoastrocytoma, ependymoma, ependymoblastoma, choroid plexus tumor, medulloblastoma, meningioma, schwannoma, hemangioblastoma, hemangioma, hemangiopericytoma, neuroma, ganglioma, neuroblastoma, retinoblastoma, schwannoma (e.g. acoustic), spinal tumor;

[0359] Cancers of the peripheral nervous system;

[0360] Lymphomas and leukemias: such as B-cell non-Hodgkin lymphomas (NHL) (including small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphoma (LPL), mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLCL), Burkitt's lymphoma (BL)), T-cell non-Hodgkin lymphomas (including anaplastic large cell lymphoma (ALCL), adult T-cell leukemia / lymphoma (ATLL), cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL)), lymphoblastic T-cell lymphoma (T-LBL), adult T-cell lymphoma, lymphoblastic B-cell lymphoma (B-LBL), immunocytoma, chronic B-cell lymphocytic leukemia (BchlorineL), chronic T-cell lymphocytic leukemia (TchlorineL), B-cell small lymphocytic lymphoma (B-SLL), cutaneous T-cell lymphoma (CTLC), primary central nervous system lymphoma (PCNSL), immunoblastic sarcoma, Hodgkin's disease (HD) (including nodular lymphocyte-predominant HD (NLPHD), nodular sclerosis HD (NSHD), mixed cellularity HD (MCHD), lymphocyte-rich classical HD, lymphocyte-depleted HD (LDHD)), large granular lymphocyte leukemia (LGL), chronic myelogenous leukemia (CML), acute myeloid / myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), acute promyelocytic leukemia (APL), chronic lymphocytic / lymphoblastic leukemia (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia, chronic myeloid / myelogenous leukemia (CML), myeloma, plasmacytoma, multiple myeloma (MM), plasmacytoma, myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML);

[0361] Cancers of unknown primary site (CUP).

[0362] All of the cancers / tumors / carcinomas mentioned above (characterized by their specific location / origin in the body) are intended to include primary tumors and metastatic tumors derived therefrom. Preferably, cancers as defined herein (including those referred to as (e.g.) cancer types in any of the embodiments) are metastatic, advanced, and / or unresectable.

[0363] All of the cancers / tumors / carcinomas mentioned above can be further differentiated by their histopathological classification:

[0364] Epithelial carcinomas (e.g., squamous cell carcinoma (SCC) (carcinoma in situ, superficially invasive, verrucous carcinoma, pseudosarcoma, undifferentiated, transitional cell, lymphoepithelial)), adenocarcinomas (AC) (well-differentiated, mucinous, papillary, pleomorphic giant cell, ductal, small cell, signet ring cell, spindle cell, clear cell, oat cell, colloid, adenosquamous, mucoepidermoid, adenoid cystic), mucinous cystadenocarcinoma, acinar cell carcinoma, large cell carcinoma, small cell carcinoma, neuroendocrine tumors (small cell carcinoma, paraganglioma, carcinoid); eosinophilic carcinoma;

[0365] Non-epithelial cancers, such as sarcomas (fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, angiosarcoma, giant cell sarcoma, lymphosarcoma, fibrous histiocytoma, liposarcoma, angiosarcoma, lymphangiosarcoma, neurofibrosarcoma), lymphomas, melanomas, germ cell tumors, hematological neoplasms, mixed and undifferentiated carcinomas.

[0366] In some embodiments, the cancer is selected from the group consisting of: brain cancer, breast cancer, endocrine cancer, gastrointestinal cancer, gynecological cancer, head and neck tumors, lung cancer, nervous system cancer, and skin cancer.

[0367] Preferably, the brain cancer is glioblastoma or glioma.

[0368] Preferably, the breast cancer is lobular breast cancer. Additionally or alternatively, the breast cancer is preferably metastatic.

[0369] Preferably, the endocrine cancer is a schwannoma, more preferably a HER2-mutated schwannoma.

[0370] Preferably, the gastrointestinal cancer is selected from the group consisting of: anal cancer, appendiceal cancer, biliary tract cancer, bladder cancer, colorectal cancer, esophagogastric cancer, gastric cancer, esophageal tumor, gastroesophageal cancer, gallbladder tumor, hepatobiliary cancer, kidney cancer, liver cancer, pancreatic cancer, prostate cancer, and small intestine cancer. Additionally or alternatively, the gastrointestinal cancer can be a gastrointestinal neuroendocrine tumor, preferably a HER2-mutated cancer. More preferably, the gastrointestinal cancer is selected from the group consisting of: gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, and esophageal adenocarcinoma, specifically metastatic gastric adenocarcinoma, metastatic gastroesophageal junction adenocarcinoma, and metastatic esophageal adenocarcinoma.

[0371] Preferably, the gynecological cancer is selected from the group consisting of: cervical cancer, uterine cancer, endometrial cancer, and ovarian cancer.

[0372] Preferably, the head and neck tumor is a salivary gland carcinoma or tumor.

[0373] Preferably, the lung cancer is non-small cell lung cancer (NSCLC).

[0374] Preferably, the nervous system cancer is a peripheral nervous system cancer, more preferably a HER2 - amplified peripheral nervous system cancer.

[0375] Preferably, the skin cancer is not melanoma (i.e., non - melanoma skin cancer).

[0376] In some embodiments, the cancer is selected from the group consisting of: glioblastoma, glioma, lobular breast cancer, metastatic breast cancer, schwannoma, anal cancer, appendiceal cancer, biliary tract cancer, bladder cancer, colorectal cancer, esophagogastric cancer, gastric cancer, esophageal tumor, gastroesophageal cancer, gallbladder tumor, hepatobiliary cancer, kidney cancer, liver cancer, pancreatic cancer, prostate cancer, small intestine cancer, neuroendocrine gastrointestinal cancer, metastatic gastric adenocarcinoma, metastatic gastroesophageal junction adenocarcinoma, metastatic esophageal adenocarcinoma, cervical cancer, uterine cancer, endometrial cancer, ovarian cancer, salivary gland cancer, non - small cell lung cancer (NSCLC), peripheral nervous system cancer, and non - melanoma skin cancer.

[0377] In some embodiments, the cancer is a HER2 - overexpressing, HER2 - amplified, and / or HER2 - mutated (specifically, HER2 exon 20 mutation) cancer, and is selected from the group consisting of: glioblastoma, glioma, lobular breast cancer, metastatic breast cancer, schwannoma, anal cancer, appendiceal cancer, biliary tract cancer, bladder cancer, colorectal cancer, esophagogastric cancer, gastric cancer, esophageal tumor, gastroesophageal cancer, gallbladder tumor, hepatobiliary cancer, kidney cancer, liver cancer, pancreatic cancer, prostate cancer, small intestine cancer, neuroendocrine gastrointestinal cancer, metastatic gastric adenocarcinoma, metastatic gastroesophageal junction adenocarcinoma, metastatic esophageal adenocarcinoma, cervical cancer, uterine cancer, endometrial cancer, ovarian cancer, salivary gland cancer, non - small cell lung cancer (NSCLC), peripheral nervous system cancer, and non - melanoma skin cancer.

[0378] In some embodiments, the cancer is selected from the group consisting of: brain cancer, breast cancer, biliary tract cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, ovarian cancer, skin cancer, gastric cancer, esophageal tumor, head and neck tumor, salivary gland cancer, gastrointestinal cancer, small intestine cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer, and prostate cancer.

[0379] In some embodiments, the cancer is a HER2 - overexpressing, HER2 - amplified, and / or HER2 - mutated (specifically, HER2 exon 20 mutation) cancer, and is selected from the group consisting of: brain cancer, breast cancer, biliary tract cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, ovarian cancer, skin cancer, gastric cancer, esophageal tumor, head and neck tumor, salivary gland cancer, gastrointestinal cancer, small intestine cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer, and prostate cancer.

[0380] In some embodiments, the cancer is selected from the group consisting of: brain cancer, breast cancer, bile duct cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, skin cancer, gastric cancer, esophageal tumor, head and neck tumor, gastrointestinal cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer, and prostate cancer.

[0381] In an embodiment, the cancer is a HER2 overexpressing, HER2 amplified, and / or HER2 mutated (specifically a HER2 exon 20 mutation) cancer, which is selected from brain cancer, breast cancer, bile duct cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, skin cancer, gastric cancer, esophageal tumor, head and neck tumor, gastrointestinal cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer, and prostate cancer.

[0382] In other embodiments, the cancer is selected from the group consisting of: breast cancer, bladder cancer, colorectal cancer, gastrointestinal cancer, esophageal cancer, or lung cancer. In other embodiments, the cancer is a cancer / tumor / carcinoma of the lung: for example, non-small cell lung cancer (NSCLC) (squamous cell carcinoma, spindle cell carcinoma, adenocarcinoma, large cell carcinoma, clear cell carcinoma, bronchioloalveolar carcinoma), small cell lung cancer (SCLC) (oat cell carcinoma, intermediate cell carcinoma, combined oat cell carcinoma). In still other embodiments, the cancer is NSCLC. In still other embodiments, the cancer is a HER2 exon 20 mutated NSCLC.

[0383] In one embodiment, the cancer is advanced, unresectable, or metastatic NSCLC with a HER2 mutation, wherein the HER2 mutation is in the tyrosine kinase domain. Preferably, in this embodiment, the solid dispersion or pharmaceutical composition as described herein is administered as a first-line therapy. More preferably, in this embodiment, the solid dispersion or pharmaceutical composition as described herein is administered as a second-line or other-line therapy.

[0384] In an embodiment, the cancer is HER2 positive metastatic breast cancer. Preferably, in this embodiment, the solid dispersion or pharmaceutical composition as described herein is administered as a first-line therapy. More preferably, in this embodiment, the solid dispersion or pharmaceutical composition as described herein is administered as a second-line or other-line therapy.

[0385] In an embodiment, the cancer is HER2 positive metastatic gastric adenocarcinoma, metastatic gastroesophageal junction adenocarcinoma, or metastatic esophageal adenocarcinoma. Preferably, in this embodiment, the solid dispersion or pharmaceutical composition as described herein is administered as a first-line therapy. More preferably, in this embodiment, the solid dispersion or pharmaceutical composition as described herein is administered as a second-line or other-line therapy.

[0386] In another aspect, the present invention refers to Form I, III or V (in the broadest form or in any embodiment) or a mixture thereof as described above for the treatment and / or prevention of tumors and / or hyperproliferative diseases as defined herein, wherein the crystalline Form I, III or IV or a mixture thereof is administered in combination with a cytostatic and / or cytotoxic active substance and / or in combination with radiotherapy and / or immunotherapy.

[0387] In another aspect, the present invention refers to a combination of the crystalline Form I, III or IV (in the broadest form or in any embodiment) or a mixture thereof as described above for the treatment and / or prevention of cancer with a cytostatic and / or cytotoxic active substance and / or in combination with radiotherapy and / or immunotherapy.

[0388] The crystalline Form I, III or IV (in the broadest form or in any embodiment) as described above can be used alone or in combination with one or more other pharmacologically active substances (such as prior art or standard of care compounds (e.g., cell proliferation inhibitors, anti-angiogenic substances, steroids or immunomodulators / checkpoint inhibitors) and the like).

[0389] Pharmacologically active substances administered in combination with the crystalline forms as described herein include (but are not limited to) hormones, hormone analogs, and antihormones (such as tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone, octreotide), aromatase inhibitors (such as anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane), LHRH agonists and antagonists (such as goserelin acetate, luprolide), growth factors and / or their corresponding receptors (growth factors such as platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insulin-like growth factor (IGF), human epidermal growth factor (HER (e.g., HER2, HER3, HER4)) and hepatocyte growth factor (HGF) and / or their corresponding receptors), inhibitors of which are (e.g.) (anti)growth factor antibodies, (anti)growth factor receptor antibodies, and tyrosine kinase inhibitors (such as cetuximab, gefitinib, afatinib, nintedanib, imatinib, lapatinib, bosutinib, bevacizumab, pertuzumab, and trastuzumab));Antimetabolites (e.g., antifolates (e.g., methotrexate, raltitrexed), pyrimidine analogs (e.g., 5-fluorouracil (5-FU)), ribonucleoside and deoxyribonucleoside analogs, capecitabine, and gemcitabine, purine and adenosine analogs (e.g., mercaptopurine, thioguanine), cladribine, and pentostatin, cytarabine (ara C), fludarabine); antitumor antibiotics (e.g., anthracyclins (e.g., doxorubicin, doxil (pegylated liposomal doxorubicin hydrochloride), myocet (non-pegylated liposomal doxorubicin), daunorubicin, epirubicin, and idarubicin), mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin); platinum derivatives (e.g., cisplatin, oxaliplatin, carboplatin); alkylating agents (e.g., estramustin, meclorethamine, melphalan, chlorambucil, busulphan, dacarbazine, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas (e.g., carmustin and lomustine), thiotepa); antimitotic agents (e.g., Vinca alkaloids (e.g., vinblastine, vindesin, vinorelbin, and vincristine) and taxanes (e.g., paclitaxel, docetaxel));Angiogenesis inhibitors (such as tasquinimod), tubulin inhibitors; DNA synthesis inhibitors, PARP inhibitors, topoisomerase inhibitors (such as epipodophyllotoxins (such as etoposide and etopophos), teniposide, amsacrin, topotecan, irinotecan, mitoxantrone), serine / threonine kinase inhibitors (such as PDK 1 inhibitors, Raf inhibitors, A-Raf inhibitors, B-Raf inhibitors, C-Raf inhibitors, mTOR inhibitors, mTORC1 / 2 inhibitors, PI3K inhibitors, PI3Kα inhibitors, dual mTOR / PI3K inhibitors, STK 33 inhibitors, AKT inhibitors, PLK 1 inhibitors, CDK inhibitors, aurora kinase inhibitors), tyrosine kinase inhibitors (such as PTK2 / FAK inhibitors), protein-protein interaction inhibitors (such as IAP activators, Mcl-1, MDM2 / MDMX), MEK inhibitors, ERK inhibitors, KRAS inhibitors (such as KRAS G12C inhibitors), signal transduction pathway inhibitors (such as SOS1 inhibitors), FLT3 inhibitors, BRD4 inhibitors, IGF-1R inhibitors, TRAILR2 agonists, Bcl-xL inhibitors, Bcl-2 inhibitors, Bcl-2 / Bcl-xL inhibitors, ErbB receptor inhibitors, BCR-ABL inhibitors, ABL inhibitors, Src inhibitors, rapamycin analogs (such as everolimus, temsirolimus, ridaforolimus, sirolimus), androgen synthesis inhibitors, androgen receptor inhibitors, DNMT inhibitors, HDAC inhibitors, ANG1 / 2 inhibitors, CYP17 inhibitors, radiopharmaceuticals, proteasome inhibitors, immunotherapeutic agents (such as immune checkpoint inhibitors (such as CTLA4, PD1, PD-L1, PD-L2, LAG3 and TIM3 binding molecules / immunoglobulins (such as ipilimumab, nivolumab, pembrolizumab))), ADCC (antibody-dependent cell-mediated cytotoxicity) enhancers (such as anti-CD33 antibodies, anti-CD37 antibodies, anti-CD20 antibodies), T-cell engagers (such as bispecific T-cell engagers; (e.g., CD3×BCMA, CD3×CD33, CD3×CD19), PSMA×CD3), tumor vaccines, and various chemotherapeutic agents (e.g., amifostin, anagrelid, clodronat, filgrastin, interferon, interferon α, leucovorin, procarbazine, levamisole, mesna, mitotane, pamidronate, and porfimer).

[0390] Pharmaceutical composition

[0391] According to another aspect, the present invention refers to a pharmaceutical composition comprising crystalline form I, III, or IV as described above (in the broadest form or in any one embodiment) and one or more pharmaceutically acceptable excipients.

[0392] According to another aspect, the present invention refers to a pharmaceutical composition comprising a therapeutically effective amount of crystalline form I, III, or IV as described above (in the broadest form or in any one embodiment) or a mixture thereof and one or more pharmaceutically acceptable excipients. Another embodiment of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of the solid dispersion as described herein and one or more pharmaceutically acceptable excipients.

[0393] As used herein, the term "therapeutically effective amount" refers to the amount of a substance capable of eliminating the symptoms of a disease or preventing or alleviating these symptoms or prolonging the survival period of a treated patient.

[0394] The term "pharmaceutically acceptable excipient" refers to a non-toxic component that does not destroy the pharmacological activity of the compound being formulated. Pharmaceutically acceptable excipients used in the compositions of the present invention include fillers, disintegrants, glidants, lubricants, and coating agents. The composition may further include a pharmaceutically acceptable excipient selected from buffering agents, dispersing agents, surfactants, wetting agents, emulsifying agents, suspending agents, preservatives, antioxidants, opacifying agents, processing aids, coloring agents, sweetening agents, flavoring agents, diluents, and other known additives for manufacturing pharmaceutical products.

[0395] The pharmaceutical composition may contain conventional non-toxic pharmaceutically acceptable excipients. In an embodiment of the pharmaceutical composition, one or more pharmaceutically acceptable excipients are selected from the group consisting of fillers, disintegrants, glidants, lubricants, and coating agents. In an embodiment, the pharmaceutical composition includes a filler, a disintegrant, a glidant, and a lubricant. In an embodiment, the pharmaceutical composition includes a filler, a disintegrant, a glidant, a lubricant, and a coating agent. It should be understood that the pharmaceutical composition may include one or more excipients for each function (e.g., one or more fillers, one or more disintegrants, one or more glidants, one or more lubricants, one or more coating agents).

[0396] In an embodiment, the filler is selected from the group consisting of microcrystalline cellulose, mannitol, and mixtures thereof. In an embodiment, the disintegrant is selected from the group consisting of sodium carboxymethylcellulose cross-linked (also denoted as cross-linked sodium carboxymethylcellulose) or sodium bicarbonate, crospovidone, sodium starch glycolate, and mixtures thereof. In certain embodiments, the disintegrant is cross-linked sodium carboxymethylcellulose. In an embodiment, the glidant is colloidal silicon dioxide. In an embodiment, the lubricant is selected from the group consisting of sodium stearyl fumarate, magnesium stearate, and mixtures thereof. In certain embodiments, the lubricant is sodium stearyl fumarate.

[0397] In an embodiment of the pharmaceutical composition, one or more pharmaceutically acceptable excipients include mannitol, microcrystalline cellulose, cross-linked sodium carboxymethylcellulose, colloidal silicon dioxide, and sodium stearyl fumarate.

[0398] In certain embodiments, for example when formulated as enteric-coated tablets, the pharmaceutical composition may include a coating agent. In an embodiment, the coating agent may include a film-forming agent (e.g., partially hydrolyzed polyvinyl alcohol), an anti-adhesive agent (e.g., talc), a pigment (e.g., titanium dioxide), mono- and di-octanoyl decanoyl glycerol (GMDCC), and iron oxide (e.g., iron oxide yellow), and a lubricant (e.g., sodium lauryl sulfate). The coating agent may be commercially available (e.g.) under the trade name Yellow AMB II is commercially available. In a preferred embodiment, the coating agent does not contain titanium dioxide (e.g., is titanium dioxide-free).

[0399] The crystalline forms present in the solid dispersion may be as defined in any of the above aspects, objectives, and / or embodiments and thus in particular according to at least one of crystalline forms I, III, and IV.

[0400] The crystalline forms present in the pharmaceutical composition may be as defined in any of the above aspects, objectives, and / or embodiments and thus in particular according to at least one of crystalline forms I, III, and IV.

[0401] Specifically, the present invention provides a pharmaceutical composition comprising crystalline form I as defined herein and one or more pharmaceutically acceptable excipients.

[0402] Specifically, the present invention provides a pharmaceutical composition comprising crystalline form III as defined herein and one or more pharmaceutically acceptable excipients.

[0403] Specifically, the present invention provides a pharmaceutical composition comprising crystalline form IV as defined herein and one or more pharmaceutically acceptable excipients.

[0404] In one embodiment, a pharmaceutical composition comprising a crystalline form as defined herein comprises one or more pharmaceutically acceptable excipients and an additional therapeutic agent.

[0405] According to yet another embodiment, the pharmaceutical composition comprises at least one other cell growth inhibitory and / or cytotoxic active substance.

[0406] Those skilled in the art will appreciate suitable formulations for administering the compounds of the present invention and these formulations include, for example, tablets, pills, capsules, suppositories, lozenges, troches, solutions (especially solutions for injection (subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.)) and infusion (injectables)), elixirs, syrups, cachets, emulsions, inhalants or dispersible powders.

[0407] Suitable tablets can be obtained, for example, by mixing a compound of one or more crystalline forms with known excipients such as inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and / or lubricants.

[0408] The dosage range of the crystalline form as described that can be administered per day is generally from 1 mg to 2000 mg, preferably from 10 mg to 1000 mg.

[0409] The dosage for intravenous use is from 1 mg to 1000 mg at different infusion rates, preferably between 5 mg and 500 mg at different infusion rates.

[0410] However, depending on body weight, age, route of administration, severity of the disease, individual response to the drug, nature of its formulation and the time or interval of drug administration (continuous or intermittent treatment in one or more daily doses), it may sometimes be necessary to deviate from the specified amount. Thus, in some cases, it may be sufficient to use a lower dose than the lowest dose given above, while in other cases the upper limit may have to be exceeded. When administered in large amounts, it may be appropriately divided into many smaller doses and administered at different times of the day.

[0411] Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0412] It should be understood that any one of the aspects or embodiments described above can be combined with any other of the aspects or embodiments described above to provide additional aspects or embodiments. Specifically, for Form IV, each embodiment of the crystalline form characterized by its X-ray diffraction pattern can be combined with any other embodiment of the crystalline form characterized by its Raman spectrum to provide yet another embodiment, wherein the crystalline form is characterized by its X-ray diffraction pattern and its Raman spectrum. The same applies to Forms III and I.

[0413] In the various embodiments set forth above, the peaks included in the X-ray diffraction pattern (i.e., the X-ray diffraction peaks) are referred to by the absolute value of the added error range (e.g., (6.2 ± 0.2)°, where 6.2 is the absolute value and ±0.2 is the error range such that the peak is between 6.0° and 6.4°). The error range is typically ±0.1 or ±0.2. For all aspects or embodiments with an error range of ±0.2 for XRPD, corresponding embodiments with an error range of ±0.1 are disclosed herein. This means that in any aspect or embodiment where an error range of ±0.2 is mentioned, 0.2 can be replaced by 0.1 to provide additional embodiments of the invention.

[0414] Similarly, in the various embodiments set forth above, the peaks included in the Raman spectrum (i.e., the Raman peaks) are referred to by the absolute value of the added error range (e.g., 831 ± 2, where 831 is the absolute value and ±2 is the error range such that the peak is between 829 and 833). The error range is typically ±2. For all aspects or embodiments with an error range of ±2 for the Raman spectrum, corresponding embodiments with an error range of ±1 are disclosed herein. This means that in any aspect or embodiment where an error range of ±2 is mentioned, 2 can be replaced by 1 to provide additional embodiments of the invention.

[0415] In all embodiments where X-ray diffraction peaks are mentioned, the peaks preferably have a relative intensity greater than 5%, particularly where an X-ray diffraction pattern is obtained with the experimental parameters reported in Table 1.

[0416] The characteristics and advantages of the present invention will become apparent from the following more detailed examples, which illustrate the principles of the invention by way of example and do not limit its scope.

[0417] Examples

[0418] Abbreviations

[0419] The following abbreviations are used herein.

[0420] °C degrees Celsius

[0421] 2-Me-THF 2-Methyltetrahydrofuran

[0422] AcCl Acetyl chloride

[0423] Boc tert-Butyloxycarbonyl

[0424] cat. Catalytic

[0425] DCM Dichloromethane

[0426] DMSO Dimethyl sulfoxide

[0427] DMSO-d6 Deuterated dimethyl sulfoxide

[0428] DMAc N,N-Dimethylacetamide

[0429] equiv. Equivalent

[0430] Et3N Triethylamine

[0431] h, hr or hrs Hour(s)

[0432] HCl Hydrochloric acid

[0433] IPA Isopropyl alcohol

[0434] IPAc Isopropyl acetate

[0435] KOH Potassium hydroxide

[0436] LR EIMS Low resolution electron ionization mass spectrometry

[0437] m, min or mins Minute(s)

[0438] M Molarity

[0439] Me Methyl

[0440] MeCN Acetonitrile

[0441] MeOH Methanol

[0442] mol% Mole percentage

[0443] MS Mass spectrometry

[0444] NaOH Sodium hydroxide

[0445] NMR Nuclear magnetic resonance

[0446] PG Protecting group

[0447] ROI Residue on ignition

[0448] THF Tetrahydrofuran

[0449] V Volume

[0450] The solid crystalline forms of compound (1) can be produced in polymorphic forms I, III, and IV. Examples of the respective methods for producing the defined polymorphic forms are given in Examples 1 and 2 below.

[0451] Example 1 - Preparation of the Crystalline Forms of Compound (1)

[0452] Overview

[0453] Unless otherwise stated, all reactions are carried out using methods common in chemical laboratories in commercially available equipment. Starting materials sensitive to air and / or humidity are stored under a protective gas, and the corresponding reactions and operations using them are carried out under a protective gas (nitrogen or argon).

[0454] If it is desired to represent a compound by both its structural formula and its nomenclature, in case of conflict the structural formula shall be decisive.

[0455] Analytical Methods

[0456] Recorded on a Bruker (400 MHz) spectrometer in dimethyl sulfoxide-d6 (DMSO-d6) 1 1H NMR spectra.

[0457] MS measurements were carried out using a Waters ACQuITY QDa detector paired with an LC system. The ionization parameters were as follows: 100 - 800 mass range; 15 V cone voltage; 15 pts / s sampling rate; 0.8 V + / - capillary voltage; 600 °C probe temperature.

[0458] HPLC method for measuring the ratio of compound (5a) to compound (5b):

[0459] The HPLC was equipped with a gradient pump (600 bar), a column thermostat, a UV-detector, and a thermostatic autosampler.

[0460]

[0461]

[0462] Example 1.1 - Route 1 to Obtain Crystalline Forms I and III

[0463] Reaction Figure 1 . Synthesis of compound (1) from compound (9), compound (10), and compound (6b) based on a halogen leaving group

[0464]

[0465] The starting materials (9) and (10) are commercially available and can be prepared according to procedures known in the art. For example, compound (9) can be prepared as described in WO 97 / 32880, WO 2010 / 026262 or WO 2020 / 239999 and compound (10) can be prepared as described in WO 2019 / 214634, WO 2021 / 156178, WO 2021 / 213800 or WO 2022 / 003575.

[0466] Step 1. Preparation of compound (8’) from compound (9) and compound (10).

[0467] General procedure.

[0468] All calculations are carried out for compound (9).

[0469] Charge compound (9) (1.0 eq), compound (10) (1.0 eq) and toluene (2.0 V) into a clean N2-purged vessel. Start stirring and add IPA (10.0 V). After the addition is complete, heat the mixture to 43 °C and hold until the reaction is complete. Then, cool the reaction mixture to 22 °C, stir for 30 minutes and filter. Wash the solid twice with IPA (1.5 V) and dry in vacuo at 50 °C to obtain the solid compound (8’) in 93% yield.

[0470] Analytical information

[0471] Compound (8’): 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.21 (s, 3H) 2.77 (s, 3H) 4.05 (s, 3H) 7.09 (d, J = 8.76 Hz, 1H) 7.15 (d, J = 2.50 Hz, 1H) 7.34 (dd, J = 9.01, 2.25 Hz, 1H) 7.85 (dd, J = 8.63, 2.63 Hz, 1H) 7.89 (d, J = 2.50 Hz, 1H) 7.97 (d, J = 9.01 Hz, 1H) 8.66 (s, 1H) 9.27 (s, 1H) 9.48 (s, 1H) 10.04 (br s, 1H); LR EIMS m / z: 430.14

[0472] Step 2. Preparation of compound (5a) / (5b) from compound (8’).

[0473] General procedure.

[0474] All calculations are carried out for compound (8’).

[0475] Charge compound (8’) (1.0 eq., HCl salt) and ethanol (5.5 V) into a clean N2-purged vessel. Start stirring, purge the contents with N2 and adjust the internal temperature of the vessel to 25 °C. Charge a solution of Na2MoO4 (1.1 mol%) in water (2.2 V) into the mixture, then charge 30% aq. H2O2 (1.20 eq.) while maintaining the internal temperature of the vessel at 25 °C. After the addition is complete, stir the mixture at 25 °C for not less than 3 h. Then, quench the excess H2O2 with a solution of sodium L-ascorbate (0.10 eq.) in water (0.3 V). Stir the mixture at 25 °C for 15 min, then add DMSO (6.1 V) and water (0.2 V). Adjust the pH of the mixture to 5.0 - 6.0 with triethylamine and heat the mixture to 40 °C, then add water (6 V) while maintaining the internal temperature of the vessel at 40 °C. Then, allow the mixture to reach 25 °C and filter the solid. Wash the solid with a solution of water (2.0 V) and ethanol (0.5 V) and dry in vacuo at ambient temperature to obtain the solid compounds (5a) / (5b) (in 94% yield and in 95:5 to 70:30 respective ratios, as measured by the analytical methods reported above).

[0476] Analytical information

[0477] Compound (5a): 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.27 (s, 3H) 3.10 (s, 3H) 3.84 (s, 4H) 6.88 (d, J = 8.76 Hz, 1H) 7.02 (dd, J = 8.69, 2.19 Hz, 1H) 7.13 (d, J = 2.25 Hz, 1H) 7.59 (d, J = 8.75 Hz, 1H) 7.73 (dd, J = 8.69, 2.56 Hz, 1H) 0.00 (d, J = 6.50 Hz, 1H) 8.21 (s, 1H) 8.78 (s, 1H) 9.60 (s, 1H) 10.46 (s, 1H); LR EIMS m / z: 446.15

[0478] Step 3. Preparation of compound (4’) from compounds (5a) / (5b) and compound (6b).

[0479] General procedure.

[0480] The stoichiometric calculations for compound (6b) are based on the calculated contents of compounds (5a) and (5b). The calculated contents are obtained by subtracting the residual solvents, KF, ROI, and total impurities from the theoretical value of 100% rather than by comparing with a reference standard of known potency. The calculation of the THF amount is based on the weight input of the mixture of compounds (5a) and (5b).

[0481] Charge compound (5a) / (5b) (1.0 eq), compound (6b) (1.3 eq) and THF (9.0 V) into a clean N2-purged vessel and start stirring. Heat the mixture to 60 °C and stir for no less than 6 h. After the reaction is complete, cool the mixture to -10 °C, stir for one hour and filter. Re-charge the wet filter cake into the vessel and triturate with THF (2 V) at 5 °C for one hour, then filter and wash with THF (1 V). Dry the product in vacuo at ambient temperature. Yield: 87%.

[0482] Analysis information

[0483] Compound (4’): 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.40 (m, 11H) 1.86 (br d, J = 10.01 Hz, 2H) 2.26 (s, 3H) 3.17 (br t, J = 11.38 Hz, 2H) -3.50 - 3.70 (m, 2H) 3.84 (s, 3H) -4.69 - 5.06 (br.S., 2H) -6.86 - 6.95 (m, 2H) 7.00 (dd, J = 8.63, 2.38 Hz, 1H) 7.10 (d, J = 2.25 Hz, 1H) 7.57 (d, J = 8.76 Hz, 1H) 7.78 (dd, J = 8.76, 2.50 Hz, 1H) 7.84 (d, J = 2.25 Hz, 1H) 8.18 (s, 1H) 8.38 (s, 1H) 9.06 (s, 1H) 9.57 (s, 1H); LR EIMS m / z: 582.25

[0484] Step 4. Prepare compound (3’) from compound (4’).

[0485] General procedure.

[0486] All calculations were performed for compound (4’).

[0487] Charge IPA (6.0 V) into a clean N2-purged vessel #1 and start stirring. Then, charge acetyl chloride (7.50 eq) while maintaining the internal temperature of the vessel below 45 °C. Heat the mixture to 65 °C and stir for about 1 h.

[0488] Charge compound (4') (1 equivalent) and DMSO (4.0 V) into a clean, N2-purged container #2 and agitate the mixture to obtain a homogeneous slurry. Charge the contents of container #2 into container #1 while maintaining the internal temperature of the container at 65 °C. Agitate the reaction solution for not less than 5 hours, then cool to ambient temperature and filter. Wash the solid with IPA (2.0 V) and dry in vacuo at 50 °C to obtain compound (3') in quantitative yield.

[0489] Analysis information

[0490] Compound (3'): 1 H NMR (400 MHz, DMSO-d6) δ ppm -1.51 - 1.72 (m, 2H) 2.10 (br d, J = 9.76 Hz, 2H) 2.24 (s, 3H) 3.17 (m, 2H) - 3.29 - 3.51 (m, 1H) 4.07 (s, 3H) - 4.82 - 5.32 (broad signal) 7.13 (d, J = 8.50 Hz, 1H) 7.17 (d, J = 2.25 Hz, 1H) 7.39 (dd, J = 9.01, 2.25 Hz, 1H) - 7.76 - 7.86 (m, 2H) 8.01 (d, J = 9.01 Hz, 1H) 8.41 (br d, J = 3.50 Hz, 3H) 8.62 (s, 1H) 9.21 (s, 1H) 9.57 (s, 1H) 10.53 (br s, 1H); LR EIMS m / z: 482.29

[0491] Step 5. Preparation of compound (2a') from compound (3').

[0492] General procedure.

[0493] All calculations were performed for compound (3').

[0494] Charge compound (3’) (1.0 eq) and THF (8.0 V) into a clean N2-purged vessel and start stirring. Charge a solution of K3PO4-5H2O (4.0 eq) in water (6.0 V) into the mixture while maintaining the internal temperature of the vessel at 22 °C. Stir the mixture until completely dissolved (e.g., between 15 minutes and 1 hr depending on scale), then stop stirring, allow the layers to settle and separate. Charge a solution of K3PO4-5H2O (1.02 eq) in water (1.5 V) into the organic layer, start stirring, and cool the mixture to 6 °C. Charge a solution of 3-chloropropionyl chloride (1.02 eq) in anhydrous THF (0.92 V) into the mixture while maintaining the internal temperature at 6 °C. Stir the reaction mixture for no less than 3 hours, then allow the mixture to reach ambient temperature, stop stirring, allow the layers to settle and separate. Add DCM (4.0 V) and brine (2.0 V) to the organic layer. Separate the layers and filter the organic matter through a charcoal filter. Subject the resulting solution to azeotropic distillation at atmospheric pressure to remove water (target final volume is 8 V). Allow the resulting slurry to reach ambient temperature and filter. Wash the solid with IPA (2.0 V) and dry in vacuo to obtain compound (2a’) in 69% yield.

[0495] Analytical information

[0496] Compound (2a’): 1 1H NMR (400 MHz, DMSO-d6) δ ppm -1.33 - 1.51 (m, 2H) 1.89 (br dd, J = 12.76, 3.00 Hz, 2H) 2.26 (s, 3H) 2.58 (t, J = 6.38 Hz, 2H) -3.20 - 3.32 (m, 2H) -3.76 - 3.87 (m, 5H) -3.88 - 4.02 (m, 1H) 4.83 (br signal, 2H) 6.89 (d, J = 8.76 Hz, 1H) 7.00 (dd, J = 8.76, 2.25 Hz, 1H) 7.10 (d, J = 2.25 Hz, 1H) 7.57 (d, J = 8.76 Hz, 1H) 7.77 (dd, J = 8.76, 2.50 Hz, 1H) 7.84 (d, J = 2.50 Hz, 1H) 8.04 (d, J = 7.50 Hz, 1H) 8.17 (s, 1H) 8.39 (s, 1H) 9.07 (s, 1H) 9.58 (s, 1H); LREIMS m / z: 572.17

[0497] Step 6. Preparation of Form I of compound (1) from compound (2a’).

[0498] General procedure.

[0499] All calculations were performed for compound (2a’).

[0500] Charge compound (2a') (1.0 eq) and THF (8.0 V) into a clean N2-purged vessel and start stirring. Charge a solution of KOH (2.0 eq) in water (3.5 V) into the mixture while maintaining the internal temperature of the vessel at 23 °C. Heat the reaction mixture to 38 °C and stir for no less than 18 h. After completion of the reaction, allow the mixture to reach ambient temperature, stop stirring, and remove the aqueous layer. Concentrate the organic matter under vacuum to a target volume of 4.0 V and dilute with DCM (6.0 V) and MeOH (3.0 V). Wash the resulting solution with brine (2.0 V) and separate the organic matter. Replace DCM and MeOH with THF via atmospheric distillation until a target volume of 8.0 V. Allow the mixture to reach ambient temperature and filter the slurry. Wash the solid with THF (2.0 V) and dry in vacuo to obtain the crystalline form I of compound (1) in 91% yield.

[0501] Step 7. Conversion of form I of compound (1) to form III of compound (1).

[0502] General procedure.

[0503] All calculations were performed for form I of compound (1).

[0504] Charge crude form I of compound (1) (1.0 eq), isopropanol or isopropyl acetate (8.0 V) into a clean N2-purged vessel and start stirring. If applicable, seed with form III of compound (1). Stir the slurry at ambient temperature for 2 h and filter. Wash the solid with isopropanol or isopropyl acetate (2.0 V) and dry in vacuo to obtain form III of compound (1) in 97% yield.

[0505] Example 1.2 - Route 2 to obtain crystalline forms I and IV

[0506] Reaction Figure 2 . Synthesis of compound (1) from compound (9), compound (10) and compound (7') based on a sulfur-containing leaving group

[0507]

[0508] Perform steps 1 and 2 as described in Example 1.1.

[0509] Step 3. Preparation of compound (2b') from compound (5a) / (5b) and compound (7').

[0510] General procedure.

[0511] All calculations were performed for compound (5a).

[0512] Charge compound (7’) (1.4 eq), water (1.0 V), brine (0.75 V), and 2-Me-THF (9.0 V) into a clean N2-purged vessel No. 1 and start stirring. Cool the mixture to 10 °C and add 50% aqueous NaOH (0.47 V) while maintaining the internal temperature of the vessel below 20 °C. Stir the two-phase mixture vigorously. Stop stirring after the formation of the layers or after about 30 to 60 minutes, allow the layers to settle and separate. Back-extract the aqueous layer with 2-Me-THF (4 V). Then, combine the organics and replace 2-Me-THF with DMAc until the target volume of ~7 V. Store the solution of the free base of compound (7’) thus obtained in DMAc until use in the next step.

[0513] Charge compound (5a) / compound (5b) (1.0 eq) into a clean N2-purged vessel No. 2, followed by adding the solution of compound (7’) in DMAc. Start stirring, heat the mixture to 68 °C and hold for about 6 hours. Then, allow the mixture to reach ambient temperature and filter. Wash the solid with MeOH (4 V) and dry in vacuo to obtain the solid compound (2b’) in 76% yield.

[0514] Analytical Information

[0515] Compound (2b’): 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.33 - 1.49 (m, 1H) 1.83 - 1.95 (m, 1H) 2.06 (s, 1H) 2.26 (s, 1H) 2.37 (t, J = 7.25 Hz, 1H) 2.67 (t, J = 7.25 Hz, 1H) 3.26 (br t, J = 11.51 Hz, 1H) 3.84 (s, 1H) 3.88 - 3.98 (m, 1H) 4.75 - 4.90 (m, 1H) 6.89 (d, J = 8.75 Hz, 1H) 7.00 (dd, J = 8.50, 2.00 Hz, 1H) 7.10 (d, J = 2.00 Hz, 1H) 7.57 (d, J = 8.76 Hz, 1H) 7.77 (dd, J = 8.76, 2.25 Hz, 1H) 7.84 (d, J = 2.00 Hz, 1H) 7.91 (br d, J = 7.50 Hz, 1H) 8.17 (s, 1H) 8.39 (s, 1H) 9.07 (s, 1H) 9.57 (s, 1H); LR EIMS m / z: 292.74.

[0516] Step 4. Preparation of compound (2d’) from compound (2b’).

[0517] General Procedure.

[0518] All calculations were performed for compound (2b’).

[0519] A solution of compound (2b’) (1.0 equiv), DMAc (8.0 V), and Na2WO4 (2 mol %) in water (0.45 V) was charged into a clean N2-purged container No. 1. Stirring was started and the mixture was heated to 70 °C. An aqueous solution of 30% H2O2 (2.6 equiv) was slowly charged while maintaining the internal temperature of the container at 70 °C. After the addition was complete, the mixture was stirred at 70 °C for about 16 h, then cooled to 50 °C and DMSO (0.22 equiv) was added. The mixture was further cooled to 4 °C, followed by the addition of IPAc (4.0 V). The resulting slurry was stirred at 4 °C for another 4 h and filtered. The solid was washed with a mixture of DMAc (0.76 V) and IPAc (2.25 V) and dried in vacuo. The obtained compound (2d’) was charged back into the container and ground in water (16 V) at 72 °C for 18 h. Then, the slurry was cooled, the product was filtered and dried in vacuo.

[0520] If desired, compound (2c’) can be enriched in the reaction mixture using a sub-stoichiometric amount of the oxidant and then isolated by standard purification methods. Compound (2c’) was characterized below on a 300 MHz NMR spectrometer and infusion MS.

[0521] Analytical information

[0522] Compound (2d’): 1 1H NMR (400 MHz, DMSO-d6) δ ppm -1.34 - 1.48 (m, 2H) -1.85 - 1.95 (m, 2H) -2.54 - 2.62 (m, 2H) 2.99 (s, 3H) -3.22 - 3.38 (m, 4H) 3.84 (s, 3H) -3.87 - 4.00 (m, 1H) 4.82 (br d, 2H) 6.89 (d, J = 8.75 Hz, 1H) 7.00 (dd, J = 8.76, 2.25 Hz, 1H) 7.10 (d, J = 2.25 Hz, 1H) 7.57 (d, J = 8.50 Hz, 1H) 7.77 (dd, J = 8.76, 2.75 Hz, 1H) 7.84 (d, J = 2.50 Hz, 1H) 8.10 (d, J = 7.75 Hz, 1H) 8.17 (s, 1H) 8.39 (s, 1H) 9.06 (s, 1H) 9.56 (s, 1H); LR EIMS m / z: 616.22.

[0523] Compound (2c’): 11H NMR (300 MHz, DMSO-d6) δ ppm -1.34 - 1.58 (m, 2H) -1.83 - 2.02 (m, 2H) 2.27 (s, 3H) -2.50 - 2.66 (m, 4H) -2.77 - 3.41 (m, 6H) 3.84 (s, 3H) -3.88 - 4.05 (m, 1H) 4.77 (brd, J = 13.33 Hz, 1H) 6.90 (d, J = 8.65 Hz, 1H) 6.99 (dd, J = 8.72, 2.27 Hz, 1H) 7.13 (d, J = 2.20 Hz, 1H) 7.53 (d, J = 8.79 Hz, 1H) -7.73 - 7.85 (m, 2H) 7.94 (d, J = 7.47 Hz, 1H) 8.13 (s, 1H) 8.38 (s, 1H) 9.02 (s, 1H) 9.37 (s, 1H); LR MS: 600.25。

[0524] Step 5. Preparation of Form I of Compound (1) from Compound (2d').

[0525] General procedure.

[0526] All calculations were performed for Compound (2d').

[0527] Charge Compound (2d') (1.0 eq), aqueous 45% KOH (1.5 eq), THF (8.9 V), and MeCN (1.6 V) into a clean N2-purged container No. 2 and start stirring. Heat the mixture to 42 °C and stir for ~14 h, then cool to 30 °C and stir for an additional 10 h. After the reaction is complete, reheat the mixture to 45 °C, stop stirring, and separate the layers. Wash the organic layer successively with 2.5 M phosphate buffer and brine. Subject the organic matter to azeotropic distillation with THF to remove water (target final volume is 6 V). After the distillation is complete, bring the slurry to ambient temperature, filter, and wash with THF. Dry the solid in vacuo at 50 °C to obtain crystalline Form I of Compound (1) in 81% yield.

[0528] Step 6. Conversion of Form I of Compound (1) to Form IV of Compound (1).

[0529] General procedure.

[0530] All calculations were performed for Compound (1).

[0531] Charge compound (1) (1.0 eq), a seed of Form IV of compound (1) (2 wt%) and IPAc (20 V) into a clean N2-purged vessel and start agitation. Heat the mixture to 70 °C and agitate for ~20 hr, then cool to 20 °C. Filter the slurry and wash the solid successively with IPAc and water. Dry the solid in vacuo at 50 °C to afford Form IV of compound (1) in 95% yield.

[0532] Example 2 - Preparation of Solid Forms of Compound (1)

[0533] It should be noted that if complete dissolution is achieved prior to crystallization, the input form of compound (1) has no significant effect on the crystallization procedure. In the case of complete dissolution, the compound (1) starting material can be generated, for example, according to the synthesis described in WO 2021 / 213800 or according to the procedure disclosed in Example 1 herein.

[0534] Example 2.1 - Preparation of Form I

[0535] First example procedure for preparing Form I (crystalline): Dissolve 19 kg of compound (1) (any solid form) in a mixture of ~54 kg of THF, ~160 kg of DCM and ~48 kg of MeOH. Remove residual inorganic salts by washing with brine (48 kg). Remove undissolved particles by polishing filtration of the organic layer. Then distill the organic layer to ~160 L and dilute the mixture with 78 kg of THF. Repeat the distillation, THF dilution, distillation sequence until the respective contents of water and MeOH are ≤ 1.0% w / w. After completion of distillation, hold the obtained slurry at ambient temperature for no longer than 12 hr and filter to obtain Form I.

[0536] Second example procedure for preparing Form I (crystalline): Dissolve 6 g of Form IV or any other solid form of compound (1) (prepared, for example, according to one of the examples described herein) in 75 g of a 5% w / w H2O solution in IPA at 90 °C. Slowly cool the solution to 75 °C and seed with 60 mg of Form I. Agitate the mixture at 75 °C for 2 hours, then cool to 20 °C at a rate of 0.3 °C / min. After completion of cooling, filter the solid and dry to obtain Form I.

[0537] Example 2.2 - Preparation of Form III

[0538] Example procedure for preparing Form III (slurry): Mix 17 kg of Form I of Compound (1) with 271 kg of IPAc. Heat the slurry to 70 °C. Add 0.2 kg of seeds of Form III of Compound (1) (prepared, for example, according to one of the examples set forth herein) to the slurry and agitate the mixture for ~16 hr. After completion of the hold, cool the mixture gradually to 53 °C over ~40 min, then to 33 °C over ~40 min, and then to 25 °C. Agitate the resulting slurry for ~1 hr and filter. Wash the solid with 27 kg of IPAc and dry to obtain Form III.

[0539] This procedure can also be carried out without adding seeds.

[0540] Example 2.3 - Manufacture of Form IV

[0541] First example procedure for preparing Form IV (crystalline): Disperse 300 mg of Form I of Compound (1) in 3 ml of 1-BuOH. Heat the mixture to 90 °C with overhead agitation. Dissolution is observed. Cool the solution to 75 °C at a rate of 0.2 °C / min, followed by rapid cooling to 20 °C. Hold the resulting slurry at 20 °C for ~12 hr with simultaneous agitation and filter to obtain Form IV.

[0542] Second example procedure for preparing Form IV (crystalline): Dissolve Form III or any other solid form of Compound (1) in a 10 volume 1-BuOH / anisole (1:1) mixture at 110 °C. Subject the solution to a microvacuum distillation during which most of the 1-BuOH is removed. Seed the solution with Form III seeds, maintaining at 110 °C and obtaining a slurry. Cool the mixture to ambient temperature with simultaneous agitation and filter to obtain the isolated Compound (1) in Form IV. This procedure can be carried out without seeding with Form III.

[0543] Third example procedure for preparing Form IV (slurry): Slurry a slurry of Forms I and IV of Compound (1) in IPAc in the temperature range of 25 to 75 °C for 72 - 168 hr. If applicable, bring the mixture to ambient temperature and filter to obtain Compound (1) in Form IV. When Compound (1) is obtained as described in Example 1.2 above, this third example procedure for preparing Form IV can also be carried out starting only from Form I (with or without seeding).

[0544] Example 2.4 - Manufacture of Reference Form II

[0545] Example Procedure for Preparing Form II (Slurry): Form I (30 mg) of Compound (1) was slurried in methanol (1.5 mL) at 55 °C for 2 h. The mixture was cooled to room temperature and filtered to obtain Compound (1) in Form II. XRPD diffraction patterns of Form II and other forms are shown in Figure 25 below.

[0546] Example 2.5 - Preparation of Reference Form VI

[0547] Example Procedure for Preparing Form VI (Slurry): Form III of Compound (1) was slurried in water at 50 °C for 2 h, cooled to room temperature and reslurried for 168 h. The mixture was filtered to obtain Compound (1) in Form VI. XRPD diffraction patterns of Form VI and other forms are shown in Figure 25 below.

[0548] Example 2.6 - Preparation of Reference Form VII

[0549] Example Procedure for Preparing Form VII (Crystalline): A mixture of Compound (1) (30 mg) in methyl ethyl ketone (1.5 mL) was heated to 55 °C and maintained for 30 - 60 min. The obtained clear solution was filtered into a clean vial and kept undisturbed at room temperature to obtain Form VII. XRPD diffraction patterns of Form VII and other forms are shown in Figure 25 below.

[0550] Example 3 - Characterization of Solid Forms of Compound (1)

[0551] The solid crystalline forms I, III, and IV of Compound (1) can be characterized by powder X - ray diffraction (XRPD or PXRD), Raman spectroscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), scanning electron microscopy (EMS), and, if applicable, single - crystal X - ray diffraction (SXRD) (e.g., as described below).

[0552] Example 3.1 - Characterization by Powder X - ray Diffraction (XRPD or PXRD)

[0553] The solid forms of Compound (1) were analyzed and can be identified by XRPD. Generally, XRPD measurements were performed using CuKα radiation (CuKα1,2 radiation) with a wavelength of at a temperature in the range of 20 to 30 °C. The Kα2 was removed by software to obtain CuKα radiation (CuKα1 radiation) with a wavelength of For XRPD analysis, the method can be as described below.

[0554]

[0555] Each individual solid compound (ca. 0.2 g) was typically subsampled into a stainless-steel sample holder equipped with a zero-diffraction plate (ZDP). The sample holder was then leveled using a glass slide to form a flat sample surface flush with the sample holder. The instrument used for analysis was a Bruker D2 Phaser (system EQ-SSRD-XRD-01). A corundum reference standard was run daily to evaluate system performance. Two peaks had to be within ±0.02° 2θ to achieve acceptable system suitability. The instrument settings for measuring the solid compound samples are shown in Table 1. Processing (Kα2 contribution removal, peak marking) was completed using DIFFRAC.EVA software (version 5.0). Below, the experimental parameters for XRPD measurement are given:

[0556]

[0557]

[0558] Table 1: Experimental parameters for XRPD measurement

[0559] The processed XRPD diffraction patterns of each of the polymorphic forms are shown in Figure 1 (Form I), Figure 2 (Form III), and Figure 3 (Form IV). The XRPD overlays of all three forms are shown in Figure 4 . It can be seen that each of the three polymorphic forms has its unique XRPD fingerprint, and each form can be identified by XRPD. Table 2 lists the peaks (relative intensity greater than 5%) for each form. Table 3 lists the most preferred characteristic peaks used when attempting to identify a given polymorphic form in the presence of another form. Identification peaks indicate the peak positions of impurities with relatively high-intensity peaks, and the major form of the sample has a flat baseline.

[0560]

[0561] Table 2: XRPD peak comparison

[0562] Regarding Table 2, the bold peaks were determined to be characteristic peaks, the peaks marked with "*" have a relative intensity greater than 10%. The peaks marked with "**" have a relative intensity greater than 50%. Additionally, the peaks are listed in order of peak position (° 2θ), with similar peak positions on the same column.

[0563]

[0564] Table 3: XRPD characteristic peaks (° 2θ) for polymorph impurity identification

[0565] Example 3.2 - Characterization by Raman spectroscopy

[0566] The crystalline forms I, III, and IV of the resulting compound (1) can be further analyzed and identified by Raman spectroscopy. The method for this can be described as follows. The solid compound is typically subsampled twice into a vial cap until a thickness of approximately 0.5 mm or more. The instrument used for analysis is the BWTek i-Raman Plus probe. The instrument settings for measuring the solid compound sample can be seen in Table 4. Processing (blur reduction, background removal, peak marking, diffraction pattern formation) is completed using BWSpec 4 software. The experimental parameters are further detailed in Table 4 below:

[0567]

[0568] Table 4: Raman measurement experimental parameters

[0569] The processed Raman spectra can be seen individually in Figure 5 a to 5d, where Figure 5 a shows the background Raman spectrum; Figure 5 b shows the Raman spectrum of crystalline form I; Figure 5 c shows the Raman spectrum of crystalline form III; and Figure 5 d shows the Raman spectrum of crystalline form IV. A summary of the peaks is presented in Table 5. In Table 5, only the peaks that do not exist in the background are listed, the bold peaks are determined to be characteristic peaks and the peaks are listed in order of Raman shift (cm -1 ) with similar shifts on the same column.

[0570] In addition, Table 6 only shows the Raman peak (cm -1 ) characteristics for the identification of polymorphic impurities.

[0571]

[0572]

[0573] Table 5: Raman peak comparison

[0574]

[0575] Table 6: Characteristic Raman peaks (cm -1 ) for the identification of polymorphic impurities

[0576] Example 3.3 - Characterization by differential scanning calorimetry (DSC)

[0577] The crystalline forms I, III, and IV of the resulting compound (1) can be further analyzed and identified by differential scanning calorimetry (DSC). The method for this can be described as follows. The solid form (∼5 mg) is placed in an aluminum pan and sealed. The instrument used for analysis is a TA Instruments DSC 25. The experimental settings are listed in Table 7. Processing is done using TRIOS software.

[0578]

[0579] Table 7: Experimental settings for DSC analysis

[0580] The DSC curves for each polymorphic form of compound (1) can be seen in Figure 6 (Form I), Figure 7 (Form III), and Figure 8 (Form IV).

[0581] A summary of the DSC events is listed in Table 8. From the comparison of the melting points of each form, Form IV is expected to be the most thermodynamically stable, followed by Form III. Form I is expected to have poor thermodynamic stability. An exothermic event at approximately 240 °C was observed in all three polymorphic forms I, III, and IV.

[0582]

[0583] Table 8: DSC events

[0584] Example 3.4 - Characterization by thermogravimetric analysis (TGA)

[0585] The crystalline forms I, III, and IV of the resulting compound (1) can be further analyzed and identified by thermogravimetric analysis (TGA). The method for this can be described as follows. The solid compound (∼5 mg) is placed in an aluminum pan and sealed. The instrument used for analysis is a TA Instruments TGA 550. The experimental settings are listed in Table 9. The TGA test is performed using the same sample batch as the DSC test. Processing is done using TRIOS software.

[0586]

[0587] Table 9: Experimental settings for TGA analysis

[0588] The TGA curves for each polymorphic form of compound (1) can be seen in Figure 9 (Form I), Figure 10 (Form III), and Figure 11(Form IV). A summary of the TGA events is presented in Table 10. All three forms decompose at approximately 440 °C. The event of approximately 1% mass loss is associated with the melting temperature (approximately 235 °C) of Forms III and IV. This small mass loss may be due to the release of solvent from the lattice of Forms III and IV solids upon melting.

[0589]

[0590] Table 10: TGA Events

[0591] Example 3.5 - Characterization by Dynamic Vapor Sorption (DVS)

[0592] To study the hygroscopic behavior of crystalline Forms I, III, and IV of compound (1), adsorption isotherms obtained by DVS were recorded using an in-house DVS-1 or DVS from Surface Measurement Systems. The method for this can be described as follows. As the relative humidity (RH) was deliberately changed, the mass of the solid was monitored. The RH was cycled twice from 0% to 90% to 0% in 10% steps. The temperature during the measurement was kept constant at (25.0 ± 1.0) °C. Each step was held until mass stability was achieved. A camera inside the instrument captured images at the end of each stage, allowing any visual changes in the solid form to be observed during analysis.

[0593] Figure 12 The isotherm curve of Form I is shown. A maximum water uptake of 7.3 wt% ( = mass change, Δm) was observed at a maximum of 90% RH, which was completely reversible. The sample absorbed 5.4 wt% moisture at 80% RH. Therefore, Form I was classified as a hygroscopic material. Although a significant hysteresis was observed between the adsorption and desorption curves (specifically in the range above approximately 40% RH), it was confirmed by PXRD (performed using samples before and after the DVS run) that no irreversible phase transformation occurred during the DVS experiment ( Figure 13 ).

[0594] Figure 14 The isotherm curve of Form III is shown. A maximum water uptake of 1.7 wt% was observed at a maximum of 90% RH, which was completely reversible. The sample absorbed 1.2 wt% moisture at 80% RH. Therefore, Form III was classified as a slightly hygroscopic material. There was no indication of irreversible phase transformation or hydrate formation due to water vapor adsorption, as indicated by the absence of hysteresis between the adsorption and desorption curves. No visual appearance changes were observed for Form III during the humidity cycle.

[0595] Figure 15An isotherm curve of Form IV is shown. A maximum water uptake of 0.5 wt% was observed at up to 90% RH, which is completely reversible. The sample absorbs 0.4 wt% moisture at 80% RH. Thus, Form IV is classified as a slightly hygroscopic material. There is no indication of irreversible phase transformation or hydrate formation due to water vapor adsorption, as indicated by no hysteresis between the adsorption and desorption curves. No visual appearance change was observed for Form IV during the humidity cycle. Table 11 summarizes the events of the different crystalline forms of compound (1) observed during the DVS experiment.

[0596]

[0597] Table 11: DVS Events

[0598] Example 3.6 - Characterization by Scanning Electron Microscopy (SEM)

[0599] SEM images of each of the polymorphic forms are shown in Figure 16 (Form I), Figure 17 (Form III) and Figure 18 (Form IV). Although Forms III and IV mainly consist of plate-like crystals, Form I shows a needle-like morphology.

[0600] Example 3.7 - Characterization by Single Crystal X-ray Diffraction (SXRD)

[0601] Single crystals of the crystalline form IV of compound (1) were grown by slow evaporation from a solution of anisole:1-butanol (8:1) at room temperature. A clear and colorless block with approximate dimensions of 0.170 × 0.07 × 0.05 mm was selected and mounted on a MiTeGen MicroMount using Paratone-N oil. TM Three frames separated in reciprocal lattice space were recorded to provide an orientation matrix and initial cell parameters. The final cell parameters were obtained and refined based on the full data set. Minimal diffraction was observed at typical collection times (≤60 s), so the full data set was collected with an exposure collection time of 360 s / degree data.

[0602] Diffraction data were acquired at room temperature on a Rigaku R-AXIS RAPID diffractometer equipped with a sealed tube copper source of 50 kV / 40 mA and a Spider curved imaging plate detector. For each frame at The diffraction data set in reciprocal lattice space was obtained with a resolution using a 5° oscillation step and a 300 s exposure. The diffraction images were processed and scaled using Rigaku Oxford Diffraction software (RapidAuto; Rigaku OD: The Woodlands, TX, 2015). Observation of the crystal after data collection showed no signs of decomposition.

[0603] The structure was solved using direct methods with Olex2 16 embedded with the SHELXT17 structure program (strurogram). The structure was refined using the SHELXL18 refinement package with least-squares minimization. All non-hydrogen atoms were refined anisotropically. Hydrogen atoms were included in geometrically calculated positions in the model and refined using a riding model. The initial structure solution provided a calculated powder diffraction pattern consistent with form IV (see Figure 19 the bottom diffraction pattern).

[0604]

[0605] Table 12: Crystal data and structure refinement

[0606] Example 4 - Polymorphic stability of the solid forms of compound (1)

[0607] Example 4.1 - Polymorphic stability of form III and form IV

[0608] Forms III and IV were stored open at 90 °C / 3% RH and 90 °C / 78% RH stress conditions for a period of 21 days and the polymorphic stability was analyzed by powder X-ray diffraction.

[0609] The samples were characterized using a Bruker D2 Phaser X-Ray diffractometer (XRD, EQ-SSRD-XRD-01). The settings used during sample measurement are listed in Table 13. The raw results were evaluated using DIFFRAC.EVA (Bruker, V5.0) software. The Kα2 contribution was removed and a peak search was performed using peak search parameters (width 0.302 and threshold 1.0).

[0610]

[0611] Table 13: Experimental parameters for PXRD measurement

[0612] The test sample (approx. 0.3 g) was typically subsampled twice into an agate type mortar and pestle. The sample was ground for approximately one minute to achieve a fine homogeneous powder. The sample was then transferred to a stainless-steel sample holder equipped with a zero-diffraction plate (ZDP). The sample holder was then leveled using a glass slide to form a flat sample surface flush with the sample holder.

[0613] The overlays of the x-ray diffraction patterns of the treated powders of Forms III and IV under different stress conditions are shown respectively in Figure 20 and Figure 21 . The Form III control and test samples for the 21-day period stored at 90 °C / 3% relative humidity (RH) and 90 °C / 78% RH were stable and conformed to the Form III reference standard, and no loss or additional reflections were observed. Similarly, the Form IV control and test samples for the 21-day period stored at 90 °C / 3% relative humidity (RH) and 90 °C / 78% RH were stable and conformed to the Form IV reference standard.

[0614] Example 4.2 - Polymorphic Stability of Forms I, II and VI

[0615] The crystalline forms I, II and VI of compound (1) were exposed to temperature stress under the conditions outlined in Table 14, and the polymorphic stability of the samples was analyzed by powder X-ray diffraction as described in Example 4.1.

[0616] Initial crystalline form Storage conditions pXRD of stressed samples Form I At 150 °C for 6 h (sealed vial) Form I Form II Vacuum dried at 40 °C for 2 h (open vial) Form V Form VI At 120 °C for 1 h (sealed vial) Amorphous

[0617] Table 14: Summary of Temperature Stress Tests Using Forms I, II and VI

[0618] As can be seen from Table 14, although Form I was exposed to the most severe temperature stress, it was the only form that remained unchanged (see also Figure 22 ), while Form II underwent a phase change to Form V (see also Figure 23 ) and Form VI became amorphous compound (1) (see also Figure 24 ). The reference XRPD diffraction patterns of Forms I and V and other forms are shown in Figure 25 .

[0619] Example 5 - Chemical Stability of the Solid Forms of Compound (1)

[0620] To study Forms III and IV under severe stress conditions, the two crystalline forms were exposed to a range of high temperatures (between 60 °C and 90 °C) and humidities (between 3% RH and 79% RH) for up to 21 days. For this purpose, the control samples were stored frozen in the presence of a desiccant for the duration of the study and measured simultaneously with the stressed samples by HPLC at a wavelength of 252 nm.

[0621] The related substance results for Forms III and IV are summarized in Tables 15 and 16 respectively. No color change was observed for either Form III or Form IV after stress.

[0622]

[0623] *Samples measured after 21 days; **Samples measured after 17 days; ***Samples measured after 10 days

[0624] Table 15: Summary of results for Form III samples under stress

[0625] For Form III, there was no significant increase in any related substances under any accelerated stress conditions. The absence of degradation products formed under extreme stress (up to 21 days at 90 °C / 78% RH) confirmed that Form III is highly chemically stable in the solid state.

[0626]

[0627]

[0628] **Samples measured after 17 days; ***Samples measured after 10 days

[0629] Table 16: Summary of results for Form IV samples under stress

[0630] Like Form III, Form IV showed no significant increase in any related substances under any accelerated stress conditions. The absence of degradation products formed under extreme stress (up to 21 days at 90 °C / 78% RH) confirmed that Form IV is also highly chemically stable in the solid state.

[0631] Example 6 - Preparation of solid dispersions comprising compound (1) and different dispersion polymers

[0632] In this example, solid dispersions containing 25 wt% or 50 wt% of compound (1) and 75 wt% or 50 wt% of the dispersion carriers HPMCAS-M (Shin-Etsu AQOAT), PVP-VA, L100 or HPMC HME 15LV were prepared.

[0633] The solid dispersions of this example were prepared according to the following protocol: spray drying the solid dispersions from a spray solution composition comprising crystalline Forms I, III, IV (as described herein in the broadest form or in any of its embodiments) of compound (1) or mixtures thereof, a dispersion carrier, and a DCM:MeOH (1:1 (w / w)) solvent system with a solids content of 8 wt% total solids. The solid dispersions were manufactured using a Procept 4M8TRX spray dryer with a 2-fluid nozzle type and a nozzle cap / tip size of 1.0 mm / 1.0 mm, an inlet temperature of 85 - 90 °C, an outlet temperature of 45 - 50 °C, atomization at 3.0 bar, 0.50 m 3A drying gas air flow rate of / min and a solution feed rate of approximately 15 g / min. Secondary drying of the dispersion was carried out at 40 °C for 22.5 hours in a vacuum dryer of the tray dryer type in the collection container.

[0634] The spray drying yield results obtained following the protocol from the previous paragraph are summarized in Table 17, where gA represents grams of API (active pharmaceutical ingredient, i.e., compound (1)).

[0635]

[0636] Table 17: Batch and yield of solid dispersions of compound (1) with dispersion carriers HPMCAS-M, PVP-VA, L100 or HPMC HME 15LV

[0637] Example 7 - Characterization of solid dispersions by X-ray powder diffraction (XRPD)

[0638] XRPD can be obtained according to the following protocol: XRPD analysis was performed using a Rigaku Miniflexx 600 diffractometer. A sample of approximately 10 mg of a solid dispersion of compound (1) with a dispersion carrier (e.g., with HPMCAS-M, PVP-VA, L100 or HPMC HME 15LV as in Example 6) was placed on a zero-background sample disk and placed in the autosampler of the Rigaku Miniflex 600. The sample was analyzed using the instrument parameters set forth in Table 18 below.

[0639]

[0640] Table 18: Summary of XRPD collection parameters

[0641] The XRPD obtained following the protocol from the previous paragraph using the various solid dispersions prepared under Example 6 is shown in Figures 26 to 29 . Comparison of it with the XRPD of crystalline compound (1) in the same figure indicates the absence of crystalline material in the sample. Specifically, the XRPD of solid dispersions of 25 wt% or 50 wt% compound (1) and dispersion carriers HPMCAS-M, PVP-VA, L100 or HPMC HME 15LV shows no spikes and the presence of an amorphous halo. The absence of sharp diffraction peaks indicates that the solid dispersion is consistent with the non-amorphous form of compound (1).

Claims

1. A crystalline form of a compound (1), characterized in that: (a) When measured using CuKα radiation having a wavelength of or in the temperature range of 20 to 30 °C, the powder X-ray diffraction pattern includes peaks at the following 2θ values: (5.9 ± 0.2)°, (11.7 ± 0.2)° and (16.7 ± 0.2)°; and / or (b) When measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the Raman spectrum includes peaks at any of the wavenumbers represented below as cm -1 : 640 ± 2 and / or 831 ± 2.

2. The crystalline form according to claim 1, wherein when measured using CuKα radiation having a wavelength of or in the temperature range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern comprising peaks at the following 2θ values: (5.9 ± 0.2)°, (11.7 ± 0.2)° and (16.7 ± 0.2)°.

3. The crystalline form according to claim 1 or 2, wherein when measured using CuKα radiation having a wavelength of or in the temperature range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern comprising peaks at the following 2θ values: (5.9 ± 0.2)°, (11.7 ± 0.2)°, (14.7 ± 0.2)°, (16.7 ± 0.2)°, (18.8 ± 0.2)° and (19.2 ± 0.2)°.

4. The crystalline form according to any one of claims 1 to 3, wherein when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum having a peak at any one of the wave numbers represented by the following cm -1 : 640 ± 2 and / or 831 ± 2.

5. The crystalline form according to any one of claims 1 to 4, wherein when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum comprising peaks at wavenumbers represented as cm -1 as follows: 238 ± 2, 640 ± 2 and 831 ± 2.

6. A crystalline form of a compound (1), characterized in that: (a) When measured using CuKα radiation having a wavelength of or in the temperature range of 20 to 30 °C, the powder X-ray diffraction pattern includes peaks at the following 2θ values: (6.2 ± 0.2)°, (9.5 ± 0.2)°, (11.4 ± 0.2)°, (12.4 ± 0.2)° and (16.2 ± 0.2)°; or (b) When measured using CuKα radiation having a wavelength of or in the temperature range of 20 to 30 °C, the powder X-ray diffraction pattern includes peaks at the following 2θ values: (6.2 ± 0.1)°, (9.5 ± 0.1)°, (11.4 ± 0.1)°, and (12.4 ± 0.1)°; or (c) When measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the Raman spectrum includes a peak at any of the wavenumbers represented below as cm -1 : 1310 ± 2 and / or 1400 ± 2; or (d) When measured using CuKα radiation having a wavelength of or in the temperature range of 20 to 30 °C, the powder X-ray diffraction pattern includes peaks at the following 2θ values: (6.2 ± 0.2)°, (9.5 ± 0.2)°, (11.4 ± 0.2)°, (12.4 ± 0.2)° and (16.2 ± 0.2)°, and when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the Raman spectrum includes peaks at any of the following wavenumbers expressed as cm -1 : 1310 ± 2 and / or 1400 ± 2; or (e) When measured using CuKα radiation having a wavelength of or in the temperature range of 20 to 30 °C, the powder X-ray diffraction pattern includes peaks at the following 2θ values: (6.2 ± 0.1)°, (9.5 ± 0.1)°, (11.4 ± 0.1)°, and (12.4 ± 0.1)°, and when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the Raman spectrum includes peaks at any of the following wavenumbers expressed as cm -1 : 1310 ± 2 and / or 1400 ± 2.

7. The crystalline form according to claim 6, wherein when measured using CuKα radiation having a wavelength of or in the temperature range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern comprising peaks at the following 2θ values: (6.2 ± 0.2)°, (9.5 ± 0.2)°, (11.4 ± 0.2)°, (12.4 ± 0.2)° and (16.2 ± 0.2)°.

8. The crystalline form according to claim 6 or 7, wherein when measured at a temperature in the range of 20 to 30 °C using CuKα radiation having a wavelength of or , the crystalline form has a powder X-ray diffraction pattern comprising peaks at the following 2θ values: (6.2 ± 0.2)°, (9.5 ± 0.2)°, (11.4 ± 0.2)°, (12.4 ± 0.2)°, (16.2 ± 0.2)° and (18.3 ± 0.2)°.

9. The crystalline form according to any one of claims 6 to 8, wherein when measured at a temperature in the range of 20 to 30 °C using CuKα radiation having a wavelength of or , the crystalline form has a powder X-ray diffraction pattern comprising peaks at the following 2θ values: (6.2 ± 0.1)°, (9.5 ± 0.1)°, (11.4 ± 0.1)°, and (12.4 ± 0.1)°.

10. The crystalline form according to any one of claims 6 to 9, wherein when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum having a peak at any one of the wavenumbers represented as cm -1 : 1310 ± 2 and / or 1400 ± 2.

11. The crystalline form according to any one of claims 6 to 10, wherein when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum comprising peaks at the wavenumbers represented below as cm -1 : 485 ± 2, 610 ± 2, 1029 ± 2, 1310 ± 2 and 1400 ± 2.

12. The crystalline form according to any one of claims 6 to 11, wherein when measured using CuKα radiation having a wavelength of or in the temperature range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern comprising peaks at the following 2θ values: (6.2 ± 0.2)°, (9.5 ± 0.2)°, (11.4 ± 0.2)°, (12.4 ± 0.2)° and (16.2 ± 0.2)°, and when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum comprising peaks at any one of the following wave numbers expressed as cm -1 : 1310 ± 2 and / or 1400 ± 2.

13. The crystalline form according to any one of claims 6 to 12, wherein when measured using CuKα radiation having a wavelength of or in the temperature range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern comprising peaks at the following 2θ values: (6.2 ± 0.1)°, (9.5 ± 0.1)°, (11.4 ± 0.1)° and (12.4 ± 0.1)°, and when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum comprising peaks at any one of the following wave numbers expressed as cm -1 : 1310 ± 2 and / or 1400 ± 2.

14. A crystalline form of a compound (1), characterized in that: (a) When measured using CuKα radiation having a wavelength of or in the temperature range of 20 to 30 °C, the powder X-ray diffraction pattern includes peaks at the following 2θ values: (7.9 ± 0.2)° and (12.0 ± 0.2)°; and / or (b) When measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the Raman spectrum includes peaks at any of the wavenumbers represented as cm -1 : 1411 ± 2 and / or 1602 ± 2.

15. The crystalline form according to claim 14, wherein when measured using CuKα radiation having a wavelength of or in the temperature range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern comprising peaks at the following 2θ values: (7.9 ± 0.2)° and (12.0 ± 0.2)°.

16. The crystalline form according to claim 14 or 15, wherein when measured using CuKα radiation having a wavelength of or in the temperature range of 20 to 30 °C, the crystalline form has a powder X-ray diffraction pattern comprising peaks at the following 2θ values: (6.1 ± 0.2)°, (7.9 ± 0.2)°, (11.1 ± 0.2)°, (12.0 ± 0.2)°, (17.2 ± 0.2)° and (17.9 ± 0.2)°.

17. The crystalline form according to any one of claims 14 to 16, wherein when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum having a peak at any one of the wavenumbers represented as cm -1 : 1411 ± 2 and / or 1602 ± 2.

18. The crystalline form according to any one of claims 14 to 17, wherein when measured in the temperature range of 20 to 30 °C and at a wavelength of 785 nm, the crystalline form has a Raman spectrum comprising peaks at the wavenumbers represented below as cm -1 : 824 ± 2, 1411 ± 2, and 1602 ± 2.

19. A method for preparing a crystalline form of a compound (1), comprising the steps of: i) dissolving the compound (1) in at least one organic solvent under heating; ii) cooling the solution obtained in step (i), wherein a crystalline form of the compound (1) is formed; and iii) separating at least a portion of the crystalline form of the compound (1) obtained in step (ii).

20. The method according to claim 19, wherein at least in part a crystalline form of the compound (1) as defined in any one of claims 1 to 5 is formed.

21. A crystalline form obtainable by or by the method according to claim 19 or 20.

22. The crystalline form according to claim 21, wherein the crystalline form has a powder X-ray diffraction pattern comprising peaks as defined in any one of claims 1 to 5 and / or a Raman spectrum comprising peaks at wave numbers as defined in any one of claims 1 to 5.

23. A method for preparing a crystalline form of a compound (1), comprising the steps of: i) providing a suspension of the compound (1) in at least one organic solvent; ii) agitating the suspension obtained in step (i) until a crystalline form of the compound (1) is formed; and iii) separating at least a portion of the crystalline form of the compound (1) obtained in step (ii).

24. The method according to claim 23, wherein at least in part a crystalline form of the compound (1) as defined in any one of claims 6 to 13 is formed.

25. A crystalline form obtainable by or by the method according to claim 23 or 24.

26. The crystalline form according to claim 25, wherein the crystalline form has a powder X-ray diffraction pattern comprising peaks as defined in any one of claims 6 to 13 and / or a Raman spectrum comprising peaks at wave numbers as defined in any one of claims 6 to 13.

27. A method for preparing a crystalline form of a compound (1), comprising the steps of: i) dissolving the compound (1) in a mixture of solvents comprising at least one water-miscible organic solvent and water under heating; ii) cooling the solution obtained in step (i), wherein a crystalline form of the compound (1) is formed; and iii) separating at least a portion of the crystalline form of the compound (1) obtained in step (ii).

28. The method according to claim 27, wherein at least in part a crystalline form of the compound (1) as defined in any one of claims 14 to 18 is formed.

29. A crystalline form obtainable by or by the method according to any one of claims 27 or 28.

30. The crystalline form according to claim 29, wherein the crystalline form has a powder X-ray diffraction pattern comprising peaks as defined in any one of claims 14 to 18 and / or a Raman spectrum comprising peaks at the wavenumbers as defined in any one of claims 14 to 18.

31. The crystalline form according to any one of claims 1 to 18, 21, 22, 25, 26, 29 or 30, which is used as a medicament.

32. The crystalline form according to any one of claims 1 to 18, 21, 22, 25, 26, 29 or 30, which is used for treating and / or preventing tumors and / or hyperproliferative diseases, specifically cancer.

33. The crystalline form used according to claim 32, wherein the tumor and / or hyperproliferative disease is cancer selected from the group consisting of: brain cancer, breast cancer, biliary tract cancer, bladder cancer, cervical cancer, uterine cancer, colorectal cancer, endometrial cancer, ovarian cancer, skin cancer, gastric cancer, esophageal tumor, head and neck tumor, salivary gland cancer, gastrointestinal cancer, small intestine cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer and prostate cancer.

34. The crystalline form used according to claim 32 or 33, wherein the tumor and / or hyperproliferative disease is HER2 overexpressing, HER2 amplified and / or HER2 mutant cancer.

35. A pharmaceutical composition, which comprises the crystalline form according to any one of claims 1 to 18, 21, 22, 25, 26, 29 or 30 and one or more pharmaceutically acceptable excipients.

36. Use of a crystalline form or a mixture thereof as defined in any one of claims 1 to 18, 21, 22, 25, 26, 29 or 30 for preparing a solid dispersion comprising compound (1) and a pharmaceutically acceptable dispersion carrier.

37. The use according to claim 36, wherein the solid dispersion comprises compound (1) in an amorphous form.

38. A method for preparing a solid dispersion, which comprises the following steps: a) providing a mixture of compound (1) and a pharmaceutically acceptable dispersion carrier and adding a solvent to obtain a solution or a suspension; and b) removing the solvent from the solution or the suspension to form the solid dispersion, wherein in step a), compound (1) is provided in the crystalline form or a mixture thereof as defined in any one of claims 1 to 18, 21, 22, 25, 26, 29 or 30.

39. The method according to claim 38, wherein in step b), the solid dispersion comprises compound (1) in an amorphous form.

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