Drug forms of quinazoline ERBB inhibitors

Abstract

A pharmaceutical form of (S)-N-(4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidine-4-yl)oxy)-7-methoxyquinazoline-4-amine (compound I) having inhibitory activity against ErbB (e.g., Her2) is disclosed. Further disclosure herein includes the identification, preparation and formulation of the quinazoline compound by a spray-drying dispersion process, the manufacture of its tablets by a dry granulation process, and the use of such pharmaceutical products in the treatment of cancer, such as breast cancer or other tumors.

Description

[Technical Field]

[0001] This disclosure relates to an inhibitor of ErbB receptor tyrosine kinase, its crystalline polymorph, a pharmaceutical composition containing the same, a preparation process therefor, and its use. [Background technology]

[0002] The ErbB receptor tyrosine kinase family consists of four closely related receptors: EGFR (ErbB1 or HER1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4) (Riese and Stern, Bioessays (1998) 20:41-48; Olayioye et al, EMBO Journal (2000) 19:3159-3167; Schlessinger, Cell (2002) 110:669-672). These receptors transmit signals from outside the cell to inside the cell by activating secondary messaging effectors through phosphorylation of their tyrosine phosphorylated residues. These signals regulate a variety of cellular processes, including proliferation, carbohydrate utilization, protein synthesis, angiogenesis, cell growth, and cell survival. De-distortion of ErbB family signaling modulates proliferation, invasion, metastasis, angiogenesis, and tumor cell survival and may be associated with many human cancers, including lung cancer, head and neck cancer, and breast cancer. Detailed reviews of ErbB receptor signaling and its involvement in oncogenesis are published in the New England Journal of Medicine, 2008, Vol.358:1160-74, and Biochemical and Biophysical Research Communications, 2004, Vol.319:1-11.

[0003] Several researchers have demonstrated the role of ErbB2 in cancer progression (Salomon et al., Crit. Rev. Oncol. Hematol. (1995) 19:183-232; Klapper et al., Adv. Cancer Res. (2000) 77:25-79; and Hynes and Stern, Biochim. Biophys. Acta (1994) 1198:165-184). ErbB2 overexpression occurs in approximately 30% of all breast cancers and is associated with various other cancers, including ovarian cancer, colon cancer, bladder cancer, gastric cancer, esophageal cancer, lung cancer, uterine cancer, and prostate cancer. ErbB2 overexpression is also correlated with poor prognosis in human cancers, including metastasis and early recurrence.

[0004] HER2 is a proven target for several FDA-approved anti-HER2 antibodies and tyrosine kinase inhibitors (TKIs) in HER2-positive breast cancer. Clinically, patients with HER2-positive breast cancer are at high risk of developing central nervous system (CNS) metastases, and the proportion of patients dying from intracranial progression after antibody treatment is increasing. While macromolecules such as trastuzumab, pertuzumab, and T-DM1 contribute to controlling extracranial disease progression in metastatic HER2-positive breast cancer, these antibodies have limited blood-brain barrier (BBB) ​​permeability, resulting in CNS metastases being a major problem for treatment failure.

[0005] Regarding TKIs, lapatinib was approved in 2007 for use in combination with capecitabine in patients with metastatic HER2-positive breast cancer that had progressed after prior trastuzumab and taxane therapy. Neratinib was approved in 2017 as extended adjuvant therapy for adult patients with early-stage HER2-positive breast cancer. The combination of neratinib and capecitabine is also being investigated in patients with metastatic HER2-positive breast cancer. However, the applicability of these TKIs is limited by their low selectivity for wild-type EGFR, which can lead to toxicity such as rash and diarrhea. Therefore, HER2 TKIs with improved selectivity for wild-type EGFR may be administered at higher doses to achieve better clinical efficacy.

[0006] Clinical trials have shown that lapatinib has a modest effect in patients with HER2-positive breast cancer and CNS metastases, with an objective response rate (ORR) of 20–38% and a progression-free survival (PFS) of 3.6 months. Since increasing the dose of lapatinib has improved clinical outcomes in HER2-positive breast cancer with CNS metastases, it is suggested that drugs with relatively high blood-bone barrier permeability may be clinically beneficial for unmet medical needs. Neratinib monotherapy and combination therapy with capecitabine have also been investigated in patients with HER2-positive breast cancer and brain metastases. These studies have shown a PFS of 5.5 months and a CNS response rate of 24% in patients without RA-mediated brain metastases. Therefore, new approaches to treating CNS diseases are needed. [Overview of the project]

[0007] This disclosure relates to a novel pharmaceutical salt of (S)-N-(4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidine-4-yl)oxy)-7-methoxyquinazoline-4-amine (hereinafter referred to as "Compound I" having the structure shown below), [ka]

[0008] This invention relates to crystalline polymorphs of compound I or its pharmaceutical salts, compositions containing the same, the preparation process and use thereof. Spray-dried dispersion (SDD) formulations containing compound I or its pharmaceutical salts, the preparation process and use thereof are also provided.

[0009] In one embodiment, the present disclosure provides a pharmaceutical form of compound I.

[0010] In some embodiments, the pharmaceutical salts of compound I provided herein are selected from hydrochloride, sulfate, phosphate, maleate, fumarate, oxalate, p-toluenesulfonate, succinate, L-(+)-tartrate, monoadipate, and hemiadipate of compound I. In certain embodiments, the pharmaceutical salt of compound I is in amorphous form. In certain embodiments, the pharmaceutical salt of compound I is in crystalline form. In certain embodiments, the pharmaceutical salt of compound I is hydrochloride, sulfate, phosphate, maleate, fumarate, oxalate, p-toluenesulfonate, succinate, L-(+)-tartrate, monoadipate, and hemiadipate of compound I in crystalline form.

[0011] In another embodiment, the disclosure also provides crystalline forms of compound I or pharmaceutically acceptable salts thereof.

[0012] In some embodiments, the crystalline forms are form A of compound I, form B of compound I, form C of compound I, form D of compound I, and the crystalline forms of compound I's hydrochloride, sulfate, phosphate, maleate, fumarate, oxalate, p-toluenesulfonate, succinate, L-(+)-tartrate, monoadipate, and hemiadipate.

[0013] In another embodiment, the present disclosure provides pharmaceutical compositions, as disclosed herein, each comprising one or more pharmaceutical salts of compound I, or crystalline forms of compound I or its pharmaceutical salts.

[0014] In another aspect, the Disclosure provides a method for treating an ErbB-related disorder in a subject, the method comprising administering to the subject in question a therapeutically effective amount of a pharmaceutical salt of Compound I, a crystalline form of Compound I or a pharmaceutical salt thereof, or a pharmaceutical composition, as provided herein.

[0015] In yet another aspect, the present disclosure provides the use of a pharmaceutical salt of Compound I provided herein, a crystalline form of Compound I or its pharmaceutical salt, or a pharmaceutical composition, for the inhibition of ErbB (e.g., ErbB2), or in the manufacture of a medicament for inhibiting ErbB (e.g., ErbB2).

[0016] In a further aspect, the present disclosure also provides a process for preparing a pharmaceutical salt of Compound I, or a crystalline form of Compound I or its pharmaceutical salt.

[0017] In a further aspect, the present disclosure also provides a process for preparing Compound I in high yield on an industrial scale (e.g., more than 10 kilograms).

[0018] In a further aspect, the present disclosure also provides a spray-dried dispersion comprising Compound I or its pharmaceutical salt and a polymer for spray-dried dispersions.

[0019] In a further aspect, the present disclosure also provides a process for preparing a spray-dried dispersion.

Brief Description of the Drawings

[0020] [[ID=2L]] [Figure 1] 1H NMR spectrum of Compound I.

[0021] [Figure 2] Single crystal X-ray diffraction ORTEP of Compound I.

[0022] [Figure 3] XRPD pattern overlay of the equilibration experiment for Form A of Compound I conducted at 25 °C for 10 days using the solvents (listed in Table 1 below).

[0023] [Figure 4] XRPD pattern overlay of the equilibration experiment for Form A of Compound I conducted at 50 °C for 10 days using the solvents (listed in Table 1 below).

[0024] [Figure 5] This is an XRPD pattern overlay from an evaporation experiment at room temperature.

[0025] [Figure 6] This is an XRPD pattern overlay from a rapid cooling experiment to crystallize compound I from a high-temperature saturated solution.

[0026] [Figure 7] This is an XRPD pattern overlay from a slow cooling experiment to crystallize compound I from a high-temperature saturated solution.

[0027] [Figure 8] This is an XRPD pattern overlay from a reverse solvent experiment of compound I.

[0028] [Figure 9] This is an XRPD pattern overlay from a compression experiment of compound I, form A.

[0029] [Figure 10] This is an XRPD pattern overlay from grinding and granulation experiments of compound I, form A.

[0030] [Figure 11] This is the XRPD pattern of compound I, form A.

[0031] [Figure 12] This is the TGA of compound I in form A.

[0032] [Figure 13] This is a DSC of compound I in form A.

[0033] [Figure 14] This is a DVS plot of compound I, form A.

[0034] [Figure 15] This is the XRPD pattern of compound I, form B.

[0035] [Figure 16] These are the TGA and DSC forms of compound I, form B.

[0036] [Figure 17] This is the XRPD pattern of compound I in morphology C.

[0037] [Figure 18] These are the TGA and DSC forms of compound I, form C.

[0038] [Figure 19] This is the XRPD pattern of compound I in morphology D.

[0039] [Figure 20] These are the TGA and DSC forms of compound I, form D.

[0040] [Figure 21] This is the XRPD pattern of the fumarate of compound I.

[0041] [Figure 22] This is the XRPD pattern of the fumarate of compound I in comparison with form A of compound I.

[0042] [Figure 23] This is a differential scanning calorimetry (DSC) thermogram of the fumarate of compound I in comparison with form A of compound I.

[0043] [Figure 24] This is the thermogravimetric analysis (TGA) of the fumarate of compound I.

[0044] [Figure 25] This is a vapor adsorption analysis of the fumarate of compound I.

[0045] [Figure 26]This is the XRPD pattern of succinate of compound I in comparison with form A of compound I.

[0046] [Figure 27] This is the DSC of succinate of compound I in comparison with form A of compound I.

[0047] [Figure 28] This is the TGA of the succinate salt of compound I.

[0048] [Figure 29] This is a vapor adsorption analysis of the succinate salt of compound I.

[0049] [Figure 30] These are the DSC and TGA of the hydrochloride salt of compound I.

[0050] [Figure 31] This is a vapor adsorption analysis of the hydrochloride salt of compound I.

[0051] [Figure 32] This is the XRPD pattern of the phosphate of compound I in comparison with form A of compound I.

[0052] [Figure 33] These are the DSC and TGA of the phosphate of compound I.

[0053] [Figure 34] This is a vapor adsorption analysis of the phosphate of compound I.

[0054] [Figure 35] This is the XRPD pattern of the sulfate salt of compound I in comparison with form A of compound I.

[0055] [Figure 36] These are the DSC and TGA of the sulfate of compound I.

[0056] [Figure 37] This is a vapor adsorption analysis of the sulfate of compound I.

[0057] [Figure 38] This is the XRPD pattern of the hemiadipinate of compound I.

[0058] [Figure 39] These are the DSC and TGA of the hemiadipate salt of compound I.

[0059] [Figure 40] This is a DVS plot of the hemiadipinate of compound I.

[0060] [Figure 41] This is the XRPD pattern of p-toluenesulfonate of compound I.

[0061] [Figure 42] These are the DSC and TGA of compound I's p-toluenesulfonate.

[0062] [Figure 43] This is the DVS plot for p-toluenesulfonate of compound I.

[0063] [Figure 44] This is the XRPD pattern of the maleate of compound I.

[0064] [Figure 45] These are the DSC and TGA of the maleate of compound I.

[0065] [Figure 46] This is a DVS plot of the maleate of compound I.

[0066] [Figure 47] This is the XRPD pattern of the oxalate of compound I in comparison with form A of compound I.

[0067] [Figure 48] This is the TGA of the oxalate of compound I.

[0068] [Figure 49] This is the XRPD pattern of the tartrate salt of compound I in comparison with form A of compound I.

[0069] [Figure 50] These are the DSC and TGA of the tartrate salt of compound I.

[0070] [Figure 51] This is the XRPD pattern of the monoadipate of compound I in comparison with form A of compound I.

[0071] [Figure 52] These are the DSC and TGA of the monoadipine salt of compound I.

[0072] [Figure 53] This is an XRPD pattern overlay of the SDD for compound I and each of the following polymers: PVP-VA64 polymer (40:60, w / w), Soluplus polymer (40:60, w / w), HPMC-AS MF polymer (40:60, w / w), HPMC-AS LF polymer (40:60, w / w), Eudragit E100 polymer (40:60, w / w), and Eudragit L100-55 polymer (40:60, w / w).

[0073] [Figure 54] This is a modulated DSC (MDSC) of the SDD between compound I and the PVP-VA64 polymer (40:60, w / w).

[0074] [Figure 55] This is the MDSC of the SDD between compound I and Soluplus polymer (40:60, w / w).

[0075] [Figure 56]This is the MDSC of the SDD between compound I and HPMC-AS LF polymer (40:60, w / w).

[0076] [Figure 57] This is the MDSC of the SDD between compound I and HPMC-AS MF polymer (40:60, w / w).

[0077] [Figure 58] This is the MDSC of the SDD between compound I and Eudragit E100 polymer (40:60, w / w).

[0078] [Figure 59] This is the MDSC of the SDD between compound I and Eudragit L100-55 polymer (40:60, w / w).

[0079] [Figure 60] This is an XRPD pattern overlay of the SDD for compound I and each of the following polymers: HPbCD polymer (40:60, w / w), PVP K30 LP polymer (40:60, w / w), HPC (klucel LF) polymer (40:60, w / w), HPC (klucel MF) polymer (40:60, w / w), HPMC E5 LV polymer (40:60, w / w), HPMC E15 polymer (40:60, w / w), and HPMCP-HP50 polymer (40:60, w / w).

[0080] [Figure 61] This is the MDSC of the SDD between compound I and HPbCD polymer (40:60, w / w).

[0081] [Figure 62] This is the MDSC of SDD between compound I and PVP K30 LP polymer (40:60, w / w).

[0082] [Figure 63] This is the MDSC of the SDD between compound I and HPC (Klucel LF) polymer (40:60, w / w).

[0083] [Figure 64] This is the MDSC of the SDD between compound I and HPC (Klucel MF) polymer (40:60, w / w).

[0084] [Figure 65] This is the MDSC of the SDD between compound I and HPMC E5 LV polymer (40:60, w / w).

[0085] [Figure 66] This is the MDSC of the SDD between compound I and HPMC E15 polymer (40:60, w / w).

[0086] [Figure 67] This is the MDSC of the SDD between compound I and HPMCP-HP50 polymer (40:60, w / w).

[0087] [Figure 68] This is the XRPD pattern of the SSD with compound I and HPMC-AS MG polymer (20:80, w / w) before drying.

[0088] [Figure 69] This is the MDSC of an SSD with compound I before drying and HPMC-AS MG polymer (20:80, w / w).

[0089] [Figure 70] This is the XRPD pattern of the SDD of compound I and HPMC-AS MG polymer (20:80, w / w) after drying at 30°C for 10 hours.

[0090] [Figure 71] This is the MDSC of the SDD of compound I and HPMC-AS MG polymer (20:80, w / w) after drying at 30°C for 10 hours.

[0091] [Figure 72]This is an XRPD pattern overlay of SDD with compound I using dichloromethane and acetone (7:3, v / v) as solvents and HPMC-AS MG polymer (20:80 w / w, 30:70 w / w, and 40:60 w / w, respectively).

[0092] [Figure 73] This is an MDSC of an SSD using compound I and HPMC-AS MG polymer (20:80, w / w).

[0093] [Figure 74] This is an MDSC of an SSD with compound I and HPMC-AS MG polymer (30:70, w / w).

[0094] [Figure 75] This is an MDSC of an SSD using compound I and HPMC-AS MG polymer (40:60, w / w).

[0095] [Figure 76] These are XRPD pattern overlays of the SDDs of compound I from each of the systems A, B, C, D, and E (listed in Table 19 below) with polymers and surfactants.

[0096] [Figure 77] This is the MDSC of the SDD of compound I from system A with HPMC-AS MF and TPGS.

[0097] [Figure 78] This is the MDSC of compound I of system B with Klucel LF and SDS.

[0098] [Figure 79] This is an MDSC of compound I of system C with HPMC-AS MF and SDS.

[0099] [Figure 80] This is an MDSC of compound I from system D with HPMC-AS MF and SDS.

[0100] [Figure 81] This is an MDSC of compound I of system E with HPMC-AS MF and SDS.

[0101] [Figure 82] These are XRPD pattern overlays of the SDDs of compound I from each of the systems A, B, C, D, and E with polymers and surfactants after a one-week stability test at 40°C, 75% relative humidity (RH), or 25°C, 60% RH.

[0102] [Figure 83] This is a flowchart illustrating the manufacturing process of an SSD using compound I and HPMC-AS MG polymer.

[0103] [Figure 84] This is a flowchart illustrating the manufacturing process for Compound I tablets.

[0104] [Figure 85] This is the dissolution curve of the SDD tablet of compound I. [Modes for carrying out the invention]

[0105] Before discussing this in more detail, let's define the following terms.

[0106] definition

[0107] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which the present invention pertains. As used herein, the following terms shall have the following meanings:

[0108] As used herein and in the claims, the singular forms "one," "one," and "the" include multiple references unless explicitly indicated otherwise in the context. Therefore, a reference to, for example, "compound" includes both a single compound and multiple different compounds.

[0109] As used herein, the term “approximately” indicates that the cited value should not be interpreted as an absolute value, and that measurement errors, batch-to-batch variations, and / or inter-instrument variations should also be taken into consideration. Unless a range of measurement error or variation is specified in this application (for example, the measurement error for the diffraction angle 2θ in XRPD is ±0.2°, the measurement error for the endothermic melting of crystalline polymorphs in DSC is ±10°C, the measurement error for the endothermic dehydration / solvation of polymorphs is ±20°C, the measurement error for the glass transition temperature (Tg) in MDSC is ±10°C, and the measurement error for TGA is ±20°C), the term “approximately” used before a numerical specification that includes a range (e.g., temperature, time, quantity, and concentration) indicates an approximation that may vary by ±10%, ±5%, or ±1%.

[0110] As used herein, “inhibitor” refers to a compound or drug that has the ability to inhibit the biological function of a target protein or polypeptide, such as by inhibiting the activity or expression of the target protein or polypeptide. Therefore, the term “inhibitor” is defined in the context of the biological role of the target protein or polypeptide. Some inhibitors herein interact specifically with (e.g., bind to) the target, but compounds that inhibit the biological activity of the target protein or polypeptide by interacting with other members of the target protein or polypeptide's signaling pathway are also specifically included in this definition. Non-limiting examples of biological activity inhibited by inhibitors include those associated with tumor progression, growth, or spread. As used herein, “selective inhibition” or “selectively inhibiting” as applied to a bioactive agent refers to the ability of a drug to selectively reduce target signaling activity compared to off-target signaling activity through direct or indirect interaction with the target protein or polypeptide.

[0111] It should be understood that the “compounds” of this disclosure can exist in solvated and non-solvated forms, such as hydrated and solid forms, and this disclosure is intended to encompass all such solvated and non-solvated forms. Furthermore, it should be understood that the “compounds” of this disclosure can exist in the form of pharmaceutically acceptable salts.

[0112] As used herein, the term “pharmaceutically acceptable” means a compound, material, composition, and / or dosage form that, within the bounds of sound medical judgment, is suitable for use in contact with human and other animal tissues without undue toxicity, irritation, allergic reactions, or other problems or complications, and is commensurate with a reasonable benefit / risk ratio. In some embodiments, a pharmaceutically acceptable compound, material, composition, and / or dosage form means one that is approved for use in animals, more specifically in humans, by a regulatory authority (such as the U.S. Food and Drug Administration, the National Medicines Agency, or the European Medicines Agency) or listed in a generally accepted pharmacopoeia (such as the United States Pharmacopoeia, the Chinese Pharmacopoeia, or the European Pharmacopoeia).

[0113] As used herein, “pharmaceutically acceptable salt” or “medicinal salt” refers to a derivative of a compound obtained by modifying the parent compound by converting an existing acidic (e.g., carboxyl) or basic (e.g., amine, alkali) moiety into its salt form. In many cases, the compounds of this disclosure can form acid addition salts and / or base salts in the presence of amino, alkali, or similar groups. “pharmaceutically acceptable salts” include acid addition salts or base salts that retain the biological effects and properties (typically not biologically or otherwise undesirable) of the parent compound. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds provided herein include those derived from appropriate inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoroacetic acid, benzoic acid, cinnamic acid, mandelic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, malonic acid, fumaric acid, citric acid, malic acid, maleic acid, tartaric acid, succinic acid, and methanesulfonic acid, or amino group salts formed by other methods used in this field, such as ion exchange.Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, besilate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxyethanesulfate. Examples of salts include honate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate. In some embodiments, examples of inorganic acids that can induce salts include hydrochloride, sulfate, and phosphate. In some embodiments, examples of organic acids that can induce salts include maleate, fumarate, oxalate, p-toluenesulfonate, succinate, L-(+)-tartrate, monoadipate, and hemiadipate. In certain embodiments, pharmaceutically acceptable salts are hydrochlorides, sulfates, phosphates, maleates, fumarates, oxalates, p-toluenesulfonates, succinates, L-(+)-tartrates, monoadipates, or hemiadipates.

[0114] As used herein, the terms “polymorph,” “polymorph,” or “crystalline form” refer to the solid form of a compound in which the constituent atoms, molecules, or ions are packed together in a regularly arranged, repeating three-dimensional pattern having a highly regular chemical structure. In particular, a compound or a salt thereof may be produced in one or more crystalline forms. Different crystalline forms can be identified by X-ray powder diffraction (XRPD) patterns (e.g., X-ray diffraction peak positions and / or peak intensities at various diffraction angles (2θ)), melting point onset (and dehydration onset in hydrated forms) indicated by endothermic differential scanning calorimetry (DSC) thermograms, thermogravimetric analysis (TGA), and solid form. 1 It can be characterized by its 1H nuclear magnetic resonance (NMR) spectrum, water solubility, high-intensity light conditions, physical and chemical storage stability, and any other known measurements in the art.

[0115] An "XRPD pattern" refers to an experimentally observed diffractogram, or the parameters derived therefrom, and is shown as an xy graph with the peak position on the x-axis as the diffraction angle (2θ) and the peak intensity on the y-axis. The peaks within this pattern may be used to characterize the crystalline solid morphology.

[0116] As used herein, the term "peak position" refers to the X-ray reflection position measured and observed in X-ray powder diffraction experiments. The peak position is directly related to the dimensions of the unit cell. The peak position may be affected by the precise height at which the sample is positioned within the diffractometer, as well as the zero calibration of the diffractometer.

[0117] The term "peak intensity" refers to the relative signal intensity within a given X-ray powder diffraction pattern. Factors that can affect relative peak intensity include sample thickness and preferred orientation (i.e., whether the crystal grains are randomly distributed).

[0118] As with all data measurements, XRPD data exhibits variability. Because peak intensity can be particularly sensitive to sample preparation (e.g., particle size, water content, solvent content, and preferred orientation effects affect sensitivity), data is often presented only in terms of peak diffraction angles, without including peak intensity. Therefore, samples of the same material prepared under different conditions may yield slightly different patterns. This variability is usually greater than the variability in diffraction angles. Variability in diffraction angles can also be sensitive to sample preparation. Other sources of variability stem from instrument parameters and the processing of raw X-ray data. For example, different X-ray instruments operate with different parameters, which can result in slightly different XRPD patterns from the same solid; similarly, different software packages process X-ray data differently, also leading to variability. These and other sources of variability are known to those skilled in the pharmaceutical field. Due to such sources of variability, the measurement error of the diffraction angle in XRPD is approximately 2θ (±0.2°), and the degree of such measurement error should be considered when considering the XRPD patterns in the figures and when reading the data contained in the tables included herein.

[0119] DSC measures the difference in thermal energy between a solid sample and a suitable reference as the temperature rises. A DSC thermogram is typically characterized by endothermic (indicating energy absorption) and exothermic (indicating energy release) phenomena during heating of the sample. Those skilled in the art will also understand that the values ​​or ranges of values ​​observed in the DSC thermogram of a particular compound may vary between batches of different purities. Depending on the heating rate (i.e., scanning rate) when performing the DSC analysis, the definition and method of determining the DSC start temperature, the calibration standards used, the calibration of the instruments, and the relative humidity (RH) and chemical purity of the sample, the endothermic values ​​shown by the compounds in this disclosure may vary (endothermic values ​​for crystalline polymorph melting are ±10°C, and endothermic values ​​for polymorph dehydration / desolvation are ±20°C), and the degree of such variation should be considered when considering the DSC data contained herein. For further clarification, compounds prepared in different batches may show variations in the DSC thermogram, but these variable DSC thermograms should still be considered "substantially similar" to one another. In any given example, the observed endothermic values ​​may differ from instrument to instrument, but generally fall within the range defined herein, provided the instruments are similarly calibrated. Furthermore, it will be understood that the removal of residual solvent in the prepared compound may alter the DSC's starting and peak temperatures.

[0120] Modulated thermal sensing (MDSC) is a technique that uses sinusoidal temperature oscillations to separate the total heat flow into reversible and irreversible components. It is more accurate than DSC in measuring heat capacity, crystallinity, and phase transition temperature. Those skilled in the art will understand that factors (e.g., heat capacity along the heat path within the apparatus, temperature distribution within the sample, thermal contact between the sample, sample cell, and its holder plate) affect the steady state of MDSC and cause measurement errors. As a result, the measurement error of the glass transition temperature (Tg) in MDSC is ±10°C, and the degree of such variation should be taken into consideration when considering the MDSC data contained herein.

[0121] Thermal Gravitation (TGA) is a test procedure that records the weight change of a sample when it is heated in air or a controlled atmosphere such as nitrogen. The thermogravimetric curve (thermogram) provides information about the solvent and water content, as well as the thermal stability of the material. Since TGA thermograms exhibit similar variability (a measurement error of approximately 20°C) as DSCs, those skilled in the art recognize that measurement errors should be taken into account when determining the substantial identity of TGA thermograms.

[0122] Unless otherwise specified, “wild-type ErbB” refers to a normal ErbB family member that exists in the natural environment and performs the normal function of ErbB. In one embodiment, the disclosure provides inhibitory compounds of ErbB family kinases (e.g., HER2). In some embodiments, the compounds of the disclosure selectively inhibit ErbB2 (i.e., HER2) but do not inhibit other ErbB family kinases (e.g., EGFR). In some embodiments, the compounds of the disclosure can inhibit both wild-type (WT) and mutant forms of ErbB2.

[0123] As used herein, the term “mutation” refers to any mutation in the ErbB2 protein, and “variant” or “mutant type” refers to the protein containing such mutation. Exemplary mutations of ErbB2 include, but are not limited to, exon 20 YVMA insertions and p95 cleavage variants of HER2. In some embodiments, the compounds of the present disclosure are 0.1-200nM, 0.1-150nM, 0.1-130nM, 0.1-120nM, 0.1-100nM, 0.1-50nM, 0.1-40nM, 0.1-30nM, 0.1-25nM, 0.1-20nM, 0.1-10nM, 0.5-200nM, 0.5-150nM, 0.5-130nM, 0.5-120nM, 0.5-100nM, 0.5-50nM, 0.5-40nM, 0.5-30nM, 0.5-25nM, 0.5-20nM, 0.5-1 ICs with a molecular weight of 0nM, 1-200nM, 1-150nM, 1-130nM, 1-120nM, 1-100nM, 1-50nM, 1-40nM, 1-30nM, 1-25nM, 1-20nM, 1-10nM, 2-200nM, 2-150nM, 2-130nM, 2-120nM, 2-100nM, 2-50nM, 2-40nM, 2-30nM, 2-25nM, 2-20nM, 2-10nM, 0.1-150nM, 0.1-130nM, 1-150nM, 1-130nM, 2-130nM, or 2-150nM 50 This value inhibits the phosphorylation of WT HER2.

[0124] In some embodiments, the ICs of the compounds of this disclosure 50 The values ​​are measured by a mesoscale discovery (MSD) assay.

[0125] The growth inhibitory effect refers to the "50% growth inhibitory concentration" (GI), which is the concentration at which 50% of the compound's maximum growth inhibitory effect is observed. 50 ) can be represented by a value. GI 50The values ​​can be measured by methods known in the art, such as colorimetric methods (MTS assay). In some embodiments, the compounds of the present disclosure are measured by MTS at concentrations of 0.1-200 nM, 0.1-150 nM, 0.1-130 nM, 0.1-120 nM, 0.1-100 nM, 0.1-50 nM, 0.1-40 nM, 0.1-30 nM, 0.1-20 nM, 0.1-10 nM, 1-200 nM, 1-150 nM, 1-130 nM, 1-120 nM, 1-100 nM, 1-50 nM, 1-40 nM, 1-30 nM, 1-20 nM, 1-10 nM, 2-200 nM, and 2-150 nM. nM, 2-130nM, 2-120nM, 2-100nM, 2-50nM, 2-40nM, 2-30nM, 2-25nM, 2-20nM, 2-10nM, 4-200nM, 4-150nM, 4-130nM, 4-120nM, 4-50nM, 4-40nM, 4-30nM, 4-20nM, 4-10nM, more preferably 0.1-150nM, 0.1-130nM, 1-150nM, 1-130nM, 2-150nM, 2-130nM, 4-150nM, or GI of 4-130nM 50 The value inhibits the proliferation of WT HER2 and / or mutant HER2-carrying cells. As used herein, "selectively inhibits" HER2 means that the provided compound is at least 1000-fold, at least 500-fold, at least 200-fold, at least 100-fold, at least 50-fold, at least 45-fold, at least 40-fold, at least 35-fold, at least 30-fold, at least 25-fold, at least 20-fold, at least 15-fold, or at least 10-fold potency as an inhibitor of WT (and / or mutant HER2) compared to other types of ErbB kinases (e.g., EGFR).

[0126] In some embodiments, "selectively inhibiting" HER2 means that the provided compound is up to 1500-fold, up to 1200-fold, up to 1000-fold, up to 800-fold, up to 600-fold, up to 400-fold, up to 200-fold, up to 100-fold, up to 50-fold more potent as an inhibitor of HER2 (WT and / or mutant forms) compared to other types of ErbB kinases (e.g., EGFR). In some embodiments, "not inhibiting" other types of ErbB kinases (e.g., EGFR) means that the provided compound has an IC 50 of at least 500 nM to inhibit other types of ErbB kinases (e.g., WT EGFR).

[0127] In some embodiments, such compounds have an IC 50 of at least 10 μM, at least 9 μM, at least 8 μM, at least 7 μM, at least 6 μM, at least 5 μM, at least 3 μM, at least 2 μM, or at least 1 μM to inhibit other types of ErbB kinases.

[0128] In some embodiments, the IC 50 and / or GI 50 of a compound for inhibiting WT-EGFR is at least 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, 200-fold, 500-fold, 1000-fold higher than the IC 50 and / or GI 50 of a compound for inhibiting WT-HER2. The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure with other chemical components such as pharmaceutically acceptable diluents, excipients, or carriers. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to a subject.

[0129]

[0130] ​As used herein, the term “sustained-release form” means that the active ingredient is released from the pharmaceutical composition so that it can be bioabsorbed by the subject, primarily in the subject’s gastrointestinal tract, over a long period of time (long-release) or at a specific location (controlled-release).

[0131] As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in transporting or carrying the compounds provided herein from one location, body fluid, tissue, organ (internal or external), or part of the body to another location, body fluid, tissue, organ, or part of the body. A pharmaceutically acceptable carrier may be a vehicle, diluent, excipient, or other material that can be used for contact with animal tissue without excessive toxicity or adverse effects.Non-limiting examples of pharmaceutically acceptable carriers include sugars (lactose, glucose, sucrose, etc.), starches (corn starch, potato starch, etc.), cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate, tragacanth powder, malt, gelatin, talc, cocoa butter and suppository waxes, oils (peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil, etc.), glycols (polyethylene glycol and propylene glycol, etc.), esters (ethyl oleate and ethyl laurate, etc.), agar, buffers (magnesium hydroxide and aluminum hydroxide, etc.), alginic acid, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer, and non-toxic compatible lubricants (sodium lauryl sulfate and magnesium stearate). Examples include surfactants used in pharmaceutical dosage forms such as alumina, colorants, release agents, coating agents, sweeteners, flavorings, fragrances, preservatives, antioxidants, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) (such as d-α-tocopherol polyethylene glycol 1000 succinate), Tween or other similar polymer delivery matrices, serum proteins (such as human serum albumin), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyacrylates, waxes, and polyethylene polyoxypropylene barrier polymers. Cyclodextrins such as α-, β-, and γ-cyclodextrins, chemically modified derivatives such as hydroxyalkylcyclodextrins including 2- and 3-hydroxypropylcyclodextrins, or other solubilizing derivatives may also be used to facilitate the delivery of the compounds described herein.Pharmaceutically acceptable carriers that may be used in this disclosure include those commonly known in the art, such as those disclosed in "Remington Pharmaceutical Sciences," Mack Pub. Co., New Jersey (1991), which is incorporated herein by reference.

[0132] As used herein, “administration” of a disclosed compound includes delivering the compound described herein, or its prodrug or other pharmaceutically acceptable derivative, to a subject using any suitable formulation or route of administration discussed herein.

[0133] The term “effective dose” or “therapeutic dose” refers to the amount of a compound or pharmaceutical composition described herein that is sufficient to prevent, treat, alleviate, and / or improve any symptom and / or underlying cause of any disorder or disease in a subject, or the amount of a drug sufficient to produce a desired effect on target cells, such as a reduction in cell migration. In one embodiment, the “therapeutic dose” is an amount sufficient to alleviate or eliminate the symptoms of a disease. In another embodiment, the therapeutic dose is an amount sufficient to overcome the disease itself. In a particular embodiment, the “therapeutic dose” is an amount that is effective in detecting the death or inhibition of the proliferation or spread of cancer cells, or in reducing the size or number of tumors, or other measures of the level, stage, progression, or severity of cancer. The therapeutic dose varies depending on the subject being treated and their condition, the subject’s weight and age, the severity of the condition, the specific composition or excipient selected, the administration regimen to be followed, the timing of administration, the method of administration, etc., all of which can be readily determined by those skilled in the art. Complete therapeutic effect is not necessarily obtained with a single dose, but may only be obtained after a series of doses. The specific dose will vary depending, for example, the selected compound, the species of the subject, its age / pre-existing health condition or health risk, the administration regimen to be followed, the severity of the disease, whether or not it is administered in combination with other drugs, the timing of administration, the target tissue, and the physical delivery system that carries the compound. Therefore, the therapeutically effective dose may be administered in one or more doses. For example, but not limited to, a therapeutically effective dose of a drug refers to the amount of drug that alleviates, improves, relieves, or eliminates one or more symptoms of cancer in a patient.

[0134] As used herein, the terms “treatment,” “to treat,” and “to treat” mean, as described herein, reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder, or one or more of its symptoms. In some embodiments, treatment may be administered after the progression of one or more symptoms. In other embodiments, treatment may be administered when there are no symptoms. For example, treatment may be administered to a susceptible individual before the onset of symptoms (for example, taking into account a history of symptoms and / or genetic or other susceptibility factors). Treatment may be continued after the disappearance of symptoms, for example, to suppress or delay recurrence.

[0135] As used herein, “anticancer agent,” “antineoplastic agent,” or “chemotherapeutic agent” means any agent useful for treating a neoplastic condition. One class of anticancer agents includes chemotherapeutic agents. “Chemotherapy” means administering one or more chemotherapeutic agents and / or other agents to a cancer patient by various means, including intravenous, oral, intramuscular, intraperitoneal, intravesical, subcutaneous, percutaneous, buccal, inhalation, or suppository forms.

[0136] The term “subject” to which the drug is intended to be administered includes, but is not limited to, humans (i.e., males or females of any age, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly)) and / or other primates (e.g., crab-eating macaques, rhesus macaques), mammals (including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, rabbits, hamsters, mice, cats, and / or dogs), and / or birds (including commercially relevant birds such as chicks, ducks, geese, quail, and / or turkeys).

[0137] Compound I and its pharmaceutical salts

[0138] Compound (S)-N-(4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidine-4-yl)oxy)-7-methoxyquinazoline-4-amine (compound I), described in WO2019214634A1, is a potent ErbB inhibitor and has the following structure. [ka]

[0139] In one embodiment, the present disclosure provides a novel pharmaceutical salt of compound I.

[0140] In some embodiments, the pharmaceutical salts of compound I provided herein are selected from hydrochloride, sulfate, phosphate, maleate, fumarate, oxalate, p-toluenesulfonate, succinate, L-(+)-tartrate, monoadipate, and hemiadipate of compound I.

[0141] In certain embodiments, the medicinal salt of compound I is a monosalt. In certain embodiments, the medicinal salt of compound I is in amorphous form. In certain embodiments, the medicinal salt of compound I is in crystalline form. In certain embodiments, the medicinal salt of compound I is a crystalline hydrochloride, sulfate, phosphate, maleate, fumarate, oxalate, p-toluenesulfonate, succinate, L-(+)-tartrate, monoadipate, or hemiadipate.

[0142] Characterization of crystal morphology

[0143] In one embodiment, the present disclosure provides several polymorphic crystalline forms of compound I or a pharmaceutically acceptable salt thereof.

[0144] In one embodiment, the disclosure provides crystalline forms of compound I, particularly forms A, B, C, or D of compound I. In another embodiment, the disclosure provides crystalline forms of pharmaceutically acceptable salts of compound I, particularly crystalline forms of hydrochloride, sulfate, phosphate, maleate, fumarate, oxalate, p-toluenesulfonate, succinate, L-(+)-tartrate, monoadipate, and hemiadipate.

[0145] 1. Form A of Compound I

[0146] In some embodiments, the crystalline form (free base) of compound I, which is crystalline form A of compound I, is disclosed.

[0147] In some embodiments, form A of compound I has an X-ray powder diffraction (XRPD) pattern that includes peaks at diffraction angle (2θ) values ​​of 7.09±0.20°, 15.15±0.20°, and 21.55±0.20°.

[0148] In some embodiments, form A of compound I has an XRPD pattern that includes peaks at 2θ of 7.09±0.20°, 11.92±0.20°, 15.15±0.20°, and 21.55±0.20°.

[0149] In some embodiments, form A of compound I has an XRPD pattern that includes peaks at 2θ of 7.09±0.20°, 15.15±0.20°, 21.55±0.20°, and 23.93±0.20°.

[0150] In some embodiments, form A of compound I has an XRPD pattern that includes peaks at 2θ of 7.09±0.20°, 11.92±0.20°, 15.15±0.20°, 21.55±0.20°, and 23.93±0.20°.

[0151] In some embodiments, form A of compound I has an XRPD pattern that includes peaks at 2θ of 6.45±0.20°, 7.09±0.20°, 11.92±0.20°, 15.15±0.20°, 21.55±0.20°, and 23.93±0.20°.

[0152] In some embodiments, form A of compound I has an XRPD pattern that includes peaks at 2θ of 7.09±0.20°, 11.92±0.20°, 15.15±0.20°, 17.85±0.20°, 21.55±0.20°, and 23.93±0.20°.

[0153] In some embodiments, form A of compound I has an XRPD pattern that includes peaks at 2θ of 6.45±0.20°, 7.09±0.20°, 11.92±0.20°, 15.15±0.20°, 17.85±0.20°, 21.55±0.20°, and 23.93±0.20°.

[0154] In some embodiments, form A of compound I has an XRPD pattern containing at least seven (e.g., eight, nine, or ten) peaks at 2θ selected from 6.45±0.20°, 7.09±0.20°, 11.92±0.20°, 14.19±0.20°, 15.15±0.20°, 17.85±0.20°, 18.94±0.20°, 21.55±0.20°, 23.93±0.20°, and 26.86±0.20°.

[0155] In some embodiments, form A of compound I has an XRPD pattern that includes peaks at 2θ of 6.45±0.20°, 7.09±0.20°, 11.92±0.20°, 14.19±0.20°, 15.15±0.20°, 17.85±0.20°, 18.94±0.20°, 21.55±0.20°, 23.93±0.20°, and 26.86±0.20°.

[0156] In some embodiments, form A of compound I has an XRPD pattern containing at least 10 peaks (e.g., 11, 12, 13, 14, or 15) at 2θ selected from 6.45±0.20°, 7.09±0.20°, 10.75±0.20°, 11.32±0.20°, 11.92±0.20°, 12.88±0.20°, 14.19±0.20°, 15.15±0.20°, 17.85±0.20°, 18.94±0.20°, 20.79±0.20°, 21.55±0.20°, 23.93±0.20°, 25.69±0.20°, and 26.86±0.20°.

[0157] In some embodiments, form A of compound I has an XRPD pattern that includes peaks at 2θ of 6.45±0.20°, 7.09±0.20°, 10.75±0.20°, 11.32±0.20°, 11.92±0.20°, 12.88±0.20°, 14.19±0.20°, 15.15±0.20°, 17.85±0.20°, 18.94±0.20°, 20.79±0.20°, 21.55±0.20°, 23.93±0.20°, 25.69±0.20° and 26.86±0.20°.

[0158] In some embodiments, form A of compound I has an XRPD pattern substantially similar to the XRPD data shown in Table 7.

[0159] In some embodiments, form A of compound I has an XRPD pattern substantially similar to the XRPD pattern shown in Figure 11.

[0160] In some embodiments, form A of compound I has a DSC thermogram that includes endothermic activity starting at approximately 199.5°C and having a peak at approximately 201.5°C.

[0161] In some embodiments, form A of compound I has a DSC thermogram substantially similar to the thermogram shown in Figure 13.

[0162] In some embodiments, form A of compound I has a TGA thermogram showing a mass loss of about 0.02% when heated from about 30°C to about 120°C.

[0163] In some embodiments, form A of compound I has a TGA thermogram substantially similar to the thermogram shown in Figure 12.

[0164] In some embodiments, form A of compound I has a DVS water vapor adsorption plot substantially similar to that shown in Figure 14.

[0165] 2. Form B of Compound I

[0166] In some embodiments, the crystalline form of compound I (free base), which is crystalline form B of compound I, is disclosed.

[0167] In some embodiments, form B of compound I has an XRPD pattern that includes peaks at 2θ of 7.42±0.20°, 13.21±0.20°, and 19.24±0.20°.

[0168] In some embodiments, form B of compound I has an XRPD pattern that includes peaks at 2θ of 6.62±0.20°, 7.42±0.20°, 13.21±0.20°, and 19.24±0.20°.

[0169] In some embodiments, form B of compound I has an XRPD pattern that includes peaks at 2θ of 7.17±0.20°, 7.42±0.20°, 13.21±0.20°, and 19.24±0.20°.

[0170] In some embodiments, form B of compound I has an XRPD pattern that includes peaks at 2θ of 6.62±0.20°, 7.17±0.20°, 7.42±0.20°, 13.21±0.20°, and 19.24±0.20°.

[0171] In some embodiments, form B of compound I has an XRPD pattern that includes peaks at 2θ of 6.62±0.20°, 7.17±0.20°, 7.42±0.20°, 13.21±0.20°, 14.25±0.20°, and 19.24±0.20°.

[0172] In some embodiments, form B of compound I has an XRPD pattern that includes peaks at 2θ of 6.62±0.20°, 7.17±0.20°, 7.42±0.20°, 13.21±0.20°, 17.94±0.20°, and 19.24±0.20°.

[0173] In some embodiments, form B of compound I has an XRPD pattern that includes peaks at 2θ of 6.62±0.20°, 7.17±0.20°, 7.42±0.20°, 13.21±0.20°, 14.25±0.20°, 17.94±0.20°, and 19.24±0.20°.

[0174] In some embodiments, form B of compound I has an XRPD pattern containing at least seven (e.g., eight, nine, or ten) peaks at 2θ selected from 6.62±0.20°, 7.17±0.20°, 7.42±0.20°, 11.61±0.20°, 13.21±0.20°, 14.25±0.20°, 16.89±0.20°, 17.94±0.20°, 19.24±0.20°, and 21.89±0.20°.

[0175] In some embodiments, form B of compound I has an XRPD pattern that includes peaks at 6.62±0.20°, 7.17±0.20°, 7.42±0.20°, 11.61±0.20°, 13.21±0.20°, 14.25±0.20°, 16.89±0.20°, 17.94±0.20°, 19.24±0.20° and 21.89±0.20°.

[0176] In some embodiments, form B of compound I has an XRPD pattern containing at least 10 peaks (e.g., 11, 12, 13, 14, or 15) at 2θ selected from 6.62±0.20°, 7.17±0.20°, 7.42±0.20°, 11.61±0.20°, 13.21±0.20°, 13.92±0.20°, 14.25±0.20°, 16.89±0.20°, 17.24±0.20°, 17.94±0.20°, 19.24±0.20°, 21.89±0.20°, 27.21±0.20°, 27.35±0.20°, and 27.87±0.20°.

[0177] In some embodiments, form B of compound I has an XRPD pattern that includes peaks at 6.62±0.20°, 7.17±0.20°, 7.42±0.20°, 11.61±0.20°, 13.21±0.20°, 13.92±0.20°, 14.25±0.20°, 16.89±0.20°, 17.24±0.20°, 17.94±0.20°, 19.24±0.20°, 21.89±0.20°, 27.21±0.20°, 27.35±0.20° and 27.87±0.20°.

[0178] In some embodiments, form B of compound I has an XRPD pattern substantially similar to the XRPD data shown in Table 8.

[0179] In some embodiments, form B of compound I has an XRPD pattern substantially similar to the XRPD pattern shown in Figure 15.

[0180] In some embodiments, form B of compound I has a DSC thermogram that includes three endothermic transitions with onset temperatures and peak temperatures of 116.3°C and 125.4°C, 182.4°C and 187.5°C, and 199.2°C and 200.3°C, respectively.

[0181] In some embodiments, form B of compound I has a DSC thermogram substantially similar to the thermogram shown in Figure 16.

[0182] In some embodiments, form B of compound I has a TGA thermogram showing a mass loss of less than 1.68% when heated from about 30°C to about 100°C.

[0183] In some embodiments, form B of compound I has a TGA thermogram substantially similar to the thermogram shown in Figure 16.

[0184] 3. Form C of Compound I

[0185] In some embodiments, the crystalline form of compound I (free base), which is crystalline form C of compound I, is disclosed.

[0186] In some embodiments, form C of compound I has an XRPD pattern that includes peaks at 2θ of 5.95±0.20°, 8.58±0.20°, and 19.56±0.20°.

[0187] In some embodiments, form C of compound I has an XRPD pattern that includes peaks at 2θ of 5.95±0.20°, 8.58±0.20°, 11.89±0.20°, and 19.56±0.20°.

[0188] In some embodiments, form C of compound I has an XRPD pattern that includes peaks at 2θ of 5.95±0.20°, 8.58±0.20°, 13.75±0.20°, and 19.56±0.20°.

[0189] In some embodiments, form C of compound I has an XRPD pattern that includes peaks at 2θ of 5.95±0.20°, 8.58±0.20°, 11.89±0.20°, 13.75±0.20°, and 19.56±0.20°.

[0190] In some embodiments, form C of compound I has an XRPD pattern that includes peaks at 2θ of 5.95±0.20°, 8.58±0.20°, 11.89±0.20°, 12.39±0.20°, 13.75±0.20°, and 19.56±0.20°.

[0191] In some embodiments, form C of compound I has an XRPD pattern that includes peaks at 2θ of 5.95±0.20°, 8.58±0.20°, 11.89±0.20°, 13.40±0.20°, 13.75±0.20°, and 19.56±0.20°.

[0192] In some embodiments, form C of compound I has an XRPD pattern that includes peaks at 2θ of 5.95±0.20°, 8.58±0.20°, 11.89±0.20°, 12.39±0.20°, 13.40±0.20°, 13.75±0.20°, and 19.56±0.20°.

[0193] In some embodiments, form C of compound I has an XRPD pattern containing at least seven (e.g., eight, nine, or ten) peaks at 2θ selected from 5.95±0.20°, 8.58±0.20°, 11.89±0.20°, 12.39±0.20°, 13.40±0.20°, 13.75±0.20°, 17.23±0.20°, 18.91±0.20°, 19.56±0.20°, and 23.51±0.20°.

[0194] In some embodiments, form C of compound I has an XRPD pattern that includes peaks at 2θ of 5.95±0.20°, 8.58±0.20°, 11.89±0.20°, 12.39±0.20°, 13.40±0.20°, 13.75±0.20°, 17.23±0.20°, 18.91±0.20°, 19.56±0.20° and 23.51±0.20°.

[0195] In some embodiments, form C of compound I has an XRPD pattern containing at least 10 peaks (e.g., 11, 12, 13, 14, or 15) at 2θ selected from 5.95±0.20°, 8.58±0.20°, 11.89±0.20°, 12.39±0.20°, 13.40±0.20°, 13.75±0.20°, 15.54±0.20°, 15.90±0.20°, 17.23±0.20°, 18.91±0.20°, 19.56±0.20°, 23.51±0.20°, 24.91±0.20°, 25.29±0.20°, and 25.55±0.20°.

[0196] In some embodiments, form C of compound I has an XRPD pattern that includes peaks at 2θ of 5.95±0.20°, 8.58±0.20°, 11.89±0.20°, 12.39±0.20°, 13.40±0.20°, 13.75±0.20°, 15.54±0.20°, 15.90±0.20°, 17.23±0.20°, 18.91±0.20°, 19.56±0.20°, 23.51±0.20°, 24.91±0.20°, 25.29±0.20° and 25.55±0.20°.

[0197] In some embodiments, form C of compound I has an XRPD pattern substantially similar to the XRPD data shown in Table 9.

[0198] In some embodiments, form C of compound I has an XRPD pattern substantially similar to the XRPD pattern shown in Figure 17.

[0199] In some embodiments, form C of compound I has a DSC thermogram that includes endothermic activity starting at approximately 193.8°C and having a peak at approximately 194.6°C.

[0200] In some embodiments, form C of compound I has a DSC thermogram substantially similar to the thermogram shown in Figure 18.

[0201] In some embodiments, form C of compound I has a TGA thermogram showing a mass loss of less than 0.70% when heated from about 30°C to about 180°C.

[0202] In some embodiments, form C of compound I has a TGA thermogram substantially similar to the thermogram shown in Figure 18.

[0203] 4. Form D of Compound I

[0204] In some embodiments, the crystalline form of compound I (free base), which is crystalline form D of compound I, is disclosed.

[0205] In some embodiments, form D of compound I has an XRPD pattern that includes peaks at 2θ of 6.85±0.20°, 14.81±0.20°, and 21.38±0.20°.

[0206] In some embodiments, form D of compound I has an XRPD pattern that includes peaks at 2θ of 6.85±0.20°, 13.71±0.20°, 14.81±0.20°, and 21.38±0.20°.

[0207] In some embodiments, form D of compound I has an XRPD pattern that includes peaks at 2θ of 6.85±0.20°, 14.81±0.20°, 17.69±0.20°, and 21.38±0.20°.

[0208] In some embodiments, form D of compound I has an XRPD pattern that includes peaks at 2θ of 6.85±0.20°, 13.71±0.20°, 14.81±0.20°, 17.69±0.20°, and 21.38±0.20°.

[0209] In some embodiments, form D of compound I has an XRPD pattern that includes peaks at 2θ of 6.85±0.20°, 11.13±0.20°, 13.71±0.20°, 14.81±0.20°, 17.69±0.20°, and 21.38±0.20°.

[0210] In some embodiments, form D of compound I has an XRPD pattern that includes peaks at 2θ of 6.85±0.20°, 13.71±0.20°, 14.81±0.20°, 17.69±0.20°, 21.38±0.20°, and 23.49±0.20°.

[0211] In some embodiments, form D of compound I has an XRPD pattern that includes peaks at 2θ of 6.85±0.20°, 11.13±0.20°, 13.71±0.20°, 14.81±0.20°, 17.69±0.20°, 21.38±0.20°, and 23.49±0.20°.

[0212] In some embodiments, form D of compound I has an XRPD pattern containing at least seven peaks (e.g., eight, nine, ten, or eleven) at 2θ selected from 6.85±0.20°, 11.13±0.20°, 13.07±0.20°, 13.71±0.20°, 14.81±0.20°, 15.08±0.20°, 17.69±0.20°, 18.37±0.20°, 21.38±0.20°, 21.67±0.20°, and 23.49±0.20°.

[0213] In some embodiments, form D of compound I has an XRPD pattern that includes peaks at 6.85±0.20°, 11.13±0.20°, 13.07±0.20°, 13.71±0.20°, 14.81±0.20°, 15.08±0.20°, 17.69±0.20°, 18.37±0.20°, 21.38±0.20°, 21.67±0.20° and 23.49±0.20°.

[0214] In some embodiments, form D of compound I has an XRPD pattern containing at least 11 peaks (e.g., 12, 13, 14, or 15) at 2θ selected from 6.85±0.20°, 11.13±0.20°, 13.07±0.20°, 13.71±0.20°, 14.81±0.20°, 15.08±0.20°, 17.69±0.20°, 18.37±0.20°, 21.38±0.20°, 21.67±0.20°, 22.25±0.20°, 23.49±0.20°, 24.65±0.20°, 26.69±0.20°, and 28.60±0.20°.

[0215] In some embodiments, form D of compound I has an XRPD pattern that includes peaks at 6.85±0.20°, 11.13±0.20°, 13.07±0.20°, 13.71±0.20°, 14.81±0.20°, 15.08±0.20°, 17.69±0.20°, 18.37±0.20°, 21.38±0.20°, 21.67±0.20°, 22.25±0.20°, 23.49±0.20°, 24.65±0.20°, 26.69±0.20° and 28.60±0.20°.

[0216] In some embodiments, form D of compound I has an XRPD pattern substantially similar to the XRPD data shown in Table 10.

[0217] In some embodiments, form D of compound I has an XRPD pattern substantially similar to the XRPD pattern shown in Figure 19.

[0218] In some embodiments, form D of compound I has a DSC thermogram that includes two endothermic transitions with onset temperatures of 186.9°C and 190.5°C, and peak temperatures of 199.5°C and 200.4°C, respectively.

[0219] In some embodiments, form D of compound I has a DSC thermogram substantially similar to the thermogram shown in Figure 20.

[0220] In some embodiments, Form D of Compound I has a TGA thermogram showing a mass loss of less than 0.67% upon heating from about 30 °C to about 100 °C.

[0221] In some embodiments, Form D of Compound I has a TGA thermogram substantially similar to the thermogram shown in Figure 20.

[0222] 5. Crystalline form of fumarate of compound I

[0223] In some embodiments, crystalline forms of pharmaceutically acceptable salts of Compound I, which are crystalline forms of the fumarate of Compound I, are disclosed.

[0224] In some embodiments, the crystalline form of the fumarate of Compound I has an XRPD pattern comprising peaks at 2θ of 5.98 ± 0.20°, 10.02 ± 0.20° and 16.47 ± 0.20°.

[0225] In some embodiments, the crystalline form of the fumarate of Compound I has an XRPD pattern comprising peaks at 2θ of 5.98 ± 0.20°, 10.02 ± 0.20°, 15.36 ± 0.20° and 16.47 ± 0.20°.

[0226] In some embodiments, the crystalline form of the fumarate of Compound I has an XRPD pattern comprising peaks at 2θ of 5.98 ± 0.20°, 10.02 ± 0.20°, 16.47 ± 0.20° and 25.17 ± 0.20°.

[0227] In some embodiments, the crystalline form of the fumarate of Compound I has an XRPD pattern comprising peaks at 2θ of 5.98 ± 0.20°, 10.02 ± �.20°, 15.36 ± 0.20°, 16.47 ± 0.20° and 25.17 ± 0.20°.

[0228] In some embodiments, the crystalline form of the fumarate of compound I has an XRPD pattern containing peaks at 2θ of 5.98±0.20°, 10.02±0.20°, 15.36±0.20°, 16.47±0.20°, 17.30±0.20°, and 25.17±0.20°.

[0229] In some embodiments, the crystalline form of the fumarate of compound I has an XRPD pattern containing peaks at 2θ of 5.98±0.20°, 10.02±0.20°, 15.36±0.20°, 16.47±0.20°, 20.32±0.20°, and 25.17±0.20°.

[0230] In some embodiments, the crystalline form of the fumarate of compound I has an XRPD pattern with peaks at 2θ of 5.98±0.20°, 10.02±0.20°, 15.36±0.20°, 16.47±0.20°, 17.30±0.20°, 20.32±0.20°, and 25.17±0.20°.

[0231] In some embodiments, the crystalline form of the fumarate of compound I has an XRPD pattern containing at least seven (e.g., eight, nine, or ten) peaks at 2θ of 5.98±0.20°, 8.49±0.20°, 10.02±0.20°, 10.70±0.20°, 15.36±0.20°, 16.47±0.20°, 17.30±0.20°, 20.32±0.20°, 25.17±0.20°, and 25.80±0.20°.

[0232] In some embodiments, the crystalline form of the fumarate of compound I has an XRPD pattern containing peaks at 2θ of 5.98±0.20°, 8.49±0.20°, 10.02±0.20°, 10.70±0.20°, 15.36±0.20°, 16.47±0.20°, 17.30±0.20°, 20.32±0.20°, 25.17±0.20°, and 25.80±0.20°.

[0233] In some embodiments, the crystalline form of the fumarate of compound I has an XRPD pattern containing at least 10 peaks (e.g., 11, 12, 13, 14, or 15) at 2θ selected from 5.42±0.20°, 5.98±0.20°, 6.56±0.20°, 8.49±0.20°, 10.02±0.20°, 10.70±0.20°, 12.49±0.20°, 15.36±0.20°, 16.47±0.20°, 17.30±0.20°, 20.32±0.20°, 25.17±0.20°, 25.80±0.20°, and 27.45±0.20°.

[0234] In some embodiments, the crystalline form of the fumarate of compound I has an XRPD pattern containing peaks at 2θ of 5.42±0.20°, 5.98±0.20°, 6.56±0.20°, 8.49±0.20°, 10.02±0.20°, 10.70±0.20°, 12.49±0.20°, 15.36±0.20°, 16.47±0.20°, 17.30±0.20°, 20.32±0.20°, 25.17±0.20°, 25.80±0.20°, and 27.45±0.20°.

[0235] In some embodiments, the crystalline form of the fumarate of compound I has an XRPD pattern substantially similar to the XRPD pattern shown in Table 14.

[0236] In some embodiments, the crystalline form of the fumarate of compound I has an XRPD pattern substantially similar to the XRPD pattern shown in Figure 21 or Figure 22.

[0237] In some embodiments, the crystalline form of the fumarate of compound I has a DSC thermogram that includes endothermic activity, starting at approximately 162.8°C and having a peak at approximately 169.8°C.

[0238] In some embodiments, the crystalline form of the fumarate of compound I has a DSC thermogram substantially similar to that shown in Figure 23.

[0239] In some embodiments, the crystalline form of the fumarate of Compound I has a TGA thermogram showing a mass loss of about 0.70% upon heating from about 40 °C to about 110 °C.

[0240] In some embodiments, the crystalline form of the fumarate of Compound I has a TGA thermogram substantially similar to that shown in Figure 24.

[0241] In some embodiments, the crystalline form of the fumarate of Compound I has a DVS water vapor adsorption plot substantially similar to that shown in Figure 25.

[0242] 6. Crystalline form of hemisuccinate of compound I

[0243] In some embodiments, the crystalline form of the hemisuccinate of Compound I has an XRPD pattern substantially similar to the XRPD pattern shown in Figure 26.

[0244] In some embodiments, the crystalline form of the hemisuccinate of Compound I has a DSC thermogram including an endotherm that starts at about 173.9 °C and has a peak at about 184.3 °C.

[0245] In some embodiments, the crystalline form of the hemisuccinate of Compound I has a DSC thermogram substantially similar to that shown in Figure 27.

[0246] In some embodiments, the crystalline form of the hemisuccinate of Compound I has a TGA thermogram showing a mass loss of about 4.10% upon heating from about 30 °C to about 125 °C.

[0247] In some embodiments, the crystalline form of the hemisuccinate of Compound I has a TGA thermogram substantially similar to that shown in Figure 28.

[0248] In some embodiments, the crystalline form of the hemisuccinate of Compound I has a DVS water vapor adsorption plot substantially similar to that shown in Figure 29.

[0249] [[ID=四十]] 7. Crystalline form of the hydrochloride salt of compound I

[0250] In some embodiments, the crystalline form of the hydrochloride salt of compound I has a DSC thermogram that includes endothermic activity, starting at approximately 220.8°C and having a peak at approximately 227.6°C.

[0251] In some embodiments, the crystalline form of the hydrochloride salt of compound I has a TGA thermogram showing a mass loss of about 0.26% when heated from about 40°C to about 150°C.

[0252] In some embodiments, the crystalline form of the hydrochloride salt of compound I has DSC and TGA thermograms substantially similar to those in Figure 30.

[0253] In some embodiments, the crystalline form of the hydrochloride salt of compound I has a DVS water vapor adsorption plot substantially similar to that shown in Figure 31.

[0254] 8. Crystalline form of phosphate of compound I

[0255] In some embodiments, the crystalline form of the phosphate of compound I has an XRPD pattern substantially similar to the XRPD pattern shown in Figure 32.

[0256] In some embodiments, the crystalline form of the phosphate of compound I has a DSC thermogram that includes four endothermic peaks: one starting at approximately 30.8°C with a peak at approximately 50.1°C, one starting at approximately 145.5°C with a peak at approximately 149.1°C, one starting at approximately 191.1°C with a peak at approximately 195.5°C, and one starting at approximately 213.2°C with a peak at approximately 239.0°C.

[0257] In some embodiments, the crystalline form of the phosphate of compound I has a TGA thermogram showing a mass loss of about 4.66% when heated from about 30°C to about 200°C.

[0258] In some embodiments, the crystalline form of the phosphate of compound I has DSC and TGA thermograms substantially similar to those in Figure 33.

[0259] In some embodiments, the crystalline form of the phosphate of compound I has a DVS water vapor adsorption plot substantially similar to that in Figure 34.

[0260] 9. Crystalline form of the sulfate of compound I

[0261] In some embodiments, the crystalline form of the sulfate of compound I has an XRPD pattern substantially similar to the XRPD pattern shown in Figure 35.

[0262] In some embodiments, the crystalline form of the sulfate of compound I has a DSC thermogram that includes three endothermic phases: one starting at approximately 34.5°C with a peak at approximately 57.3°C, one starting at approximately 157.5°C with a peak at approximately 169.4°C, and one starting at approximately 227.6°C with a peak at approximately 247.4°C.

[0263] In some embodiments, the crystalline form of the sulfate of compound I has a TGA thermogram showing a mass loss of about 5.47% when heated from about 30°C to about 200°C.

[0264] In some embodiments, the crystalline form of the sulfate of compound I has DSC and TGA thermograms substantially similar to those in Figure 36.

[0265] In some embodiments, the crystalline form of the sulfate of compound I has a DVS water vapor adsorption plot substantially similar to that in Figure 37.

[0266] 10. Crystalline form of hemiadipine salt of compound I

[0267] In some embodiments, crystalline forms of pharmaceutically acceptable salts of compound I, which are crystalline forms of the hemiadipine salt of compound I, are disclosed.

[0268] In some embodiments, the crystalline form of the hemiadipinate of compound I has an XRPD pattern containing peaks at 2θ of 8.49±0.20°, 9.30±0.20°, and 24.93±0.20°.

[0269] In some embodiments, the crystalline form of the hemiadipinate of compound I has an XRPD pattern containing peaks at 2θ of 8.49±0.20°, 9.30±0.20°, 18.04±0.20°, and 24.93±0.20°.

[0270] In some embodiments, the crystalline form of the hemiadipinate of compound I has an XRPD pattern containing peaks at 2θ of 8.49±0.20°, 9.30±0.20°, 18.12±0.20°, and 24.93±0.20°.

[0271] In some embodiments, the crystalline form of the hemiadipinate of compound I has an XRPD pattern containing peaks at 2θ of 8.49±0.20°, 9.30±0.20°, 18.04±0.20°, 18.12±0.20°, and 24.93±0.20°.

[0272] In some embodiments, the crystalline form of the hemiadipinate of compound I has an XRPD pattern containing peaks at 2θ of 8.49±0.20°, 9.30±0.20°, 18.04±0.20°, 18.12±0.20°, 18.59±0.20°, and 24.93±0.20°.

[0273] In some embodiments, the crystalline form of the hemiadipinate of compound I has an XRPD pattern containing peaks at 2θ of 8.49±0.20°, 9.30±0.20°, 18.12±0.20°, 18.59±0.20°, 20.70±0.20°, and 24.93±0.20°.

[0274] In some embodiments, the crystalline form of the hemiadipinate of compound I has an XRPD pattern with peaks at 2θ of 8.49±0.20°, 9.30±0.20°, 18.04±0.20°, 18.12±0.20°, 18.59±0.20°, 20.70±0.20°, and 24.93±0.20°.

[0275] In some embodiments, the crystalline form of the hemiadipinate of compound I has an XRPD pattern containing at least seven (e.g., eight, nine, or ten) peaks at 2θ of 8.49±0.20°, 9.30±0.20°, 12.32±0.20°, 17.27±0.20°, 18.04±0.20°, 18.12±0.20°, 18.59±0.20°, 20.70±0.20°, 23.87±0.20°, and 24.93±0.20°.

[0276] In some embodiments, the crystalline form of the hemiadipinate of compound I has an XRPD pattern with peaks at 2θ of 8.49±0.20°, 9.30±0.20°, 12.32±0.20°, 17.27±0.20°, 18.04±0.20°, 18.12±0.20°, 18.59±0.20°, 20.70±0.20°, 23.87±0.20°, and 24.93±0.20°.

[0277] In some embodiments, the crystalline form of the hemiadipinate of compound I has an XRPD pattern containing at least 10 peaks (e.g., 11, 12, 13, 14, or 15) at 2θ selected from 8.49±0.20°, 9.30±0.20°, 10.28±0.20°, 12.32±0.20°, 12.72±0.20°, 15.05±0.20°, 16.42±0.20°, 17.27±0.20°, 18.04±0.20°, 18.12±0.20°, 18.59±0.20°, 20.70±0.20°, 23.87±0.20°, 24.93±0.20°, and 28.09±0.20°.

[0278] In some embodiments, the crystalline form of the hemiadipinate of compound I has an XRPD pattern containing peaks at 2θ of 8.49±0.20°, 9.30±0.20°, 10.28±0.20°, 12.32±0.20°, 12.72±0.20°, 15.05±0.20°, 16.42±0.20°, 17.27±0.20°, 18.04±0.20°, 18.12±0.20°, 18.59±0.20°, 20.70±0.20°, 23.87±0.20°, 24.93±0.20° and 28.09±0.20°.

[0279] In some embodiments, the crystalline form of the hemiadipinate of compound I has an XRPD pattern substantially similar to the XRPD pattern shown in Table 15.

[0280] In some embodiments, the crystalline form of the hemiadipinate of compound I has an XRPD pattern substantially similar to the XRPD pattern shown in Figure 38.

[0281] In some embodiments, the crystalline form of the hemiadipinate of compound I has a DSC thermogram that includes endothermic activity, starting at approximately 173.3°C and having a peak at approximately 175.0°C.

[0282] In some embodiments, the crystalline form of the hemiadipinate of compound I has a TGA thermogram showing a mass loss of about 0.25% when heated from about 40°C to about 145°C.

[0283] In some embodiments, the crystalline form of the hemiadipinate of compound I has DSC and TGA thermograms substantially similar to those in Figure 39.

[0284] In some embodiments, the crystalline form of the hemiadipinate of compound I has a DVS water vapor adsorption plot substantially similar to that in Figure 40.

[0285] 11. Crystalline form of p-toluenesulfonate of compound I

[0286] In some embodiments, crystalline forms of pharmaceutically acceptable salts of compound I are disclosed, which are crystalline forms of p-toluenesulfonate of compound I.

[0287] In some embodiments, the crystalline form of the p-toluenesulfonate of compound I has an XRPD pattern containing peaks at 2θ of 6.56±0.20°, 7.13±0.20°, and 7.48±0.20°.

[0288] In some embodiments, the crystalline form of the p-toluenesulfonate of compound I has an XRPD pattern containing peaks at 2θ of 6.56±0.20°, 7.13±0.20°, 7.48±0.20°, and 15.69±0.20°.

[0289] In some embodiments, the crystalline form of the p-toluenesulfonate of compound I has an XRPD pattern containing peaks at 2θ of 6.56±0.20°, 7.13±0.20°, 7.48±0.20°, and 18.14±0.20°.

[0290] In some embodiments, the crystalline form of the p-toluenesulfonate of compound I has an XRPD pattern containing peaks at 2θ of 6.56±0.20°, 7.13±0.20°, 7.48±0.20°, 15.69±0.20°, and 18.14±0.20°.

[0291] In some embodiments, the crystalline form of the p-toluenesulfonate of compound I has an XRPD pattern containing peaks at 2θ of 6.56±0.20°, 7.13±0.20°, 7.48±0.20°, 14.54±0.20°, 15.69±0.20°, and 18.14±0.20°.

[0292] In some embodiments, the crystalline form of the p-toluenesulfonate of compound I has an XRPD pattern containing peaks at 2θ of 6.56±0.20°, 7.13±0.20°, 7.48±0.20°, 15.69±0.20°, 18.14±0.20°, and 19.00±0.20°.

[0293] In some embodiments, the crystalline form of the p-toluenesulfonate of compound I has an XRPD pattern containing peaks at 2θ of 6.56±0.20°, 7.13±0.20°, 7.48±0.20°, 14.54±0.20°, 15.69±0.20°, 18.14±0.20°, and 19.00±0.20°.

[0294] In some embodiments, the crystalline form of the p-toluenesulfonate of compound I has an XRPD pattern containing at least seven (e.g., eight, nine, or ten) peaks at 2θ of 6.56±0.20°, 7.13±0.20°, 7.48±0.20°, 7.86±0.20°, 14.54±0.20°, 15.69±0.20°, 18.14±0.20°, 19.00±0.20°, 21.59±0.20°, and 24.04±0.20°.

[0295] In some embodiments, the crystalline form of the p-toluenesulfonate of compound I has an XRPD pattern containing peaks at 2θ of 6.56±0.20°, 7.13±0.20°, 7.48±0.20°, 7.86±0.20°, 14.54±0.20°, 15.69±0.20°, 18.14±0.20°, 19.00±0.20°, 21.59±0.20°, and 24.04±0.20°.

[0296] In some embodiments, the crystalline form of the p-toluenesulfonate of compound I has an XRPD pattern containing at least 10 peaks (e.g., 11, 12, 13, 14, or 15) at 2θ selected from 6.56±0.20°, 7.13±0.20°, 7.48±0.20°, 7.86±0.20°, 10.47±0.20°, 11.94±0.20°, 14.54±0.20°, 15.69±0.20°, 17.89±0.20°, 18.14±0.20°, 19.00±0.20°, 19.70±0.20°, 21.59±0.20°, 22.41±0.20°, and 24.04±0.20°.

[0297] In some embodiments, the crystalline form of the p-toluenesulfonate of compound I has an XRPD pattern containing peaks at 6.56±0.20°, 7.13±0.20°, 7.48±0.20°, 7.86±0.20°, 10.47±0.20°, 11.94±0.20°, 14.54±0.20°, 15.69±0.20°, 17.89±0.20°, 18.14±0.20°, 19.00±0.20°, 19.70±0.20°, 21.59±0.20°, 22.41±0.20° and 24.04±0.20°.

[0298] In some embodiments, the crystalline form of the p-toluenesulfonate of compound I has an XRPD pattern substantially similar to the XRPD pattern shown in Table 16.

[0299] In some embodiments, the crystalline form of the p-toluenesulfonate of compound I has an XRPD pattern substantially similar to the XRPD pattern shown in Figure 41.

[0300] In some embodiments, the crystalline form of the p-toluenesulfonate of compound I has a DSC thermogram that includes endothermic activity, starting at approximately 168.2°C and having a peak at approximately 175.2°C.

[0301] In some embodiments, the crystalline form of the p-toluenesulfonate of compound I has a TGA thermogram showing a mass loss of about 0.79% when heated from about 30°C to about 150°C.

[0302] In some embodiments, the crystalline form of the p-toluenesulfonate of compound I has DSC and TGA thermograms substantially similar to those in Figure 42.

[0303] In some embodiments, the crystalline form of the p-toluenesulfonate of compound I has a DVS water vapor adsorption plot substantially similar to that shown in Figure 43.

[0304] 12. Crystalline form of maleate of compound I

[0305] In some embodiments, crystalline forms of pharmaceutically acceptable salts of compound I, which are crystalline forms of the maleate of compound I, are disclosed.

[0306] In some embodiments, the crystalline form of the maleate of compound I has an XRPD pattern containing peaks at 2θ of 5.65±0.20°, 14.67±0.20°, and 20.12±0.20°.

[0307] In some embodiments, the crystalline form of the maleate of compound I has an XRPD pattern containing peaks at 2θ of 5.65±0.20°, 14.11±0.20°, 14.67±0.20°, and 20.12±0.20°.

[0308] In some embodiments, the crystalline form of the maleate of compound I has an XRPD pattern containing peaks at 2θ of 5.65±0.20°, 14.67±0.20°, 20.12±0.20°, and 21.48±0.20°.

[0309] In some embodiments, the crystalline form of the maleate of compound I has an XRPD pattern containing peaks at 2θ of 5.65±0.20°, 14.11±0.20°, 14.67±0.20°, 20.12±0.20°, and 21.48±0.20°.

[0310] In some embodiments, the crystalline form of the maleate of compound I has an XRPD pattern containing peaks at 2θ of 5.65±0.20°, 7.13±0.20°, 14.11±0.20°, 14.67±0.20°, 20.12±0.20°, and 21.48±0.20°.

[0311] In some embodiments, the crystalline form of the maleate of compound I has an XRPD pattern containing peaks at 2θ of 5.65±0.20°, 14.11±0.20°, 14.67±0.20°, 20.12±0.20°, 21.48±0.20°, and 27.28±0.20°.

[0312] In some embodiments, the crystalline form of the maleate of compound I has an XRPD pattern with peaks at 2θ of 5.65±0.20°, 7.13±0.20°, 14.11±0.20°, 14.67±0.20°, 20.12±0.20°, 21.48±0.20°, and 27.28±0.20°.

[0313] In some embodiments, the crystalline form of the maleate of compound I has an XRPD pattern containing at least seven (e.g., eight, nine, or ten) peaks at 2θ of 5.65±0.20°, 7.13±0.20°, 14.11±0.20°, 14.67±0.20°, 18.59±0.20°, 19.96±0.20°, 20.12±0.20°, 21.48±0.20°, 23.95±0.20°, and 27.28±0.20°.

[0314] In some embodiments, the crystalline form of the maleate of compound I has an XRPD pattern with peaks at 2θ of 5.65±0.20°, 7.13±0.20°, 14.11±0.20°, 14.67±0.20°, 18.59±0.20°, 19.96±0.20°, 20.12±0.20°, 21.48±0.20°, 23.95±0.20°, and 27.28±0.20°.

[0315] In some embodiments, the crystalline form of the maleate of compound I has an XRPD pattern containing at least 10 peaks (e.g., 11, 12, 13, 14, or 15) at 2θ selected from 5.65±0.20°, 6.45±0.20°, 7.13±0.20°, 7.35±0.20°, 11.95±0.20°, 13.56±0.20°, 14.11±0.20°, 14.67±0.20°, 18.59±0.20°, 19.96±0.20°, 20.12±0.20°, 20.42±0.20°, 21.48±0.20°, 23.95±0.20°, and 27.28±0.20°.

[0316] In some embodiments, the crystalline form of the maleate of compound I has an XRPD pattern containing peaks at 2θ of 5.65±0.20°, 6.45±0.20°, 7.13±0.20°, 7.35±0.20°, 11.95±0.20°, 13.56±0.20°, 14.11±0.20°, 14.67±0.20°, 18.59±0.20°, 19.96±0.20°, 20.12±0.20°, 20.42±0.20°, 21.48±0.20°, 23.95±0.20° and 27.28±0.20°.

[0317] In some embodiments, the crystalline form of the maleate of compound I has an XRPD pattern substantially similar to the XRPD pattern shown in Table 17.

[0318] In some embodiments, the crystalline form of the maleate of compound I has an XRPD pattern substantially similar to the XRPD pattern shown in Figure 44.

[0319] In some embodiments, the crystalline form of the maleate of compound I has a DSC thermogram that includes endothermic activity, starting at approximately 159.6°C and having a peak at approximately 162.5°C.

[0320] In some embodiments, the crystalline form of the maleate of compound I has a TGA thermogram showing a mass loss of about 0.44% when heated from about 30°C to about 140°C.

[0321] In some embodiments, the crystalline form of the maleate of compound I has DSC and TGA thermograms substantially similar to those in Figure 45.

[0322] In some embodiments, the crystalline form of the maleate of compound I has a DVS water vapor adsorption plot substantially similar to that in Figure 46.

[0323] 13. Crystalline form of oxalate of compound I

[0324] In some embodiments, the crystalline morphology of the oxalate of compound I has an XRPD pattern substantially similar to the XRPD pattern shown in Figure 47.

[0325] In some embodiments, the crystalline form of the oxalate of compound I has a DSC thermogram that includes three endothermic phases: one starting at approximately 30.5°C with a peak at approximately 63.2°C, one starting at approximately 129.9°C with a peak at approximately 139.5°C, and one starting at approximately 193.2°C with a peak at approximately 211.4°C.

[0326] In some embodiments, the crystalline form of the oxalate of compound I has a TGA thermogram showing a mass loss of about 7.92% when heated from about 37°C to about 147°C.

[0327] In some embodiments, the crystalline form of the oxalate of compound I has DSC and TGA thermograms substantially similar to those in Figure 48.

[0328] 14. Crystalline form of L-(+)-tartrate of compound I

[0329] In some embodiments, the crystalline form of the L-(+)-tartrate of compound I has an XRPD pattern substantially similar to the XRPD pattern shown in Figure 49.

[0330] In some embodiments, the crystalline form of the L-(+)-tartrate of compound I has a DSC thermogram that includes three endothermic phases: one starting at approximately 144.5°C with a peak at approximately 156.1°C, one starting at approximately 172.3°C with a peak at approximately 187.5°C, and one starting at approximately 203.5°C with a peak at approximately 224.0°C.

[0331] In some embodiments, the crystalline form of the L-(+)-tartrate of compound I has a TGA thermogram showing a mass loss of about 0.59% when heated from about 40°C to about 150°C.

[0332] In some embodiments, the crystalline form of the L-(+)-tartrate of compound I has DSC and TGA thermograms substantially similar to those in Figure 50.

[0333] 15. Crystalline form of monoadipine salt of compound I

[0334] In some embodiments, the crystalline form of the monoadipate of compound I has an XRPD pattern substantially similar to the XRPD pattern shown in Figure 51.

[0335] In some embodiments, the crystalline form of the monoadipate of compound I has a DSC thermogram that includes two endothermic peaks: one starting at approximately 146.1°C with a peak at approximately 148.7°C, and another starting at approximately 167.1°C with a peak at approximately 171.9°C.

[0336] In some embodiments, the crystalline form of the monoadipate of compound I has a TGA thermogram showing a mass loss of about 0.33% when heated from about 40°C to about 125°C.

[0337] In some embodiments, the crystalline form of the monoadipate of compound I has DSC and TGA thermograms substantially similar to those in Figure 52.

[0338] Where crystalline form is referred to herein, the degree of crystallinity is, conveniently, greater than about 60%, more conveniently greater than about 80%, conveniently greater than about 90%, and more conveniently greater than about 95%. Most conveniently, the degree of crystallinity is greater than about 98%.

[0339] In some embodiments, the crystalline forms of the Disclosure are preferably substantially pure, meaning that each crystalline form contains no more than 10% by weight, 5% by weight, or 1% by weight of any apparent impurities, including other polymorphs of the compound. In certain embodiments, the “substantially pure” crystalline forms of the Disclosure have a purity of more than 90%, more than 95%, more than 98%, or even more than 99%.

[0340] In some embodiments, the crystalline forms of the Disclosure may exist as a mixture. A mixture of the crystalline forms of the Disclosure has an XRPD peak characteristic of each of the crystalline forms present in the mixture. For example, a mixture of two crystalline forms has an XRPD pattern which is a convolution of X-ray powder diffraction patterns corresponding to substantially pure crystalline forms.

[0341] Preparation process

[0342] This specification further provides a process for preparing crystalline forms of compound I and its pharmaceutically acceptable salts.

[0343] Further details of the preparation process for compound I are provided herein. This process is summarized in the following scheme. [ka]

[0344] Compound I was previously described in International Patent Publication WO2019 / 214634, the full text of which is incorporated herein by reference, and which describes, in particular, Compound I, its synthesis, and demonstration of its ErbB inhibitory activity.

[0345] This specification further provides a process useful for preparing compound I on a large scale, for example, on a scale of tens of kilograms, in high yield. This process is summarized in the following scheme. [ka]

[0346] The pharmaceutical salts and crystalline forms of the present disclosure may be prepared by methods known in the art. In some embodiments, pharmaceutically acceptable salt crystals of compound I are prepared by dissolving compound I in methyl ethyl ketone, ethanol, or ethyl acetate, adding the corresponding acid in the methyl ethyl ketone, ethanol, or ethyl acetate solution, allowing the solution to stand and crystallize, and isolating the pharmaceutically acceptable salt crystals of compound I, where the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, phosphate, maleate, fumarate, oxalate, p-toluenesulfonate, succinate, L-(+)-tartrate, monoadipate, and hemiadipate. However, these do not limit the methods for preparing the pharmaceutical salts and crystalline forms of the present disclosure.

[0347] This specification further provides a crystallization process for preparing form A of compound I, which includes the steps of dissolving compound I in an H2O / EtOH / MTBE solution, adding a crystalline species of form A to the solution, allowing the solution to stand to crystallize, and isolating form A of compound I.

[0348] This specification further provides a crystallization process for preparing form B of compound I, which includes the steps of suspending the hemiadipinate of compound I in a pH 6.8 buffer to form a free base of compound I, and then filtering and drying the suspension to isolate form B of compound I.

[0349] This specification further provides a crystallization process for preparing form C of compound I, which includes the steps of dissolving compound I in a hot methanol solution, cooling the solution, allowing the solution to stand to crystallize, and isolating form C of compound I.

[0350] This specification further provides a crystallization process for preparing form D of compound I, which includes the steps of dissolving compound I in a hot (e.g., 50°C) 1,4-dioxane or THF solution, adding a reverse solvent (e.g., n-heptane, water, or MTBE) to the solution, allowing the solution to stand to crystallize, and isolating form D of compound I.

[0351] This specification further provides a crystallization process for preparing form D of compound I, which includes the steps of dissolving compound I in a suitable thermal (e.g., 50°C) solvent (e.g., THF, 1,4-dioxane, acetone, acetonitrile, or ethyl acetate), evaporating the solution at a lower temperature (e.g., 25°C), allowing the solution to stand to crystallize, and isolating form D of compound I.

[0352] spray dried dispersion

[0353] "Spray-dried dispersion" or "SDD" refers to powder obtained from a spray-drying process. "Spray drying" refers to a method of producing a dry powder from a solution or slurry. The solution or slurry is atomized or rapidly dried with a hot gas (e.g., air or nitrogen), which causes the solvent to evaporate rapidly and uniformly.

[0354] In certain embodiments, the disclosure provides a spray-dried dispersion comprising compound I and a polymer for spray-dried dispersions.

[0355] Non-limiting examples of polymers used in spray-dried dispersions include HPMC-AS polymer, PVP-VA64 copolymer, Soluplus polymer, Eudragit E100 polymer, Eudragit L100-55 polymer, hydroxypropyl-β-cyclodextrin (HP-β-CD), PVP K30 LP polymer, HPC (hydroxypropyl cellulose, Klucel LF) polymer, HPC (Klucel MF) polymer, HPMC E5 LV polymer, HPMC E15 polymer, and / or HPMCP-HP50 polymer. In certain embodiments, the polymer is HPMC-AS polymer. In certain embodiments, the HPMC-AS polymer is HPMC-AS MG polymer, HPMC-AS MF polymer, or HPMC-AS LF polymer. In certain embodiments, the HPMC-AS polymer is HPMC-AS MG polymer. In certain embodiments, the polymer is PVP-VA64 copolymer. In certain embodiments, the polymer is HPC (Klucel LF) polymer.

[0356] In certain embodiments, compound I is present in the spray-dried dispersion at an amount of about 5% w / w to about 70% w / w. In certain embodiments, the polymer is present in the spray-dried dispersion at an amount of about 95% w / w to about 30% w / w.

[0357] In certain embodiments, compound I is present in the spray-dried dispersion at an amount of about 20% w / w to about 60% w / w. In certain embodiments, the polymer is present in the spray-dried dispersion at an amount of about 80% w / w to about 40% w / w.

[0358] In certain embodiments, compound I is present in the spray-dried dispersion at an amount of about 20% w / w to about 40% w / w. In certain embodiments, compound I is present in the spray-dried dispersion at an amount of about 20% w / w, about 30% w / w, or about 40% w / w. In certain embodiments, the polymer is present in the spray-dried dispersion at an amount of about 80% w / w, about 70% w / w, about 60% w / w, about 55% w / w, about 50% w / w, or about 40% w / w. In certain embodiments, the polymer is present in the spray-dried dispersion at an amount of about 77.5% w / w.

[0359] In certain embodiments, the spray-dried dispersions described herein contain compound I in an amount of about 20% w / w to about 60% w / w and HPMC-AS MG polymer in an amount of about 80% w / w to about 40% w / w.

[0360] In certain embodiments, the spray-dried dispersion described herein contains compound I in an amount of about 20% w / w and HPMC-AS MG polymer in an amount of about 80% w / w. In certain embodiments, the spray-dried dispersion described herein contains compound I in an amount of about 30% w / w and HPMC-AS MG polymer in an amount of about 70% w / w. In certain embodiments, the spray-dried dispersion described herein contains compound I in an amount of about 40% w / w and HPMC-AS MG polymer in an amount of about 60% w / w.

[0361] In certain embodiments, the spray-dried dispersions disclosed herein further comprise one or more surfactants. In certain embodiments, the surfactant is vitamin E polyethylene glycol succinate (TPGS). In certain embodiments, the surfactant is sodium dodecyl sulfate (SDS). In certain embodiments, the surfactant is polysorbate 80 (Tween 80). In certain embodiments, the surfactant is present in amounts from about 0.5% w / w to about 20% w / w. In certain embodiments, the surfactant is present in amounts from about 2.5% w / w to about 10% w / w. In certain embodiments, the surfactant is present in amounts from about 2.5% w / w, about 5% w / w, or about 10% w / w.

[0362] In certain embodiments, the spray-dried dispersion described herein comprises compound I in an amount of about 40% w / w, HPMC-AS MF polymer in an amount of about 50% w / w, and TPGS in an amount of about 10% w / w.

[0363] In certain embodiments, the spray-dried dispersion described herein comprises compound I in an amount of about 40% w / w, HPC (Klucel LF) polymer in an amount of about 55% w / w, and SDS in an amount of about 5% w / w.

[0364] In certain embodiments, the spray-dried dispersion described herein comprises compound I in an amount of about 40% w / w, HPMC-AS MF polymer in an amount of about 55% w / w, and SDS in an amount of about 5% w / w.

[0365] In certain embodiments, the spray-dried dispersion described herein contains compound I in an amount of about 20% w / w, HPMC-AS MF polymer in an amount of about 77.5% w / w, and SDS in an amount of about 2.5% w / w.

[0366] In certain embodiments, the formulation is produced by a spray-drying process involving a solvent selected from water, acetone, methanol, dichloromethane, and any combination thereof.

[0367] In certain embodiments, the solvent includes acetone.

[0368] In certain embodiments, the solvent comprises acetone and water. In certain embodiments, the solvent comprises 99% acetone and 1% water. In certain embodiments, the solvent comprises 98.2% acetone and 1.8% water.

[0369] In certain embodiments, the solvent comprises acetone and dichloromethane. In certain embodiments, the solvent comprises 30% acetone and 70% dichloromethane. In certain embodiments, the solvent comprises 40% acetone and 60% dichloromethane.

[0370] In certain embodiments, the solvent includes methanol.

[0371] In certain embodiments, the solvent comprises methanol and dichloromethane. In certain embodiments, the solvent comprises methanol in an amount of 50% and dichloromethane in an amount of 50%.

[0372] This specification also provides a process for preparing a spray-dried dispersion.

[0373] In certain embodiments, the spray-dried dispersions described herein have a drug assay of higher than 90%. In certain embodiments, the formulations have a drug assay of higher than 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%. The “drug assay” or “API assay” may be measured by methods of the United States Pharmacopeia (USP). In some embodiments, the drug assay is measured by chromatograms of the test sample and standard samples provided from UPLC or HPLC.

[0374] In certain embodiments, the spray-dried dispersions described herein have a drug assay of higher than 90% after storage for one week at 25°C and 60% relative humidity (RH). In certain embodiments, the formulations have a drug assay of higher than 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% after storage for one week at 25°C and 60% RH.

[0375] In certain embodiments, the spray-dried dispersions described herein have a drug assay of higher than 90% after storage for one week at 25°C and 60% relative humidity (RH). In certain embodiments, the formulations have a drug assay of higher than 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% after storage for one week at 40°C and 75% RH.

[0376] In certain embodiments, the spray-dried dispersion of compound I is formulated as a tablet.

[0377] In certain embodiments, the above-described pharmaceutical composition of tablets contains compound I in amounts ranging from about 5 mg to about 1000 mg. In certain embodiments, the above-described pharmaceutical composition of tablets contains compound I in amounts ranging from about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, or about 200 mg.

[0378] In certain embodiments, the pharmaceutical composition of the tablet described above comprises compound I, a polymer used in the spray-dried dispersion, and a binder, disintegrant, lubricant, coating agent, or a combination thereof.

[0379] In certain embodiments, the pharmaceutical composition of the tablets described above comprises compound I, a polymer used in the spray-dried dispersion, microcrystalline cellulose PH-101, mannitol, croscarmellose sodium, colloidal silica dioxide, magnesium stearate, microcrystalline cellulose PH-102, poloxamer 188, and a coating material.

[0380] In certain embodiments, the pharmaceutical composition of the tablets described above comprises compound I, HPMC-AS polymer, microcrystalline cellulose PH-101, mannitol, croscarmellose sodium, colloidal silica dioxide, magnesium stearate, microcrystalline cellulose PH-102, poloxamer 188, and a coating material.

[0381] In certain embodiments, the pharmaceutical composition of the tablets described above comprises compound I, HPMC-AS MG polymer, microcrystalline cellulose PH-101, mannitol, croscarmellose sodium, colloidal silica dioxide, magnesium stearate, microcrystalline cellulose PH-102, poloxamer 188, and a coating material.

[0382] In a particular embodiment, the pharmaceutical composition of the tablet described above comprises compound I in an amount between about 10% w / w and 30% w / w, HPMC-AS MG polymer in an amount between about 30% w / w and 50% w / w, microcrystalline cellulose PH-101 in an amount between about 10% w / w and 25% w / w, mannitol in an amount between about 5% w / w and 15% w / w, croscarmellose sodium in an amount between about 1% w / w and 10% w / w, colloidal silica dioxide in an amount between about 0.1% w / w and 1% w / w, magnesium stearate in an amount between about 0.1% w / w and 1% w / w, microcrystalline cellulose PH-102 in an amount between about 5% w / w and 15% w / w, and poloxamer 188 in an amount between about 0% w / w and 5% w / w.

[0383] In a particular embodiment, the pharmaceutical composition of the tablet described above comprises compound I in an amount between about 10% w / w and 30% w / w, HPMC-AS MG polymer in an amount between about 30% w / w and 50% w / w, microcrystalline cellulose PH-101 in an amount between about 10% w / w and 25% w / w, mannitol in an amount between about 5% w / w and 15% w / w, croscarmellose sodium in an amount between about 1% w / w and 10% w / w, colloidal silica dioxide in an amount between about 0.1% w / w and 1% w / w, magnesium stearate in an amount between about 0.1% w / w and 1% w / w, microcrystalline cellulose PH-102 in an amount between about 5% w / w and 15% w / w, and poloxamer 188 in an amount between about 0% w / w and 5% w / w. The above-mentioned pharmaceutical composition of the tablets also contains an additional coating material in an amount between approximately 1% w / w and 5% w / w.

[0384] In certain embodiments, the pharmaceutical composition of the tablet described above includes an intragranular portion and an extragranular portion.

[0385] In a particular embodiment, the pharmaceutical composition of the tablet described above contains compound I in an amount of about 12% w / w, HPMC-AS MG polymer in an amount of about 48% w / w, microcrystalline cellulose PH-101 in an amount of about 12.4% w / w, mannitol in an amount of about 10% w / w, croscarmellose sodium in an amount of about 2% w / w, colloidal silica dioxide in an amount of about 0.5% w / w, magnesium stearate in an amount of about 0.25% w / w, microcrystalline cellulose PH-102 in an amount of about 9.4% w / w, and poloxamer 188 in an amount of about 3.0% w / w.

[0386] In a particular embodiment, the pharmaceutical composition of the tablet described above contains compound I in an amount of about 18% w / w, HPMC-AS MG polymer in an amount of about 42% w / w, microcrystalline cellulose PH-101 in an amount of about 11.4% w / w, mannitol in an amount of about 10% w / w, croscarmellose sodium in an amount of about 3% w / w, colloidal silica dioxide in an amount of about 0.5% w / w, magnesium stearate in an amount of about 0.25% w / w, microcrystalline cellulose PH-102 in an amount of about 9.4% w / w, and poloxamer 188 in an amount of about 3.0% w / w.

[0387] In a particular embodiment, the pharmaceutical composition of the tablet described above contains compound I in an amount of about 24% w / w, HPMC-AS MG polymer in an amount of about 36% w / w, microcrystalline cellulose PH-101 in an amount of about 11.4% w / w, mannitol in an amount of about 10% w / w, croscarmellose sodium in an amount of about 3% w / w, colloidal silica dioxide in an amount of about 0.5% w / w, magnesium stearate in an amount of about 0.25% w / w, microcrystalline cellulose PH-102 in an amount of about 9.4% w / w, and poloxamer 188 in an amount of about 3.0% w / w.

[0388] In a particular embodiment, the pharmaceutical composition of the tablet described above contains compound I in an amount of about 12% w / w, HPMC-AS MG polymer in an amount of about 48% w / w, microcrystalline cellulose PH-101 in an amount of about 12.4% w / w, mannitol in an amount of about 10% w / w, croscarmellose sodium in an amount of about 2% w / w, colloidal silica dioxide in an amount of about 0.5% w / w, magnesium stearate in an amount of about 0.25% w / w, microcrystalline cellulose PH-102 in an amount of about 9.4% w / w, and poloxamer 188 in an amount of about 3.0% w / w. The pharmaceutical composition of the tablet also contains an additional coating material in an amount of about 2.0% w / w.

[0389] In a particular embodiment, the pharmaceutical composition of the tablet described above contains compound I in an amount of about 18% w / w, HPMC-AS MG polymer in an amount of about 42% w / w, microcrystalline cellulose PH-101 in an amount of about 11.4% w / w, mannitol in an amount of about 10% w / w, croscarmellose sodium in an amount of about 3% w / w, colloidal silica dioxide in an amount of about 0.5% w / w, magnesium stearate in an amount of about 0.25% w / w, microcrystalline cellulose PH-102 in an amount of about 9.4% w / w, and poloxamer 188 in an amount of about 3.0% w / w. The pharmaceutical composition of the tablet also contains an additional coating material in an amount of about 2.0% w / w.

[0390] In a particular embodiment, the pharmaceutical composition of the tablet described above contains compound I in an amount of about 24% w / w, HPMC-AS MG polymer in an amount of about 36% w / w, microcrystalline cellulose PH-101 in an amount of about 11.4% w / w, mannitol in an amount of about 10% w / w, croscarmellose sodium in an amount of about 3% w / w, colloidal silica dioxide in an amount of about 0.5% w / w, magnesium stearate in an amount of about 0.25% w / w, microcrystalline cellulose PH-102 in an amount of about 9.4% w / w, and poloxamer 188 in an amount of about 3.0% w / w. The pharmaceutical composition of the tablet also contains an additional coating material in an amount of about 2.0% w / w.

[0391] In certain embodiments, the coating material is Opadry(R). In certain embodiments, the coating material is 03K620011-CN Yellow.

[0392] This specification further provides a process for producing spray-dried dispersions of tablets.

[0393] Pharmaceutical composition

[0394] In one embodiment, the disclosure also provides a pharmaceutical composition comprising one or more crystalline polymorphs as described above, and a pharmaceutically acceptable carrier.

[0395] A pharmaceutically acceptable carrier is a conventional drug carrier in the art and can be prepared by methods well known in the pharmaceutical technology. In some embodiments, the compounds of this disclosure may be mixed with a pharmaceutically acceptable carrier to prepare a pharmaceutical composition.

[0396] Some examples of materials that can function as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) propylene Examples of suitable non-toxic substances used in pharmaceutical formulations include glycols such as ethylene glycol, (11) polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol, (12) esters such as ethyl oleate and ethyl laurate, (13) agar, (14) buffering agents such as magnesium hydroxide and aluminum hydroxide, (15) alginic acid, (16) water free of pyrogens, (17) isotonic saline, (18) Ringer's solution, (19) alcohols such as ethyl alcohol and propane alcohol, (20) phosphate buffer, and (21) acetone.

[0397] The pharmaceutical composition may contain, as necessary, pharmaceutically acceptable auxiliary substances such as pH adjusters, buffers, and toxicity modifiers, including sodium acetate, sodium chloride, potassium chloride, calcium chloride, and sodium lactate, in order to approximate physiological conditions.

[0398] The form of a pharmaceutical composition depends on several criteria, including but not limited to the route of administration, the severity of the disease, or the dose administered.

[0399] Pharmaceutical compositions may be formulated for oral, nasal, rectal, transdermal, intravenous, or intramuscular administration. Depending on the desired route of administration, pharmaceutical compositions may be formulated in the form of tablets, capsules, pills, sugar-coated tablets, powders, granules, sachets, cachets, lozenges, suspensions, emulsions, solutions, syrups, aerosols (solid or liquid medium), sprays, ointments, pastes, creams, lotions, gels, patches, inhalants, or suppositories.

[0400] Pharmaceutical compositions can be formulated to release the active ingredient rapidly, slowly, or with a delay after administration to a patient by using procedures known in the art. In some embodiments, pharmaceutical compositions are formulated in a sustained-release form. In some embodiments, a sustained-release period may be about 1 to 24 hours, 2 to 12 hours, 3 to 8 hours, 4 to 6 hours, 1 to 2 days, or longer. In certain embodiments, a sustained-release period is at least about 4 hours, at least about 8 hours, at least about 12 hours, or at least about 24 hours. Pharmaceutical compositions can be formulated in the form of tablets. For example, the release rate of the activator can be controlled not only by the activator dissolving in gastrointestinal fluid independently of pH and then diffusing from the tablet or pill, but also by physical processes such as tablet disintegration and erosion. In some embodiments, polymer materials disclosed in "Medical Applications of Controlled Release" Langer and Wise (eds.), CRC Pres., Boca Raton, Florida (1974), "Controlled Drug Bioavailability" Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984), Ranger and Peppas, 1983, J Macromol. Sci. Rev. Macromol Chem. 23:61, and Levy et al., 1985, Science 228:190, During et al., 1989, Ann. Neurol. 25:351, and Howard et al., 1989, J. Neurosurg. 71:105 may be used for controlled release. The full texts of the above references are incorporated herein by reference.

[0401] In certain embodiments, the pharmaceutical composition may contain approximately 0.0001 mg to approximately 5000 mg (for example, approximately 0.0001 mg to approximately 10 mg, approximately 0.001 mg to approximately 10 mg, approximately 0.01 mg to approximately 10 mg, approximately 0.1 mg to approximately 10 mg, approximately 1 mg to approximately 10 mg, approximately 5 mg to approximately 10 mg, approximately 5 mg to approximately 20 mg, approximately 5 mg to approximately 30 mg, approximately 5 mg to approximately 40 mg, approximately 5 mg to approximately 50 mg, approximately 10 mg to approximately 100 mg, approximately 20 mg to approximately 100 mg, approximately 30 mg to approximately 100 mg, approximately 40 mg to approximately 100 mg, approximately 50 mg to approximately 100 mg, approximately 50 mg to approximately 200 mg, approximately 50 mg to approximately 300 mg, approximately 50 mg to approximately 400 mg) g, including the compounds of this disclosure in amounts of approximately 50 mg to 500 mg, approximately 100 mg to 200 mg, approximately 100 mg to 300 mg, approximately 100 mg to 400 mg, approximately 100 mg to 500 mg, approximately 200 mg to 500 mg, approximately 300 mg to 500 mg, approximately 400 mg to 500 mg, approximately 500 mg to 1000 mg, approximately 600 mg to 1000 mg, approximately 700 mg to 1000 mg, approximately 800 mg to 1000 mg, approximately 900 mg to 1000 mg, approximately 1000 mg to 2000 mg, approximately 2000 mg to 3000 mg, approximately 3000 mg to 4000 mg, or approximately 4000 mg to 5000 mg. An appropriate daily dose per subject may range from approximately 5 mg to approximately 500 mg, preferably from approximately 5 mg to approximately 50 mg, from approximately 50 mg to approximately 100 mg, or from approximately 50 mg to approximately 500 mg.

[0402] In certain embodiments, the pharmaceutical composition may be formulated in unit dosage forms, with each dose being approximately 0.0001 mg to 10 mg, approximately 0.001 mg to 10 mg, approximately 0.01 mg to 10 mg, approximately 0.1 mg to 10 mg, approximately 1 mg to 10 mg, approximately 5 mg to 10 mg, approximately 5 mg to 20 mg, approximately 5 mg to 30 mg, approximately 5 mg to 40 mg, approximately 5 mg to 50 mg, approximately 10 mg to 100 mg, approximately 20 mg to 100 mg, approximately 30 mg to 100 mg, approximately 40 mg to 100 mg, approximately 50 mg to 100 mg, approximately 50 mg to 200 mg, approximately 50 mg to 300 mg, approximately 50 mg to 400 mg, and approximately The compounds contained herein range from 50 mg to approximately 500 mg, approximately 100 mg to approximately 200 mg, approximately 100 mg to approximately 300 mg, approximately 100 mg to approximately 400 mg, approximately 100 mg to approximately 500 mg, approximately 200 mg to approximately 500 mg, approximately 300 mg to approximately 500 mg, approximately 400 mg to approximately 500 mg, approximately 500 mg to approximately 1000 mg, approximately 600 mg to approximately 1000 mg, approximately 700 mg to approximately 1000 mg, approximately 800 mg to approximately 1000 mg, approximately 900 mg to approximately 1000 mg, approximately 1000 mg to approximately 2000 mg, approximately 2000 mg to approximately 3000 mg, approximately 3000 mg to approximately 4000 mg, or approximately 4000 mg to approximately 5000 mg. The term "unit dosage form" refers to a physically distinct unit appropriate as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect in conjunction with an appropriate drug carrier.

[0403] The term "unit dosage form" refers to a physically distinct unit appropriate as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of active substance calculated to produce the desired therapeutic effect in conjunction with an appropriate drug carrier.

[0404] Use and methods for treatment

[0405] This disclosure provides a method for treating diseases associated with ErbB (e.g., HER2), the method comprising administering to a subject a therapeutically effective amount of one or more compounds, their pharmaceutically acceptable salts, esters, hydrates, solvates or stereoisomers, or the pharmaceutical compositions of this disclosure.

[0406] As used herein, the term “ErbB-associated disease” means a disease whose onset, progression, or both are associated with the genomic modification, expression, overexpression, or activity of ErbB. Examples include, but are not limited to, immune-associated disorders, proliferative disorders, cancer, and other diseases.

[0407] As used herein, the term “HER2-associated disease” means a disease or disorder whose onset, progression, or both are, as may be, associated with HER2 genomic modification, expression, overexpression, or activity. Examples include, but are not limited to, immune-associated disorders, proliferative disorders, cancer, and other diseases.

[0408] In some embodiments, the disease associated with ErbB is cancer, preferably ErbB-expressing cancer or ErbB-overexpressing cancer. "ErbB-expressing cancer" involves cancer cells or tumor cells in which ErbB proteins, such as HER2, are present on the cell surface. "ErbB-overexpressing cancer" is characterized by significantly higher levels of ErbB proteins, such as HER2, on the cell surface of cancer cells or tumor cells compared to non-cancerous cells of the same tissue type. Such overexpression may be caused by increased gene amplification, transcription, or translation. Expression or overexpression of the ErbB receptor may be determined in diagnostic or prognostic assays by assessing the increased level of ErbB protein present on the cell surface (e.g., via immunohistochemistry assays (IHC)). Alternatively or additionally, the level of intracellular ErbB-encoding nucleic acid may be measured by, for example, fluorescence insight hybridization (FISH, see WO98 / 45479 published October 1998), Southern blotting, or polymerase chain reaction (PCR) techniques such as real-time quantitative PCR (RT-PCR) method 132:73-80 (1990). In addition to the assays described above, a variety of in vivo assays are available to a skilled physician. For example, cells in a patient's body may be exposed to an antibody labeled with a selectively detectable label (e.g., a radioisotope), and the binding of the antibody to cells in the patient may be assessed, for example, by external radioactivity scanning or by analyzing a biopsy taken from a patient previously exposed to the antibody.

[0409] In particular, cancers include, but are not limited to, leukemia, glioblastoma, melanoma, chondrosarcoma, cholangiocarcinoma, osteosarcoma, lymphoma, lung cancer, adenoma, myeloma, hepatocellular carcinoma, adrenocortical carcinoma, pancreatic cancer, breast cancer, bladder cancer, prostate cancer, liver cancer, stomach cancer, colon cancer, colorectal cancer, ovarian cancer, cervical cancer, brain cancer, esophageal cancer, bone cancer, testicular cancer, skin cancer, kidney cancer, mesothelioma, neuroblastoma, thyroid cancer, head and neck cancer, esophageal cancer, eye cancer, prostate cancer, nasopharyngeal cancer, or oral cancer. In some embodiments, the cancer is lung cancer, breast cancer, ovarian cancer, bladder cancer, or glioblastoma. In some embodiments, the cancer is breast cancer, stomach cancer, colorectal cancer, pancreatic cancer, prostate cancer, bladder cancer, ovarian cancer, or lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, adenocarcinoma, squamous cell carcinoma, and large cell lung cancer). In some embodiments, the disease associated with ErbB (e.g., HER2) is cancer that has metastasized to the central nervous system (CNS), particularly cancer with brain and leptomeningeal metastases.

[0410] As used herein, the terms “treatment” and “to treat” mean, as described herein, reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder, or one or more of its symptoms. In some embodiments, treatment may be performed after the progression of one or more symptoms. In other embodiments, treatment may be performed when there are no symptoms. For example, treatment may be performed before the onset of symptoms in a susceptible individual (for example, taking into account a history of symptoms and / or genetic or other susceptibility factors). Treatment may be continued after the disappearance of symptoms, for example, to prevent or delay relapse.

[0411] The therapeutically effective dose of the compounds provided herein depends on various factors known in the art, such as body weight, age, medical history, current medications, the subject's health status, cross-reactivity, allergies, sensitivity, potential side effects, as well as the route of administration and the extent of disease progression. The dose may be proportionally reduced or increased by a person skilled in the art (e.g., a physician or veterinarian) as indicated by these and other circumstances or requirements.

[0412] As used herein, the terms “subject” and “individual” are used interchangeably and refer to warm-blooded animals, including humans or any non-human animals (e.g., mice, rats, rabbits, dogs, cats, cattle, pigs, sheep, horses, or primates). Humans include prenatal and postnatal forms. In some embodiments, the subject is human. The subject may be suspected of having a disease associated with ErbB (e.g., HER2), but may or may not exhibit symptoms of the disease.

[0413] In some embodiments, one or more compounds provided herein, their pharmaceutically acceptable salts, esters, hydrates, solvates, or stereoisomers, or pharmaceutical compositions are administered via extra-intestinal or non-extra-intestinal routes. In some embodiments, one or more compounds, their pharmaceutically acceptable salts, hydrates, solvates, or stereoisomers, or pharmaceutical compositions are administered orally, enterally, buccally, nasally, intranasally, transmucosa, epidermis, transdermally, skin, ophthalmologically, pulmonaryly, sublingually, rectally, vaginally, topically, subcutaneously, intravenously, intramuscularly, intraarterially, intrathecally, intra-articularly, intraorbitally, intracardiacly, intradermally, intraperitoneally, transtracheally, subcutaneously, intra-articularly, sub-articularly, subarachnoidally, intraspinally, or intrasternally.

[0414] The compounds provided herein may be administered in their pure form, in combination with other active ingredients, or in the form of the pharmaceutical compositions of this disclosure. In some embodiments, the compounds provided herein may be administered concurrently or sequentially to the subject in question in combination with one or more anticancer agents known in the art. In some embodiments, administration may be performed once daily, twice daily, three times daily, or once every two days, once every three days, once every four days, once every five days, once every six days, or once a week.

[0415] In some embodiments, one or more compounds provided herein, their pharmaceutically acceptable salts, esters, hydrates, solvates, or stereoisomers, or pharmaceutical compositions are administered orally. For oral administration, any dose that achieves the desired target is appropriate. In some embodiments, appropriate daily doses are approximately 0.001 to 5000 mg, 0.1 mg to 5 g, 5 mg to 1 g, or 10 mg to 500 mg, and administration is carried out once daily, twice daily, three times daily, daily, or 3 to 5 days per week. In some embodiments, doses of one or more compounds provided herein, their pharmaceutically acceptable salts, esters, hydrates, solvates, or stereoisomers, or pharmaceutical compositions are approximately 0.0001 mg, 0.001 mg, 0.01 mg, 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 200 mg, 250 mg, 500 mg, 750 mg, 1000 mg, 2000 mg, 3000 mg, 4000 mg, or up to approximately 5000 mg per day.

[0416] In some embodiments, one or more compounds provided herein, their pharmaceutically acceptable salts, esters, hydrates, solvates, or stereoisomers, or pharmaceutical compositions can cross the blood-brain barrier (BBB) ​​of a subject after administration.

[0417] In some embodiments, the present disclosure provides the use of the compounds of the present disclosure, their pharmaceutically acceptable salts, esters, hydrates, solvates, or stereoisomers, or pharmaceutical compositions in the manufacture of pharmaceuticals for the treatment of diseases associated with ErbB (e.g., HER2).

[0418] The compounds and their pharmaceutical compositions described herein may be used both in vivo and in vitro to inhibit ErbB (expression or activity), particularly HER2 (expression or activity). In some embodiments, the compounds and their pharmaceutical compositions described herein may be used in non-diagnostic, non-therapeutic methods (e.g., for research purposes) to inhibit ErbB (expression or activity), particularly HER2 (expression or activity).

[0419] The compounds and pharmaceutical compositions described herein may be used to prevent or treat the onset or progression of any of the diseases associated with ErbB (e.g., HER2) in warm-blooded animals, particularly humans.

[0420] This disclosure also includes the following embodiments.

[0421] Embodiment 1 A crystalline form of compound I or a pharmaceutically acceptable salt of compound I, wherein compound I is (S)-N-(4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidine-4-yl)oxy)-7-methoxyquinazoline-4-amine.

[0422] Embodiment 2: The crystalline form described in Embodiment 1, which is form A of compound I.

[0423] Embodiment 3: The crystal morphology according to Embodiment 2, having an X-ray powder diffraction (XRPD) pattern that includes peaks at diffraction angle (2θ) values ​​of 7.09±0.20°, 15.15±0.20°, and 21.55±0.20°.

[0424] Embodiment 4: The crystal morphology according to Embodiment 3, having an XRPD pattern further comprising at least one or two peaks at 2θ selected from 11.92±0.20° and 23.93±0.20°.

[0425] Embodiment 5: The crystal morphology according to Embodiment 2, having an XRPD pattern with peaks at 2θ of 7.09±0.20°, 11.92±0.20°, 15.15±0.20°, 21.55±0.20°, and 23.93±0.20°.

[0426] Embodiment 6: The crystal morphology according to Embodiment 5, having an XRPD pattern further comprising at least one or two peaks at 2θ selected from 6.45±0.20° and 17.85±0.20°.

[0427] Embodiment 7: The crystal morphology according to Embodiment 2, having an XRPD pattern with peaks at 2θ of 6.45±0.20°, 7.09±0.20°, 11.92±0.20°, 15.15±0.20°, 17.85±0.20°, 21.55±0.20°, and 23.93±0.20°.

[0428] Embodiment 8: The crystal morphology according to Embodiment 7, having an XRPD pattern further comprising at least one, two, or three peaks at 2θ selected from 14.19±0.20°, 18.94±0.20°, and 26.86±0.20°.

[0429] Embodiment 9: The crystal morphology according to Embodiment 2, having an XRPD pattern with peaks at 2θ of 6.45±0.20°, 7.09±0.20°, 11.92±0.20°, 14.19±0.20°, 15.15±0.20°, 17.85±0.20°, 18.94±0.20°, 21.55±0.20°, 23.93±0.20° and 26.86±0.20°.

[0430] Embodiment 10: The crystal morphology according to Embodiment 9, having an XRPD pattern further comprising at least one, two, three or more peaks at 2θ selected from 10.75±0.20°, 11.32±0.20°, 12.88±0.20°, 20.79±0.20°, and 25.69±0.20°.

[0431] Embodiment 11: The crystal morphology according to Embodiment 2, having an XRPD pattern with peaks at 2θ of 6.45±0.20°, 7.09±0.20°, 10.75±0.20°, 11.32±0.20°, 11.92±0.20°, 12.88±0.20°, 14.19±0.20°, 15.15±0.20°, 17.85±0.20°, 18.94±0.20°, 20.79±0.20°, 21.55±0.20°, 23.93±0.20°, 25.69±0.20° and 26.86±0.20°.

[0432] Embodiment 12: The crystal morphology according to Embodiment 2, having an XRPD pattern substantially similar to that shown in Table 7.

[0433] Embodiment 13: The crystal morphology according to Embodiment 2, having an XRPD pattern substantially similar to that shown in Figure 11.

[0434] Embodiment 14: The crystalline form according to Embodiment 3, having a TGA thermogram showing a weight loss of approximately 0.02% when heated from approximately 30°C to approximately 120°C.

[0435] Embodiment 15: The crystalline morphology according to Embodiment 3, having a TGA thermogram substantially similar to that shown in Figure 12.

[0436] Embodiment 16: The crystal morphology according to Embodiment 3, having a DSC thermogram that includes endothermic activity starting at approximately 199.5°C and having a peak at approximately 201.5°C.

[0437] Embodiment 17: The crystal morphology according to Embodiment 3, having a DSC thermogram substantially similar to that shown in Figure 13.

[0438] Embodiment 18: The crystalline morphology according to Embodiment 3, having a DVS water vapor adsorption plot substantially similar to that shown in Figure 14.

[0439] Embodiment 19: The crystalline form described in Embodiment 1, which is form B of compound I.

[0440] Embodiment 20: The crystal morphology according to Embodiment 19, having an XRPD pattern with peaks at 2θ of 7.42±0.20°, 13.21±0.20°, and 19.24±0.20°.

[0441] Embodiment 21 The crystal morphology according to Embodiment 20, having an XRPD pattern further comprising at least one or two peaks at 2θ selected from 6.62±0.20° and 7.17±0.20°.

[0442] Embodiment 22: The crystal morphology according to Embodiment 19, having an XRPD pattern with peaks at 2θ of 6.62±0.20°, 7.17±0.20°, 7.42±0.20°, 13.21±0.20°, and 19.24±0.20°.

[0443] Embodiment 23: The crystal morphology according to Embodiment 22, having an XRPD pattern further comprising at least one or two peaks at 2θ selected from 14.25±0.20° and 17.94±0.20°.

[0444] Embodiment 24: The crystal morphology according to Embodiment 19, having an XRPD pattern with peaks at 2θ of 6.62±0.20°, 7.17±0.20°, 7.42±0.20°, 13.21±0.20°, 14.25±0.20°, 17.94±0.20° and 19.24±0.20°.

[0445] Embodiment 25 The crystal morphology according to Embodiment 24, having an XRPD pattern further comprising at least one, two, or three peaks at 2θ selected from 11.61±0.20°, 16.89±0.20°, and 21.89±0.20°.

[0446] Embodiment 26: The crystal morphology according to Embodiment 19, having an XRPD pattern with peaks at 2θ of 6.62±0.20°, 7.17±0.20°, 7.42±0.20°, 11.61±0.20°, 13.21±0.20°, 14.25±0.20°, 16.89±0.20°, 17.94±0.20°, 19.24±0.20° and 21.89±0.20°.

[0447] Embodiment 27 The crystal morphology according to Embodiment 26, having an XRPD pattern further comprising at least one, two, three or more peaks at 2θ selected from 13.92±0.20°, 17.24±0.20°, 27.21±0.20°, 27.35±0.20° and 27.87±0.20°.

[0448] Embodiment 28: The crystal morphology according to Embodiment 19, having an XRPD pattern with peaks at 2θ of 6.62±0.20°, 7.17±0.20°, 7.42±0.20°, 11.61±0.20°, 13.21±0.20°, 13.92±0.20°, 14.25±0.20°, 16.89±0.20°, 17.24±0.20°, 17.94±0.20°, 19.24±0.20°, 21.89±0.20°, 27.21±0.20°, 27.35±0.20° and 27.87±0.20°.

[0449] Embodiment 29: The crystal morphology according to Embodiment 19, having an XRPD pattern substantially similar to that shown in Table 8.

[0450] Embodiment 30: The crystal morphology according to Embodiment 19, having substantially the same XRPD pattern as that shown in Figure 15.

[0451] Embodiment 31: The crystalline form according to Embodiment 20, having a TGA thermogram showing a weight loss of approximately 1.68% when heated from approximately 30°C to approximately 100°C.

[0452] Embodiment 32 The crystalline morphology according to Embodiment 20, having a DSC thermogram that includes three endothermic phases, each starting at approximately 116.3°C and having a peak at approximately 125.4°C, starting at approximately 182.4°C and having a peak at approximately 187.5°C, and starting at approximately 199.2°C and having a peak at approximately 200.3°C.

[0453] Embodiment 33: The crystalline morphology according to Embodiment 20, having TGA and DSC thermograms substantially similar to those shown in Figure 16.

[0454] Embodiment 34: The crystalline form described in Embodiment 1, which is form C of compound I.

[0455] Embodiment 35: The crystal morphology according to Embodiment 34, having an XRPD pattern with peaks at 2θ of 5.95±0.20°, 8.58±0.20°, and 19.56±0.20°.

[0456] Embodiment 36 The crystal morphology according to Embodiment 35, having an XRPD pattern further comprising at least one or two peaks at 2θ selected from 11.89±0.20° and 13.75±0.20°.

[0457] Embodiment 37: The crystal morphology according to Embodiment 34, having an XRPD pattern with peaks at 2θ of 5.95±0.20°, 8.58±0.20°, 11.89±0.20°, 13.75±0.20°, and 19.56±0.20°.

[0458] Embodiment 38 The crystal morphology according to Embodiment 37, having an XRPD pattern further comprising at least one or two peaks at 2θ selected from 12.39±0.20° and 13.40±0.20°.

[0459] Embodiment 39: The crystal morphology according to Embodiment 34, having an XRPD pattern with peaks at 2θ of 5.95±0.20°, 8.58±0.20°, 11.89±0.20°, 12.39±0.20°, 13.40±0.20°, 13.75±0.20° and 19.56±0.20°.

[0460] Embodiment 40 The crystal morphology according to Embodiment 39, having an XRPD pattern further comprising at least one, two, or three peaks at 2θ selected from 17.23±0.20°, 18.91±0.20°, and 23.51±0.20°.

[0461] Embodiment 41: The crystal morphology according to Embodiment 34, having an XRPD pattern that includes peaks at 2θ of 5.95±0.20°, 8.58±0.20°, 11.89±0.20°, 12.39±0.20°, 13.40±0.20°, 13.75±0.20°, 17.23±0.20°, 18.91±0.20°, 19.56±0.20° and 23.51±0.20°.

[0462] Embodiment 42 The crystal morphology according to Embodiment 41, having an XRPD pattern further comprising at least one, two, three or more peaks at 2θ selected from 15.54±0.20°, 15.90±0.20°, 24.91±0.20°, 25.29±0.20° and 25.55±0.20°.

[0463] Embodiment 43: The crystal morphology according to Embodiment 34, having an XRPD pattern with peaks at 2θ of 5.95±0.20°, 8.58±0.20°, 11.89±0.20°, 12.39±0.20°, 13.40±0.20°, 13.75±0.20°, 15.54±0.20°, 15.90±0.20°, 17.23±0.20°, 18.91±0.20°, 19.56±0.20°, 23.51±0.20°, 24.91±0.20°, 25.29±0.20° and 25.55±0.20°.

[0464] Embodiment 44: The crystal morphology according to Embodiment 34, having an XRPD pattern substantially similar to that shown in Table 9.

[0465] Embodiment 45: The crystal morphology according to Embodiment 34, having an XRPD pattern substantially similar to that shown in Figure 17.

[0466] Embodiment 46: The crystal morphology according to Embodiment 35, having a TGA thermogram showing a weight loss of approximately 0.5-1% when heated from approximately 30°C to approximately 180°C.

[0467] Embodiment 47: The crystal morphology according to Embodiment 35, having a DSC thermogram that includes endothermic activity starting at approximately 193.8°C and having a peak at approximately 194.6°C.

[0468] Embodiment 48: The crystalline morphology according to Embodiment 35, having TGA and DSC thermograms substantially similar to those shown in Figure 18.

[0469] Embodiment 49 The crystalline form described in Embodiment 1, which is form D of compound I.

[0470] Embodiment 50: The crystal morphology according to Embodiment 49, having an XRPD pattern with peaks at 2θ of 6.85±0.20°, 14.81±0.20°, and 21.38±0.20°.

[0471] Embodiment 51 The crystal morphology according to Embodiment 50, having an XRPD pattern further comprising at least one or two peaks at 2θ selected from 13.71±0.20° and 17.69±0.20°.

[0472] Embodiment 52: The crystal morphology according to Embodiment 49, having an XRPD pattern with peaks at 2θ of 6.85±0.20°, 13.71±0.20°, 14.81±0.20°, 17.69±0.20°, and 21.38±0.20°.

[0473] Embodiment 53 The crystal morphology according to Embodiment 52, having an XRPD pattern further comprising at least one or two peaks at 2θ selected from 11.13±0.20° and 23.49±0.20°.

[0474] Embodiment 54: The crystal morphology according to Embodiment 49, having an XRPD pattern with peaks at 2θ of 6.85±0.20°, 11.13±0.20°, 13.71±0.20°, 14.81±0.20°, 17.69±0.20°, 21.38±0.20°, and 23.49±0.20°.

[0475] Embodiment 55 The crystal morphology according to Embodiment 54, having an XRPD pattern further comprising at least one, two, three or more peaks at 2θ selected from 13.07±0.20°, 15.08±0.20°, 18.37±0.20°, and 21.67±0.20°.

[0476] Embodiment 56: The crystal morphology according to Embodiment 49, having an XRPD pattern with peaks at 2θ of 6.85±0.20°, 11.13±0.20°, 13.07±0.20°, 13.71±0.20°, 14.81±0.20°, 15.08±0.20°, 17.69±0.20°, 18.37±0.20°, 21.38±0.20°, 21.67±0.20° and 23.49±0.20°.

[0477] Embodiment 57 The crystal morphology according to Embodiment 56, having an XRPD pattern further comprising at least one, two, three or more peaks at 2θ selected from 22.25±0.20°, 24.65±0.20°, 26.69±0.20°, and 28.60±0.20°.

[0478] Embodiment 58: The crystal morphology according to Embodiment 49, having an XRPD pattern with peaks at 2θ of 6.85±0.20°, 11.13±0.20°, 13.07±0.20°, 13.71±0.20°, 14.81±0.20°, 15.08±0.20°, 17.69±0.20°, 18.37±0.20°, 21.38±0.20°, 21.67±0.20°, 22.25±0.20°, 23.49±0.20°, 24.65±0.20°, 26.69±0.20° and 28.60±0.20°.

[0479] Embodiment 59: The crystal morphology according to Embodiment 49, having an XRPD pattern substantially similar to that shown in Table 10.

[0480] Embodiment 60: The crystal morphology according to Embodiment 49, having an XRPD pattern substantially similar to that shown in Figure 19.

[0481] Embodiment 61: The crystal morphology according to Embodiment 50, having a TGA thermogram showing a weight loss of approximately 0.5-0.8% when heated from approximately 30°C to approximately 100°C.

[0482] Embodiment 62 The crystalline morphology according to Embodiment 50, having a DSC thermogram that includes two endothermic phases, one starting at approximately 186.9°C and having a peak at approximately 190.5°C, and the other starting at approximately 199.5°C and having a peak at approximately 200.4°C.

[0483] Embodiment 63: The crystalline morphology according to Embodiment 50, having TGA and DSC thermograms substantially similar to those shown in Figure 20.

[0484] Embodiment 64 The crystalline form according to Embodiment 1, wherein the pharmaceutically acceptable salt of compound I is selected from the group consisting of hydrochloride, sulfate, phosphate, maleate, fumarate, oxalate, p-toluenesulfonate, succinate, L-(+)-tartrate, monoadipate, and hemiadipate.

[0485] Embodiment 65 A spray-dried dispersion (SDD) formulation comprising compound I and a polymer.

[0486] Embodiment 66 The formulation according to Embodiment 65, wherein the polymer is selected from the group consisting of HPMC-AS polymer, PVP-VA64 copolymer, Soluplus polymer, Eudragit E100 polymer, Eudragit L100-55 polymer, hydroxypropyl-β-cyclodextrin (HP-β-CD), PVP K30 LP polymer, HPC (hydroxypropyl cellulose, Klucel LF) polymer, HPC (Klucel MF) polymer, HPMC E5 LV polymer, HPMC E15 polymer, HPMCP-HP50 polymer, and any combination thereof.

[0487] Embodiment 67 The formulation according to Embodiment 65, wherein the polymer is an HPMC-AS polymer.

[0488] Embodiment 68 The formulation according to Embodiment 67, wherein the HPMC-AS polymer is selected from the group consisting of HPMC-AS MG polymer, HPMC-AS MF polymer, HPMC-AS LF polymer, and any combination thereof.

[0489] Embodiment 69 The formulation according to Embodiment 65, wherein the polymer is an HPC (Klucel LF) polymer.

[0490] Embodiment 70 A formulation according to any one of Embodiments 65 to 69, further comprising a surfactant.

[0491] Embodiment 71 The formulation according to Embodiment 70, wherein the surfactant is selected from the group consisting of vitamin E polyethylene glycol succinate (TPGS), sodium dodecyl sulfate (SDS), polysorbate 80 (Tween 80), and combinations thereof.

[0492] Embodiment 72 The formulation according to any one of Embodiments 65 to 71, wherein compound I is present in an amount of about 5% w / w to about 70% w / w.

[0493] Embodiment 73: The formulation according to any one of Embodiments 65 to 72, wherein compound I is present in an amount of about 20% w / w to about 60% w / w.

[0494] Embodiment 74 The formulation according to any one of Embodiments 65 to 73, wherein compound I is present in an amount of about 20% w / w, about 30% w / w, or about 40% w / w.

[0495] Embodiment 75: The formulation according to any one of Embodiments 65 to 74, wherein the polymer is present in an amount of about 95% w / w to about 30% w / w.

[0496] Embodiment 76: The formulation according to any one of Embodiments 65 to 75, wherein the polymer is present in an amount of about 80% w / w to about 40% w / w.

[0497] Embodiment 77 The formulation according to any one of Embodiments 65 to 76, wherein the polymer is present in an amount of about 80% w / w, about 77.5% w / w, about 70% w / w, about 60% w / w, about 55% w / w, about 50% w / w, or about 40% w / w.

[0498] Embodiment 78: The formulation according to any one of Embodiments 65 to 77, wherein the amount of surfactant is about 0.5% w / w to about 20% w / w.

[0499] Embodiment 79 The formulation according to any one of Embodiments 65 to 78, wherein the amount of surfactant is about 2.5% w / w to about 10% w / w.

[0500] Embodiment 80 The formulation according to any one of Embodiments 65 to 79, wherein the surfactant is present in an amount of about 2.5% w / w, about 5% w / w, or about 10% w / w.

[0501] Embodiment 81 The formulation according to any one of Embodiments 65 to 68 or 72 to 75, wherein the formulation comprises compound I in an amount of about 20% w / w and HPMC-AS MG polymer in an amount of about 80% w / w.

[0502] Embodiment 82 The formulation according to any one of Embodiments 65 to 68 or 72 to 75, wherein the formulation comprises compound I in an amount of about 30% w / w and HPMC-AS MG polymer in an amount of about 70% w / w.

[0503] Embodiment 83 The formulation according to any one of Embodiments 65 to 68 or 72 to 75, wherein the formulation comprises compound I in an amount of about 40% w / w and HPMC-AS MG polymer in an amount of about 60% w / w.

[0504] Embodiment 84 The formulation according to any one of Embodiments 65-68 or 70-80, wherein the formulation comprises compound I in an amount of about 40% w / w, HPMC-AS MF polymer in an amount of about 50% w / w, and TPGS in an amount of about 10% w / w.

[0505] Embodiment 85 The formulation according to any one of Embodiments 65, 66, or 69-80, wherein the formulation comprises compound I in an amount of about 40% w / w, HPC (Klucel LF) polymer in an amount of about 55% w / w, and SDS in an amount of about 5% w / w.

[0506] Embodiment 86 The formulation according to any one of Embodiments 65-68 or 70-80, wherein the formulation comprises compound I in an amount of about 40% w / w, HPMC-AS MF polymer in an amount of about 55% w / w, and SDS in an amount of about 5% w / w.

[0507] Embodiment 87 The formulation according to any one of Embodiments 65-68 or 70-80, wherein the formulation comprises compound I in an amount of about 20% w / w, HPMC-AS MF polymer in an amount of about 77.5% w / w, and SDS in an amount of about 2.5% w / w.

[0508] Embodiment 88 The formulation according to any one of Embodiments 65 to 87, wherein the formulation is produced by a spray-drying process and comprises a solvent selected from water, acetone, methanol, dichloromethane, and any combination thereof.

[0509] Embodiment 89 The formulation according to Embodiment 88, wherein the solvent comprises acetone.

[0510] Embodiment 90 The formulation according to Embodiment 88, wherein the solvent comprises acetone and water.

[0511] Embodiment 91 The formulation according to Embodiment 90, wherein the solvent contains acetone in an amount of about 99% and water in an amount of about 1%.

[0512] Embodiment 92 The formulation according to Embodiment 90, wherein the solvent comprises acetone in an amount of about 98.2% and water in an amount of about 1.8%.

[0513] Embodiment 93 The formulation according to Embodiment 88, wherein the solvent comprises acetone and dichloromethane.

[0514] Embodiment 94 The formulation according to Embodiment 93, wherein the solvent comprises about 30% acetone and about 70% dichloromethane.

[0515] Embodiment 95 The formulation according to Embodiment 88, wherein the solvent comprises methanol.

[0516] Embodiment 96 The formulation according to Embodiment 88, wherein the solvent comprises methanol and dichloromethane.

[0517] Embodiment 97 The formulation according to Embodiment 96, wherein the solvent comprises methanol in an amount of about 50% and dichloromethane in an amount of about 50%.

[0518] Embodiment 98 The formulation according to any one of Embodiments 65 to 97, wherein compound I in the formulation is amorphous.

[0519] Embodiment 99 The formulation according to Embodiment 81, wherein the formulation has an XRPD pattern substantially similar to that shown in Figure 68 or Figure 70.

[0520] Embodiment 100 The formulation according to Embodiment 81, wherein the formulation has an MDSC profile including a glass transition temperature (Tg) of approximately 107 ± 3°C.

[0521] Embodiment 101 The formulation according to Embodiment 81, wherein the formulation has a substantially similar MDSC profile to that shown in Figure 69, Figure 71, or Figure 73.

[0522] Embodiment 102 The formulation according to any one of Embodiments 81 to 83, wherein the formulation has an XRPD pattern substantially similar to that shown in Figure 72.

[0523] Embodiment 103 The formulation according to Embodiment 82, wherein the formulation has an MDSC profile including a glass transition temperature (Tg) of approximately 103.5°C.

[0524] Embodiment 104 The formulation according to Embodiment 82, wherein the formulation has substantially the same MDSC profile as that shown in Figure 74.

[0525] Embodiment 105 The formulation according to Embodiment 83, wherein the formulation has an MDSC profile including a glass transition temperature (Tg) of approximately 99.7°C.

[0526] Embodiment 106 The formulation according to Embodiment 83, wherein the formulation has substantially the same MDSC profile as that shown in Figure 75.

[0527] Embodiment 107 The formulation according to any one of Embodiments 84 to 87, wherein the formulation has an XRPD pattern substantially similar to that shown in Figure 76.

[0528] Embodiment 108 The formulation according to Embodiment 84, wherein the formulation has an MDSC profile containing a Tg of approximately 67.7°C.

[0529] Embodiment 109 The formulation according to Embodiment 84, wherein the formulation has a substantially the same MDSC profile as that shown in Figure 77.

[0530] Embodiment 110 The formulation according to Embodiment 85, wherein the formulation has an MDSC profile including a Tg of approximately 61.5°C.

[0531] Embodiment 111 The formulation according to Embodiment 85, wherein the formulation has substantially the same MDSC profile as that shown in Figure 78.

[0532] Embodiment 112 The formulation according to Embodiment 86, wherein the formulation has an MDSC profile comprising two Tg values ​​of approximately 96.3°C and approximately 110.4°C, or approximately 95.8°C and approximately 107.9°C.

[0533] Embodiment 113 The formulation according to Embodiment 86, wherein the formulation has a substantially similar MDSC profile to that shown in Figure 79 or Figure 81.

[0534] Embodiment 114 The formulation according to Embodiment 87, wherein the formulation has an MDSC profile containing a Tg of approximately 104.6°C.

[0535] Embodiment 115 The formulation according to Embodiment 87, wherein the formulation has a substantially the same MDSC profile as that shown in Figure 80.

[0536] Embodiment 116 The formulation according to any one of Embodiments 65 to 115, wherein the formulation has a drug assay with a drug content higher than 98%.

[0537] Embodiment 117 The formulation according to any one of Embodiments 65 to 116, wherein the formulation has a drug assay with a drug content of more than 99%.

[0538] Embodiment 118 The formulation according to any one of Embodiments 65 to 117, wherein the formulation has a drug assay with a drug content higher than 99.5%.

[0539] Embodiment 119 The formulation according to any one of Embodiments 65 to 118, wherein the formulation has a drug assay of more than 98% after storage for one week at 25°C and 60% relative humidity (RH).

[0540] Embodiment 120 The formulation according to any one of Embodiments 65 to 119, wherein the formulation has a drug assay of more than 99% after storage at 25°C and 60% RH for one week.

[0541] Embodiment 121 The formulation according to any one of Embodiments 65 to 120, wherein the formulation has a drug assay of more than 99.4% after storage at 25°C and 60% RH for one week.

[0542] Embodiment 122 The formulation according to any one of Embodiments 65 to 121, wherein the formulation has a drug assay of more than 98% after storage at 40°C and 75% RH for one week.

[0543] Embodiment 123 The formulation according to any one of Embodiments 65 to 122, wherein the formulation has a drug assay of more than 99% after storage at 40°C and 75% RH for one week.

[0544] Embodiment 124 The formulation according to any one of Embodiments 65 to 123, wherein the formulation has a drug assay of more than 99.2% after storage at 40°C and 75% RH for one week.

[0545] Embodiment 125 The formulation according to any one of Embodiments 65 to 124, wherein the formulation is formulated as a tablet.

[0546] Embodiment 126: The formulation according to Embodiment 125, wherein the tablet contains compound I in an amount between approximately 5 mg and approximately 1000 mg.

[0547] Embodiment 127 The formulation according to Embodiment 125 or 126, wherein the tablet contains compound I in an amount of about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, or about 200 mg.

[0548] Embodiment 128 A formulation according to any one of Embodiments 125 to 127, wherein the tablet comprises compound I, a polymer used in a spray-dried dispersion, a binder, a disintegrant, and a lubricant.

[0549] Embodiment 129 A formulation according to any one of Embodiments 125 to 128, wherein the tablet comprises compound I, a polymer used in a spray-dried dispersion, microcrystalline cellulose PH-101, mannitol, croscarmellose sodium, colloidal silica dioxide, magnesium stearate, microcrystalline cellulose PH-102, poloxamer 188, and a coating material.

[0550] Embodiment 130 The formulation according to Embodiment 129, wherein the polymer is an HPMS-AS polymer.

[0551] Embodiment 131 The formulation according to Embodiment 130, wherein the polymer is HPMS-AS MG polymer.

[0552] Embodiment 132 The tablet contains compound I in an amount between about 10% w / w and about 30% w / w, and is made of HPMC-AS A formulation according to any one of Embodiments 125 to 128, comprising MG polymer in an amount between approximately 30% w / w and approximately 50% w / w, microcrystalline cellulose PH-101 in an amount between approximately 10% w / w and approximately 25% w / w, mannitol in an amount between approximately 5% w / w and approximately 15% w / w, croscarmellose sodium in an amount between approximately 1% w / w and approximately 10% w / w, colloidal silica dioxide in an amount between approximately 0.1% w / w and approximately 1% w / w, magnesium stearate in an amount between approximately 0.1% w / w and approximately 1% w / w, microcrystalline cellulose PH-102 in an amount between approximately 5% w / w and approximately 15% w / w, and poloxamer 188 in an amount between approximately 0% w / w and approximately 5% w / w.

[0553] Embodiment 133 The formulation according to Embodiment 132, wherein the tablet comprises an internal granule portion containing compound I in an amount of about 12% w / w, HPMC-AS MG polymer in an amount of about 48% w / w, microcrystalline cellulose PH-101 in an amount of about 12.4% w / w, mannitol in an amount of about 10% w / w, croscarmellose sodium in an amount of about 2% w / w, colloidal silica dioxide in an amount of about 0.5% w / w, and magnesium stearate in an amount of about 0.25% w / w, and an external granule portion containing croscarmellose sodium in an amount of about 2% w / w, microcrystalline cellulose PH-102 in an amount of about 9.4% w / w, poloxamer 188 in an amount of about 3% w / w, and magnesium stearate in an amount of about 0.5% w / w.

[0554] Embodiment 134 The formulation according to Embodiment 132, wherein the tablet comprises an internal granule portion containing compound I in an amount of about 18% w / w, HPMC-AS MG polymer in an amount of about 42% w / w, microcrystalline cellulose PH-101 in an amount of about 11.4% w / w, mannitol in an amount of about 10% w / w, croscarmellose sodium in an amount of about 3% w / w, colloidal silica dioxide in an amount of about 0.5% w / w, and magnesium stearate in an amount of about 0.25% w / w, and an external granule portion containing croscarmellose sodium in an amount of about 3% w / w, microcrystalline cellulose PH-102 in an amount of about 8.4% w / w, poloxamer 188 in an amount of about 3.0% w / w, and magnesium stearate in an amount of about 0.5% w / w.

[0555] Embodiment 135 The formulation according to Embodiment 132, wherein the tablet comprises an internal granule portion containing compound I in an amount of about 24% w / w, HPMC-AS MG polymer in an amount of about 36% w / w, microcrystalline cellulose PH-101 in an amount of about 11.4% w / w, mannitol in an amount of about 10% w / w, croscarmellose sodium in an amount of about 3% w / w, colloidal silica dioxide in an amount of about 0.5% w / w, and magnesium stearate in an amount of about 0.25% w / w, and an external granule portion containing croscarmellose sodium in an amount of about 3% w / w, microcrystalline cellulose PH-102 in an amount of about 11.4% w / w, and magnesium stearate in an amount of about 0.5% w / w.

[0556] Embodiment 136 The formulation according to any one of Embodiments 132 to 135, wherein the tablet further comprises an additional coating material in an amount between about 1% w / w and about 5% w / w.

[0557] Embodiment 137 The formulation according to Embodiment 136, wherein the additional coating material is present in an amount of approximately 2.0% w / w.

[0558] Embodiment 138 The formulation according to any one of Embodiments 129 to 131 or 136 to 137, wherein the coating material is Opadry(R).

[0559] Embodiment 139: A formulation according to any one of Embodiments 137 to 138, wherein the tablet has a dissolution performance of 60% or more of the active pharmaceutical ingredient (API) in 45 minutes.

[0560] Embodiment 140: A formulation according to any one of Embodiments 137 to 139, wherein the tablet has a dissolution performance of 80% or more of the API in 45 minutes.

[0561] Embodiment 141 The formulation according to Embodiment 137, wherein the tablet has a dissolution curve substantially similar to that shown in Figure 85.

[0562] Embodiment 142 A method for treating a disease associated with ErbB, comprising administering to a subject a therapeutically effective amount of a polymorph of compound I or a pharmaceutically acceptable salt of compound I, or a spray-dried dispersion (SDD) comprising compound I and a polymer.

[0563] Embodiment 143: The method according to Embodiment 142, wherein ErbB is HER2.

[0564] Embodiment 144 The method according to Embodiment 142 or 143, wherein the disease is cancer.

[0565] Embodiment 145 The method according to Embodiment 144, wherein the cancer is selected from the group consisting of leukemia, glioblastoma, melanoma, chondrosarcoma, cholangiocarcinoma, osteosarcoma, lymphoma, lung cancer, adenoma, myeloma, hepatocellular carcinoma, adrenocortical carcinoma, pancreatic cancer, breast cancer, bladder cancer, prostate cancer, liver cancer, gastric cancer, colon cancer, colorectal cancer, ovarian cancer, cervical cancer, brain cancer, esophageal cancer, bone cancer, testicular cancer, skin cancer, kidney cancer, mesothelioma, neuroblastoma, glioblastoma, thyroid cancer, head and neck cancer, esophageal cancer, eye cancer, prostate cancer, nasopharyngeal cancer, and oral cancer.

[0566] Embodiment 146 The method according to Embodiment 144, wherein the cancer is selected from the group consisting of lung cancer, breast cancer, gastric cancer, colorectal cancer, pancreatic cancer, prostate cancer, bladder cancer, ovarian cancer, and glioblastoma.

[0567] Embodiment 147 The method according to Embodiment 144, wherein the cancer is selected from the group consisting of lung cancer, breast cancer, bladder cancer, ovarian cancer, and glioblastoma.

[0568] Embodiment 148 The method according to any one of Embodiments 144 to 147, wherein the cancer has metastasized to the central nervous system (CNS).

[0569] Embodiment 149 The method according to Embodiment 148, wherein the cancer has brain and leptomeningeal metastases.

[0570] Examples

[0571] The following abbreviations have the definitions described below. [Table 1-1] [Table 1-2]

[0572] For clarity, the following table summarizes the compound identifiers, chemical names, and structures used interchangeably throughout this application for each compound discussed. [Table 2-1] [Table 2-2]

[0573] Example 1: Analytical Method

[0574] 1 H NMR analysis

[0575] 1 1H NMR was performed using a Bruker AVANCE III, Bruker Ultrashield400, or Bruker Advance300 equipped with an automated sampler (B-ACS120).

[0576] X-ray powder diffraction (XRPD)

[0577] Solid samples were measured using a D8 Advance diffractometer (Bruker). This system was equipped with a LynxEye detector. The sample was scanned from 3° to 40°2θ in steps of 0.02°2θ. The tube voltage and tube current were 40KV and 40mA (D8 Advance).

[0578] For the XRPD test, the sample was scattered onto a Si substrate using the following parameters: Tube:Cu:K-α (λ=1.54179A)

[0579] Generator: Voltage: 40kV, Current: 40mA

[0580] Scanning range: 3-40 degrees.

[0581] Scanning speed: 10 deg. / min

[0582] Sample rotation speed: 15 rpm

[0583] Thermogravimetric analysis (TGA)

[0584] TGA was performed using a TGA Q5000IR, Q500, Discovery TGA 55 (TA Instruments, USA), or Mettler-Toledo TGA2. Samples were placed in open aluminum pans coated with tar, automatically weighed, and then inserted into the TGA furnace. Samples were heated at 10°C / min to the final temperature.

[0585] Approximately 5-10 mg of the sample was used in a TGA test with the following parameters. The sample was heated to 300°C at 10°C / min, and the next segment was stopped if the ratio was less than 80.00.

[0586] Differential scanning calorimeter (DSC)

[0587] DSC analysis was performed using a DSC Q2000, Q200, Discovery DSC 250 (TA Instruments, USA), or Mettler-Toledo DSC3+. Weighed samples were placed in a DSC pinhole pan and their weight was accurately recorded. The samples were heated at 10°C / min to the final temperature.

[0588] Heating-Cooling-Heating DSC

[0589] The powder was weighed using a Tzero aluminum sample pan manufactured by TA Instruments.

[0590] For the DSC test using the following parameters, the apparatus was covered with a pinhole lid. The system was equilibrated at 30°C, heated to 220°C at 10°C / min (first heating run), kept isothermally for 1.00 min, cooled to 20°C at 10°C / min (cooling run), kept isothermally for 1.00 min, heated to 220°C at 10°C / min (second heating run), with a nitrogen flow rate of 50 mL / min.

[0591] MDSC

[0592] For the MDSC test using the following parameters, SDD powder was weighed in a Tzero aluminum sample pan from TA Instruments, covered with a pinhole lid. The sample was equilibrated at 10°C, adjusted by + / - 1°C every 60 seconds, held isothermally for 5.00 min, and then heated to 200°C at a rate of 2°C / min.

[0593] Dynamic water adsorption analysis (DVS)

[0594] DVS was determined using DVS Advantage-1 or Intrinsic (SMS, UK). Samples were tested in step mode at target relative humidity (RH) of 10–90% throughout all cycles. The analysis was performed by increasing RH by 10% increments. Equilibrium time: 60 min, RH (%) measurement points: Cycle 1: 0, 10, 20, 30, 40, 50, 60, 70, 80, 90, Cycle 2: 90, 80, 70, 60, 50, 40, 30, 20, 10, 0.

[0595] Example 2: Preparation procedure for (S)-N-(4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidine-4-yl)oxy)-7-methoxyquinazoline-4-amine (Compound I)

[0596] Laboratory-scale synthesis of (S)-N-(4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidine-4-yl)oxy)-7-methoxyquinazoline-4-amine (compound I) and (R)-N-(4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidine-4-yl)oxy)-7-methoxyquinazoline-4-amine (compound II) [ka]

[0597] Laboratory-scale synthesis of compound I

[0598] Preparation procedure for compound (8): [ka]

[0599] To a solution of compound (7) (130 g, 0.948 mol) in an ice-cooled cold bath, 98% HCOOH (200 mL, 4.47 mol) was added. The resulting mixture was heated to 25°C, and 40% HCHO (137 mL, 1.896 mol) was added. A large amount of gas was released while heating to 40°C. After completion, the solution was adjusted to pH=9-10 by adding concentrated NaOH, extracted with SiO2 (1.5 L x 3), and washed with water and saline solution (1.6 L). The organic layer was dried over Na2SO4 and concentrated to obtain compound (8) (116.8 g, crude) as a white solid.

[0600] Preparation procedure for compound (2):

[0601] A mixture of compound (1) (2.5 g, 11.2 mmol) and CuCN (2.9 g, 22.4 mmol) in NMP (25 mL) was stirred at 160 °C for 5 hours. After cooling to room temperature, the mixture was filtered and concentrated, and the crude product, compound (2), was used directly in the next step without further purification.

[0602] Preparation procedure for compound (3):

[0603] After pumping NH3 gas into 100 mL of EtOH at 0°C for 15 minutes, compound (2) (3 g, crude) was dissolved in 30 mL of MeOH, and the mixture was stirred overnight at 120°C in a sealed tube. The solution was concentrated, and the residue was purified by silica gel column chromatography (PE / siRNA = 1 / 1) to obtain compound (3) (450 mg, 24% yield in 2 steps) as a white solid.

[0604] Compound (3) 1 H NMR:(400MHz,DMSO-d6)δ6.38(s,2H),6.17(d,J=2Hz,1H),6.13(dd,J1=2.0Hz,J2=9.2Hz,1H),3.73(s,3H).

[0605] Preparation procedure for compound (4):

[0606] A mixture of compound (3) (2 g, crude) in DMF-DMA (8 mL) was stirred at 100°C for 2 hours. After cooling to room temperature, the mixture was filtered, and the precipitate was washed with ethyl acetate to obtain compound (4) (800 mg, crude) as a yellow solid, which was used directly in the next step without further purification.

[0607] Preparation procedure for compound (6):

[0608] A mixture of compound (4) (800 mg, 3.62 mmol) and compound (5) (1.303 g, 5.43 mmol) in AcOH (15 mL) was stirred overnight at 40-60°C. The mixture was concentrated, the pH was adjusted to 8-9 with K2CO3 (aq.), and the mixture was filtered. The residue was washed with ethyl acetate to obtain compound (6) (1.6 g, crude) as a brown solid.

[0609] LC-MS of compound (6):R t =0.702min(Xtimate C18 2.1×30mm), MS(ESI)m / z 417.0[M+H] + .

[0610] Compound (6) 1 ¹H NMR: (400MHz, methanol-d4)δ 8.74 (d, J=7.2Hz, 1H), 8.46 (s, 1H), 8.29 (s, 1H), 7.71 (s, 1H), 7.67 (dd, J1=2.4Hz, J2=8.4Hz, 1H), 7.18 (d, J=8.4Hz, 1H), 7.09-7.00 (m, 3H), 6.85 (d, J=2.4Hz, 1H), 3.98 (s, 3H), 2.25 (s, 3H).

[0611] Preparation procedure for Compound I and Compound II:

[0612] A mixture of compound (6) (1.1 g, 2.64 mmol), compound (8) (991 mg, 5.28 mmol), and t-BuOK (889 mg, 7.92 mmol) in THF / DMF (15 / 6 mL) was stirred overnight at 80-100°C under an N2 atmosphere. The mixture was concentrated, and the residue was purified by reverse-phase preparative HPLC (column: SYNERGI 250 × 50, 10 μm, gradient: 40-70% B and 60-30% A (A = water / 0.05% NH4HCO3, B = acetonitrile), flow rate: 80 mL / min) to obtain compound (9). Next, compound (9) was separated by SFC to obtain 170 mg of compound I and 170 mg of compound II.

[0613] Chiral SFC separation conditions for compound I and compound II: t R For compound I, the incubation period was 1.582 min, and for compound II, it was 1.741 min. The column was a Chiralcel OD-3 50×4.6 mm ID, 3 μm, and the mobile phase was A: CO2, B: ethanol (0.05% diethylamine). The gradient was 5% B and 95% A held for 0.2 min, then B was increased from 5% to 40% over 1.4 min, 40% B and 60% A held for 1.05 min, and then 5% B held for 0.35 min. The flow rate was 4 mL / min, and the column temperature was 40°C.

[0614] Compound I:

[0615] LCMS:R t=2.001min(Xtimate C18, 2.1×30mm, 3μm), MS(ESI)m / z=548.1[M+H] + .

[0616] 1 H NMR:(400MHz,メタノール-d4)δ8.89(d,J=7.6Hz,1H),8.77(s,1H),8.58(s,1H),7.82(d,J=2.4Hz,1H ),7.77(dd,J1=9.2Hz,J2=2.8Hz,1H),7.31(d,J=8.4Hz,1H),7.26(dd,J1=13.6Hz,J2=2.0Hz,2H) ,6.95(d,J=2.0Hz,1H),6.92(s,1H),5.67-5.59(m,1H),4.28(brs,1H),4.08(s,3H),3.91-3.76 (m,2H),3.53-3.47(m,1H),3.07(s,3H),2.88(d,J=13.2Hz,1H),2.43-2.40(m,1H),2.29(s,3H).

[0617] Compound II:

[0618] LCMS:R t =2.009min(Xtimate C18, 2.1×30mm, 3μm), MS(ESI)m / z=548.0[M+H] + .

[0619] 1¹H NMR: (400MHz, methanol-d4)δ 8.89 (d, J=7.2Hz, 1H), 8.76 (s, 1H), 8.57 (s, 1H), 7.82 (d, J=2.4Hz, 1H), 7.77 (dd, J1=8.4Hz, J2=2.4Hz, 1H), 7.30 (d, J=8.8Hz, 1H), 7.22 (dd, J1=7.6Hz, J2=2.4Hz, 2H), 6.96 ( d,J=2.4Hz,1H),6.91(d,J=2.4Hz,1H),5.72-5.63(m,1H),4.26-4.24(m,1H),4.08(s,3H),3.94-3. 76(m,2H),3.57-3.51(m,1H),3.07(s,3H),2.87(d,J=14.4Hz,1H),2.48-2.42(m,1H),2.29(s,3H).

[0620] Scale-up manufacturing process for (S)-N-(4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidine-4-yl)oxy)-7-methoxyquinazoline-4-amine (compound I)

[0621] Compound I was prepared by a four-step synthesis (including recrystallization) using compounds (3), (5), and (10) as starting materials. The detailed synthesis route is shown in the scheme in Scheme 2 and in the following description. [ka]

[0622] Step 1: Preparation of compound (4)

[0623] The mixture of compound (3) in IPA and DMF-DMA was heated at 75-80°C until the reaction was complete, and then the reaction solution was cooled. Compound (4) was isolated by filtration, washed with IPA, and dried.

[0624] Step 2: Preparation of compound (6)

[0625] Compound (5) was added to the AcOH solution of heated compound (4), and the resulting mixture was heated at 70-75°C until the reaction was complete. After the reaction solution cooled, water was added. The solid was isolated by filtration, washed with water, and prepared as a slurry with NaOH aqueous solution. Compound (6) was isolated by filtration, washed with water, and dried.

[0626] Step 3: Preparation of Crude Compound I Product

[0627] Compound (6) was added to a solution of compound (10) in DMF / THF and t-BuOK. The resulting mixture was heated at 70-80°C until the reaction was complete. The solution was collected by filtration through diatomaceous earth, cooled, and then water was added. The solid was isolated by filtration, washed with water, and the wet cake was made into a slurry with water. Compound I (crude) was isolated by filtration, washed with water, and dried.

[0628] Step 4: Recrystallization of Compound I

[0629] A crude solution of compound I in EtOH / water was filtered through a cartridge filter, and then seed crystals were added. The mixture was concentrated, MTBE was added, and the resulting mixture was cooled. Compound I (recrystallized) was isolated by filtration, washed with MTBE, and dried.

[0630] Step 1 procedure: [ka]

[0631] Compound (3) (19.5 kg, 1.00 wt) and DMF-DMA (1.06-1.09 wt) were added together with IPA (4.0-4.2 wt) under an N2 atmosphere. The resulting mixture was heated and stirred at 75-80°C until the reaction was complete as shown by HPLC (intended reaction time 6-8 hours). The reaction mixture was cooled to 15-25°C within 4-6 hours, the solid was collected by filtration, and washed with IPA (0.79-0.95 wt). The wet cake was dried under vacuum at 40-45°C to obtain compound (4) (24.85 kg, purity: 100.0%, yield: 96%). 1 H NMR:(CDCl3,400MHz),2.88-3.23(m,6H),3.61-3.97(m,3H),6.00-6.51(m,2H),7.26-7.79(m,1H).

[0632] Step 2 procedure: [ka]

[0633] Compound (4) (22.4 kg, 1.0 wt) was dissolved in AcOH (5.4-5.5 wt) at 70-75°C, and compound (5) (1.08-1.14 wt) was added little by little at 65-75°C within 1-3 hours, followed by the addition of AcOH (1.0-1.1 wt) to rinse the reactor. The resulting mixture was heated and stirred at 70-75°C until the reaction was complete as shown by HPLC (intended reaction time 15-20 h). The reaction mixture was cooled to 15-25°C within 4-6 hours, process water (10.0-10.5 wt) was added, and the mixture was stirred at this temperature for 4-6 hours. The solid was recovered by filtration and washed with water (1.9-2.1 wt). After adding the wet cake and process water (10.0-10.5 wt) to the reactor, 2N NaOH (3.5-4.5 wt) was added at 15-25°C to adjust the pH to 13-14. The mixture was stirred at this temperature for 4-6 hours, and the solid was recovered by filtration and washed with water (1.9-2.1 wt). The wet cake was dried at 50-55°C to obtain compound (6) (37.45 kg, purity: 99.7%, assay: 98.9%, yield: 88%). 1 H NMR:(DMSO-d6,400MHz):2.18(s,3H),3.940(s,3H),6.78-6.79(d,1H),7.01-7.21(m,4 H),7.69-7.74(m,2H),8.38(s,1H),8.52(s,1H),8.92-8.94(d,1H),9.03-9.06(d,1H).

[0634] Step 3 procedure: [ka]

[0635] To a solution of compound (10) (15.9 kg, 0.43-0.44 wt) in THF (5.0-5.2 wt) and DMF (2.7-2.9 wt), t-BuOK (0.302-0.323 wt) was added, and the resulting mixture was stirred at 20-30°C for 0.5-1.0 hours. Then, compound (6) (36.9 kg, 1.00 wt) and THF (1.0-1.2 wt) were added, and the mixture was stirred at 70-80°C until the reaction was complete as shown by HPLC (intended reaction time 16-20 hours). The reaction mixture was filtered, and purified water (20.0-24.0 wt) was added dropwise at 15-25°C (addition time ≥ 8 hours), followed by stirring at 15-25°C for 4-8 hours. The solid was recovered by filtration and washed with purified water (1.5-2.5 wt). The wet cake and purified water (9.0-10.0 wt) were added, and the mixture was adjusted to 15-25°C and stirred at this temperature for 4-8 hours. The solid was recovered by filtration and washed with purified water (1.5-2.5 wt). The wet cake was dried under reduced pressure at 50-55°C to obtain compound I (crude) (44.1 kg, purity: 99.8%, chiral purity: 100.0%, yield: 91.0%).

[0636] Step 4 procedure: [ka]

[0637] The crude product of compound I (43.5 kg, 1.0 wt) was dissolved in purified water (0.50-0.54 wt) and EtOH (7.5-8.0 wt) at 70-75°C under nitrogen protection, and the resulting mixture was transferred to another reactor via a cartridge filter. After cooling the clarified liquid to 58-63°C, crystal species (0.005-0.010 wt) were added, and the mixture was stirred at this temperature for 2-6 hours. The mixture was concentrated to 6-8V at below 60°C, the temperature was adjusted to 45-55°C, and MTBE (4.0-6.0 wt) was added dropwise over 6 hours or more. The reaction mixture was stirred at 45-55°C for 2-8 hours, then cooled to -2-2°C over 5-10 hours (preferably 10°C / 1-2 hours), and stirred at this temperature for 6-12 hours. The solid was recovered by filtration and washed with MTBE (1.3-1.6 wt x 2). The wet cake was dried under reduced pressure at 45-50°C to obtain recrystallized compound I (36.2 kg, purity: 99.9%, assay: 99.0%, chiral purity: 100.0%, yield: 82%). [α]20D = +12.2° (c 10 mg / mL, MeOH). Form A of compound I was obtained.

[0638] Compound I 1 The 1H NMR spectrum is shown in Figure 1.

[0639] Single crystal of compound I

[0640] Approximately 20 mg of compound I was placed in an 8 mL vial, and approximately 2-3 mL of a mixed solvent of ethanol / water (50:50, v / v) was added. The solution was stirred at room temperature for 10 minutes, and the turbid solution was filtered through a syringe membrane. The filtered clarified solution was wrapped in plastic wrap with a pinhole and evaporated at 60°C in a fume hood. The evaporation method at 60°C in ethanol / water (50:50, v / v) produced plate-like crystals of compound I with a size and transparency suitable for single crystal determination. The absolute configuration of the single chiral center of compound I was determined to be (S). The single-crystal X-ray diffraction ORTEP of compound I is shown in Figure 2.

[0641] Crystal data [Table 3]

[0642] Data collection [Table 4]

[0643] Improvement [Table 5]

[0644] Preparation procedure for form B of compound I

[0645] 150 mg of hemiadipate of compound I was suspended in 75 mL of pH 6.8 buffer at 25°C. The mixture was stirred at 25°C for 24 hours to form the free base of compound I. The suspension was filtered and dried in a vacuum oven at 35°C for 24 hours to obtain crystalline form B of compound I.

[0646] Preparation procedure for form C of compound I

[0647] 300 mg of compound I and 15 mL of methanol were added to a 40 mL vial at 50°C. The mixture was held at 50°C for 30 min. The suspension was filtered, and the filtrate was rapidly cooled to 0°C until a solid formed in the solution. The suspension was filtered to obtain crystalline form C of compound I.

[0648] Preparation procedure for form D of compound I

[0649] Method 1

[0650] 300 mg of compound I was suspended in 4 mL of 1,4-dioxane or THF at 50°C. The mixture was held at 50°C for 30 min. The suspension was filtered. A reverse solvent (e.g., n-heptane, water, or MTBE) was added dropwise to the filtrate until the solvent / reverse solvent ratio was 1:5 (v / v). The suspension was filtered to obtain crystalline form D of compound I.

[0651] Method 2

[0652] 30 mg of compound I was suspended in 1 mL of a suitable solvent (e.g., THF, 1,4-dioxane, acetone, acetonitrile, or ethyl acetate) at 50°C. The mixture was held at 50°C for 30 min. The suspension was filtered, and the filtrate was evaporated at 25°C for 7 days. The suspension was filtered to obtain crystalline form D of compound I.

[0653] Equilibration of compound I in form A using a solvent at 25°C:

[0654] Approximately 30 mg of compound I, form A, was equilibrated at 25°C for 10 days using 0.5 mL of solvent (listed in Table 1 below). The suspension was filtered and dried under ambient conditions for 10 minutes. The solid portion was examined by XRPD. If differences were observed, additional investigations (e.g., DSC, TGA, NMR) were performed.

[0655] Equilibration of compound I in form A using a solvent at 50°C:

[0656] The results were the same as above, except for 50°C. To prevent decomposition at high temperatures, the equilibrium time may have been shorter than at 25°C.

[0657] Table 1. Equilibrium of compound I in form A using solvents at 25°C and 50°C. [Table 6]

[0658] The XRPD pattern overlays for equilibration experiments performed on form A of compound I at 25°C or 50°C for 10 days using a solvent are shown in Figures 3 and 4, respectively.

[0659] Crystallization of compound I by slow evaporation at room temperature:

[0660] A saturated solution of compound I in the minimum amount of solvent (listed in Table 2 below) was prepared at 50°C. The supernatant was slowly evaporated at ambient temperature, and its polymorphisms were examined.

[0661] Table 2 Crystallization of compound I by evaporation at room temperature [Table 7]

[0662] The XRPD pattern overlay from the evaporation experiment at room temperature is shown in Figure 5.

[0663] Crystallization of compound I from a heat-saturated solution:

[0664] Approximately 30 mg of compound I was dissolved in the minimum amount of solvent (listed in Table 3 below) at 60°C. Filtration was performed to confirm that no crystals remained in the solution. A portion of the saturated solution was placed in an ice bath and stirred for rapid cooling. Another portion was slowly cooled to 5°C at a rate of 0.1°C / min and held at 5°C overnight. The solid portion was examined by XRPD. If differences were observed, additional investigations (e.g., DSC, TGA, NMR) were performed.

[0665] Table 3 Crystallization of compound I from a heat-saturated solution [Table 8]

[0666] XRPD pattern overlays of rapid cooling experiments and slow cooling experiments of the crystallization of compound I from a heat-saturated solution are shown in Figures 6 and 7, respectively.

[0667] Precipitation of compound I by addition of reverse solvent:

[0668] Two different solvent combinations were tested. Compound I was dissolved in a solvent with high solubility, and then a solvent in which compound I was highly insoluble was added. The solid portion was investigated by XRPD. If differences were observed, additional investigations (e.g., DSC, TGA, NMR) were performed.

[0669] Table 4 Precipitation of compound I by addition of reverse solvent [Table 9]

[0670] The XRPD pattern overlay from the reverse solvent experiment of compound I is shown in Figure 8.

[0671] Behavior of compound I in form A during compression:

[0672] Approximately 100 mg of compound I was compressed at 20 MPa for 5 minutes using a hydraulic press (tablet diameter 8 mm). XRPD was performed to investigate the polymorphic behavior during compression. If differences were observed, additional investigations (e.g., DSC, TGA, NMR) were conducted.

[0673] The XRPD pattern overlay from the compression experiment is shown in Figure 9. For compound I, morphology A, no change in the XRPD pattern was observed after compression at 20 MPa for 5 minutes.

[0674] Grinding simulation experiment of compound I in form A:

[0675] Approximately 20 mg of compound I was manually ground in a mortar for 1 minute. Solid morphology and crystallinity were evaluated by XRPD. If differences were observed, additional investigations (e.g., DSC, TGA, NMR) were performed.

[0676] Granulation simulation experiment of compound I in form A:

[0677] Granulation solvent was added dropwise to compound I until the solid was sufficiently moist. The mixture was stirred between additions. It was dried to less than 2% under ambient conditions. Solid morphology and crystallinity were evaluated by XRPD. Granulation solvents included, for example, water and ethanol.

[0678] The overlay of XRPD scans from the grinding and granulation experiments is shown in Figure 10. For compound I, form A, no changes were observed in the XRPD pattern after grinding and wet granulation using water and ethanol.

[0679] Competitive equilibrium of compound I in forms A and B:

[0680] A 1:1 mass mixture of compound I in forms B and A was studied in a competitive equilibration experiment. Approximately 20 mg of compound I in form A and approximately 20 mg of compound I in form B were equilibrated in 1 mL of saturated compound I solution at 25°C for 3 days. The suspension was filtered and dried under ambient conditions for 10 minutes. The solid portion was examined by XRPD.

[0681] The hydrate of compound I was obtained by reverse solvent precipitation from a 1,4-dioxane / aqueous system to obtain the free base of compound I, or by dissociation of the hemiadipinate of compound I in phosphate buffer at pH=6.8. The hydrate of compound I was in form A but was unstable and was converted to anhydrous form B after drying under vacuum at 30°C.

[0682] Form B was obtained only by dehydrating the hydrate of compound I under vacuum at 30°C. This was a moderate crystalline form that began melting at 116.3°C and showed a weight loss of 1.68% at 100°C. Competitive equilibration was performed between Form A and Form B. After competitive equilibration, Form A was obtained in three selected solvents (listed in the table below), demonstrating that Form A was more stable than Form B. [Table 10]

[0683] Equilibrium formation of compound I in form C:

[0684] A fixed amount of morph C was equilibrated at 5°C using 10 mL of MeOH. XRPD patterns were checked at different time points. The suspension was filtered and dried under ambient conditions for 10 minutes. The solid portion was examined by XRPD.

[0685] Morphology C was obtained in a crystallization experiment of a heat-saturated solution by rapid cooling in MeOH. This could form highly crystalline particles, which began to melt at 193.8°C and were accompanied by a 0.70% weight loss. Further equilibration of morphology C in methanol for 3, 10, and 17 days demonstrated that morphology A was more stable than morphology C.

[0686] Equilibration of compound I in form D:

[0687] The suspension of morphology D obtained from the reverse solvent experiment was continuously stirred for 7 days, then filtered and dried under ambient conditions for 10 minutes. The solid portion was investigated by XRPD.

[0688] In this polymorph study, morph D can be obtained by a different method. This showed that it could form a highly crystalline solid, initiating melting at 186.9°C and accompanied by a 0.67% weight loss at 165°C. Combined with reverse solvent precipitation experiments, morph D was obtained from the outset in multiple solvent / reverse solvent pairs. After 7 days of equilibration in the corresponding solvents, morph D was converted to morph A, and it was shown that morph A was also more stable than morph D.

[0689] Physical properties of compound I in forms A, B, C, and D

[0690] Form A of compound I

[0691] Approximate measurement of solubility at 25°C

[0692] Approximately 2 mg of compound I, form A, was weighed and dissolved in the minimum amount of solvent, and its solubility was determined at 25°C. The experiment was conducted by combining manual dilution and visual observation.

[0693] Table 5 Approximate solubility of compound I in form A in different solvents [Table 11]

[0694] Table 6 Solubility of compound I in form A in different buffer solutions [Table 12]

[0695] XRPD data for compound I, form A, are shown in Figure 11 and Table 7.

[0696] Table 7 XRPD data for form A of compound I [Table 13]

[0697] Thermal behavior: DSC and TGA of compound I, form A

[0698] The thermal behavior of compound I in form A was obtained via DSC and TGA. The TGA of compound I in form A is shown in Figure 12. According to the TGA of compound I in form A, a weight loss of approximately 0.02% was observed between 30°C and 120°C.

[0699] The digital scatter sample (DSC) of compound I, form A, is shown in Figure 13. According to the DSC of compound I, form A, the onset temperature and peak temperature were 199.5°C and 201.5°C, respectively.

[0700] Hygroscopicity of compound I in form A

[0701] The DVS plot for compound I, form A, is shown in Figure 14. The DVS plot for compound I, form A, shows that it absorbs approximately 0.21% of moisture at RH 0-80%, indicating that the active pharmaceutical ingredient is slightly hygroscopic.

[0702] Form B of compound I

[0703] XRPD data for compound I, form B, are shown in Figure 15 and Table 8.

[0704] Table 8 XRPD data for form B of compound I [Table 14]

[0705] The TGA and DSC of compound I, form B, are shown in Figure 16. According to the TGA of compound I, form B, a weight loss of approximately 1.68% was observed between 30°C and 100°C. The DSC of compound I, form B, showed three endothermic transitions with onset temperatures and peak temperatures of 116.3°C and 125.4°C, 182.4°C and 187.5°C, and 199.2°C and 200.3°C, respectively.

[0706] Form C of compound I

[0707] XRPD data for compound I, form C, are shown in Figure 17 and Table 9.

[0708] Table 9 XRPD data for compound I, form C [Table 15]

[0709] The TGA and DSC of compound I, form C, are shown in Figure 18. According to the TGA of compound I, form C, a weight loss of approximately 0.70% was observed between 30°C and 180°C. The DSC of compound I, form C, showed a single endothermic transition with an onset temperature of 193.8°C and a peak temperature of 194.6°C, respectively.

[0710] Form D of compound I

[0711] XRPD data for compound I, form D, are shown in Figure 19 and Table 10.

[0712] Table 10 XRPD data for compound I, form D [Table 16]

[0713] The TGA and DSC of compound I in form D are shown in Figure 20. According to the TGA of compound I in form D, a weight loss of approximately 0.67% was observed between 30°C and 100°C. The DSC of compound I in form D showed two endothermic transitions with onset temperatures of 186.9°C and 190.5°C, and peak temperatures of 199.5°C and 200.4°C, respectively.

[0714] Example 4: Preparation of pharmaceutical salts of compound I and screening of salts

[0715] Screening procedure for salts of compound I

[0716] 50 mg of the free base form of compound I was mixed with 1 equivalent of an acid selected from hydrochloric acid, sulfuric acid, phosphoric acid, fumaric acid, adipic acid, maleic acid, p-toluenesulfonic acid, succinic acid, oxalic acid, and L-(+)-tartaric acid, and then 1 mL of solvent was added. The resulting mixture was stirred at 50°C for 2 hours, then at 25°C overnight, to form a pharmaceutical salt of compound I. The precipitate was collected by centrifugal filtration, dried overnight at 50°C, and analyzed by XRPD. Similarly, screening of salts using 0.5 equivalents of acid was also performed. If a new pattern was observed, further evaluation by TGA, DSC, NMR, and hygroscopicity was performed.

[0717] Physical properties of pharmaceutical salts of compound I

[0718] The table below summarizes the physical properties of pharmaceutical salts of Compound I, selected from the crystalline forms of Compound I: hydrochloride, sulfate, phosphate, fumarate, monoadipate, hemiadipate, maleate, p-toluenesulfonate, succinate, oxalate, and L-(+)-tartrate.

[0719] Table 13 Physical properties of novel pharmaceutical salts of compound I [Table 17]

[0720] Fumarate of Compound I

[0721] XRPD data for the fumarate of compound I, and a comparison with form A of compound I, are shown in Figures 21, 22, and Table 14.

[0722] Table 14 XRPD data for the fumarate of compound I [Table 18]

[0723] The DSC of compound I fumarate is shown in Figure 23. The DSC of compound I fumarate showed one endothermic transition with an onset temperature of 162.8°C and a peak temperature of 169.8°C, respectively. The TGA of compound I fumarate is shown in Figure 24. According to the TGA of compound I fumarate, a weight loss of approximately 0.70% was observed between 40°C and 110°C. The vapor adsorption analysis of compound I fumarate is shown in Figure 25.

[0724] Hemisuccinate of Compound I

[0725] XRPD data for hemisuccinate of compound I and free base form A of compound I are shown in Figure 26. DSC of hemisuccinate of compound I is shown in Figure 27. The DSC of hemisuccinate of compound I showed one endothermic transition with onset temperature and peak temperature of 173.9°C and 184.3°C, respectively. TGA of hemisuccinate of compound I is shown in Figure 28. According to the TGA of hemisuccinate of compound I, a weight loss of approximately 4.10% was observed between 30°C and 125°C. Vapor adsorption analysis of hemisuccinate of compound I is shown in Figure 29.

[0726] Hydrochloride of compound I

[0727] The DSC and TGA of compound I hydrochloride are shown in Figure 30. The DSC of compound I hydrochloride showed a single endothermic transition with an onset temperature of 220.8°C and a peak temperature of 227.6°C, respectively. According to the TGA of compound I hydrochloride, a weight loss of approximately 0.26% was observed between 40°C and 150°C. The vapor adsorption analysis of compound I hydrochloride is shown in Figure 31.

[0728] Phosphate of compound I

[0729] The XRPD of compound I phosphate is shown in Figure 32. The DSC and TGA of compound I phosphate are shown in Figure 33. The DSC of compound I phosphate showed four endothermic transitions with onset and peak temperatures of 30.8°C and 50.1°C, 145.5°C and 149.1°C, 191.1°C and 195.5°C, and 213.2°C and 239.0°C, respectively. The TGA of compound I phosphate showed a weight loss of approximately 4.66% between 30°C and 200°C. The vapor adsorption analysis of compound I phosphate is shown in Figure 34.

[0730] Sulfate of compound I

[0731] The XRPD of compound I sulfate is shown in Figure 35. The DSC and TGA of compound I sulfate are shown in Figure 36. The DSC of compound I sulfate showed three endothermic transitions with onset and peak temperatures of 34.5°C and 57.3°C, 157.5°C and 169.4°C, and 227.6°C and 247.4°C, respectively. According to the TGA of compound I sulfate, a weight loss of approximately 5.47% was observed between 30°C and 200°C. The vapor adsorption analysis of compound I sulfate is shown in Figure 37.

[0732] Hemiadipate of Compound I

[0733] XRPD data for the hemiadipate of compound I are shown in Figure 38 and Table 15.

[0734] Table 15 XRPD data for hemiadipate of compound I [Table 19]

[0735] The DSC and TGA of compound I hemiadipate are shown in Figure 39. The DSC of compound I hemiadipate showed a single endothermic transition with an onset temperature of 173.3°C and a peak temperature of 175.0°C, respectively. According to the TGA of compound I hemiadipate, a weight loss of approximately 0.25% was observed between 40°C and 145°C. The DVS plot of compound I hemiadipate is shown in Figure 40.

[0736] p-toluenesulfonate of compound I

[0737] XRPD data for the p-toluenesulfonate of compound I are shown in Figure 41 and Table 16.

[0738] Table 16 XRPD data for p-toluenesulfonate of compound I [Table 20]

[0739] The DSC and TGA of compound I p-toluenesulfonate are shown in Figure 42. The DSC of compound I p-toluenesulfonate showed a single endothermic transition with an onset temperature of 168.2°C and a peak temperature of 175.2°C, respectively. According to the TGA of compound I p-toluenesulfonate, a weight loss of approximately 0.79% was observed between 30°C and 150°C. The DVS plot of compound I p-toluenesulfonate is shown in Figure 43.

[0740] Maleate of Compound I

[0741] XRPD data for the maleate of compound I are shown in Figure 44 and Table 17.

[0742] Table 17 XRPD data for the maleate of compound I [Table 21]

[0743] The DSC and TGA of compound I maleate are shown in Figure 45. The DSC of compound I maleate showed a single endothermic transition with an onset temperature of 159.6°C and a peak temperature of 162.5°C, respectively. According to the TGA of compound I maleate, a weight loss of approximately 0.44% was observed between 30°C and 140°C. The DVS plot of compound I maleate is shown in Figure 46.

[0744] Oxalate of Compound I

[0745] XRPD data for compound I oxalate are shown in Figure 47. DSC and TGA for compound I oxalate are shown in Figure 48. The DSC of compound I oxalate showed three endothermic transitions with onset and peak temperatures of 30.5°C and 63.2°C, 129.9°C and 139.5°C, and 193.2°C and 211.4°C, respectively. According to the TGA of compound I oxalate, a weight loss of approximately 7.92% was observed between 37°C and 147°C.

[0746] L-(+)-tartrate of compound I

[0747] The XRPD of compound I L-(+)-tartrate is shown in Figure 49. The DSC and TGA of compound I L-(+)-tartrate are shown in Figure 50. The DSC of compound I L-(+)-tartrate showed three endothermic transfers with onset and peak temperatures of 144.5°C and 156.1°C, 172.3°C and 187.5°C, and 203.5°C and 224.0°C, respectively. According to the TGA of compound I tartrate, a weight loss of approximately 0.59% was observed between 40°C and 150°C.

[0748] Monoadipine of Compound I

[0749] XRPD data for compound I monoadipate are shown in Figure 51. DSC and TGA data for compound I monoadipate are shown in Figure 52. The DSC of compound I monoadipate showed two endothermic transitions with onset and peak temperatures of 146.1°C and 148.7°C, and 167.1°C and 171.9°C, respectively. According to the TGA of compound I monoadipate, a weight loss of approximately 0.33% was observed between 40°C and 125°C.

[0750] Example 5: Preparation of spray-dried dispersions of compound I and polymer, and screening of the polymer.

[0751] The free base form of compound I and a polymer (40:60, w / w) with a compound I concentration of 7.5 mg / mL were dissolved in the corresponding solvent (acetone, MeOH, or DCM:MeOH = 1:1 (v / v)) to prepare a spray-dried solution for solid dispersion preparation.

[0752] Approximately 200 mg of the free base form of compound I and 300 mg of the polymer were added to a 40 mL glass vial and dissolved by magnetic stirring in the corresponding volume of the corresponding solvent (acetone, MeOH, or DCM:MeOH = 1:1 (v / v)). The solutions for compound I / PVP-VA64, compound I / Soluplus, compound I / HPMC-AS LF, compound I / Eudragit E100, compound I / Eudragit L100-55, compound I / HPbCD, compound I / PVP K30 LP, compound I / HPC (Klucel LF), compound I / HPMC E5 LV, compound I / HPMC E15, and compound I / HPMCP-HP50 were clear. The compound I / HPMC-AS MF solution was nearly clear. The compound I / HPC (Klucel LF) solution had high viscosity after magnetic stirring for approximately 5 hours, so it was ultimately spray-dried. These were spray-dried with ProCept4M8-Trix. The products were collected and further dried in vacuum at 30°C for 14–47 hours, then sealed with Parafilm, wrapped in aluminum foil, and stored at 5°C away from light.

[0753] Table 18 Screening of spray-dried dispersions of Compound I and different polymers [Table 22]

[0754] Figure 53 shows the XRPD pattern overlays of the SDD for compound I and each of the following polymers: PVP-VA64 polymer (40:60, w / w), Soluplus polymer (40:60, w / w), HPMC-AS MF polymer (40:60, w / w), HPMC-AS LF polymer (40:60, w / w), Eudragit E100 polymer (40:60, w / w), and Eudragit L100-55 polymer (40:60, w / w).

[0755] According to the XRPD data, the SDD between compound I and PVP-VA64 polymer (40:60, w / w) was amorphous, the SDD between compound I and Soluplus polymer (40:60, w / w) was amorphous, the SDD between compound I and HPMC-AS MF polymer (40:60, w / w) was amorphous, the SDD between compound I and HPMC-AS LF polymer (40:60, w / w) was amorphous, the SDD between compound I and Eudragit E100 polymer (40:60, w / w) was amorphous, and the SDD between compound I and Eudragit L100-55 polymer (40:60, w / w) was amorphous.

[0756] The MDSC profile of the SDD between compound I and PVP-VA64 polymer (40:60, w / w) is shown in Figure 54. The MDSC profile indicates the glass transition temperature (Tg) of the SDD between compound I and PVP-VA64 polymer (40:60, w / w), with its midpoint (high at half maximum) being 98.1°C.

[0757] The MDSC profile of the SDD between compound I and Soluplus polymer (40:60, w / w) is shown in Figure 55. The MDSC profile indicates the glass transition temperature (Tg) of the SDD between compound I and Soluplus polymer (40:60, w / w), with its midpoint (high at half maximum) being 75.7°C.

[0758] The MDSC profile of the SDD between compound I and HPMC-AS LF polymer (40:60, w / w) is shown in Figure 56. The MDSC profile indicates the glass transition temperature (Tg) of the SDD between compound I and HPMC-AS LF polymer (40:60, w / w), with its midpoint (high at half maximum) being 102.5°C.

[0759] The MDSC profile of the SDD between compound I and HPMC-AS MF polymer (40:60, w / w) is shown in Figure 57. The MDSC profile indicates the glass transition temperature (Tg) of the SDD between compound I and HPMC-AS MF polymer (40:60, w / w), with its midpoint (high at half maximum) being 100.6°C.

[0760] The MDSC of the SDD between compound I and Eudragit E100 polymer (40:60, w / w) is shown in Figure 58. The MDSC profile indicates the glass transition temperature (Tg) of the SDD between compound I and Eudragit E100 polymer (40:60, w / w), with its midpoint (high at half maximum) being 57.0°C.

[0761] The MDSC profile of the SDD between compound I and Eudragit L100-55 polymer (40:60, w / w) is shown in Figure 59. The MDSC profile indicates the glass transition temperature (Tg) of the SDD between compound I and Eudragit L100-55 polymer (40:60, w / w), with its midpoint (high at half maximum) being 120.5°C.

[0762] Figure 60 shows the XRPD pattern overlays of the SDD for compound I and each of the following polymers: HPbCD polymer (40:60, w / w), PVP K30 LP polymer (40:60, w / w), HPC (klucel LF) polymer (40:60, w / w), HPC (klucel MF) polymer (40:60, w / w), HPMC E5 LV polymer (40:60, w / w), HPMC E15 polymer (40:60, w / w), and HPMCP-HP50 polymer (40:60, w / w).

[0763] According to the XRPD data, the SDD of compound I with HPbCD polymer (40:60, w / w) was amorphous, the SDD of compound I with PVP K30 LP polymer (40:60, w / w) was amorphous, the SDD of compound I with HPC (klucel LF) polymer (40:60, w / w) was amorphous, the SDD of compound I with HPC (klucel MF) polymer (40:60, w / w) had a very low degree of crystallinity, the SDD of compound I with HPMC E5 LV polymer (40:60, w / w) was amorphous, the SDD of compound I with HPMC E15 polymer (40:60, w / w) was amorphous, and the SDD of compound I with HPMCP-HP50 polymer (40:60, w / w) was amorphous.

[0764] The MDSC profile of the SDD between compound I and HPbCD polymer (40:60, w / w) is shown in Figure 61. The MDSC profile indicates the glass transition temperature (Tg) of the SDD between compound I and HPbCD polymer (40:60, w / w), with its midpoint (high at half maximum) being 92.7°C.

[0765] The MDSC of the SDD between compound I and PVP K30 LP polymer (40:60, w / w) is shown in Figure 62. The MDSC profile shows two glass transition temperatures (Tg) for the SDD between compound I and PVP K30 LP polymer (40:60, w / w), with their midpoints (high at half maximum) being 85.0°C and 145.0°C, respectively.

[0766] The MDSC profile of the SDD between compound I and the HPC (Klucel LF) polymer (40:60, w / w) is shown in Figure 63. The MDSC profile indicates the glass transition temperature (Tg) of the SDD between compound I and the HPC (Klucel LF) polymer (40:60, w / w), with its midpoint (high at half maximum) being 64.6°C.

[0767] The MDSC profile of the SDD between compound I and HPC (Klucel MF) polymer (40:60, w / w) is shown in Figure 64. The MDSC profile indicates the glass transition temperature of the SDD between compound I and HPC (Klucel MF) polymer (40:60, w / w), with its midpoint (high at half maximum) being 53.6°C.

[0768] The MDSC profile of the SDD between compound I and HPMC E5 LV polymer (40:60, w / w) is shown in Figure 65. The MDSC profile indicates the glass transition temperature (Tg) of the SDD between compound I and HPMC E5 LV polymer (40:60, w / w), with its midpoint (high at half maximum) being 101.4°C.

[0769] The MDSC profile of the SDD between compound I and HPMC E15 polymer (40:60, w / w) is shown in Figure 66. The MDSC profile indicates the glass transition temperature (Tg) of the SDD between compound I and HPMC E15 polymer (40:60, w / w), with its midpoint (high at half maximum) being 100.9°C.

[0770] The MDSC profile of the SDD between compound I and HPMCP-HP50 polymer (40:60, w / w) is shown in Figure 67. The MDSC profile indicates the glass transition temperature (Tg) of the SDD between compound I and HPMCP-HP50 polymer (40:60, w / w), with its midpoint (high at half maximum) being 114.6°C.

[0771] Example 6: Preparation of spray-dried dispersion of compound I and HPMC-AS MG polymer in DCM and acetone solvent systems

[0772] HPMC-ASMG-based SDD containing 20% ​​w / w compound I was prepared by spray-drying a compound I / polymer HPMC-AS MG solution with a compound I concentration of 19.3 mg / mL. Solvent (4.6 L, DCM / acetone = 6 / 4 (v / v)) was added to a 10 L glass bottle, and compound I (88.78 g) was added by magnetic stirring until all solids were completely dissolved. Next, HPMC-AS MG (355.12 g) was added to the solution and completely dissolved by magnetic stirring to obtain the SDD solution.

[0773] A 30% w / w SDD (Solid Decomposition Decomposition) solution of compound I / polymer HPMC-AS MG with a compound I concentration of 30.5 mg / mL was prepared by spray-drying. A 5 L glass bottle was added to a solvent (2.6 L, dichloromethane / acetone = 7 / 3 (v / v)), and compound I (79.30 g) was added by magnetic stirring until all solids were completely dissolved. Next, HPMC-AS MG (185.03 g) was added to the solution and completely dissolved by magnetic stirring to obtain the SDD solution.

[0774] HPMC-ASMG-based SDD containing 20% ​​w / w compound I was prepared by spray-drying a compound I / polymer HPMC-AS MG solution with a compound I concentration of 52 mg / mL. A 5 L glass bottle was added to a solvent (2.6 L, dichloromethane / acetone = 6 / 4 (v / v)), and compound I (135.20 g) was added by magnetic stirring until all solids were completely dissolved. Next, HPMC-AS MG (202.80 g) was added to the solution and completely dissolved by magnetic stirring to obtain the SDD solution.

[0775] Figure 68 shows the XRPD data of the SSD of compound I and HPMC-AS MG polymer (20:80, w / w) before drying. According to the XRPD data, the SSD of compound I and HPMC-AS MG polymer (20:80, w / w) was amorphous.

[0776] The MDSC of the SSD between compound I and HPMC-AS MG polymer (20:80, w / w) before drying is shown in Figure 69. The MDSC profile indicates the glass transition temperature (Tg) of the SSD between compound I and HPMC-AS MG polymer (20:80, w / w), with its midpoint (inflection point) being 107.3°C.

[0777] Figure 70 shows the XRPD data of the SDD of compound I and HPMC-AS MG polymer (20:80, w / w) after drying at 30°C for 10 hours. According to the XRPD data, the SDD of compound I and HPMC-AS MG polymer (20:80, w / w) after drying at 30°C for 10 hours was amorphous.

[0778] The MDSC profile of the SDD of compound I and HPMC-AS MG polymer (20:80, w / w) after drying at 30°C for 10 hours is shown in Figure 71. The MDSC profile indicates the glass transition temperature (Tg) of the SDD of compound I and HPMC-AS MG polymer (20:80, w / w), with its midpoint (inflection point) being 105.2°C.

[0779] XRPD pattern overlays of SSDs with compound I and HPMC-AS MG polymer (20:80 w / w, 30:70 w / w, or 40:60 w / w, respectively) are shown in Figure 72. According to the XRPD data, SSDs with compound I and HPMC-AS MG polymer (20:80 w / w, 30:70 w / w, or 40:60 w / w) were amorphous.

[0780] The MDSC profile of the SDD between compound I and HPMC-AS MG polymer (20:80, w / w) is shown in Figure 73. The MDSC profile indicates the glass transition temperature (Tg) of the SDD between compound I and HPMC-AS MG polymer (20:80, w / w), with its midpoint (high at half maximum) being 107.8°C.

[0781] The MDSC profile of the SDD between compound I and HPMC-AS MG polymer (30:70, w / w) is shown in Figure 74. The MDSC profile indicates the glass transition temperature (Tg) of the SDD between compound I and HPMC-AS MG polymer (30:70, w / w), with its midpoint (high at half maximum) being 103.5°C.

[0782] The MDSC profile of the SDD between compound I and HPMC-AS MG polymer (40:60, w / w) is shown in Figure 75. The MDSC profile indicates the glass transition temperature (Tg) of the SDD between compound I and HPMC-AS MG polymer (40:60, w / w), with its midpoint (high at half maximum) being 99.7°C.

[0783] Example 7: Preparation of SDD formulations of compound I, polymer, and surfactant, and screening of surfactants.

[0784] Procedure for preparing SDD with compound I, polymer, and surfactant

[0785] As shown in Table 19, the free base form, surfactant, and polymer of compound I were weighed and placed in 40 mL glass bottles. Next, the compound I / HPMC-AS / TPGS and compound I / Klucel LF / SDS systems were dissolved by magnetic stirring using 26.7 mL of acetone, while the other three compound I / HPMC-AS MF / SDS systems were dissolved in a mixed solvent of acetone / H2O. Some white flocs that had not yet dissolved in systems D and E were further centrifuged at 3000 rpm for 10 min, and the supernatant was used for spray drying. Detailed process parameters for the preparation of solid dispersions are listed in Table 20. The products were collected and dried in vacuum at 30°C for approximately 13 hours, then sealed with Parafilm, wrapped in aluminum foil, and stored at 5°C away from light.

[0786] The table below summarizes the five SDD formulations (Systems A, B, C, D, and E) of Compound I with polymers and surfactants.

[0787] Table 19 Composition of SDD between Compound I and polymers and surfactants [Table 23]

[0788] The table below summarizes the detailed process parameters for the preparation of the spray-dried dispersions of Systems A, B, C, D, and E.

[0789] Table 20 Spray drying parameters of SDD with compound I and different polymers and surfactants [Table 24]

[0790] The XRPD data for SDD of compound I in each of systems A, B, C, D, and E are shown in Figure 76.

[0791] According to the XRPD data, the SDD of compound I in system A with HPMC-AS MF and TPGS was amorphous; the SDD of compound I in system B with Klucel LF and SDS was amorphous; the SDD of compound I in system C with HPMC-AS MF and SDS was amorphous; the SDD of compound I in system D with HPMC-AS MF and SDS was amorphous; and the SDD of compound I in system E with HPMC-AS MF and SDS was amorphous.

[0792] The MDSC profiles of the SDD between compound I of system A and HPMC-AS MF and TPGS are shown in Figure 77. The MDSC profile indicates the glass transition temperature (Tg) of the SDD between compound I of system A and HPMC-AS MF and TPGS, with its midpoint (high at half maximum) being 67.7°C.

[0793] The MDSC profiles of the SDD of compound I from system B with Klucel LF and SDS are shown in Figure 78. The MDSC profile indicates the glass transition temperature (Tg) of the SDD of compound I from system B with Klucel LF and SDS, with its midpoint (high at half maximum) being 61.5°C.

[0794] The MDSCs of the SDD of compound I from system C with HPMC-AS MF and SDS are shown in Figure 79. The MDSC profiles show two glass transition temperatures (Tg) for the SDD of compound I from system C with HPMC-AS MF and SDS, with their midpoints (high at half maximum) being 96.3°C and 110.4°C, respectively.

[0795] The MDSC profiles of the SDD of compound I from system D with HPMC-AS MF and SDS are shown in Figure 80. The MDSC profile indicates the glass transition temperature (Tg) of the SDD of compound I from system D with HPMC-AS MF and SDS, with its midpoint (high at half maximum) being 104.6°C.

[0796] The MDSCs of the SDD of compound I of system E with HPMC-AS MF and SDS are shown in Figure 81. The MDSC profiles show two glass transition temperatures (Tg) of the SDD of compound I of system E with HPMC-AS MF and SDS, with their midpoints (high at half maximum) being 95.8°C and 107.9°C, respectively.

[0797] The table below summarizes the results of 1-week stability tests of compound I from systems A, B, C, D, and E against SDD at 40°C, 75% RH or 25°C, 60% RH.

[0798] Table 21 Summary of 1-week stability tests for Compound I / polymer / surfactant against SDD (Systems A, B, C, D, and E) [Table 25]

[0799] Figure 82 shows the XRPD pattern overlays of the SDD for compound I of each system A, B, C, D, and E after a one-week stability test at 40°C, 75% RH, or 25°C, 60% RH.

[0800] According to the XRPD data, the SDD of compound I in system A (25°C, RH60%) was amorphous, the SDD of compound I in system A (40°C, RH75%) had very low crystallinity, the SDD of compound I in system B (25°C, RH60%) was amorphous, the SDD of compound I in system C (40°C, RH75%) had very low crystallinity, the SDD of compound I in system D (25°C, RH60%) was amorphous, the SDD of compound I in system E (25°C, RH60%) was amorphous, and the SDD of compound I in system E (40°C, RH75%) had very low crystallinity.

[0801] Example 8: Description of the manufacturing process for spray-dried dispersion of Compound I tablets

[0802] Manufacturing process

[0803] Step 1: Spray drying

[0804] The free base of compound I was dissolved in acetone, and the mixture was stirred until the solution became clear. Next, hypromellose acetate succinate MG (HPMC-ASMG) was added to the above solution, and stirring was continued to produce a clarified solution. The solution was sprayed in small amounts using a spray dryer, and the powder was collected. Next, the resulting spray-dried dispersion of compound I was dried by secondary vacuum drying. The spray-dried dispersion powders, which were continuously collected for the downstream steps, were combined and mixed. The production flowchart for SSD with compound I and HPMC-ASMG polymer (20:80, w / w) is shown in Figure 83.

[0805] Table 22 Examples of SSD components with Compound I and HPMC-AS MG polymer [Table 26]

[0806] Step 2: Dispensing and declumping The necessary manufacturing materials were dispensed, and colloidal silicon dioxide, mannitol, croscarmellose sodium, and microcrystalline cellulose PH-101 were deaggregated using a comil.

[0807] Step 3: Pre-mixing and pre-sliding

[0808] The spray-dried dispersion of compound I was directly transferred to a high-shear granulator, and the sieved material described above was added and mixed. Next, the sieved magnesium stearate was transferred to the granulator and smoothed.

[0809] Step 4: Compression by rollers

[0810] The above mixture was compressed using a roller compressor and a mill to form granules.

[0811] Step 5: Mix and smooth

[0812] Poloxamer 188, croscarmellose sodium, microcrystalline cellulose PH-102, and magnesium stearate were sieved. The granules from step 4 were mixed with the sieved poloxamer 188, croscarmellose sodium, and microcrystalline cellulose PH-102. The sieved magnesium stearate was transferred to a blender and smoothed.

[0813] Step 6: Compression

[0814] The above mixture was compressed in a rotary tablet press to form core tablets.

[0815] Step 7: Film Coating

[0816] A coating solution was prepared by mixing purified water with the Opadry(R) coating system (a commercially available pre-mixed coating agent). Core tablets were coated until the target weight increase was reached. The coated tablets were dried and removed.

[0817] Step 8: Packaging with bottles

[0818] The containers were 45 mL (containing 25 mg) or 100 mL (containing 100 mg) pharmaceutical-grade high-density polyethylene (HDPE) bottles with safety caps for oral solid drugs. Each bottle was filled with tablets and a desiccant, and then induced sealed.

[0819] Table 23 Examples of the composition of Compound I tablets (25 mg and 100 mg, drug load 20%) [Table 27]

[0820] Table 24 Example composition of Compound I tablet (100 mg, drug load 30%) [Table 28]

[0821] Table 25 Examples of the composition of Compound I tablets (25 mg and 125 mg, drug load 40%) [Table 29]

[0822] 25 mg and 100 mg tablets were packaged in 45 mL and 100 mL white cylindrical high-density polyethylene (HDPE) bottles, respectively, and sealed with safety caps for oral solid drugs. Each bottle contained a tablet and a desiccant.

[0823] The manufacturing flow chart for Compound I tablets is shown in Figure 84.

[0824] Dissolution behavior

[0825] The SDD tablets of compound I are an oral solid dosage form, and their dissolution performance conforms to the corresponding USP guidelines for oral solid formulations. The dissolution curves for the SDD tablets of compound I are shown in Figure 85. The dissolution curves show that more than 80% of the active pharmaceutical ingredient (API) was dissolved within 45 minutes for both strengths.

Claims

1. A crystalline form of compound I or a pharmaceutically acceptable salt of compound I, wherein compound I is (S)-N-(4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-methylphenyl)-5-((3,3-difluoro-1-methylpiperidine-4-yl)oxy)-7-methoxyquinazoline-4-amine.

2. The crystalline form according to claim 1, which is form A of compound I.

3. The crystal morphology according to claim 2, having an X-ray powder diffraction (XRPD) pattern that includes peaks at diffraction angle (2θ) values ​​of 7.09±0.20°, 15.15±0.20°, and 21.55±0.20°.

4. The crystal morphology according to claim 3, having an XRPD pattern further comprising at least one or two peaks at 2θ selected from 11.92±0.20° and 23.93±0.20°.

5. The crystal morphology according to claim 2, having an XRPD pattern with peaks at 2θ of 7.09±0.20°, 11.92±0.20°, 15.15±0.20°, 21.55±0.20°, and 23.93±0.20°.

6. The crystalline morphology according to claim 5, having an XRPD pattern further comprising at least one or two peaks at 2θ selected from 6.45 ± 0.20° and 17.85 ± 0.20°.

7. The crystal morphology according to claim 2, having an XRPD pattern that includes peaks at 2θ of 6.45±0.20°, 7.09±0.20°, 11.92±0.20°, 15.15±0.20°, 17.85±0.20°, 21.55±0.20°, and 23.93±0.20°.

8. The crystal morphology according to claim 7, having an XRPD pattern further comprising at least one, two, or three peaks at 2θ selected from 14.19±0.20°, 18.94±0.20°, and 26.86±0.20°.

9. The crystal morphology according to claim 2, having an XRPD pattern that includes peaks at 2θ of 6.45±0.20°, 7.09±0.20°, 11.92±0.20°, 14.19±0.20°, 15.15±0.20°, 17.85±0.20°, 18.94±0.20°, 21.55±0.20°, 23.93±0.20° and 26.86±0.20°.

10. The crystal morphology according to claim 9, having an XRPD pattern further comprising at least one, two, three or more peaks at 2θ selected from 10.75±0.20°, 11.32±0.20°, 12.88±0.20°, 20.79±0.20°, and 25.69±0.20°.

11. The crystal morphology according to claim 2, having an XRPD pattern that includes peaks at 2θ of 6.45±0.20°, 7.09±0.20°, 10.75±0.20°, 11.32±0.20°, 11.92±0.20°, 12.88±0.20°, 14.19±0.20°, 15.15±0.20°, 17.85±0.20°, 18.94±0.20°, 20.79±0.20°, 21.55±0.20°, 23.93±0.20°, 25.69±0.20° and 26.86±0.20°.

12. The crystal morphology according to claim 2, having an XRPD pattern substantially the same as that shown in Table 7.

13. The crystal morphology according to claim 2, having an XRPD pattern substantially the same as that shown in Figure 11.

14. The crystalline form according to claim 3, having a TGA thermogram showing a weight loss of approximately 0.02% when heated from approximately 30°C to approximately 120°C.

15. The crystal morphology according to claim 3, having a TGA thermogram substantially similar to that shown in Figure 12.

16. The crystalline morphology according to claim 3, having a DSC thermogram that includes endothermic activity starting at approximately 199.5°C and having a peak at approximately 201.5°C.

17. The crystal morphology according to claim 3, having a DSC thermogram substantially similar to that shown in Figure 13.

18. The crystal morphology according to claim 3, having a DVS water vapor adsorption plot substantially similar to that shown in Figure 14.

19. The crystalline form according to claim 1, which is form B of compound I.

20. The crystal morphology according to claim 19, having an XRPD pattern with peaks at 2θ of 7.42±0.20°, 13.21±0.20°, and 19.24±0.20°.

21. The crystalline morphology according to claim 20, having an XRPD pattern further comprising at least one or two peaks at 2θ selected from 6.62±0.20° and 7.17±0.20°.

22. The crystal morphology according to claim 19, having an XRPD pattern with peaks at 6.62±0.20°, 7.17±0.20°, 7.42±0.20°, 13.21±0.20°, and 19.24±0.20°.

23. The crystal morphology according to claim 22, having an XRPD pattern further comprising at least one or two peaks at 2θ selected from 14.25±0.20° and 17.94±0.20°.

24. The crystal morphology according to claim 19, having an XRPD pattern that includes peaks at 2θ of 6.62±0.20°, 7.17±0.20°, 7.42±0.20°, 13.21±0.20°, 14.25±0.20°, 17.94±0.20°, and 19.24±0.20°.

25. The crystal morphology according to claim 24, having an XRPD pattern further comprising at least one, two, or three peaks at 2θ selected from 11.61±0.20°, 16.89±0.20°, and 21.89±0.20°.

26. The crystal morphology according to claim 19, having an XRPD pattern that includes peaks at 2θ of 6.62±0.20°, 7.17±0.20°, 7.42±0.20°, 11.61±0.20°, 13.21±0.20°, 14.25±0.20°, 16.89±0.20°, 17.94±0.20°, 19.24±0.20° and 21.89±0.20°.

27. The crystalline morphology according to claim 26, having an XRPD pattern further comprising at least one, two, three or more peaks at 2θ selected from 13.92±0.20°, 17.24±0.20°, 27.21±0.20°, 27.35±0.20°, and 27.87±0.20°.

28. The crystal morphology according to claim 19, having an XRPD pattern that includes peaks at 6.62±0.20°, 7.17±0.20°, 7.42±0.20°, 11.61±0.20°, 13.21±0.20°, 13.92±0.20°, 14.25±0.20°, 16.89±0.20°, 17.24±0.20°, 17.94±0.20°, 19.24±0.20°, 21.89±0.20°, 27.21±0.20°, 27.35±0.20° and 27.87±0.20°.

29. The crystal morphology according to claim 19, having an XRPD pattern substantially similar to that shown in Table 8.

30. The crystal morphology according to claim 19, having an XRPD pattern substantially similar to that shown in Figure 15.

31. The crystalline form according to claim 20, having a TGA thermogram showing a weight loss of approximately 1.68% when heated from approximately 30°C to approximately 100°C.

32. The crystalline morphology according to claim 20, having a DSC thermogram that includes three endothermic phases, each starting at approximately 116.3°C and having a peak at approximately 125.4°C, starting at approximately 182.4°C and having a peak at approximately 187.5°C, and starting at approximately 199.2°C and having a peak at approximately 200.3°C.

33. The crystal morphology according to claim 20, having TGA and DSC thermograms substantially similar to those shown in Figure 16.

34. The crystalline form according to claim 1, which is form C of compound I.

35. The crystal morphology according to claim 34, having an XRPD pattern with peaks at 5.95±0.20°, 8.58±0.20°, and 19.56±0.20° in 2θ.

36. The crystalline morphology according to claim 35, having an XRPD pattern further comprising at least one or two peaks at 2θ selected from 11.89±0.20° and 13.75±0.20°.

37. The crystal morphology according to claim 34, having an XRPD pattern further including peaks at 2θ of 5.95±0.20°, 8.58±0.20°, 11.89±0.20°, 13.75±0.20°, and 19.56±0.20°.

38. The crystalline morphology according to claim 37, having an XRPD pattern further comprising at least one or two peaks at 2θ selected from 12.39±0.20° and 13.40±0.20°.

39. The crystal morphology according to claim 34, having an XRPD pattern that includes peaks at 2θ of 5.95±0.20°, 8.58±0.20°, 11.89±0.20°, 12.39±0.20°, 13.40±0.20°, 13.75±0.20°, and 19.56±0.20°.

40. The crystalline morphology according to claim 39, having an XRPD pattern further comprising at least one, two, or three peaks at 2θ selected from 17.23±0.20°, 18.91±0.20°, and 23.51±0.20°.

41. The crystal morphology according to claim 34, having an XRPD pattern that includes peaks at 2θ of 5.95±0.20°, 8.58±0.20°, 11.89±0.20°, 12.39±0.20°, 13.40±0.20°, 13.75±0.20°, 17.23±0.20°, 18.91±0.20°, 19.56±0.20° and 23.51±0.20°.

42. The crystal morphology according to claim 41, having an XRPD pattern further comprising at least one, two, three or more peaks at 2θ selected from 15.54±0.20°, 15.90±0.20°, 24.91±0.20°, 25.29±0.20°, and 25.55±0.20°.

43. The crystal morphology according to claim 34, having an XRPD pattern that includes peaks at 2θ of 5.95±0.20°, 8.58±0.20°, 11.89±0.20°, 12.39±0.20°, 13.40±0.20°, 13.75±0.20°, 15.54±0.20°, 15.90±0.20°, 17.23±0.20°, 18.91±0.20°, 19.56±0.20°, 23.51±0.20°, 24.91±0.20°, 25.29±0.20° and 25.55±0.20°.

44. The crystal morphology according to claim 34, having an XRPD pattern substantially the same as that shown in Table 9.

45. The crystal morphology according to claim 34, having an XRPD pattern substantially similar to that shown in Figure 17.

46. The crystalline form according to claim 35, having a TGA thermogram showing a weight loss of approximately 0.5 to 1% when heated from approximately 30°C to approximately 180°C.

47. The crystalline morphology according to claim 35, having a DSC thermogram that includes endothermic activity starting at approximately 193.8°C and having a peak at approximately 194.6°C.

48. The crystalline morphology according to claim 35, having TGA and DSC thermograms substantially similar to those shown in Figure 18.

49. The crystalline form according to claim 1, which is form D of compound I.

50. The crystal morphology according to claim 49, having an XRPD pattern with peaks at 6.85±0.20°, 14.81±0.20°, and 21.38±0.20° in 2θ.

51. The crystalline morphology according to claim 50, having an XRPD pattern further comprising at least one or two peaks at 2θ selected from 13.71±0.20° and 17.69±0.20°.

52. The crystal morphology according to claim 49, having an XRPD pattern with peaks at 6.85±0.20°, 13.71±0.20°, 14.81±0.20°, 17.69±0.20°, and 21.38±0.20°.

53. The crystalline morphology according to claim 52, having an XRPD pattern further comprising at least one or two peaks at 2θ selected from 11.13±0.20° and 23.49±0.20°.

54. The crystal morphology according to claim 49, having an XRPD pattern that includes peaks at 2θ of 6.85±0.20°, 11.13±0.20°, 13.71±0.20°, 14.81±0.20°, 17.69±0.20°, 21.38±0.20°, and 23.49±0.20°.

55. The crystal morphology according to claim 54, having an XRPD pattern further comprising at least one, two, three or more peaks at 2θ selected from 13.07±0.20°, 15.08±0.20°, 18.37±0.20°, and 21.67±0.20°.

56. The crystal morphology according to claim 49, having an XRPD pattern that includes peaks at 2θ of 6.85±0.20°, 11.13±0.20°, 13.07±0.20°, 13.71±0.20°, 14.81±0.20°, 15.08±0.20°, 17.69±0.20°, 18.37±0.20°, 21.38±0.20°, 21.67±0.20° and 23.49±0.20°.

57. The crystalline form according to claim 56, having an XRPD pattern further comprising at least one, two, three or more peaks at 2θ selected from 22.25±0.20°, 24.65±0.20°, 26.69±0.20°, and 28.60±0.20°.

58. The crystal morphology according to claim 49, having an XRPD pattern that includes peaks at 2θ of 6.85±0.20°, 11.13±0.20°, 13.07±0.20°, 13.71±0.20°, 14.81±0.20°, 15.08±0.20°, 17.69±0.20°, 18.37±0.20°, 21.38±0.20°, 21.67±0.20°, 22.25±0.20°, 23.49±0.20°, 24.65±0.20°, 26.69±0.20° and 28.60±0.20°.

59. The crystal morphology according to claim 49, having an XRPD pattern substantially similar to that shown in Table 10.

60. The crystal morphology according to claim 49, having an XRPD pattern substantially similar to that shown in Figure 19.

61. The crystalline form according to claim 50, having a TGA thermogram that shows a weight loss of approximately 0.5 to 0.8% when heated from approximately 30°C to approximately 100°C.

62. The crystal morphology according to claim 50, having a DSC thermogram that includes two endothermic phases, one starting at approximately 186.9°C and having a peak at approximately 190.5°C, and the other starting at approximately 199.5°C and having a peak at approximately 200.4°C.

63. The crystalline morphology according to claim 50, having TGA and DSC thermograms substantially similar to those shown in Figure 20.

64. The crystalline form according to claim 1, wherein the pharmaceutically acceptable salt of compound I is selected from the group consisting of hydrochloride, sulfate, phosphate, maleate, fumarate, oxalate, p-toluenesulfonate, succinate, L-(+)-tartrate, monoadipate, and hemiadipate.

65. A spray-drying dispersion (SDD) formulation comprising compound I and a polymer.

66. The formulation according to claim 65, wherein the polymer is selected from the group consisting of HPMC-AS polymer, PVP-VA64 copolymer, Soluplus polymer, Eudragit E100 polymer, Eudragit L100-55 polymer, hydroxypropyl-β-cyclodextrin (HP-β-CD), PVP K30 LP polymer, HPC (hydroxypropylcellulose, Klucel LF) polymer, HPC (Klucel MF) polymer, HPMC E5 LV polymer, HPMC E15 polymer, HPMCP-HP50 polymer, and any combination thereof.

67. The formulation according to claim 65, wherein the polymer is HPMC-AS polymer.

68. The formulation according to claim 67, wherein the HPMC-AS polymer is selected from the group consisting of HPMC-AS MG polymer, HPMC-AS MF polymer, HPMC-AS LF polymer, and any combination thereof.

69. The formulation according to claim 65, wherein the polymer is an HPC (Klucel LF) polymer.

70. The formulation according to any one of claims 65 to 69, further comprising a surfactant.

71. The formulation according to claim 70, wherein the surfactant is selected from the group consisting of vitamin E polyethylene glycol succinate (TPGS), sodium dodecyl sulfate (SDS), polysorbate 80 (Tween 80), and combinations thereof.

72. The formulation according to any one of claims 65 to 71, wherein compound I is present in an amount of about 5% w / w to about 70% w / w.

73. The formulation according to any one of claims 65 to 72, wherein compound I is present in an amount of about 20% w / w to about 60% w / w.

74. The formulation according to any one of claims 65 to 73, wherein compound I is present in an amount of about 20% w / w, about 30% w / w, or about 40% w / w.

75. The formulation according to any one of claims 65 to 74, wherein the polymer is present in an amount of about 95% w / w to about 30% w / w.

76. The formulation according to any one of claims 65 to 75, wherein the polymer is present in an amount of about 80% w / w to about 40% w / w.

77. The formulation according to any one of claims 65 to 76, wherein the polymer is present in an amount of about 80% w / w, about 77.5% w / w, about 70% w / w, about 60% w / w, about 55% w / w, about 50% w / w, or about 40% w / w.

78. The formulation according to any one of claims 65 to 77, wherein the surfactant is present in an amount of about 0.5% w / w to about 20% w / w.

79. The formulation according to any one of claims 65 to 78, wherein the surfactant is present in an amount of about 2.5% w / w to about 10% w / w.

80. The formulation according to any one of claims 65 to 79, wherein the surfactant is present in an amount of about 2.5% w / w, about 5% w / w, or about 10% w / w.

81. The formulation according to any one of claims 65 to 68 or 72 to 75, wherein the formulation comprises compound I in an amount of about 20% w / w and HPMC-AS MG polymer in an amount of about 80% w / w.

82. The formulation according to any one of claims 65 to 68 or 72 to 75, wherein the formulation comprises compound I in an amount of about 30% w / w and HPMC-AS MG polymer in an amount of about 70% w / w.

83. The formulation according to any one of claims 65 to 68 or 72 to 75, wherein the formulation comprises compound I in an amount of about 40% w / w and HPMC-AS MG polymer in an amount of about 60% w / w.

84. The formulation according to any one of claims 65 to 68 or 70 to 80, wherein the formulation comprises compound I in an amount of about 40% w / w, HPMC-AS MF polymer in an amount of about 50% w / w, and TPGS in an amount of about 10% w / w.

85. The formulation according to any one of claims 65, 66, or 69-80, wherein the formulation comprises compound I in an amount of about 40% w / w, HPC (Klucel LF) polymer in an amount of about 55% w / w, and SDS in an amount of about 5% w / w.

86. The formulation according to any one of claims 65 to 68 or 70 to 80, wherein the formulation comprises compound I in an amount of about 40% w / w, HPMC-AS MF polymer in an amount of about 55% w / w, and SDS in an amount of about 5% w / w.

87. The formulation according to any one of claims 65 to 68 or 70 to 80, wherein the formulation comprises compound I in an amount of about 20% w / w, HPMC-AS MF polymer in an amount of about 77.5% w / w, and SDS in an amount of about 2.5% w / w.

88. The formulation according to any one of claims 65 to 87, wherein the formulation is produced by a spray-drying process and comprises a solvent selected from water, acetone, methanol, dichloromethane, and any combination thereof.

89. The formulation according to claim 88, wherein the solvent comprises acetone.

90. The formulation according to claim 88, wherein the solvent comprises acetone and water.

91. The formulation according to claim 90, wherein the solvent contains acetone in an amount of about 99% and water in an amount of about 1%.

92. The formulation according to claim 90, wherein the solvent contains acetone in an amount of about 98.2% and water in an amount of about 1.8%.

93. The formulation according to claim 88, wherein the solvent comprises acetone and dichloromethane.

94. The formulation according to claim 93, wherein the solvent comprises about 30% acetone and about 70% dichloromethane.

95. The formulation according to claim 88, wherein the solvent comprises methanol.

96. The formulation according to claim 88, wherein the solvent comprises methanol and dichloromethane.

97. The formulation according to claim 96, wherein the solvent comprises methanol in an amount of about 50% and dichloromethane in an amount of about 50%.

98. The formulation according to any one of claims 65 to 97, wherein compound I in the formulation is amorphous.

99. The formulation according to claim 81, wherein the formulation has an XRPD pattern substantially similar to that shown in Figure 68 or Figure 70.

100. The formulation according to claim 81, wherein the formulation has an MDSC profile including a glass transition temperature (Tg) of approximately 107 ± 3°C.

101. The formulation according to claim 81, wherein the formulation has substantially the same MDSC profile as that shown in Figure 69, Figure 71, or Figure 73.

102. The formulation according to any one of claims 81 to 83, wherein the formulation has an XRPD pattern substantially the same as that shown in Figure 72.

103. The formulation according to claim 82, wherein the formulation has an MDSC profile including a glass transition temperature (Tg) of about 103.5°C.

104. The formulation according to claim 82, wherein the formulation has substantially the same MDSC profile as that shown in Figure 74.

105. The formulation according to claim 83, wherein the formulation has an MDSC profile including a glass transition temperature (Tg) of approximately 99.7°C.

106. The formulation according to claim 83, wherein the formulation has substantially the same MDSC profile as that shown in Figure 75.

107. The formulation according to any one of claims 84 to 87, wherein the formulation has an XRPD pattern substantially the same as that shown in Figure 76.

108. The formulation according to claim 84, wherein the formulation has an MDSC profile including a Tg of approximately 67.7°C.

109. The formulation according to claim 84, wherein the formulation has substantially the same MDSC profile as that shown in Figure 77.

110. The formulation according to claim 85, wherein the formulation has an MDSC profile including a Tg of approximately 61.5°C.

111. The formulation according to claim 85, wherein the formulation has substantially the same MDSC profile as that shown in Figure 78.

112. The formulation according to claim 86, wherein the formulation has an MDSC profile comprising two Tg values ​​of approximately 96.3°C and approximately 110.4°C, or approximately 95.8°C and approximately 107.9°C.

113. The formulation according to claim 86, wherein the formulation has substantially the same MDSC profile as that shown in Figure 79 or Figure 81.

114. The formulation according to claim 87, wherein the formulation has an MDSC profile including a Tg of approximately 104.6°C.

115. The formulation according to claim 87, wherein the formulation has substantially the same MDSC profile as that shown in Figure 80.

116. The formulation according to any one of claims 65 to 115, wherein the formulation has a drug assay with a drug efficacy of 98% or higher.

117. The formulation according to any one of claims 65 to 116, wherein the formulation has a drug assay with a drug efficacy of more than 99%.

118. The formulation according to any one of claims 65 to 117, wherein the formulation has a drug assay with a drug content of more than 99.5%.

119. The formulation according to any one of claims 65 to 118, wherein the formulation has a drug assay of more than 98% after storage for one week at 25°C and 60% relative humidity (RH).

120. The formulation according to any one of claims 65 to 119, wherein the formulation has a drug assay of more than 99% after storage for one week at 25°C and 60% RH.

121. The formulation according to any one of claims 65 to 120, wherein the formulation has a drug assay of more than 99.4% after storage for one week at 25°C and 60% RH.

122. The formulation according to any one of claims 65 to 121, wherein the formulation has a drug assay of more than 98% after storage for one week at 40°C and 75% RH.

123. The formulation according to any one of claims 65 to 122, wherein the formulation has a drug assay of more than 99% after storage at 40°C and 75% RH for one week.

124. The formulation according to any one of claims 65 to 123, wherein the formulation has a drug assay of higher than 99.2% after storage at 40°C and 75% RH for one week.

125. The formulation according to any one of claims 65 to 124, wherein the formulation is formulated as a tablet.

126. The formulation according to claim 125, wherein the tablet contains compound I in an amount between about 5 mg and about 1000 mg.

127. The formulation according to claim 125 or 126, wherein the tablet contains compound I in an amount of about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, or about 200 mg.

128. The formulation according to any one of claims 125 to 127, wherein the tablet comprises compound I, a polymer used in a spray-dried dispersion, a binder, a disintegrant, and a lubricant.

129. The formulation according to any one of claims 125 to 128, wherein the tablet comprises compound I, a polymer used in a spray-dried dispersion, microcrystalline cellulose PH-101, mannitol, croscarmellose sodium, colloidal silica dioxide, magnesium stearate, microcrystalline cellulose PH-102, poloxamer 188, and a coating material.

130. The formulation according to claim 129, wherein the polymer is an HPMS-AS polymer.

131. The formulation according to claim 130, wherein the polymer is HPMS-AS MG polymer.

132. The tablet contains compound I in an amount between approximately 10% w / w and approximately 30% w / w, HPMC-AS MG polymer in an amount between approximately 30% w / w and approximately 50% w / w, microcrystalline cellulose PH-101 in an amount between approximately 10% w / w and approximately 25% w / w, mannitol in an amount between approximately 5% w / w and approximately 15% w / w, croscarmellose sodium in an amount between approximately 1% w / w and approximately 10% w / w, colloidal silica dioxide in an amount between approximately 0.1% w / w and approximately 1% w / w, magnesium stearate in an amount between approximately 0.1% w / w and approximately 1% w / w, microcrystalline cellulose PH-102 in an amount between approximately 5% w / w and approximately 15% w / w, and poloxamer 188 in an amount between approximately 0% w / w and approximately 5% w / w. The preparation according to any one of claims 125 to 128.

133. The formulation according to claim 132, wherein the tablet comprises an internal granular portion containing compound I in an amount of about 12% w / w, HPMC-AS MG polymer in an amount of about 48% w / w, microcrystalline cellulose PH-101 in an amount of about 12.4% w / w, mannitol in an amount of about 10% w / w, croscarmellose sodium in an amount of about 2% w / w, colloidal silica dioxide in an amount of about 0.5% w / w, and magnesium stearate in an amount of about 0.25% w / w, and an external granular portion containing croscarmellose sodium in an amount of about 2% w / w, microcrystalline cellulose PH-102 in an amount of about 9.4% w / w, poloxamer 188 in an amount of about 3% w / w, and magnesium stearate in an amount of about 0.5% w / w.

134. The formulation according to claim 132, wherein the tablet comprises an internal granular portion containing compound I in an amount of about 18% w / w, HPMC-AS MG polymer in an amount of about 42% w / w, microcrystalline cellulose PH-101 in an amount of about 11.4% w / w, mannitol in an amount of about 10% w / w, croscarmellose sodium in an amount of about 3% w / w, colloidal silica dioxide in an amount of about 0.5% w / w, and magnesium stearate in an amount of about 0.25% w / w, and an external granular portion containing croscarmellose sodium in an amount of about 3% w / w, microcrystalline cellulose PH-102 in an amount of about 8.4% w / w, poloxamer 188 in an amount of about 3.0% w / w, and magnesium stearate in an amount of about 0.5% w / w.

135. The formulation according to claim 132, wherein the tablet comprises an internal granular portion containing compound I in an amount of about 24% w / w, HPMC-AS MG polymer in an amount of about 36% w / w, microcrystalline cellulose PH-101 in an amount of about 11.4% w / w, mannitol in an amount of about 10% w / w, croscarmellose sodium in an amount of about 3% w / w, colloidal silica dioxide in an amount of about 0.5% w / w, and magnesium stearate in an amount of about 0.25% w / w, and an external granular portion containing croscarmellose sodium in an amount of about 3% w / w, microcrystalline cellulose PH-102 in an amount of about 11.4% w / w, and magnesium stearate in an amount of about 0.5% w / w.

136. The formulation according to any one of claims 132 to 135, wherein the tablet further comprises an additional coating material in an amount between about 1% w / w and about 5% w / w.

137. The formulation according to claim 136, wherein the additional coating material is present in an amount of approximately 2.0% w / w.

138. The formulation according to any one of claims 129 to 131 or 136 to 137, wherein the coating material is Opadry(R).

139. The formulation according to any one of claims 137 to 138, wherein the tablet has a dissolution performance of 60% or more of the active pharmaceutical ingredient (API) in 45 minutes.

140. The formulation according to any one of claims 137 to 139, wherein the tablet has a dissolution performance of 80% or more of the API in 45 minutes.

141. The formulation according to claim 137, wherein the tablet has a dissolution curve substantially similar to that shown in Figure 85.

142. A method for treating a disease associated with ErbB, comprising administering to a subject a therapeutically effective amount of compound I in a polymorphic form or a pharmaceutically acceptable salt of compound I, or a spray-dried dispersion (SDD) comprising compound I and a polymer.

143. The method according to claim 142, wherein ErbB is HER2.

144. The method according to claim 142 or 143, wherein the disease is cancer.

145. The method according to claim 144, wherein the cancer is selected from the group consisting of leukemia, glioblastoma, melanoma, chondrosarcoma, cholangiocarcinoma, osteosarcoma, lymphoma, lung cancer, adenoma, myeloma, hepatocellular carcinoma, adrenocortical carcinoma, pancreatic cancer, breast cancer, bladder cancer, prostate cancer, liver cancer, stomach cancer, colon cancer, colorectal cancer, ovarian cancer, cervical cancer, brain cancer, esophageal cancer, bone cancer, testicular cancer, skin cancer, kidney cancer, mesothelioma, neuroblastoma, glioblastoma, thyroid cancer, head and neck cancer, esophageal cancer, eye cancer, prostate cancer, nasopharyngeal cancer, and oral cancer.

146. The method according to claim 144, wherein the cancer is selected from the group consisting of lung cancer, breast cancer, stomach cancer, colorectal cancer, pancreatic cancer, prostate cancer, bladder cancer, ovarian cancer, and glioblastoma.

147. The method according to claim 144, wherein the cancer is selected from the group consisting of lung cancer, breast cancer, bladder cancer, ovarian cancer, and glioblastoma.

148. The method according to any one of claims 144 to 147, wherein the cancer has metastasized to the central nervous system (CNS).

149. The method according to claim 148, wherein the cancer has metastases to the brain and leptomeningeal membranes.

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